1 Six Lectures on the Nature of the Hydrogen Bond Lecture 1 Introduction to the Hydrogen Bond: Basic Concepts and Summary of Our First Studies from 1989 to 2002 Edited by Paola Gilli ([email protected]) Researcher of Physical Chemistry, and Gastone Gilli ([email protected]; www.ggilli.com) Freelance, Former Professor of Physical Chemistry Department of Chemical and Pharmaceutical Sciences and Centre for Structural Diffractometry, University of Ferrara, Italy
Transcript
1
Six Lectures on the Nature of the Hydrogen BondLecture 1
Introduction to the Hydrogen BondBasic Concepts and Summary of Our First Studies
from 1989 to 2002
Edited byPaola Gilli (paolagilliunifeit)
Researcher of Physical Chemistry and
Gastone Gilli (gastonegilliunifeit wwwggillicom)Freelance Former Professor of Physical Chemistry
Department of Chemical and Pharmaceutical Sciences and Centre for Structural Diffractometry
University of Ferrara Italy
2
Modern Hydrogen Bonding TheoryModern Hydrogen Bonding TheoryGastone Gilli
23rdEuropeanCrystallographicMeeting
6-11 August 2006Leuven Belgium
The topics of the present lecture have been previously presented to other meetings and in particular to
CUSO Summer School
2012on Hydrogen Bonding
20-24 August 2012Villars sur Ollon
Switzerland
Six Lectures on the Nature of the Hydrogen BondSix Lectures on the Nature of the Hydrogen BondGastone Gilli
3
The Birth of the HThe Birth of the H--BondBond
The first idea of HB was devised in the laboratory of Gilbert Newton Lewis at the end of 1920s while he was writing his famous bookValence and the structure of atoms and molecules (1923)
The final assessment of the HB conceptis accredited to ML Huggins and independently to WM Latimer and WH Rodebush three young men working there
The first paper was WM Latimerand WH RodebushPolarity and ionization from the standpoint of the Lewis theory of valence J Am Chem Soc 42 1419-1433 1920
The first book is due to Pauling who made the HB known to the wider chemical community Pauling L The Nature of the chemical bondand the structure of molecules and crystals An introduction to modern structural chemistry Cornell University Press Ithaca NY 1939 1940 1960 Chapter 12 55 pages
The definition of HB has not changed over the years What I like best was proposed by Vinogradov SN and Linnel RHHydrogen bonding Van Nostrand-Reinhold New York 1971
4
Hydrogen Bond DefinitionsHydrogen Bond Definitions
A Three-Center-Four-Electron Interaction RminusminusminusminusDmiddotminusminusminusminusmiddotH AminusminusminusminusRrsquo
where D is theHB Donor an electronegative atomsuch as F O N C S Cl Br Iand A the HB Acceptoror Lone Pair Carrier A second electronegative atomor
a multiple bond that isππππ-bondAlternatively
A Proton Sharing InteractionRminusminusminusminusDminusminusminusminus H+ AminusRrsquobetween two electron pairs
located on two adjacent electronegative atoms
Two Important HB PropertiesTwo Important HB Propertiesdiamsdiamsdiamsdiams The HB acceptoris not an atom but an electron pairlocated on that atomspadesspadesspadesspades Since both D and A must be more electronegative than H all HBs have polarity
RminusminusminusminusδδδδminusminusminusminusDminusminusminusminusHδδδδ++++ A δδδδminusminusminusminusminusminusminusminusRrsquo
5
Electrostatic and Covalent HBs The PaulingElectrostatic and Covalent HBs The Paulingrsquorsquo s Models Model
In The Nature of the Chemical Bond L Pauling describes two types of HBs
diamsWeak and dissymmetric HBs of electrostatic natureIt is recognized that the hydrogen atom with only one stable orbital(the 1s orbital) can form only one covalent bond that the hydrogen bond is largely ionic in character and that it is formed only between the most electronegative atoms (HB Chapter p 1)
clubsclubsclubsclubs Strong and symmetric HBs of covalent nature The ldquoexceptionsrdquoThese exceptions are described in terms of VB theory as ldquo the hydrogen bond in the [HF2]
minusminusminusminus ion lies midway the two fluorine atoms and may be considered to form a half-bond with eachrdquo (HB Chapter p 49)
TheThe CoulsonCoulsonrsquorsquo s VB s VB TreatmentTreatmentTheThe Standard HB ModelStandard HB Model
Paulingrsquos ideas acquired theoretical weight with the VB treatment by Coulson and Danielsson(1954)where the O-HO bond is depicted as a mixture of three main VB forms two covalent and one ionic
This line of thought was also adopted by Pimentel and McClellanin their famous book The Hydrogen Bond(1960)
They wrote ldquoAt the 1957 Ljubljana Conferenceone of the important pointsof fairly general accord was that the electrostatic model does not account for all of the phenomena associated with H bond formationrdquo
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
7
The Birth of the Simple Electrostatic ParadigmThe Birth of the Simple Electrostatic ParadigmFor reasons difficult to understand the Standard HB Model was discarded in the mid-
sixties and the HB became the weak electrostatic interaction not stronger than some 4-5 kcal mol-1 everyone has read of in elementary textbooks while strong HBs just disappeared from the chemical horizon The effect of this choice was disastrous and it took more than twenty years to put it right
Why the Standard Model was AbandonedWhy the Standard Model was AbandonedThe most probable reason can be ascribed to the bizarre way in wThe most probable reason can be ascribed to the bizarre way in which Pauling had arranged hich Pauling had arranged
his famous HB chapter in his famous HB chapter in The Nature of the Chemical Bond
clubsclubsclubsclubs Weak electrostatic HBs are quoted on p 1of the chapter while strong covalent onesonly on p 49 Since most people read only the first few pages of anything hellip
diamsdiamsdiamsdiams On p 50 strong HBs are called ldquoexceptionsrdquo Most readers may have thought Why to bother about exceptions when there are already so many regular HBs to bother about These are things for specialists
heartsheartsheartshearts On p 1 the Paulingrsquos statement ldquothe hydrogen atom can form only one covalent bondhelliprdquo was quite unclear and in consequence was systematically misinterpreted In correct VB terms it cannot be said that the H atom can form only one bond because in factit may also form any combination of two bonds whose bond orders sum up to one from (10) to (01) through (frac12 frac12)
8
Another Unsolved Problem Another Unsolved Problem The HB PuzzleThe HB Puzzle
Bond lengths and energies of normal chemical bondsare determined by the nature of the interacting atoms and weakly perturbed by the environment
On the contrary binding energies (EHB) and DmiddotmiddotmiddotA distances (dDmiddotmiddotmiddotA) of DminusminusminusminusHmiddotmiddotmiddotA H-bondsdo not simply depend on the donor (D) and acceptor (A) nature but show very large variations even for the same donor-acceptor couple
This is what we have often called for the sake of brevity
the HB Puzzlethe HB Puzzle
An extreme exampleof this behavior comes from the effects produced on the OminusminusminusminusHmiddotmiddotmiddotO bondby the changing acid-base propertiesof its environment
The weak HOminusminusminusminusHmiddotmiddotmiddotOH2 bond in water [EHBasympasympasympasymp5 kcal mol-1 dOmiddotmiddotmiddotOasympasympasympasymp270-275 Aring] is transformed in acidic or basic medium into the very strong [H2OmiddotmiddotmiddotHmiddotmiddotmiddotOH2]
+ or [HOmiddotmiddotmiddotHmiddotmiddotmiddotOH]minusminusminusminus bonds with EHB up to 30-31 kcal mol-1 and dOmiddotmiddotmiddotOdown to 238-242 Aring
9
How to Tackle the HB Puzzle How to Tackle the HB Puzzle the Problem of the Driving Variablethe Problem of the Driving Variable
The Electrostatic Paradigmcannot explain the HB PuzzleNeither the Standard Model provides a complete interpretation of it
it just suggests that H-bonds increase their strength with their increasing covalency but without suggesting any specific mechanism for it
To put the problem in more general terms there are a dozen of physicochemical variablescommonly measured in HB studies (energies geometries IR frequencies NMR chemical shifts NQR couplings isotopic effects not to speak of the intrinsic
properties of the interacting molecules) and most if not all appear to be systematically intercorrelated
But whatwhatrsquorsquo s the driving variables the driving variableWhatrsquos the variable which among the many intercorrelated ones
drives the transformation from weak and electrostatic to strong and covalent HB
10
AA Proposal The PApProposal The PApKKaa Equalization PrincipleEqualization Principle
Two very similar proposals come from the early thermodynamic or spectroscopic investigations on the HB and are both centered on the
matching of the acid-base properties of the HB donor and acceptors moieties what we like to call for the sake of brevity the
With reference to any generic DminusminusminusminusHmiddotmiddotmiddotA bond this principle states that the HB is the stronger the smaller becomes the difference of the donor-acceptor
-------------------------------------------------------------------------------------------------------------------------bullAult BS and Pimentel GG J Phys Chem 79 615 (1975) bullKebarle P Ann Rev Phys Chem 28 445ndash476 (1977) bullMeot-Ner (Mautner) M J Am Chem Soc 106 1257ndash1264 (1984)bullHuyskens PL and Zeegers-Huyskens Th J Chim Phys 61 81 (1964) bullMalarski Z M Rospenk and L SobczykJ Phys Chem 86 401ndash406 (1982)
11
Our First Steps into the HBOur First Steps into the HB
As usual we entered the HB field by chance In 1985 during a study on the ligands of the benzodiazepine receptor we determined the structure of CGS8216 and noticed something strange a quite short NminusminusminusminusHmiddotmiddotmiddotO bond of 2694 Aringin association with an interleaving β-enaminonemiddotmiddotmiddot O=CminusminusminusminusC=CminusminusminusminusNH middotmiddotmiddot fragment which was almost completely π-delocalized
It was the first indication of a possible correlation between ππππ-delocalizationand H-bond strengtheningminusminusminusminuswhat we later called the ResonanceResonance--Assisted HAssisted H--Bond Bond (RAHB)(RAHB)(Gilli Bellucci Ferretti amp Bertolasi JACS 1989 Bertolasi Gilli Ferretti amp Gilli JACS 1991)
Since at the time the very few crystal structures of ββββ-enaminones were known the work started on the analogous class of ββββ-enolones(or ββββ-diketone enols) compounds already known to give strong O-HO bonds in association with the equally resonant middotmiddotmiddotO=CminusminusminusminusC=CminusminusminusminusOHmiddotmiddotmiddot fragments
12
Structural Databases and Structural Databases and Crystal Structure Correlation MethodsCrystal Structure Correlation Methods
The correlation between ππππ-delocalizationand H-bond strengthening is essentially a problem of geometrical nature What has to be provedis an intercorrelation between HB strength(as measured by theOhellipO or O-H distances) and ππππ-delocalizationof the resonant fragment (as measured by thed1-d4 distances)
This was the beginning of our intense interest forspades Structural Databasesin general and Cambridge Structural Database (CSD) in particular (Allen Kennardhellip 1979 2002)clubs Structural data interpretation by the so called Crystal Structure Correlation (CSC) Method(Buumlrgi 1973 1975 Buumlrgi and Dunitz 1983) a method for obtaining information on the dynamic behavior of molecules from the inevitably rather static crystal data geometries
Some sample applications of CSD to the study of RAHB in ββββ-diketone enol structures
13
The Development of the OThe Development of the OminusminusminusminusminusminusminusminusHHO RAHBO RAHB
The HBs formed were all much stronger than normal (non-resonant) OminusminusminusminusHO bonds withd(OO)INTRA =239-255 Aringd(OO)INTER =246-265 Aring
R1-RAHBR5-RAHB
24256 Aring
N
N
O M e
N
N
OM e
M eM e
H
lt 257 gt1 Aring
P
O H
OO
O H
H P
O H
OO
O H
H
R3-RAHB
O OH
237-255 Aring
262-267 Aring
O
O H O
OH
262-270 Aring
O
O
H
O
O H
R7-RAHB24462 Aring
NOO
OO
M eM e
H
OOH
O
O
H
246-265 Aring
CARBOXYLIC ACIDS
DIBENZOYLMETHANE ENOLS
CYCLOHEXANEDIONE ENOLS
PHOPHORIC ACID
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
2
Modern Hydrogen Bonding TheoryModern Hydrogen Bonding TheoryGastone Gilli
23rdEuropeanCrystallographicMeeting
6-11 August 2006Leuven Belgium
The topics of the present lecture have been previously presented to other meetings and in particular to
CUSO Summer School
2012on Hydrogen Bonding
20-24 August 2012Villars sur Ollon
Switzerland
Six Lectures on the Nature of the Hydrogen BondSix Lectures on the Nature of the Hydrogen BondGastone Gilli
3
The Birth of the HThe Birth of the H--BondBond
The first idea of HB was devised in the laboratory of Gilbert Newton Lewis at the end of 1920s while he was writing his famous bookValence and the structure of atoms and molecules (1923)
The final assessment of the HB conceptis accredited to ML Huggins and independently to WM Latimer and WH Rodebush three young men working there
The first paper was WM Latimerand WH RodebushPolarity and ionization from the standpoint of the Lewis theory of valence J Am Chem Soc 42 1419-1433 1920
The first book is due to Pauling who made the HB known to the wider chemical community Pauling L The Nature of the chemical bondand the structure of molecules and crystals An introduction to modern structural chemistry Cornell University Press Ithaca NY 1939 1940 1960 Chapter 12 55 pages
The definition of HB has not changed over the years What I like best was proposed by Vinogradov SN and Linnel RHHydrogen bonding Van Nostrand-Reinhold New York 1971
4
Hydrogen Bond DefinitionsHydrogen Bond Definitions
A Three-Center-Four-Electron Interaction RminusminusminusminusDmiddotminusminusminusminusmiddotH AminusminusminusminusRrsquo
where D is theHB Donor an electronegative atomsuch as F O N C S Cl Br Iand A the HB Acceptoror Lone Pair Carrier A second electronegative atomor
a multiple bond that isππππ-bondAlternatively
A Proton Sharing InteractionRminusminusminusminusDminusminusminusminus H+ AminusRrsquobetween two electron pairs
located on two adjacent electronegative atoms
Two Important HB PropertiesTwo Important HB Propertiesdiamsdiamsdiamsdiams The HB acceptoris not an atom but an electron pairlocated on that atomspadesspadesspadesspades Since both D and A must be more electronegative than H all HBs have polarity
RminusminusminusminusδδδδminusminusminusminusDminusminusminusminusHδδδδ++++ A δδδδminusminusminusminusminusminusminusminusRrsquo
5
Electrostatic and Covalent HBs The PaulingElectrostatic and Covalent HBs The Paulingrsquorsquo s Models Model
In The Nature of the Chemical Bond L Pauling describes two types of HBs
diamsWeak and dissymmetric HBs of electrostatic natureIt is recognized that the hydrogen atom with only one stable orbital(the 1s orbital) can form only one covalent bond that the hydrogen bond is largely ionic in character and that it is formed only between the most electronegative atoms (HB Chapter p 1)
clubsclubsclubsclubs Strong and symmetric HBs of covalent nature The ldquoexceptionsrdquoThese exceptions are described in terms of VB theory as ldquo the hydrogen bond in the [HF2]
minusminusminusminus ion lies midway the two fluorine atoms and may be considered to form a half-bond with eachrdquo (HB Chapter p 49)
TheThe CoulsonCoulsonrsquorsquo s VB s VB TreatmentTreatmentTheThe Standard HB ModelStandard HB Model
Paulingrsquos ideas acquired theoretical weight with the VB treatment by Coulson and Danielsson(1954)where the O-HO bond is depicted as a mixture of three main VB forms two covalent and one ionic
This line of thought was also adopted by Pimentel and McClellanin their famous book The Hydrogen Bond(1960)
They wrote ldquoAt the 1957 Ljubljana Conferenceone of the important pointsof fairly general accord was that the electrostatic model does not account for all of the phenomena associated with H bond formationrdquo
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
7
The Birth of the Simple Electrostatic ParadigmThe Birth of the Simple Electrostatic ParadigmFor reasons difficult to understand the Standard HB Model was discarded in the mid-
sixties and the HB became the weak electrostatic interaction not stronger than some 4-5 kcal mol-1 everyone has read of in elementary textbooks while strong HBs just disappeared from the chemical horizon The effect of this choice was disastrous and it took more than twenty years to put it right
Why the Standard Model was AbandonedWhy the Standard Model was AbandonedThe most probable reason can be ascribed to the bizarre way in wThe most probable reason can be ascribed to the bizarre way in which Pauling had arranged hich Pauling had arranged
his famous HB chapter in his famous HB chapter in The Nature of the Chemical Bond
clubsclubsclubsclubs Weak electrostatic HBs are quoted on p 1of the chapter while strong covalent onesonly on p 49 Since most people read only the first few pages of anything hellip
diamsdiamsdiamsdiams On p 50 strong HBs are called ldquoexceptionsrdquo Most readers may have thought Why to bother about exceptions when there are already so many regular HBs to bother about These are things for specialists
heartsheartsheartshearts On p 1 the Paulingrsquos statement ldquothe hydrogen atom can form only one covalent bondhelliprdquo was quite unclear and in consequence was systematically misinterpreted In correct VB terms it cannot be said that the H atom can form only one bond because in factit may also form any combination of two bonds whose bond orders sum up to one from (10) to (01) through (frac12 frac12)
8
Another Unsolved Problem Another Unsolved Problem The HB PuzzleThe HB Puzzle
Bond lengths and energies of normal chemical bondsare determined by the nature of the interacting atoms and weakly perturbed by the environment
On the contrary binding energies (EHB) and DmiddotmiddotmiddotA distances (dDmiddotmiddotmiddotA) of DminusminusminusminusHmiddotmiddotmiddotA H-bondsdo not simply depend on the donor (D) and acceptor (A) nature but show very large variations even for the same donor-acceptor couple
This is what we have often called for the sake of brevity
the HB Puzzlethe HB Puzzle
An extreme exampleof this behavior comes from the effects produced on the OminusminusminusminusHmiddotmiddotmiddotO bondby the changing acid-base propertiesof its environment
The weak HOminusminusminusminusHmiddotmiddotmiddotOH2 bond in water [EHBasympasympasympasymp5 kcal mol-1 dOmiddotmiddotmiddotOasympasympasympasymp270-275 Aring] is transformed in acidic or basic medium into the very strong [H2OmiddotmiddotmiddotHmiddotmiddotmiddotOH2]
+ or [HOmiddotmiddotmiddotHmiddotmiddotmiddotOH]minusminusminusminus bonds with EHB up to 30-31 kcal mol-1 and dOmiddotmiddotmiddotOdown to 238-242 Aring
9
How to Tackle the HB Puzzle How to Tackle the HB Puzzle the Problem of the Driving Variablethe Problem of the Driving Variable
The Electrostatic Paradigmcannot explain the HB PuzzleNeither the Standard Model provides a complete interpretation of it
it just suggests that H-bonds increase their strength with their increasing covalency but without suggesting any specific mechanism for it
To put the problem in more general terms there are a dozen of physicochemical variablescommonly measured in HB studies (energies geometries IR frequencies NMR chemical shifts NQR couplings isotopic effects not to speak of the intrinsic
properties of the interacting molecules) and most if not all appear to be systematically intercorrelated
But whatwhatrsquorsquo s the driving variables the driving variableWhatrsquos the variable which among the many intercorrelated ones
drives the transformation from weak and electrostatic to strong and covalent HB
10
AA Proposal The PApProposal The PApKKaa Equalization PrincipleEqualization Principle
Two very similar proposals come from the early thermodynamic or spectroscopic investigations on the HB and are both centered on the
matching of the acid-base properties of the HB donor and acceptors moieties what we like to call for the sake of brevity the
With reference to any generic DminusminusminusminusHmiddotmiddotmiddotA bond this principle states that the HB is the stronger the smaller becomes the difference of the donor-acceptor
-------------------------------------------------------------------------------------------------------------------------bullAult BS and Pimentel GG J Phys Chem 79 615 (1975) bullKebarle P Ann Rev Phys Chem 28 445ndash476 (1977) bullMeot-Ner (Mautner) M J Am Chem Soc 106 1257ndash1264 (1984)bullHuyskens PL and Zeegers-Huyskens Th J Chim Phys 61 81 (1964) bullMalarski Z M Rospenk and L SobczykJ Phys Chem 86 401ndash406 (1982)
11
Our First Steps into the HBOur First Steps into the HB
As usual we entered the HB field by chance In 1985 during a study on the ligands of the benzodiazepine receptor we determined the structure of CGS8216 and noticed something strange a quite short NminusminusminusminusHmiddotmiddotmiddotO bond of 2694 Aringin association with an interleaving β-enaminonemiddotmiddotmiddot O=CminusminusminusminusC=CminusminusminusminusNH middotmiddotmiddot fragment which was almost completely π-delocalized
It was the first indication of a possible correlation between ππππ-delocalizationand H-bond strengtheningminusminusminusminuswhat we later called the ResonanceResonance--Assisted HAssisted H--Bond Bond (RAHB)(RAHB)(Gilli Bellucci Ferretti amp Bertolasi JACS 1989 Bertolasi Gilli Ferretti amp Gilli JACS 1991)
Since at the time the very few crystal structures of ββββ-enaminones were known the work started on the analogous class of ββββ-enolones(or ββββ-diketone enols) compounds already known to give strong O-HO bonds in association with the equally resonant middotmiddotmiddotO=CminusminusminusminusC=CminusminusminusminusOHmiddotmiddotmiddot fragments
12
Structural Databases and Structural Databases and Crystal Structure Correlation MethodsCrystal Structure Correlation Methods
The correlation between ππππ-delocalizationand H-bond strengthening is essentially a problem of geometrical nature What has to be provedis an intercorrelation between HB strength(as measured by theOhellipO or O-H distances) and ππππ-delocalizationof the resonant fragment (as measured by thed1-d4 distances)
This was the beginning of our intense interest forspades Structural Databasesin general and Cambridge Structural Database (CSD) in particular (Allen Kennardhellip 1979 2002)clubs Structural data interpretation by the so called Crystal Structure Correlation (CSC) Method(Buumlrgi 1973 1975 Buumlrgi and Dunitz 1983) a method for obtaining information on the dynamic behavior of molecules from the inevitably rather static crystal data geometries
Some sample applications of CSD to the study of RAHB in ββββ-diketone enol structures
13
The Development of the OThe Development of the OminusminusminusminusminusminusminusminusHHO RAHBO RAHB
The HBs formed were all much stronger than normal (non-resonant) OminusminusminusminusHO bonds withd(OO)INTRA =239-255 Aringd(OO)INTER =246-265 Aring
R1-RAHBR5-RAHB
24256 Aring
N
N
O M e
N
N
OM e
M eM e
H
lt 257 gt1 Aring
P
O H
OO
O H
H P
O H
OO
O H
H
R3-RAHB
O OH
237-255 Aring
262-267 Aring
O
O H O
OH
262-270 Aring
O
O
H
O
O H
R7-RAHB24462 Aring
NOO
OO
M eM e
H
OOH
O
O
H
246-265 Aring
CARBOXYLIC ACIDS
DIBENZOYLMETHANE ENOLS
CYCLOHEXANEDIONE ENOLS
PHOPHORIC ACID
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
3
The Birth of the HThe Birth of the H--BondBond
The first idea of HB was devised in the laboratory of Gilbert Newton Lewis at the end of 1920s while he was writing his famous bookValence and the structure of atoms and molecules (1923)
The final assessment of the HB conceptis accredited to ML Huggins and independently to WM Latimer and WH Rodebush three young men working there
The first paper was WM Latimerand WH RodebushPolarity and ionization from the standpoint of the Lewis theory of valence J Am Chem Soc 42 1419-1433 1920
The first book is due to Pauling who made the HB known to the wider chemical community Pauling L The Nature of the chemical bondand the structure of molecules and crystals An introduction to modern structural chemistry Cornell University Press Ithaca NY 1939 1940 1960 Chapter 12 55 pages
The definition of HB has not changed over the years What I like best was proposed by Vinogradov SN and Linnel RHHydrogen bonding Van Nostrand-Reinhold New York 1971
4
Hydrogen Bond DefinitionsHydrogen Bond Definitions
A Three-Center-Four-Electron Interaction RminusminusminusminusDmiddotminusminusminusminusmiddotH AminusminusminusminusRrsquo
where D is theHB Donor an electronegative atomsuch as F O N C S Cl Br Iand A the HB Acceptoror Lone Pair Carrier A second electronegative atomor
a multiple bond that isππππ-bondAlternatively
A Proton Sharing InteractionRminusminusminusminusDminusminusminusminus H+ AminusRrsquobetween two electron pairs
located on two adjacent electronegative atoms
Two Important HB PropertiesTwo Important HB Propertiesdiamsdiamsdiamsdiams The HB acceptoris not an atom but an electron pairlocated on that atomspadesspadesspadesspades Since both D and A must be more electronegative than H all HBs have polarity
RminusminusminusminusδδδδminusminusminusminusDminusminusminusminusHδδδδ++++ A δδδδminusminusminusminusminusminusminusminusRrsquo
5
Electrostatic and Covalent HBs The PaulingElectrostatic and Covalent HBs The Paulingrsquorsquo s Models Model
In The Nature of the Chemical Bond L Pauling describes two types of HBs
diamsWeak and dissymmetric HBs of electrostatic natureIt is recognized that the hydrogen atom with only one stable orbital(the 1s orbital) can form only one covalent bond that the hydrogen bond is largely ionic in character and that it is formed only between the most electronegative atoms (HB Chapter p 1)
clubsclubsclubsclubs Strong and symmetric HBs of covalent nature The ldquoexceptionsrdquoThese exceptions are described in terms of VB theory as ldquo the hydrogen bond in the [HF2]
minusminusminusminus ion lies midway the two fluorine atoms and may be considered to form a half-bond with eachrdquo (HB Chapter p 49)
TheThe CoulsonCoulsonrsquorsquo s VB s VB TreatmentTreatmentTheThe Standard HB ModelStandard HB Model
Paulingrsquos ideas acquired theoretical weight with the VB treatment by Coulson and Danielsson(1954)where the O-HO bond is depicted as a mixture of three main VB forms two covalent and one ionic
This line of thought was also adopted by Pimentel and McClellanin their famous book The Hydrogen Bond(1960)
They wrote ldquoAt the 1957 Ljubljana Conferenceone of the important pointsof fairly general accord was that the electrostatic model does not account for all of the phenomena associated with H bond formationrdquo
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
7
The Birth of the Simple Electrostatic ParadigmThe Birth of the Simple Electrostatic ParadigmFor reasons difficult to understand the Standard HB Model was discarded in the mid-
sixties and the HB became the weak electrostatic interaction not stronger than some 4-5 kcal mol-1 everyone has read of in elementary textbooks while strong HBs just disappeared from the chemical horizon The effect of this choice was disastrous and it took more than twenty years to put it right
Why the Standard Model was AbandonedWhy the Standard Model was AbandonedThe most probable reason can be ascribed to the bizarre way in wThe most probable reason can be ascribed to the bizarre way in which Pauling had arranged hich Pauling had arranged
his famous HB chapter in his famous HB chapter in The Nature of the Chemical Bond
clubsclubsclubsclubs Weak electrostatic HBs are quoted on p 1of the chapter while strong covalent onesonly on p 49 Since most people read only the first few pages of anything hellip
diamsdiamsdiamsdiams On p 50 strong HBs are called ldquoexceptionsrdquo Most readers may have thought Why to bother about exceptions when there are already so many regular HBs to bother about These are things for specialists
heartsheartsheartshearts On p 1 the Paulingrsquos statement ldquothe hydrogen atom can form only one covalent bondhelliprdquo was quite unclear and in consequence was systematically misinterpreted In correct VB terms it cannot be said that the H atom can form only one bond because in factit may also form any combination of two bonds whose bond orders sum up to one from (10) to (01) through (frac12 frac12)
8
Another Unsolved Problem Another Unsolved Problem The HB PuzzleThe HB Puzzle
Bond lengths and energies of normal chemical bondsare determined by the nature of the interacting atoms and weakly perturbed by the environment
On the contrary binding energies (EHB) and DmiddotmiddotmiddotA distances (dDmiddotmiddotmiddotA) of DminusminusminusminusHmiddotmiddotmiddotA H-bondsdo not simply depend on the donor (D) and acceptor (A) nature but show very large variations even for the same donor-acceptor couple
This is what we have often called for the sake of brevity
the HB Puzzlethe HB Puzzle
An extreme exampleof this behavior comes from the effects produced on the OminusminusminusminusHmiddotmiddotmiddotO bondby the changing acid-base propertiesof its environment
The weak HOminusminusminusminusHmiddotmiddotmiddotOH2 bond in water [EHBasympasympasympasymp5 kcal mol-1 dOmiddotmiddotmiddotOasympasympasympasymp270-275 Aring] is transformed in acidic or basic medium into the very strong [H2OmiddotmiddotmiddotHmiddotmiddotmiddotOH2]
+ or [HOmiddotmiddotmiddotHmiddotmiddotmiddotOH]minusminusminusminus bonds with EHB up to 30-31 kcal mol-1 and dOmiddotmiddotmiddotOdown to 238-242 Aring
9
How to Tackle the HB Puzzle How to Tackle the HB Puzzle the Problem of the Driving Variablethe Problem of the Driving Variable
The Electrostatic Paradigmcannot explain the HB PuzzleNeither the Standard Model provides a complete interpretation of it
it just suggests that H-bonds increase their strength with their increasing covalency but without suggesting any specific mechanism for it
To put the problem in more general terms there are a dozen of physicochemical variablescommonly measured in HB studies (energies geometries IR frequencies NMR chemical shifts NQR couplings isotopic effects not to speak of the intrinsic
properties of the interacting molecules) and most if not all appear to be systematically intercorrelated
But whatwhatrsquorsquo s the driving variables the driving variableWhatrsquos the variable which among the many intercorrelated ones
drives the transformation from weak and electrostatic to strong and covalent HB
10
AA Proposal The PApProposal The PApKKaa Equalization PrincipleEqualization Principle
Two very similar proposals come from the early thermodynamic or spectroscopic investigations on the HB and are both centered on the
matching of the acid-base properties of the HB donor and acceptors moieties what we like to call for the sake of brevity the
With reference to any generic DminusminusminusminusHmiddotmiddotmiddotA bond this principle states that the HB is the stronger the smaller becomes the difference of the donor-acceptor
-------------------------------------------------------------------------------------------------------------------------bullAult BS and Pimentel GG J Phys Chem 79 615 (1975) bullKebarle P Ann Rev Phys Chem 28 445ndash476 (1977) bullMeot-Ner (Mautner) M J Am Chem Soc 106 1257ndash1264 (1984)bullHuyskens PL and Zeegers-Huyskens Th J Chim Phys 61 81 (1964) bullMalarski Z M Rospenk and L SobczykJ Phys Chem 86 401ndash406 (1982)
11
Our First Steps into the HBOur First Steps into the HB
As usual we entered the HB field by chance In 1985 during a study on the ligands of the benzodiazepine receptor we determined the structure of CGS8216 and noticed something strange a quite short NminusminusminusminusHmiddotmiddotmiddotO bond of 2694 Aringin association with an interleaving β-enaminonemiddotmiddotmiddot O=CminusminusminusminusC=CminusminusminusminusNH middotmiddotmiddot fragment which was almost completely π-delocalized
It was the first indication of a possible correlation between ππππ-delocalizationand H-bond strengtheningminusminusminusminuswhat we later called the ResonanceResonance--Assisted HAssisted H--Bond Bond (RAHB)(RAHB)(Gilli Bellucci Ferretti amp Bertolasi JACS 1989 Bertolasi Gilli Ferretti amp Gilli JACS 1991)
Since at the time the very few crystal structures of ββββ-enaminones were known the work started on the analogous class of ββββ-enolones(or ββββ-diketone enols) compounds already known to give strong O-HO bonds in association with the equally resonant middotmiddotmiddotO=CminusminusminusminusC=CminusminusminusminusOHmiddotmiddotmiddot fragments
12
Structural Databases and Structural Databases and Crystal Structure Correlation MethodsCrystal Structure Correlation Methods
The correlation between ππππ-delocalizationand H-bond strengthening is essentially a problem of geometrical nature What has to be provedis an intercorrelation between HB strength(as measured by theOhellipO or O-H distances) and ππππ-delocalizationof the resonant fragment (as measured by thed1-d4 distances)
This was the beginning of our intense interest forspades Structural Databasesin general and Cambridge Structural Database (CSD) in particular (Allen Kennardhellip 1979 2002)clubs Structural data interpretation by the so called Crystal Structure Correlation (CSC) Method(Buumlrgi 1973 1975 Buumlrgi and Dunitz 1983) a method for obtaining information on the dynamic behavior of molecules from the inevitably rather static crystal data geometries
Some sample applications of CSD to the study of RAHB in ββββ-diketone enol structures
13
The Development of the OThe Development of the OminusminusminusminusminusminusminusminusHHO RAHBO RAHB
The HBs formed were all much stronger than normal (non-resonant) OminusminusminusminusHO bonds withd(OO)INTRA =239-255 Aringd(OO)INTER =246-265 Aring
R1-RAHBR5-RAHB
24256 Aring
N
N
O M e
N
N
OM e
M eM e
H
lt 257 gt1 Aring
P
O H
OO
O H
H P
O H
OO
O H
H
R3-RAHB
O OH
237-255 Aring
262-267 Aring
O
O H O
OH
262-270 Aring
O
O
H
O
O H
R7-RAHB24462 Aring
NOO
OO
M eM e
H
OOH
O
O
H
246-265 Aring
CARBOXYLIC ACIDS
DIBENZOYLMETHANE ENOLS
CYCLOHEXANEDIONE ENOLS
PHOPHORIC ACID
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
4
Hydrogen Bond DefinitionsHydrogen Bond Definitions
A Three-Center-Four-Electron Interaction RminusminusminusminusDmiddotminusminusminusminusmiddotH AminusminusminusminusRrsquo
where D is theHB Donor an electronegative atomsuch as F O N C S Cl Br Iand A the HB Acceptoror Lone Pair Carrier A second electronegative atomor
a multiple bond that isππππ-bondAlternatively
A Proton Sharing InteractionRminusminusminusminusDminusminusminusminus H+ AminusRrsquobetween two electron pairs
located on two adjacent electronegative atoms
Two Important HB PropertiesTwo Important HB Propertiesdiamsdiamsdiamsdiams The HB acceptoris not an atom but an electron pairlocated on that atomspadesspadesspadesspades Since both D and A must be more electronegative than H all HBs have polarity
RminusminusminusminusδδδδminusminusminusminusDminusminusminusminusHδδδδ++++ A δδδδminusminusminusminusminusminusminusminusRrsquo
5
Electrostatic and Covalent HBs The PaulingElectrostatic and Covalent HBs The Paulingrsquorsquo s Models Model
In The Nature of the Chemical Bond L Pauling describes two types of HBs
diamsWeak and dissymmetric HBs of electrostatic natureIt is recognized that the hydrogen atom with only one stable orbital(the 1s orbital) can form only one covalent bond that the hydrogen bond is largely ionic in character and that it is formed only between the most electronegative atoms (HB Chapter p 1)
clubsclubsclubsclubs Strong and symmetric HBs of covalent nature The ldquoexceptionsrdquoThese exceptions are described in terms of VB theory as ldquo the hydrogen bond in the [HF2]
minusminusminusminus ion lies midway the two fluorine atoms and may be considered to form a half-bond with eachrdquo (HB Chapter p 49)
TheThe CoulsonCoulsonrsquorsquo s VB s VB TreatmentTreatmentTheThe Standard HB ModelStandard HB Model
Paulingrsquos ideas acquired theoretical weight with the VB treatment by Coulson and Danielsson(1954)where the O-HO bond is depicted as a mixture of three main VB forms two covalent and one ionic
This line of thought was also adopted by Pimentel and McClellanin their famous book The Hydrogen Bond(1960)
They wrote ldquoAt the 1957 Ljubljana Conferenceone of the important pointsof fairly general accord was that the electrostatic model does not account for all of the phenomena associated with H bond formationrdquo
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
7
The Birth of the Simple Electrostatic ParadigmThe Birth of the Simple Electrostatic ParadigmFor reasons difficult to understand the Standard HB Model was discarded in the mid-
sixties and the HB became the weak electrostatic interaction not stronger than some 4-5 kcal mol-1 everyone has read of in elementary textbooks while strong HBs just disappeared from the chemical horizon The effect of this choice was disastrous and it took more than twenty years to put it right
Why the Standard Model was AbandonedWhy the Standard Model was AbandonedThe most probable reason can be ascribed to the bizarre way in wThe most probable reason can be ascribed to the bizarre way in which Pauling had arranged hich Pauling had arranged
his famous HB chapter in his famous HB chapter in The Nature of the Chemical Bond
clubsclubsclubsclubs Weak electrostatic HBs are quoted on p 1of the chapter while strong covalent onesonly on p 49 Since most people read only the first few pages of anything hellip
diamsdiamsdiamsdiams On p 50 strong HBs are called ldquoexceptionsrdquo Most readers may have thought Why to bother about exceptions when there are already so many regular HBs to bother about These are things for specialists
heartsheartsheartshearts On p 1 the Paulingrsquos statement ldquothe hydrogen atom can form only one covalent bondhelliprdquo was quite unclear and in consequence was systematically misinterpreted In correct VB terms it cannot be said that the H atom can form only one bond because in factit may also form any combination of two bonds whose bond orders sum up to one from (10) to (01) through (frac12 frac12)
8
Another Unsolved Problem Another Unsolved Problem The HB PuzzleThe HB Puzzle
Bond lengths and energies of normal chemical bondsare determined by the nature of the interacting atoms and weakly perturbed by the environment
On the contrary binding energies (EHB) and DmiddotmiddotmiddotA distances (dDmiddotmiddotmiddotA) of DminusminusminusminusHmiddotmiddotmiddotA H-bondsdo not simply depend on the donor (D) and acceptor (A) nature but show very large variations even for the same donor-acceptor couple
This is what we have often called for the sake of brevity
the HB Puzzlethe HB Puzzle
An extreme exampleof this behavior comes from the effects produced on the OminusminusminusminusHmiddotmiddotmiddotO bondby the changing acid-base propertiesof its environment
The weak HOminusminusminusminusHmiddotmiddotmiddotOH2 bond in water [EHBasympasympasympasymp5 kcal mol-1 dOmiddotmiddotmiddotOasympasympasympasymp270-275 Aring] is transformed in acidic or basic medium into the very strong [H2OmiddotmiddotmiddotHmiddotmiddotmiddotOH2]
+ or [HOmiddotmiddotmiddotHmiddotmiddotmiddotOH]minusminusminusminus bonds with EHB up to 30-31 kcal mol-1 and dOmiddotmiddotmiddotOdown to 238-242 Aring
9
How to Tackle the HB Puzzle How to Tackle the HB Puzzle the Problem of the Driving Variablethe Problem of the Driving Variable
The Electrostatic Paradigmcannot explain the HB PuzzleNeither the Standard Model provides a complete interpretation of it
it just suggests that H-bonds increase their strength with their increasing covalency but without suggesting any specific mechanism for it
To put the problem in more general terms there are a dozen of physicochemical variablescommonly measured in HB studies (energies geometries IR frequencies NMR chemical shifts NQR couplings isotopic effects not to speak of the intrinsic
properties of the interacting molecules) and most if not all appear to be systematically intercorrelated
But whatwhatrsquorsquo s the driving variables the driving variableWhatrsquos the variable which among the many intercorrelated ones
drives the transformation from weak and electrostatic to strong and covalent HB
10
AA Proposal The PApProposal The PApKKaa Equalization PrincipleEqualization Principle
Two very similar proposals come from the early thermodynamic or spectroscopic investigations on the HB and are both centered on the
matching of the acid-base properties of the HB donor and acceptors moieties what we like to call for the sake of brevity the
With reference to any generic DminusminusminusminusHmiddotmiddotmiddotA bond this principle states that the HB is the stronger the smaller becomes the difference of the donor-acceptor
-------------------------------------------------------------------------------------------------------------------------bullAult BS and Pimentel GG J Phys Chem 79 615 (1975) bullKebarle P Ann Rev Phys Chem 28 445ndash476 (1977) bullMeot-Ner (Mautner) M J Am Chem Soc 106 1257ndash1264 (1984)bullHuyskens PL and Zeegers-Huyskens Th J Chim Phys 61 81 (1964) bullMalarski Z M Rospenk and L SobczykJ Phys Chem 86 401ndash406 (1982)
11
Our First Steps into the HBOur First Steps into the HB
As usual we entered the HB field by chance In 1985 during a study on the ligands of the benzodiazepine receptor we determined the structure of CGS8216 and noticed something strange a quite short NminusminusminusminusHmiddotmiddotmiddotO bond of 2694 Aringin association with an interleaving β-enaminonemiddotmiddotmiddot O=CminusminusminusminusC=CminusminusminusminusNH middotmiddotmiddot fragment which was almost completely π-delocalized
It was the first indication of a possible correlation between ππππ-delocalizationand H-bond strengtheningminusminusminusminuswhat we later called the ResonanceResonance--Assisted HAssisted H--Bond Bond (RAHB)(RAHB)(Gilli Bellucci Ferretti amp Bertolasi JACS 1989 Bertolasi Gilli Ferretti amp Gilli JACS 1991)
Since at the time the very few crystal structures of ββββ-enaminones were known the work started on the analogous class of ββββ-enolones(or ββββ-diketone enols) compounds already known to give strong O-HO bonds in association with the equally resonant middotmiddotmiddotO=CminusminusminusminusC=CminusminusminusminusOHmiddotmiddotmiddot fragments
12
Structural Databases and Structural Databases and Crystal Structure Correlation MethodsCrystal Structure Correlation Methods
The correlation between ππππ-delocalizationand H-bond strengthening is essentially a problem of geometrical nature What has to be provedis an intercorrelation between HB strength(as measured by theOhellipO or O-H distances) and ππππ-delocalizationof the resonant fragment (as measured by thed1-d4 distances)
This was the beginning of our intense interest forspades Structural Databasesin general and Cambridge Structural Database (CSD) in particular (Allen Kennardhellip 1979 2002)clubs Structural data interpretation by the so called Crystal Structure Correlation (CSC) Method(Buumlrgi 1973 1975 Buumlrgi and Dunitz 1983) a method for obtaining information on the dynamic behavior of molecules from the inevitably rather static crystal data geometries
Some sample applications of CSD to the study of RAHB in ββββ-diketone enol structures
13
The Development of the OThe Development of the OminusminusminusminusminusminusminusminusHHO RAHBO RAHB
The HBs formed were all much stronger than normal (non-resonant) OminusminusminusminusHO bonds withd(OO)INTRA =239-255 Aringd(OO)INTER =246-265 Aring
R1-RAHBR5-RAHB
24256 Aring
N
N
O M e
N
N
OM e
M eM e
H
lt 257 gt1 Aring
P
O H
OO
O H
H P
O H
OO
O H
H
R3-RAHB
O OH
237-255 Aring
262-267 Aring
O
O H O
OH
262-270 Aring
O
O
H
O
O H
R7-RAHB24462 Aring
NOO
OO
M eM e
H
OOH
O
O
H
246-265 Aring
CARBOXYLIC ACIDS
DIBENZOYLMETHANE ENOLS
CYCLOHEXANEDIONE ENOLS
PHOPHORIC ACID
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
5
Electrostatic and Covalent HBs The PaulingElectrostatic and Covalent HBs The Paulingrsquorsquo s Models Model
In The Nature of the Chemical Bond L Pauling describes two types of HBs
diamsWeak and dissymmetric HBs of electrostatic natureIt is recognized that the hydrogen atom with only one stable orbital(the 1s orbital) can form only one covalent bond that the hydrogen bond is largely ionic in character and that it is formed only between the most electronegative atoms (HB Chapter p 1)
clubsclubsclubsclubs Strong and symmetric HBs of covalent nature The ldquoexceptionsrdquoThese exceptions are described in terms of VB theory as ldquo the hydrogen bond in the [HF2]
minusminusminusminus ion lies midway the two fluorine atoms and may be considered to form a half-bond with eachrdquo (HB Chapter p 49)
TheThe CoulsonCoulsonrsquorsquo s VB s VB TreatmentTreatmentTheThe Standard HB ModelStandard HB Model
Paulingrsquos ideas acquired theoretical weight with the VB treatment by Coulson and Danielsson(1954)where the O-HO bond is depicted as a mixture of three main VB forms two covalent and one ionic
This line of thought was also adopted by Pimentel and McClellanin their famous book The Hydrogen Bond(1960)
They wrote ldquoAt the 1957 Ljubljana Conferenceone of the important pointsof fairly general accord was that the electrostatic model does not account for all of the phenomena associated with H bond formationrdquo
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
7
The Birth of the Simple Electrostatic ParadigmThe Birth of the Simple Electrostatic ParadigmFor reasons difficult to understand the Standard HB Model was discarded in the mid-
sixties and the HB became the weak electrostatic interaction not stronger than some 4-5 kcal mol-1 everyone has read of in elementary textbooks while strong HBs just disappeared from the chemical horizon The effect of this choice was disastrous and it took more than twenty years to put it right
Why the Standard Model was AbandonedWhy the Standard Model was AbandonedThe most probable reason can be ascribed to the bizarre way in wThe most probable reason can be ascribed to the bizarre way in which Pauling had arranged hich Pauling had arranged
his famous HB chapter in his famous HB chapter in The Nature of the Chemical Bond
clubsclubsclubsclubs Weak electrostatic HBs are quoted on p 1of the chapter while strong covalent onesonly on p 49 Since most people read only the first few pages of anything hellip
diamsdiamsdiamsdiams On p 50 strong HBs are called ldquoexceptionsrdquo Most readers may have thought Why to bother about exceptions when there are already so many regular HBs to bother about These are things for specialists
heartsheartsheartshearts On p 1 the Paulingrsquos statement ldquothe hydrogen atom can form only one covalent bondhelliprdquo was quite unclear and in consequence was systematically misinterpreted In correct VB terms it cannot be said that the H atom can form only one bond because in factit may also form any combination of two bonds whose bond orders sum up to one from (10) to (01) through (frac12 frac12)
8
Another Unsolved Problem Another Unsolved Problem The HB PuzzleThe HB Puzzle
Bond lengths and energies of normal chemical bondsare determined by the nature of the interacting atoms and weakly perturbed by the environment
On the contrary binding energies (EHB) and DmiddotmiddotmiddotA distances (dDmiddotmiddotmiddotA) of DminusminusminusminusHmiddotmiddotmiddotA H-bondsdo not simply depend on the donor (D) and acceptor (A) nature but show very large variations even for the same donor-acceptor couple
This is what we have often called for the sake of brevity
the HB Puzzlethe HB Puzzle
An extreme exampleof this behavior comes from the effects produced on the OminusminusminusminusHmiddotmiddotmiddotO bondby the changing acid-base propertiesof its environment
The weak HOminusminusminusminusHmiddotmiddotmiddotOH2 bond in water [EHBasympasympasympasymp5 kcal mol-1 dOmiddotmiddotmiddotOasympasympasympasymp270-275 Aring] is transformed in acidic or basic medium into the very strong [H2OmiddotmiddotmiddotHmiddotmiddotmiddotOH2]
+ or [HOmiddotmiddotmiddotHmiddotmiddotmiddotOH]minusminusminusminus bonds with EHB up to 30-31 kcal mol-1 and dOmiddotmiddotmiddotOdown to 238-242 Aring
9
How to Tackle the HB Puzzle How to Tackle the HB Puzzle the Problem of the Driving Variablethe Problem of the Driving Variable
The Electrostatic Paradigmcannot explain the HB PuzzleNeither the Standard Model provides a complete interpretation of it
it just suggests that H-bonds increase their strength with their increasing covalency but without suggesting any specific mechanism for it
To put the problem in more general terms there are a dozen of physicochemical variablescommonly measured in HB studies (energies geometries IR frequencies NMR chemical shifts NQR couplings isotopic effects not to speak of the intrinsic
properties of the interacting molecules) and most if not all appear to be systematically intercorrelated
But whatwhatrsquorsquo s the driving variables the driving variableWhatrsquos the variable which among the many intercorrelated ones
drives the transformation from weak and electrostatic to strong and covalent HB
10
AA Proposal The PApProposal The PApKKaa Equalization PrincipleEqualization Principle
Two very similar proposals come from the early thermodynamic or spectroscopic investigations on the HB and are both centered on the
matching of the acid-base properties of the HB donor and acceptors moieties what we like to call for the sake of brevity the
With reference to any generic DminusminusminusminusHmiddotmiddotmiddotA bond this principle states that the HB is the stronger the smaller becomes the difference of the donor-acceptor
-------------------------------------------------------------------------------------------------------------------------bullAult BS and Pimentel GG J Phys Chem 79 615 (1975) bullKebarle P Ann Rev Phys Chem 28 445ndash476 (1977) bullMeot-Ner (Mautner) M J Am Chem Soc 106 1257ndash1264 (1984)bullHuyskens PL and Zeegers-Huyskens Th J Chim Phys 61 81 (1964) bullMalarski Z M Rospenk and L SobczykJ Phys Chem 86 401ndash406 (1982)
11
Our First Steps into the HBOur First Steps into the HB
As usual we entered the HB field by chance In 1985 during a study on the ligands of the benzodiazepine receptor we determined the structure of CGS8216 and noticed something strange a quite short NminusminusminusminusHmiddotmiddotmiddotO bond of 2694 Aringin association with an interleaving β-enaminonemiddotmiddotmiddot O=CminusminusminusminusC=CminusminusminusminusNH middotmiddotmiddot fragment which was almost completely π-delocalized
It was the first indication of a possible correlation between ππππ-delocalizationand H-bond strengtheningminusminusminusminuswhat we later called the ResonanceResonance--Assisted HAssisted H--Bond Bond (RAHB)(RAHB)(Gilli Bellucci Ferretti amp Bertolasi JACS 1989 Bertolasi Gilli Ferretti amp Gilli JACS 1991)
Since at the time the very few crystal structures of ββββ-enaminones were known the work started on the analogous class of ββββ-enolones(or ββββ-diketone enols) compounds already known to give strong O-HO bonds in association with the equally resonant middotmiddotmiddotO=CminusminusminusminusC=CminusminusminusminusOHmiddotmiddotmiddot fragments
12
Structural Databases and Structural Databases and Crystal Structure Correlation MethodsCrystal Structure Correlation Methods
The correlation between ππππ-delocalizationand H-bond strengthening is essentially a problem of geometrical nature What has to be provedis an intercorrelation between HB strength(as measured by theOhellipO or O-H distances) and ππππ-delocalizationof the resonant fragment (as measured by thed1-d4 distances)
This was the beginning of our intense interest forspades Structural Databasesin general and Cambridge Structural Database (CSD) in particular (Allen Kennardhellip 1979 2002)clubs Structural data interpretation by the so called Crystal Structure Correlation (CSC) Method(Buumlrgi 1973 1975 Buumlrgi and Dunitz 1983) a method for obtaining information on the dynamic behavior of molecules from the inevitably rather static crystal data geometries
Some sample applications of CSD to the study of RAHB in ββββ-diketone enol structures
13
The Development of the OThe Development of the OminusminusminusminusminusminusminusminusHHO RAHBO RAHB
The HBs formed were all much stronger than normal (non-resonant) OminusminusminusminusHO bonds withd(OO)INTRA =239-255 Aringd(OO)INTER =246-265 Aring
R1-RAHBR5-RAHB
24256 Aring
N
N
O M e
N
N
OM e
M eM e
H
lt 257 gt1 Aring
P
O H
OO
O H
H P
O H
OO
O H
H
R3-RAHB
O OH
237-255 Aring
262-267 Aring
O
O H O
OH
262-270 Aring
O
O
H
O
O H
R7-RAHB24462 Aring
NOO
OO
M eM e
H
OOH
O
O
H
246-265 Aring
CARBOXYLIC ACIDS
DIBENZOYLMETHANE ENOLS
CYCLOHEXANEDIONE ENOLS
PHOPHORIC ACID
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
6
TheThe CoulsonCoulsonrsquorsquo s VB s VB TreatmentTreatmentTheThe Standard HB ModelStandard HB Model
Paulingrsquos ideas acquired theoretical weight with the VB treatment by Coulson and Danielsson(1954)where the O-HO bond is depicted as a mixture of three main VB forms two covalent and one ionic
This line of thought was also adopted by Pimentel and McClellanin their famous book The Hydrogen Bond(1960)
They wrote ldquoAt the 1957 Ljubljana Conferenceone of the important pointsof fairly general accord was that the electrostatic model does not account for all of the phenomena associated with H bond formationrdquo
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
7
The Birth of the Simple Electrostatic ParadigmThe Birth of the Simple Electrostatic ParadigmFor reasons difficult to understand the Standard HB Model was discarded in the mid-
sixties and the HB became the weak electrostatic interaction not stronger than some 4-5 kcal mol-1 everyone has read of in elementary textbooks while strong HBs just disappeared from the chemical horizon The effect of this choice was disastrous and it took more than twenty years to put it right
Why the Standard Model was AbandonedWhy the Standard Model was AbandonedThe most probable reason can be ascribed to the bizarre way in wThe most probable reason can be ascribed to the bizarre way in which Pauling had arranged hich Pauling had arranged
his famous HB chapter in his famous HB chapter in The Nature of the Chemical Bond
clubsclubsclubsclubs Weak electrostatic HBs are quoted on p 1of the chapter while strong covalent onesonly on p 49 Since most people read only the first few pages of anything hellip
diamsdiamsdiamsdiams On p 50 strong HBs are called ldquoexceptionsrdquo Most readers may have thought Why to bother about exceptions when there are already so many regular HBs to bother about These are things for specialists
heartsheartsheartshearts On p 1 the Paulingrsquos statement ldquothe hydrogen atom can form only one covalent bondhelliprdquo was quite unclear and in consequence was systematically misinterpreted In correct VB terms it cannot be said that the H atom can form only one bond because in factit may also form any combination of two bonds whose bond orders sum up to one from (10) to (01) through (frac12 frac12)
8
Another Unsolved Problem Another Unsolved Problem The HB PuzzleThe HB Puzzle
Bond lengths and energies of normal chemical bondsare determined by the nature of the interacting atoms and weakly perturbed by the environment
On the contrary binding energies (EHB) and DmiddotmiddotmiddotA distances (dDmiddotmiddotmiddotA) of DminusminusminusminusHmiddotmiddotmiddotA H-bondsdo not simply depend on the donor (D) and acceptor (A) nature but show very large variations even for the same donor-acceptor couple
This is what we have often called for the sake of brevity
the HB Puzzlethe HB Puzzle
An extreme exampleof this behavior comes from the effects produced on the OminusminusminusminusHmiddotmiddotmiddotO bondby the changing acid-base propertiesof its environment
The weak HOminusminusminusminusHmiddotmiddotmiddotOH2 bond in water [EHBasympasympasympasymp5 kcal mol-1 dOmiddotmiddotmiddotOasympasympasympasymp270-275 Aring] is transformed in acidic or basic medium into the very strong [H2OmiddotmiddotmiddotHmiddotmiddotmiddotOH2]
+ or [HOmiddotmiddotmiddotHmiddotmiddotmiddotOH]minusminusminusminus bonds with EHB up to 30-31 kcal mol-1 and dOmiddotmiddotmiddotOdown to 238-242 Aring
9
How to Tackle the HB Puzzle How to Tackle the HB Puzzle the Problem of the Driving Variablethe Problem of the Driving Variable
The Electrostatic Paradigmcannot explain the HB PuzzleNeither the Standard Model provides a complete interpretation of it
it just suggests that H-bonds increase their strength with their increasing covalency but without suggesting any specific mechanism for it
To put the problem in more general terms there are a dozen of physicochemical variablescommonly measured in HB studies (energies geometries IR frequencies NMR chemical shifts NQR couplings isotopic effects not to speak of the intrinsic
properties of the interacting molecules) and most if not all appear to be systematically intercorrelated
But whatwhatrsquorsquo s the driving variables the driving variableWhatrsquos the variable which among the many intercorrelated ones
drives the transformation from weak and electrostatic to strong and covalent HB
10
AA Proposal The PApProposal The PApKKaa Equalization PrincipleEqualization Principle
Two very similar proposals come from the early thermodynamic or spectroscopic investigations on the HB and are both centered on the
matching of the acid-base properties of the HB donor and acceptors moieties what we like to call for the sake of brevity the
With reference to any generic DminusminusminusminusHmiddotmiddotmiddotA bond this principle states that the HB is the stronger the smaller becomes the difference of the donor-acceptor
-------------------------------------------------------------------------------------------------------------------------bullAult BS and Pimentel GG J Phys Chem 79 615 (1975) bullKebarle P Ann Rev Phys Chem 28 445ndash476 (1977) bullMeot-Ner (Mautner) M J Am Chem Soc 106 1257ndash1264 (1984)bullHuyskens PL and Zeegers-Huyskens Th J Chim Phys 61 81 (1964) bullMalarski Z M Rospenk and L SobczykJ Phys Chem 86 401ndash406 (1982)
11
Our First Steps into the HBOur First Steps into the HB
As usual we entered the HB field by chance In 1985 during a study on the ligands of the benzodiazepine receptor we determined the structure of CGS8216 and noticed something strange a quite short NminusminusminusminusHmiddotmiddotmiddotO bond of 2694 Aringin association with an interleaving β-enaminonemiddotmiddotmiddot O=CminusminusminusminusC=CminusminusminusminusNH middotmiddotmiddot fragment which was almost completely π-delocalized
It was the first indication of a possible correlation between ππππ-delocalizationand H-bond strengtheningminusminusminusminuswhat we later called the ResonanceResonance--Assisted HAssisted H--Bond Bond (RAHB)(RAHB)(Gilli Bellucci Ferretti amp Bertolasi JACS 1989 Bertolasi Gilli Ferretti amp Gilli JACS 1991)
Since at the time the very few crystal structures of ββββ-enaminones were known the work started on the analogous class of ββββ-enolones(or ββββ-diketone enols) compounds already known to give strong O-HO bonds in association with the equally resonant middotmiddotmiddotO=CminusminusminusminusC=CminusminusminusminusOHmiddotmiddotmiddot fragments
12
Structural Databases and Structural Databases and Crystal Structure Correlation MethodsCrystal Structure Correlation Methods
The correlation between ππππ-delocalizationand H-bond strengthening is essentially a problem of geometrical nature What has to be provedis an intercorrelation between HB strength(as measured by theOhellipO or O-H distances) and ππππ-delocalizationof the resonant fragment (as measured by thed1-d4 distances)
This was the beginning of our intense interest forspades Structural Databasesin general and Cambridge Structural Database (CSD) in particular (Allen Kennardhellip 1979 2002)clubs Structural data interpretation by the so called Crystal Structure Correlation (CSC) Method(Buumlrgi 1973 1975 Buumlrgi and Dunitz 1983) a method for obtaining information on the dynamic behavior of molecules from the inevitably rather static crystal data geometries
Some sample applications of CSD to the study of RAHB in ββββ-diketone enol structures
13
The Development of the OThe Development of the OminusminusminusminusminusminusminusminusHHO RAHBO RAHB
The HBs formed were all much stronger than normal (non-resonant) OminusminusminusminusHO bonds withd(OO)INTRA =239-255 Aringd(OO)INTER =246-265 Aring
R1-RAHBR5-RAHB
24256 Aring
N
N
O M e
N
N
OM e
M eM e
H
lt 257 gt1 Aring
P
O H
OO
O H
H P
O H
OO
O H
H
R3-RAHB
O OH
237-255 Aring
262-267 Aring
O
O H O
OH
262-270 Aring
O
O
H
O
O H
R7-RAHB24462 Aring
NOO
OO
M eM e
H
OOH
O
O
H
246-265 Aring
CARBOXYLIC ACIDS
DIBENZOYLMETHANE ENOLS
CYCLOHEXANEDIONE ENOLS
PHOPHORIC ACID
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
7
The Birth of the Simple Electrostatic ParadigmThe Birth of the Simple Electrostatic ParadigmFor reasons difficult to understand the Standard HB Model was discarded in the mid-
sixties and the HB became the weak electrostatic interaction not stronger than some 4-5 kcal mol-1 everyone has read of in elementary textbooks while strong HBs just disappeared from the chemical horizon The effect of this choice was disastrous and it took more than twenty years to put it right
Why the Standard Model was AbandonedWhy the Standard Model was AbandonedThe most probable reason can be ascribed to the bizarre way in wThe most probable reason can be ascribed to the bizarre way in which Pauling had arranged hich Pauling had arranged
his famous HB chapter in his famous HB chapter in The Nature of the Chemical Bond
clubsclubsclubsclubs Weak electrostatic HBs are quoted on p 1of the chapter while strong covalent onesonly on p 49 Since most people read only the first few pages of anything hellip
diamsdiamsdiamsdiams On p 50 strong HBs are called ldquoexceptionsrdquo Most readers may have thought Why to bother about exceptions when there are already so many regular HBs to bother about These are things for specialists
heartsheartsheartshearts On p 1 the Paulingrsquos statement ldquothe hydrogen atom can form only one covalent bondhelliprdquo was quite unclear and in consequence was systematically misinterpreted In correct VB terms it cannot be said that the H atom can form only one bond because in factit may also form any combination of two bonds whose bond orders sum up to one from (10) to (01) through (frac12 frac12)
8
Another Unsolved Problem Another Unsolved Problem The HB PuzzleThe HB Puzzle
Bond lengths and energies of normal chemical bondsare determined by the nature of the interacting atoms and weakly perturbed by the environment
On the contrary binding energies (EHB) and DmiddotmiddotmiddotA distances (dDmiddotmiddotmiddotA) of DminusminusminusminusHmiddotmiddotmiddotA H-bondsdo not simply depend on the donor (D) and acceptor (A) nature but show very large variations even for the same donor-acceptor couple
This is what we have often called for the sake of brevity
the HB Puzzlethe HB Puzzle
An extreme exampleof this behavior comes from the effects produced on the OminusminusminusminusHmiddotmiddotmiddotO bondby the changing acid-base propertiesof its environment
The weak HOminusminusminusminusHmiddotmiddotmiddotOH2 bond in water [EHBasympasympasympasymp5 kcal mol-1 dOmiddotmiddotmiddotOasympasympasympasymp270-275 Aring] is transformed in acidic or basic medium into the very strong [H2OmiddotmiddotmiddotHmiddotmiddotmiddotOH2]
+ or [HOmiddotmiddotmiddotHmiddotmiddotmiddotOH]minusminusminusminus bonds with EHB up to 30-31 kcal mol-1 and dOmiddotmiddotmiddotOdown to 238-242 Aring
9
How to Tackle the HB Puzzle How to Tackle the HB Puzzle the Problem of the Driving Variablethe Problem of the Driving Variable
The Electrostatic Paradigmcannot explain the HB PuzzleNeither the Standard Model provides a complete interpretation of it
it just suggests that H-bonds increase their strength with their increasing covalency but without suggesting any specific mechanism for it
To put the problem in more general terms there are a dozen of physicochemical variablescommonly measured in HB studies (energies geometries IR frequencies NMR chemical shifts NQR couplings isotopic effects not to speak of the intrinsic
properties of the interacting molecules) and most if not all appear to be systematically intercorrelated
But whatwhatrsquorsquo s the driving variables the driving variableWhatrsquos the variable which among the many intercorrelated ones
drives the transformation from weak and electrostatic to strong and covalent HB
10
AA Proposal The PApProposal The PApKKaa Equalization PrincipleEqualization Principle
Two very similar proposals come from the early thermodynamic or spectroscopic investigations on the HB and are both centered on the
matching of the acid-base properties of the HB donor and acceptors moieties what we like to call for the sake of brevity the
With reference to any generic DminusminusminusminusHmiddotmiddotmiddotA bond this principle states that the HB is the stronger the smaller becomes the difference of the donor-acceptor
-------------------------------------------------------------------------------------------------------------------------bullAult BS and Pimentel GG J Phys Chem 79 615 (1975) bullKebarle P Ann Rev Phys Chem 28 445ndash476 (1977) bullMeot-Ner (Mautner) M J Am Chem Soc 106 1257ndash1264 (1984)bullHuyskens PL and Zeegers-Huyskens Th J Chim Phys 61 81 (1964) bullMalarski Z M Rospenk and L SobczykJ Phys Chem 86 401ndash406 (1982)
11
Our First Steps into the HBOur First Steps into the HB
As usual we entered the HB field by chance In 1985 during a study on the ligands of the benzodiazepine receptor we determined the structure of CGS8216 and noticed something strange a quite short NminusminusminusminusHmiddotmiddotmiddotO bond of 2694 Aringin association with an interleaving β-enaminonemiddotmiddotmiddot O=CminusminusminusminusC=CminusminusminusminusNH middotmiddotmiddot fragment which was almost completely π-delocalized
It was the first indication of a possible correlation between ππππ-delocalizationand H-bond strengtheningminusminusminusminuswhat we later called the ResonanceResonance--Assisted HAssisted H--Bond Bond (RAHB)(RAHB)(Gilli Bellucci Ferretti amp Bertolasi JACS 1989 Bertolasi Gilli Ferretti amp Gilli JACS 1991)
Since at the time the very few crystal structures of ββββ-enaminones were known the work started on the analogous class of ββββ-enolones(or ββββ-diketone enols) compounds already known to give strong O-HO bonds in association with the equally resonant middotmiddotmiddotO=CminusminusminusminusC=CminusminusminusminusOHmiddotmiddotmiddot fragments
12
Structural Databases and Structural Databases and Crystal Structure Correlation MethodsCrystal Structure Correlation Methods
The correlation between ππππ-delocalizationand H-bond strengthening is essentially a problem of geometrical nature What has to be provedis an intercorrelation between HB strength(as measured by theOhellipO or O-H distances) and ππππ-delocalizationof the resonant fragment (as measured by thed1-d4 distances)
This was the beginning of our intense interest forspades Structural Databasesin general and Cambridge Structural Database (CSD) in particular (Allen Kennardhellip 1979 2002)clubs Structural data interpretation by the so called Crystal Structure Correlation (CSC) Method(Buumlrgi 1973 1975 Buumlrgi and Dunitz 1983) a method for obtaining information on the dynamic behavior of molecules from the inevitably rather static crystal data geometries
Some sample applications of CSD to the study of RAHB in ββββ-diketone enol structures
13
The Development of the OThe Development of the OminusminusminusminusminusminusminusminusHHO RAHBO RAHB
The HBs formed were all much stronger than normal (non-resonant) OminusminusminusminusHO bonds withd(OO)INTRA =239-255 Aringd(OO)INTER =246-265 Aring
R1-RAHBR5-RAHB
24256 Aring
N
N
O M e
N
N
OM e
M eM e
H
lt 257 gt1 Aring
P
O H
OO
O H
H P
O H
OO
O H
H
R3-RAHB
O OH
237-255 Aring
262-267 Aring
O
O H O
OH
262-270 Aring
O
O
H
O
O H
R7-RAHB24462 Aring
NOO
OO
M eM e
H
OOH
O
O
H
246-265 Aring
CARBOXYLIC ACIDS
DIBENZOYLMETHANE ENOLS
CYCLOHEXANEDIONE ENOLS
PHOPHORIC ACID
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
8
Another Unsolved Problem Another Unsolved Problem The HB PuzzleThe HB Puzzle
Bond lengths and energies of normal chemical bondsare determined by the nature of the interacting atoms and weakly perturbed by the environment
On the contrary binding energies (EHB) and DmiddotmiddotmiddotA distances (dDmiddotmiddotmiddotA) of DminusminusminusminusHmiddotmiddotmiddotA H-bondsdo not simply depend on the donor (D) and acceptor (A) nature but show very large variations even for the same donor-acceptor couple
This is what we have often called for the sake of brevity
the HB Puzzlethe HB Puzzle
An extreme exampleof this behavior comes from the effects produced on the OminusminusminusminusHmiddotmiddotmiddotO bondby the changing acid-base propertiesof its environment
The weak HOminusminusminusminusHmiddotmiddotmiddotOH2 bond in water [EHBasympasympasympasymp5 kcal mol-1 dOmiddotmiddotmiddotOasympasympasympasymp270-275 Aring] is transformed in acidic or basic medium into the very strong [H2OmiddotmiddotmiddotHmiddotmiddotmiddotOH2]
+ or [HOmiddotmiddotmiddotHmiddotmiddotmiddotOH]minusminusminusminus bonds with EHB up to 30-31 kcal mol-1 and dOmiddotmiddotmiddotOdown to 238-242 Aring
9
How to Tackle the HB Puzzle How to Tackle the HB Puzzle the Problem of the Driving Variablethe Problem of the Driving Variable
The Electrostatic Paradigmcannot explain the HB PuzzleNeither the Standard Model provides a complete interpretation of it
it just suggests that H-bonds increase their strength with their increasing covalency but without suggesting any specific mechanism for it
To put the problem in more general terms there are a dozen of physicochemical variablescommonly measured in HB studies (energies geometries IR frequencies NMR chemical shifts NQR couplings isotopic effects not to speak of the intrinsic
properties of the interacting molecules) and most if not all appear to be systematically intercorrelated
But whatwhatrsquorsquo s the driving variables the driving variableWhatrsquos the variable which among the many intercorrelated ones
drives the transformation from weak and electrostatic to strong and covalent HB
10
AA Proposal The PApProposal The PApKKaa Equalization PrincipleEqualization Principle
Two very similar proposals come from the early thermodynamic or spectroscopic investigations on the HB and are both centered on the
matching of the acid-base properties of the HB donor and acceptors moieties what we like to call for the sake of brevity the
With reference to any generic DminusminusminusminusHmiddotmiddotmiddotA bond this principle states that the HB is the stronger the smaller becomes the difference of the donor-acceptor
-------------------------------------------------------------------------------------------------------------------------bullAult BS and Pimentel GG J Phys Chem 79 615 (1975) bullKebarle P Ann Rev Phys Chem 28 445ndash476 (1977) bullMeot-Ner (Mautner) M J Am Chem Soc 106 1257ndash1264 (1984)bullHuyskens PL and Zeegers-Huyskens Th J Chim Phys 61 81 (1964) bullMalarski Z M Rospenk and L SobczykJ Phys Chem 86 401ndash406 (1982)
11
Our First Steps into the HBOur First Steps into the HB
As usual we entered the HB field by chance In 1985 during a study on the ligands of the benzodiazepine receptor we determined the structure of CGS8216 and noticed something strange a quite short NminusminusminusminusHmiddotmiddotmiddotO bond of 2694 Aringin association with an interleaving β-enaminonemiddotmiddotmiddot O=CminusminusminusminusC=CminusminusminusminusNH middotmiddotmiddot fragment which was almost completely π-delocalized
It was the first indication of a possible correlation between ππππ-delocalizationand H-bond strengtheningminusminusminusminuswhat we later called the ResonanceResonance--Assisted HAssisted H--Bond Bond (RAHB)(RAHB)(Gilli Bellucci Ferretti amp Bertolasi JACS 1989 Bertolasi Gilli Ferretti amp Gilli JACS 1991)
Since at the time the very few crystal structures of ββββ-enaminones were known the work started on the analogous class of ββββ-enolones(or ββββ-diketone enols) compounds already known to give strong O-HO bonds in association with the equally resonant middotmiddotmiddotO=CminusminusminusminusC=CminusminusminusminusOHmiddotmiddotmiddot fragments
12
Structural Databases and Structural Databases and Crystal Structure Correlation MethodsCrystal Structure Correlation Methods
The correlation between ππππ-delocalizationand H-bond strengthening is essentially a problem of geometrical nature What has to be provedis an intercorrelation between HB strength(as measured by theOhellipO or O-H distances) and ππππ-delocalizationof the resonant fragment (as measured by thed1-d4 distances)
This was the beginning of our intense interest forspades Structural Databasesin general and Cambridge Structural Database (CSD) in particular (Allen Kennardhellip 1979 2002)clubs Structural data interpretation by the so called Crystal Structure Correlation (CSC) Method(Buumlrgi 1973 1975 Buumlrgi and Dunitz 1983) a method for obtaining information on the dynamic behavior of molecules from the inevitably rather static crystal data geometries
Some sample applications of CSD to the study of RAHB in ββββ-diketone enol structures
13
The Development of the OThe Development of the OminusminusminusminusminusminusminusminusHHO RAHBO RAHB
The HBs formed were all much stronger than normal (non-resonant) OminusminusminusminusHO bonds withd(OO)INTRA =239-255 Aringd(OO)INTER =246-265 Aring
R1-RAHBR5-RAHB
24256 Aring
N
N
O M e
N
N
OM e
M eM e
H
lt 257 gt1 Aring
P
O H
OO
O H
H P
O H
OO
O H
H
R3-RAHB
O OH
237-255 Aring
262-267 Aring
O
O H O
OH
262-270 Aring
O
O
H
O
O H
R7-RAHB24462 Aring
NOO
OO
M eM e
H
OOH
O
O
H
246-265 Aring
CARBOXYLIC ACIDS
DIBENZOYLMETHANE ENOLS
CYCLOHEXANEDIONE ENOLS
PHOPHORIC ACID
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
9
How to Tackle the HB Puzzle How to Tackle the HB Puzzle the Problem of the Driving Variablethe Problem of the Driving Variable
The Electrostatic Paradigmcannot explain the HB PuzzleNeither the Standard Model provides a complete interpretation of it
it just suggests that H-bonds increase their strength with their increasing covalency but without suggesting any specific mechanism for it
To put the problem in more general terms there are a dozen of physicochemical variablescommonly measured in HB studies (energies geometries IR frequencies NMR chemical shifts NQR couplings isotopic effects not to speak of the intrinsic
properties of the interacting molecules) and most if not all appear to be systematically intercorrelated
But whatwhatrsquorsquo s the driving variables the driving variableWhatrsquos the variable which among the many intercorrelated ones
drives the transformation from weak and electrostatic to strong and covalent HB
10
AA Proposal The PApProposal The PApKKaa Equalization PrincipleEqualization Principle
Two very similar proposals come from the early thermodynamic or spectroscopic investigations on the HB and are both centered on the
matching of the acid-base properties of the HB donor and acceptors moieties what we like to call for the sake of brevity the
With reference to any generic DminusminusminusminusHmiddotmiddotmiddotA bond this principle states that the HB is the stronger the smaller becomes the difference of the donor-acceptor
-------------------------------------------------------------------------------------------------------------------------bullAult BS and Pimentel GG J Phys Chem 79 615 (1975) bullKebarle P Ann Rev Phys Chem 28 445ndash476 (1977) bullMeot-Ner (Mautner) M J Am Chem Soc 106 1257ndash1264 (1984)bullHuyskens PL and Zeegers-Huyskens Th J Chim Phys 61 81 (1964) bullMalarski Z M Rospenk and L SobczykJ Phys Chem 86 401ndash406 (1982)
11
Our First Steps into the HBOur First Steps into the HB
As usual we entered the HB field by chance In 1985 during a study on the ligands of the benzodiazepine receptor we determined the structure of CGS8216 and noticed something strange a quite short NminusminusminusminusHmiddotmiddotmiddotO bond of 2694 Aringin association with an interleaving β-enaminonemiddotmiddotmiddot O=CminusminusminusminusC=CminusminusminusminusNH middotmiddotmiddot fragment which was almost completely π-delocalized
It was the first indication of a possible correlation between ππππ-delocalizationand H-bond strengtheningminusminusminusminuswhat we later called the ResonanceResonance--Assisted HAssisted H--Bond Bond (RAHB)(RAHB)(Gilli Bellucci Ferretti amp Bertolasi JACS 1989 Bertolasi Gilli Ferretti amp Gilli JACS 1991)
Since at the time the very few crystal structures of ββββ-enaminones were known the work started on the analogous class of ββββ-enolones(or ββββ-diketone enols) compounds already known to give strong O-HO bonds in association with the equally resonant middotmiddotmiddotO=CminusminusminusminusC=CminusminusminusminusOHmiddotmiddotmiddot fragments
12
Structural Databases and Structural Databases and Crystal Structure Correlation MethodsCrystal Structure Correlation Methods
The correlation between ππππ-delocalizationand H-bond strengthening is essentially a problem of geometrical nature What has to be provedis an intercorrelation between HB strength(as measured by theOhellipO or O-H distances) and ππππ-delocalizationof the resonant fragment (as measured by thed1-d4 distances)
This was the beginning of our intense interest forspades Structural Databasesin general and Cambridge Structural Database (CSD) in particular (Allen Kennardhellip 1979 2002)clubs Structural data interpretation by the so called Crystal Structure Correlation (CSC) Method(Buumlrgi 1973 1975 Buumlrgi and Dunitz 1983) a method for obtaining information on the dynamic behavior of molecules from the inevitably rather static crystal data geometries
Some sample applications of CSD to the study of RAHB in ββββ-diketone enol structures
13
The Development of the OThe Development of the OminusminusminusminusminusminusminusminusHHO RAHBO RAHB
The HBs formed were all much stronger than normal (non-resonant) OminusminusminusminusHO bonds withd(OO)INTRA =239-255 Aringd(OO)INTER =246-265 Aring
R1-RAHBR5-RAHB
24256 Aring
N
N
O M e
N
N
OM e
M eM e
H
lt 257 gt1 Aring
P
O H
OO
O H
H P
O H
OO
O H
H
R3-RAHB
O OH
237-255 Aring
262-267 Aring
O
O H O
OH
262-270 Aring
O
O
H
O
O H
R7-RAHB24462 Aring
NOO
OO
M eM e
H
OOH
O
O
H
246-265 Aring
CARBOXYLIC ACIDS
DIBENZOYLMETHANE ENOLS
CYCLOHEXANEDIONE ENOLS
PHOPHORIC ACID
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
10
AA Proposal The PApProposal The PApKKaa Equalization PrincipleEqualization Principle
Two very similar proposals come from the early thermodynamic or spectroscopic investigations on the HB and are both centered on the
matching of the acid-base properties of the HB donor and acceptors moieties what we like to call for the sake of brevity the
With reference to any generic DminusminusminusminusHmiddotmiddotmiddotA bond this principle states that the HB is the stronger the smaller becomes the difference of the donor-acceptor
-------------------------------------------------------------------------------------------------------------------------bullAult BS and Pimentel GG J Phys Chem 79 615 (1975) bullKebarle P Ann Rev Phys Chem 28 445ndash476 (1977) bullMeot-Ner (Mautner) M J Am Chem Soc 106 1257ndash1264 (1984)bullHuyskens PL and Zeegers-Huyskens Th J Chim Phys 61 81 (1964) bullMalarski Z M Rospenk and L SobczykJ Phys Chem 86 401ndash406 (1982)
11
Our First Steps into the HBOur First Steps into the HB
As usual we entered the HB field by chance In 1985 during a study on the ligands of the benzodiazepine receptor we determined the structure of CGS8216 and noticed something strange a quite short NminusminusminusminusHmiddotmiddotmiddotO bond of 2694 Aringin association with an interleaving β-enaminonemiddotmiddotmiddot O=CminusminusminusminusC=CminusminusminusminusNH middotmiddotmiddot fragment which was almost completely π-delocalized
It was the first indication of a possible correlation between ππππ-delocalizationand H-bond strengtheningminusminusminusminuswhat we later called the ResonanceResonance--Assisted HAssisted H--Bond Bond (RAHB)(RAHB)(Gilli Bellucci Ferretti amp Bertolasi JACS 1989 Bertolasi Gilli Ferretti amp Gilli JACS 1991)
Since at the time the very few crystal structures of ββββ-enaminones were known the work started on the analogous class of ββββ-enolones(or ββββ-diketone enols) compounds already known to give strong O-HO bonds in association with the equally resonant middotmiddotmiddotO=CminusminusminusminusC=CminusminusminusminusOHmiddotmiddotmiddot fragments
12
Structural Databases and Structural Databases and Crystal Structure Correlation MethodsCrystal Structure Correlation Methods
The correlation between ππππ-delocalizationand H-bond strengthening is essentially a problem of geometrical nature What has to be provedis an intercorrelation between HB strength(as measured by theOhellipO or O-H distances) and ππππ-delocalizationof the resonant fragment (as measured by thed1-d4 distances)
This was the beginning of our intense interest forspades Structural Databasesin general and Cambridge Structural Database (CSD) in particular (Allen Kennardhellip 1979 2002)clubs Structural data interpretation by the so called Crystal Structure Correlation (CSC) Method(Buumlrgi 1973 1975 Buumlrgi and Dunitz 1983) a method for obtaining information on the dynamic behavior of molecules from the inevitably rather static crystal data geometries
Some sample applications of CSD to the study of RAHB in ββββ-diketone enol structures
13
The Development of the OThe Development of the OminusminusminusminusminusminusminusminusHHO RAHBO RAHB
The HBs formed were all much stronger than normal (non-resonant) OminusminusminusminusHO bonds withd(OO)INTRA =239-255 Aringd(OO)INTER =246-265 Aring
R1-RAHBR5-RAHB
24256 Aring
N
N
O M e
N
N
OM e
M eM e
H
lt 257 gt1 Aring
P
O H
OO
O H
H P
O H
OO
O H
H
R3-RAHB
O OH
237-255 Aring
262-267 Aring
O
O H O
OH
262-270 Aring
O
O
H
O
O H
R7-RAHB24462 Aring
NOO
OO
M eM e
H
OOH
O
O
H
246-265 Aring
CARBOXYLIC ACIDS
DIBENZOYLMETHANE ENOLS
CYCLOHEXANEDIONE ENOLS
PHOPHORIC ACID
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
11
Our First Steps into the HBOur First Steps into the HB
As usual we entered the HB field by chance In 1985 during a study on the ligands of the benzodiazepine receptor we determined the structure of CGS8216 and noticed something strange a quite short NminusminusminusminusHmiddotmiddotmiddotO bond of 2694 Aringin association with an interleaving β-enaminonemiddotmiddotmiddot O=CminusminusminusminusC=CminusminusminusminusNH middotmiddotmiddot fragment which was almost completely π-delocalized
It was the first indication of a possible correlation between ππππ-delocalizationand H-bond strengtheningminusminusminusminuswhat we later called the ResonanceResonance--Assisted HAssisted H--Bond Bond (RAHB)(RAHB)(Gilli Bellucci Ferretti amp Bertolasi JACS 1989 Bertolasi Gilli Ferretti amp Gilli JACS 1991)
Since at the time the very few crystal structures of ββββ-enaminones were known the work started on the analogous class of ββββ-enolones(or ββββ-diketone enols) compounds already known to give strong O-HO bonds in association with the equally resonant middotmiddotmiddotO=CminusminusminusminusC=CminusminusminusminusOHmiddotmiddotmiddot fragments
12
Structural Databases and Structural Databases and Crystal Structure Correlation MethodsCrystal Structure Correlation Methods
The correlation between ππππ-delocalizationand H-bond strengthening is essentially a problem of geometrical nature What has to be provedis an intercorrelation between HB strength(as measured by theOhellipO or O-H distances) and ππππ-delocalizationof the resonant fragment (as measured by thed1-d4 distances)
This was the beginning of our intense interest forspades Structural Databasesin general and Cambridge Structural Database (CSD) in particular (Allen Kennardhellip 1979 2002)clubs Structural data interpretation by the so called Crystal Structure Correlation (CSC) Method(Buumlrgi 1973 1975 Buumlrgi and Dunitz 1983) a method for obtaining information on the dynamic behavior of molecules from the inevitably rather static crystal data geometries
Some sample applications of CSD to the study of RAHB in ββββ-diketone enol structures
13
The Development of the OThe Development of the OminusminusminusminusminusminusminusminusHHO RAHBO RAHB
The HBs formed were all much stronger than normal (non-resonant) OminusminusminusminusHO bonds withd(OO)INTRA =239-255 Aringd(OO)INTER =246-265 Aring
R1-RAHBR5-RAHB
24256 Aring
N
N
O M e
N
N
OM e
M eM e
H
lt 257 gt1 Aring
P
O H
OO
O H
H P
O H
OO
O H
H
R3-RAHB
O OH
237-255 Aring
262-267 Aring
O
O H O
OH
262-270 Aring
O
O
H
O
O H
R7-RAHB24462 Aring
NOO
OO
M eM e
H
OOH
O
O
H
246-265 Aring
CARBOXYLIC ACIDS
DIBENZOYLMETHANE ENOLS
CYCLOHEXANEDIONE ENOLS
PHOPHORIC ACID
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
12
Structural Databases and Structural Databases and Crystal Structure Correlation MethodsCrystal Structure Correlation Methods
The correlation between ππππ-delocalizationand H-bond strengthening is essentially a problem of geometrical nature What has to be provedis an intercorrelation between HB strength(as measured by theOhellipO or O-H distances) and ππππ-delocalizationof the resonant fragment (as measured by thed1-d4 distances)
This was the beginning of our intense interest forspades Structural Databasesin general and Cambridge Structural Database (CSD) in particular (Allen Kennardhellip 1979 2002)clubs Structural data interpretation by the so called Crystal Structure Correlation (CSC) Method(Buumlrgi 1973 1975 Buumlrgi and Dunitz 1983) a method for obtaining information on the dynamic behavior of molecules from the inevitably rather static crystal data geometries
Some sample applications of CSD to the study of RAHB in ββββ-diketone enol structures
13
The Development of the OThe Development of the OminusminusminusminusminusminusminusminusHHO RAHBO RAHB
The HBs formed were all much stronger than normal (non-resonant) OminusminusminusminusHO bonds withd(OO)INTRA =239-255 Aringd(OO)INTER =246-265 Aring
R1-RAHBR5-RAHB
24256 Aring
N
N
O M e
N
N
OM e
M eM e
H
lt 257 gt1 Aring
P
O H
OO
O H
H P
O H
OO
O H
H
R3-RAHB
O OH
237-255 Aring
262-267 Aring
O
O H O
OH
262-270 Aring
O
O
H
O
O H
R7-RAHB24462 Aring
NOO
OO
M eM e
H
OOH
O
O
H
246-265 Aring
CARBOXYLIC ACIDS
DIBENZOYLMETHANE ENOLS
CYCLOHEXANEDIONE ENOLS
PHOPHORIC ACID
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
13
The Development of the OThe Development of the OminusminusminusminusminusminusminusminusHHO RAHBO RAHB
The HBs formed were all much stronger than normal (non-resonant) OminusminusminusminusHO bonds withd(OO)INTRA =239-255 Aringd(OO)INTER =246-265 Aring
R1-RAHBR5-RAHB
24256 Aring
N
N
O M e
N
N
OM e
M eM e
H
lt 257 gt1 Aring
P
O H
OO
O H
H P
O H
OO
O H
H
R3-RAHB
O OH
237-255 Aring
262-267 Aring
O
O H O
OH
262-270 Aring
O
O
H
O
O H
R7-RAHB24462 Aring
NOO
OO
M eM e
H
OOH
O
O
H
246-265 Aring
CARBOXYLIC ACIDS
DIBENZOYLMETHANE ENOLS
CYCLOHEXANEDIONE ENOLS
PHOPHORIC ACID
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
The HBs formed were all much stronger than normal (non-resonant) OminusminusminusminusHO bonds withd(OO)INTRA =239-255 Aringd(OO)INTER =246-265 Aring
R1-RAHBR5-RAHB
24256 Aring
N
N
O M e
N
N
OM e
M eM e
H
lt 257 gt1 Aring
P
O H
OO
O H
H P
O H
OO
O H
H
R3-RAHB
O OH
237-255 Aring
262-267 Aring
O
O H O
OH
262-270 Aring
O
O
H
O
O H
R7-RAHB24462 Aring
NOO
OO
M eM e
H
OOH
O
O
H
246-265 Aring
CARBOXYLIC ACIDS
DIBENZOYLMETHANE ENOLS
CYCLOHEXANEDIONE ENOLS
PHOPHORIC ACID
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
15
A Model for RAHB Electrostatic or CovalentA Model for RAHB Electrostatic or Covalent
The RAHB Electrostatic Model (The RAHB Electrostatic Model (JACS 1989JACS 1989)) (a) The resonance causes delocalization of the ππππ-conjugated system and sets up opposite charges on the terminal oxygens(b) The charges have the correct sign for strengthening the H-bond (OmiddotmiddotO shortening and O-H lengthening)(c) Moving the proton to the right is equivalent to moving the electron to the left Previous charges are cancelled out ππππ-delocalization can proceed generating new charges and the H-bond is further strengthened(d) Iteration of this imaginary process will inevitably lead to the full delocalization of the ππππ-conjugated system and to a very short OHO bond with centered proton
The RAHB Covalent Model (JACS 1994 2004) The RAHB Covalent Model (JACS 1994 2004) Based on the VB enolketo harr ketoenol resonance it has become later the Standard Model for RAHB interpretation
Initial incongruities (wrong spin parity of the resonant forms) of the model were later mended (2004) by its fusion with theState Correlation (or Avoided-Crossing) Diagrams (Shaik et al 1992)
RAHB Electrostatic ModelRAHB Electrostatic Model RAHB Covalent ModelRAHB Covalent Model
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
16
Starting Again The Empirical ApproachStarting Again The Empirical Approach
The substantial success obtained in assessing and interpreting the OminusminusminusminusHmiddotmiddotmiddotO RAHB aroused our interest in a more general problem RAHB gives often rise to H-bonds which are considerably stronger than ordinary bonds (say 15-20 against the usual 4-5 kcal mol-1) But then how many classes of strong Hhow many classes of strong H--bonds are therebonds are there
To tackle this problem in 1994 we decidedto change approachand to restart to investigate the O-HO bond from the very beginningby adopting a purely empirical strategy (i) Suspend any previous ideas on theelectrostatic or covalent nature of the HB(ii) Suspend what we had already learned onOminusminusminusminusHmiddotmiddotmiddotO RAHB(iii) D efine the OminusminusminusminusHmiddotmiddotmiddotO bond as a simple topological structurewhere a H atom is
connected to two or more oxygen atoms(iv) Collect all crystal structureshaving OminusminusminusminusHmiddotmiddotmiddotO bonds with d(OmiddotmiddotmiddotO)lelelele 270 Aring(v) Collect all available IR νννν(O-H) and NMR δδδδ(H) dataof H-bonded protons(vi) Collect all available HB energy datafrom thermodynamic measurements in gas
phase and non-polar solvents(vii) Try to infer a conclusion on the very nature of the OminusminusminusminusHmiddotmiddotmiddotO bond from the
ensemble of the data collected
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
17
A Full Classification of Strong HBsA Full Classification of Strong HBs
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
18
The Six HB Chemical Leitmotifs (The Six HB Chemical Leitmotifs (CLsCLs))CHARGE CHARGE -- ASSISTED HBsASSISTED HBs
ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLARIZATION BOND POLARIZATION -- ASSISTED HBsASSISTED HBs
237-255 Aring
O OH
ArAr
DIBENZOYLMETHAN E ENOLS
CL 4 RAHB rArrrArrrArrrArr SHB VSHB Resonance-Assisted or ππππ-Cooperative HB
PApKa Matching by ππππ-Conjugated-Bond Polarization27501 Aring
OO
O
O O
WATER
CL 5 PAHB rArrrArrrArrrArr MHBPolarization-Assisted or σσσσ-Cooperative HB
(Partial) PApKa Matching by σσσσ-Bond Polarization
NEITHER CHARGENEITHER CHARGE minusminusminusminusminusminusminusminus NOR NOR ΣΠΣΠΣΠΣΠΣΠΣΠΣΠΣΠ--BOND POLBOND POLminusminusminusminusminusminusminusminusASSISTED HBsASSISTED HBs
DH
A
CL 6 OHB rArrrArrrArrrArr WOrdinary HB
No PApKa Matching DH
A
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
19
The Five HB Chemical Leitmotifs (The Five HB Chemical Leitmotifs (CLsCLs))
The most interesting aspect of a HB classification based on HB strengthis that strong HBs belong only to a small number of chemical schemes that we have called Chemical Leitmotifs
The Alchemic Piper plays the Five Magic Tunes that make any Hydrogen Bond stronger
The Chemical Leitmotifs
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
20
A Gallery of the Most Famous Strong HA Gallery of the Most Famous Strong H--BondsBonds
P Gilli et al Acc Chem Res (2009) EHB values(kcal molminusminusminusminus1) calculated by the exponential equation
3242
2235
1289
2450
2239
2217
2217
2480 2623
2430
2309
1280 2139
2369
2183
2321 1499 1530
2254 1829 20882056
2217
2217
2139
2381
900
1331
1452
1087
1387
1352
1278
(+)C
AH
B(+
)CA
HB
(( minusminus minusminusminusminus minusminus )CA
HB
)CA
HB
(( plusmnplusmn )CA
HB
)CA
HB
(( --3 3
lele lelelele lele∆∆ ∆∆∆∆ ∆∆ p
p KKaa
lele lelelele lele1)1
)
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
21
Symmetry and Covalency (1)Symmetry and Covalency (1)
Not surprisingly Chemical Leitmotifs became the main theme of our research and the first topic systematically studied was still not surprisingly theirCovalent or Electrostatic Nature
The covalent nature of the strong OminusminusminusminusHmiddotmiddotmiddotO bondwas mainly assessed by reinterpreting the experimental results in terms of the Coulsonrsquos VB formalism
We cannot measure covalencybut can evaluate molecular symmetry the Coulsonrsquos model being the algorithm able to translate one concept into the other because the total symmetry across the HBimplies energy equivalence between its two covalent VB forms ie E(ΨCOV1) =E(ΨCOV2) which is just the situation associated with formation of the covalent HB
E E
NCT
CT
CTNCT
ΨΨΨΨCOV2
ΨΨΨΨIONIC
ΨΨΨΨCOV1
ΨΨΨΨIONIC
ΨΨΨΨCOV1 ΨΨΨΨCOV2
NCT
NCT
(a) Electrostatic HB (b) Covalent HB
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
ndashO ndash ndash ndash H Olt ΨΨΨΨCOV1 NCT
ndashOndash +H Olt
ndashOndash H ndash ndash ndash ndash ndash +Olt
ΨΨΨΨIONIC NCT
ΨΨΨΨCOV2 CT
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
22
Symmetry and Covalency (2)Symmetry and Covalency (2)
In summary - H-bonds are neither electrostatic or covalentbut rather a mixture of the twos
- the degree of covalencyincreases with the H-bond strength and reaches a maximum when the bond is perfectly symmetric which maximizes the OminusminusminusminusHmiddotmiddotmiddotO harr minusminusminusminusOmiddotmiddotmiddotHminusminusminusminusO+ VBmixing
- the symmetry displacement is measured by the VB variable ∆∆∆∆∆∆∆∆EE= E(ΨCOV2) minusminusminusminus E(ΨCOV1) a quantity which is quite difficult to be evaluated in practice
- the ∆∆∆∆∆∆∆∆EE termtermhowever can be tentatively estimated in terms of extra-thermodynamic quantities wiz Proton Affinities (PA) and relatedAcid-Base Dissociation Constants (∆∆∆∆pKa)
STRONGSTRONGCOVCOVSYMSYM
STRONGSTRONGCOVCOVSYMSYM
WEAKWEAKIONICIONICASYMASYM
WEAKWEAKIONICIONICASYMASYM
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
23
Symmetry and Covalency (3)Symmetry and Covalency (3)The ECHBM (ElectrostaticThe ECHBM (Electrostatic--Covalent HB Model)Covalent HB Model)
The The PApKa Equalization PrinciplePApKa Equalization Principle
Empirical analysis of experimental data joined with homeopathic doses of VB theory has led us to formulate the ECHBM (ElectrostaticECHBM (Electrostatic --Covalent HB ModelCovalent HB Model Gilli amp Gilli J Mol Struct 2000) that can be summarized as follows
diamsdiamsdiamsdiams Any given D-HA systemmay form HBs in a wide range of strengths lengths symmetriesand proton locations the two extremes being represented
by the weak long dissymmetric and proton-out-centred HBof electrostatic nature
and by the very strong very short symmetric and proton-centred HB
classifiable as a true 3-center-4-electron covalent bond
spadesspadesspadesspades The driving variableThe driving variable able to transform strong into weak HBs isan energyan energy(the ∆∆∆∆∆∆∆∆EEtermterm of the VB theory) ) that can be semiempirically evaluated as
minusminusminusminus the difference of proton affinities [∆∆∆∆PA = PA(Dminusminusminusminus) minusminusminusminus PA(A)] ) or minusminusminusminus the difference of acid-base constants [∆∆∆∆pKa = pKAH(DminusminusminusminusH) minusminusminusminus pKBH+(AminusminusminusminusH+)]
between the donor (D) and acceptor (A) of the DminusminusminusminusHmiddotmiddotmiddotA bond
spadesspadesspadesspades Finally tFinally the principle for which all strong HBs must be associated with the condition ∆∆∆∆∆∆∆∆PA PA ∆∆∆∆∆∆∆∆pKpK aa congcongcongcongcongcongcongcong 00 is known as PApKa Equalization Principle PApKa Equalization Principle ((Gilli et al JACS 2004 2005Gilli et al JACS 2004 2005))
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
24
The Origin of the Chemical LeitmotifsThe Origin of the Chemical Leitmotifsaccording to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
which collects by definition all strong HBs formed by the acid-base pairs witha pKa matching within say from -3 to +3 ∆∆∆∆pKa units
diams clubs hearts spadesBut what about the other leitmotifs Can we prove that
all chemical leitmotifsare simple artificesthat molecules can use to obliterate the normally
very large ∆∆∆∆pKa between HB donor and acceptor atoms
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
25
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
26
The Origin of the Chemical Leitmotifs The Origin of the Chemical Leitmotifs according to the PApaccording to the PApKKaa Equalization PrincipleEqualization Principle
Chemical Leitmotif 4RAHB
Resonance-Assisted or ππππ-Bond Cooperative HBPApKa Matching by ππππ-Conjugated-Bond Polarization
R-D-HA=R hArr R=DH-A-R
pKAH(RO-H) = 1518
pKBH(R2C=O-H+) = -(67)
O OH
O H O
R
R
R
Rn-RAHB ∆∆∆∆pKa = ~ 21-25
WEAK ~ 4- 5kcalmol
EKO O
H
KEOO
H
∆∆∆∆pKa = 00
STRONG ~ 15-22 kcalmol
2IV
2IVa
2IVb
2VIb
OHB
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
27
Chemical Leitmotifs and PApChemical Leitmotifs and PApKKaa Equalization RulesEqualization Rules
RAHB RAHB cannot be treated by pKa equalization methodsbecause π-delocalization modifies the pKarsquos of the donor and acceptor moieties
(+minusminusminusminus)CAHB is a true proton transfer from an acid (HB donor) to a base(HB acceptor)RndashDndashHAndashRrsquo hArrhArrhArrhArr Rndash12minusminusminusminusDH+A12ndashndashRrsquo hArrhArrhArrhArr RndashminusminusminusminusDHndashA+ndashRrsquo
∆pK a = pKAH(RminusminusminusminusDminusminusminusminusH) minusminusminusminus pKBH+(RrsquominusminusminusminusA)
(minusminusminusminus)CAHB is a proton sharing between two acids(HB donors) RndashDndashHDrsquo ndashminusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusDHDrsquominusminusminusminusRrsquo] minusminusminusminus hArrhArrhArrhArr RminusminusminusminusminusminusminusminusDHminusminusminusminusDrsquominusminusminusminusRrsquo
(+)CAHB is a proton sharingbetween two bases(HB acceptors) Rminusminusminusminus+AminusminusminusminusHArsquo minusminusminusminusRrsquo hArrhArrhArrhArr [RminusminusminusminusAHArsquo minusminusminusminusRrsquo] + hArrhArrhArrhArr RminusminusminusminusAHminusminusminusminusArsquo +minusminusminusminusRrsquo
∆pK a = pKBH+(RminusminusminusminusA) minusminusminusminus pKBH+(RrsquominusminusminusminusArsquo)
Whenever (minusminusminusminus) and (+)CAHBs are both homonuclear (D = Drsquo or A = Arsquo ) and homomolecular(R = Rrsquo) the matching condition ∆pKa= 0 will hold irrespective of the actual pKarsquos of the two interacting moieties All HBs formed will be strong
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
28
Topics Developed in the Following LecturesTopics Developed in the Following Lectures
Results obtained from 1989 to 2002Results obtained from 1989 to 2002
clubsclubsclubsclubs Definition of a new type of strong HB The ResonanceThe Resonance--Assisted HB (RAHB)Assisted HB (RAHB)diamsdiamsdiamsdiams Chemical classification of all HBsThe Chemical Leitmotifs (CAHB RAHB PAHB OHB)The Chemical Leitmotifs (CAHB RAHB PAHB OHB)clubsclubsclubsclubs Covalent nature of the strong HBThe ElectrostaticThe Electrostatic--Covalent HB Model (ECHBM)Covalent HB Model (ECHBM)diamsdiamsdiamsdiams Thermodynamic HB driving variable The PApKa Equalization PrincipleThe PApKa Equalization Principle
New Projects from 2002 to 2012New Projects from 2002 to 2012
11 Generalization of the PApKa Equalization Principle to the most common organic compounds The pKa Slide RuleThe pKa Slide Rule
22 Getting over the HB empirical rules and formulation of a comprehensive HB theory The TransitionThe Transition--State HB Theory (TSHBT)State HB Theory (TSHBT)and The Dual HThe Dual H--Bond ModelBond Model
33 Redefinition of the Hthe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interaction An attempt of unify the forces acting in neutral molecular crystals
44 H-Bond Patterns in Nature A Gallery of Functional HFunctional H--Bonds Bonds
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
29
The pThe pKKa Slide Rulea Slide Rule
The pKa slide rule is a tool for the graphical evaluation of the difference
∆∆∆∆∆∆∆∆ppKKaa = = ppKKAHAH (D(DminusminusminusminusminusminusminusminusH) H) -- ppKKBH+BH+(A(AminusminusminusminusminusminusminusminusHH++))for the most common classes of organic
compoundsHB Acceptors on the left and
HB Donors on the right pKa values are given for chemical class
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
30
-1 0 1
DmiddotmiddotmiddotHmiddotmiddotmiddotA
D-HmiddotmiddotmiddotADmiddotmiddotmiddotH-A
AmiddotmiddotmiddotBmiddotmiddotmiddotC
A-B + CA + B-C
Reaction Coordinate
∆∆∆∆DaggerE2
∆∆∆∆DaggerE1
∆∆∆∆Er
E
RC = [d(D-H) - d(A-H)] (Aring)
The TransitionThe Transition--State HB Theory State HB Theory (TSHBT)(TSHBT)The Dual HThe Dual H--Bond ModelBond Model
(Gilli et al JACS2002 2005 Gilli et al J Mol Struct 2006 Gilli and Gilli J Mol Struct 2010)
The basic idea is very simpleAny DndashHmiddotmiddotmiddotA bond can be considered as a chemical reaction which is
bimolecular in both directions and proceeds via transition-state (TS) formation
AndashB + C hArrhArrhArrhArr AmiddotmiddotmiddotBmiddotmiddotmiddotC hArrhArrhArrhArr A + BndashCDndashHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHmiddotmiddotmiddotA hArrhArrhArrhArr DmiddotmiddotmiddotHndashA
Changes of nomenclatureReaction Pathway rArrrArrrArrrArr PTminusminusminusminusPathwayActivation Energy ∆∆∆∆DaggerE rArrrArrrArrrArr PTminusminusminusminusBarrierReaction Energy ∆∆∆∆Er rArrrArrrArrrArr ∆∆∆∆PA∆∆∆∆pKaTransition State (TS) rArrrArrrArrrArr PTminusminusminusminusTS
Experimentals Variable-Temperature CrystallographyCalculations DFTminusminusminusminusEmulated PT PathwaysInterpretation Marcus Rate-Equilibrium Theory Leffler minusminusminusminusHammond Postulate
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
31
The HThe H--bond as a bond as a σσσσσσσσlarrlarrnn CT or EDA interactionCT or EDA interactionMost EDA Interactions are HMost EDA Interactions are H--Bonds in DisguiseBonds in Disguise
HH--BONDS OF DIFFERENT SPECIESBONDS OF DIFFERENT SPECIES1a1aXminusHlarrY σσlarrlarrnn EDA oror XminusH middotmiddotmiddotY (X Y = N O) H-Bonds1b1b CminusHlarrY σσlarrlarrnn EDA oror weak CminusHmiddotmiddotmiddotY (Y = N Ohellip) H-Bonds
Packing geometryPacking geometryPlanes or ribbonsPlanes or ribbonsof planar molecules
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
32
A Gallery of Functional HA Gallery of Functional H--Bonds Bonds Anticooperative water-without-proton transmission in aquaporin channels
Functional HFunctional H--BondsBondsare bonds (usually strong bonds) that are known to exert a to exert a control rolecontrol role in the working mechanisms of chemical and biological processes (Examples prototropic tautomerism acid-base catalysis enzymatic catalysis or water transmission in aquaporin biological channels)
Membrane proteinsdeputed to form water-specific membrane channelswere firstly discovered in red blood cells and called aquaporin-1(AQP1 Preston Carrol Guggino Agre Science 1992)
The drawing shows a scheme of the structure ofaquaporin-1 embedded in the cell membrane(Murata et al Nature 2000 407599) cut along the seven αααα-helicesat the eight of thecentral water channel
The partial charges from the helix dipolesrestrict the orientation of the waterspassing through the pore in opposite directionsin the two halves of the chain
The inversion of the water-chain directionis caused by the simultaneous H-binding of the central water to the two asparagine residues (Asn76 and Asn192) so introducing a singlepoint of σσσσ-bond anticooperativity in the chain itself
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
CCDCCambridge Crystallographic Data
Centrefor the use of the
Cambridge Structural Database
NIST National Institute of Standards and
Technologyfor the use of the
NIST Chemistry WebBook
34
End of Lecture 1End of Lecture 1
33
AcknowledgmentsAcknowledgments
I have to thank my direct coworkers without whose help this work could have not been accomplished
Valerio BERTOLASI Paola GILLI
Valeria FERRETTI Loretta PRETTO
and the scientific institutions which made available to us the databases without which this work could not even be started
