Hydrogen bonding Hydrogen bonding and weak and weak

interactionsinteractions

““Symmetry E72 Symmetry E72 (Fish and Boats)”(Fish and Boats)”

by M.C. Escher - 1949by M.C. Escher - 1949

““Symmetry E70 Symmetry E70 (Butterflies)”(Butterflies)”by M.C. Escher - 1948by M.C. Escher - 1948

Factors important in solid state pharmaceutical Factors important in solid state pharmaceutical chemistrychemistry

As shown in the “Patenting” lecture, characterizing and As shown in the “Patenting” lecture, characterizing and understanding the structure of the solid state is very understanding the structure of the solid state is very important when improving the performance of a drug as important when improving the performance of a drug as well as other materialswell as other materials

In order to do this at least the following has to be In order to do this at least the following has to be understood:understood:• Materials (and drugs) can often exist in many formsMaterials (and drugs) can often exist in many forms including including

polymorphs, solvates and amorphous materials. Understanding polymorphs, solvates and amorphous materials. Understanding why and learning how to control these is very important.why and learning how to control these is very important.

• Various forms of a material/drug may interconvertVarious forms of a material/drug may interconvert under under various conditions. Even air humidity may drive the conversion various conditions. Even air humidity may drive the conversion process to another more stable (perhaps patented) form.process to another more stable (perhaps patented) form.

• Once a form of a material/drug has been chosen Once a form of a material/drug has been chosen methods for methods for analysis and control of the form have to be establishedanalysis and control of the form have to be established..

Intermolecular Forces – forces keeping Intermolecular Forces – forces keeping crystals togethercrystals together

Ion-ion interactionsIon-ion interactions – obvious – going to mostly ignore as it – obvious – going to mostly ignore as it was covered in 2was covered in 2ndnd year year

Ion-dipoleIon-dipole – between an ion and an opposite partial charge – between an ion and an opposite partial charge on a moleculeon a molecule

Dipole-dipoleDipole-dipole – between the electric dipoles of polar – between the electric dipoles of polar moleculesmolecules

Induced-dipoleInduced-dipole – between a polar molecule and neighboring – between a polar molecule and neighboring polarizable moleculepolarizable molecule

Dispersion forces (London forces)Dispersion forces (London forces) – arises from fluctuations – arises from fluctuations in electron distributions with moleculesin electron distributions with molecules

H-bondingH-bonding – special case formed by a H-atom lying between – special case formed by a H-atom lying between two strongly electronegative atomstwo strongly electronegative atoms

Intermolecular Forces Intermolecular Forces contd.contd.

The strongest interaction listed above is the ion-ion The strongest interaction listed above is the ion-ion interaction - very important in mineralsinteraction - very important in minerals

However, the rest are more important in molecular crystals However, the rest are more important in molecular crystals and in the chemistry of life itself. Examples will be given of and in the chemistry of life itself. Examples will be given of both.both.

H-bonding is the next most important interactionH-bonding is the next most important interaction

Dispersion forces are the next most important when viewed Dispersion forces are the next most important when viewed from the point of view of how much they contribute to the from the point of view of how much they contribute to the total lattice energy of a molecular crystaltotal lattice energy of a molecular crystal

H-bonding, dipole-dipole and ion-dipole interactions play a H-bonding, dipole-dipole and ion-dipole interactions play a huge role in determining the structure of a material/crystal huge role in determining the structure of a material/crystal – can drive the crystallization process or a protein catalysis – can drive the crystallization process or a protein catalysis processprocess

Some examples containingSome examples containingDipole-dipole and/or dipole-Dipole-dipole and/or dipole-induced dipole interactionsinduced dipole interactions

benzoquinonebenzoquinone

Structure composed of C-H…O stabilized layers of molecules

O

O

1,4-anthraquinone1,4-anthraquinone

Each pair of molecules in the structure is stabilized by dipole-induced dipole interactions between the C=O and benzene ring. This is just one amongst many other interactions.

O

O

p-iodobenzonitrilep-iodobenzonitrile

I N

In this case the N atom induces a dipole on the I atom creating a favorable interaction. N…I distance 3.18 Å, c.f. VDW contact dist. 3.65 Å.

In an O…Hal or N…Hal interaction the strength of the interaction increases in the following order Cl<Br<I. Note that the C-Hal…O/N angle is almost linear.

IN

OOCH2CH3

OCH2CH3

P

C CICH3CH2CH2CH2

IO

* = O…I # = C-H…π

ππ......ππ interactions interactions

Caused by intermolecular overlapping of p-orbitals in π-conjugated systems

Become stronger as the number of π-electrons increases

Some examples of structures Some examples of structures stabilized by dispersion forcesstabilized by dispersion forces

naphthalenenaphthalene anthraceneanthracene

These two structures are stabilized by dispersion forces and not specific interactions though the structures do have very weak C-H…π interactions

benzenebenzene

H-bondingH-bonding

H-bonding as taught in 1H-bonding as taught in 1stst year year As typically taught limited to a few elements – N, O and F As typically taught limited to a few elements – N, O and F

forming O-H…O, O-H…N, N-H…F, etc.forming O-H…O, O-H…N, N-H…F, etc.

This is wrong. Though much weaker between other This is wrong. Though much weaker between other elements, elements, even weak H-bonding has a very significant even weak H-bonding has a very significant effect on a crystal structures as well as biological effect on a crystal structures as well as biological processesprocesses

Examples of weak H-bonds are C-H…O, C-H…Examples of weak H-bonds are C-H…O, C-H…ππ, O-H…, O-H…ππ, , C-H…Cl, C-H…N, O-H…Cl, etc.C-H…Cl, C-H…N, O-H…Cl, etc.

H

H

H

O O

O O

H

H

H O

H

OH

H

CH3

O

O

O

O

O

O

a) b) c)

So why do 1So why do 1stst year text books insist that H- year text books insist that H-bonding only occurs between O, N and F?bonding only occurs between O, N and F?

To get round this issue H-bonds not involving O, N and F as donor and acceptor are referred to as weak H-bonds

H-bonding and polymorphism in OETCAH-bonding and polymorphism in OETCA The following example illustrates the influence of weak H-The following example illustrates the influence of weak H-

bonding on the structure of several polymorphs of bonding on the structure of several polymorphs of oo--ethoxyethoxy-trans--trans-cinnamic acid (OETCA)cinnamic acid (OETCA)

O

OH

O

So far OETCA has been found to form 3 polymorphs (So far OETCA has been found to form 3 polymorphs (αα, , αα', ', and and γγ) and 2 solvated forms () and 2 solvated forms (ββ))• A polymorph is a solid crystalline phase of a compound A polymorph is a solid crystalline phase of a compound

resulting from resulting from two or more different arrangementstwo or more different arrangements of of molecules in the solid state - it is restricted to molecules in the solid state - it is restricted to pure pure compoundscompounds

• Solvates share a similar definition except that a Solvates share a similar definition except that a guest guest compoundcompound (such as a solvent molecule) is (such as a solvent molecule) is includedincluded in the in the crystal structurecrystal structure

The The αα polymorph of polymorph of OETCA OETCA

P-16.69 Å 8.68 Å 10.01 Å72.01º 71.46º 67.86º

$$ = C-H…O

** = O-H…O

$$

$$

$$

$$**

**

O

OH

O

O

OH

O

H

H

H

O O

O O

H

H

H O

H

OH

H

CH3

O

O

O

O

O

O

a) b) c)

The The αα polymorph of polymorph of OETCA OETCA contd.contd.Centrosymmetric C-H…π interactions between neighboring layers

Layered structure

The The γγ polymorph of polymorph of OETCA OETCA

C2/c16.99 Å 5.46 Å 23.21 Å90º 110.85º 90º

The The γγ polymorph of polymorph of OETCA OETCA contd.contd.

Herring bone type structure

In this case each OETCA

molecule acts as a C-H…π interaction donor to one layer and as an acceptor to another

Acceptor

Donor

The The ββ polymorph of polymorph of OETCA OETCA

R-337.51 Å 37.51 Å 3.93 Å

90º 90º 120º

In this case each OETCA molecule is H-bonded to another OETCA molecule to form a dimer which then arranges in such a way that it surrounds a benzene molecule in a channel

H-bonding and polymorphism in OETCA H-bonding and polymorphism in OETCA contd.contd.

The H-bonded dimer is common to all the polymorphs. The layered structure is found in the α, α' and γ polymorphs. The difference between these is subtle and driven by weak H-bonding and dispersive forces.

The reliability H-bonding of donors and acceptorsThe reliability H-bonding of donors and acceptors When a molecule is capable of both intra- and inter-molecular When a molecule is capable of both intra- and inter-molecular

H-bonding, predicting which will occur is often unreliableH-bonding, predicting which will occur is often unreliable

CH3

O

O

O

HO

O

H

CH3

O

O

O

H

SolutionSolid state

o-methoxybenzoic acid

O

O

O

H

C2H5

o-ethoxybenzoic acid

Solid state and solution

In this case the addition of a single CH2 changes the solid state H-bonding pattern.Just how does one predict when this will happen?This is currently a huge problem in SS chemistry.

The reliability H-bonding of donors and acceptors The reliability H-bonding of donors and acceptors contd.contd.

To get around this problem workers in this field have created To get around this problem workers in this field have created tables of reliable and unreliable donors and acceptorstables of reliable and unreliable donors and acceptors

TypeType Functional group involvedFunctional group involved

Reliable donorReliable donor -OH, -NH-OH, -NH22, -NHR, -CONH, -NHR, -CONH22, -CONHR, -COOH, -CONHR, -COOH

Occasional donorOccasional donor -COH, -XH, -SH, -CH-COH, -XH, -SH, -CH

Reliable Reliable acceptoracceptor

-COOH, -CONHCO-, -NHCONH-, -CON<, >P=O, -COOH, -CONHCO-, -NHCONH-, -CON<, >P=O, >S=O, -OH>S=O, -OH

Occasional Occasional acceptoracceptor

>O, -NO>O, -NO22, -CN, -CO, -COOR, -N<, -Cl, -CN, -CO, -COOR, -N<, -Cl

The reliability H-bonding of donors and acceptors The reliability H-bonding of donors and acceptors contd.contd.

In addition, some rules governing H-bonding in solids have In addition, some rules governing H-bonding in solids have been proposedbeen proposed

These rely on the classification of H-bond donors and These rely on the classification of H-bond donors and acceptors into reliable and unreliableacceptors into reliable and unreliable

Using the above the following 3 rules have been devised:Using the above the following 3 rules have been devised:

1.1. AllAll (or as many as possible) (or as many as possible) good proton donors and acceptorsgood proton donors and acceptors are used in H-bondingare used in H-bonding

2.2. 6-membered intramolecular H-bond rings6-membered intramolecular H-bond rings form in preference to form in preference to intermolecular H-bondsintermolecular H-bonds

3.3. The best proton acceptors and donors The best proton acceptors and donors remainingremaining after the after the formation of an intramolecular H-bond formation of an intramolecular H-bond will form intermolecular will form intermolecular H-bondsH-bonds

CH3

O

O

O

HO

O

H

CH3

O

O

O

H

SolutionSolid state

o-methoxybenzoic acid

O

O

O

H

C2H5

o-ethoxybenzoic acid

Solid state and solution

Therefore according to the above rules the intramolecular H-bond is the one usually favoured

However, these rules often break down for large molecules

HO

O

O

OH

H2N

O

O

NH2

H-bonding in two very similar moleculesH-bonding in two very similar molecules

NB!! AllNB!! All (or as many as (or as many as possible) possible) good proton good proton donors and acceptorsdonors and acceptors are used in H-bondingare used in H-bonding

What do carboxylic acids do in the solid state?What do carboxylic acids do in the solid state?

O

O

H

O

O

H

O

O

H

Syn,syn-Catemer

O

O

H

O

O

H

O

O

H

syn,anti-Catemer

O

O

H

O

O

H

Dimer

O

O

O

O

H

H

O

O

H

anti,anti-Catemer

O

O

HO

O

H

Synplanar Antiplanar

Carboxylic acid groups occur in two distinct conformations, synplanar and antiplanar. The syn conformation is more stable by about 10 kJ/mol and as a consequence H-bond patterns based on it are more stable.

Graph Set NotationGraph Set Notation

Graph set notation examplesGraph set notation examples

A pattern composed of only one type of H-bond pattern composed of only one type of H-bond is referred to as a Motif - each of the above is a motif

Graph set notationGraph set notation Used to Used to describe H-bonding patternsdescribe H-bonding patterns in crystal structures in crystal structures

Reasonable to expect that the more H-bond donors and Reasonable to expect that the more H-bond donors and acceptors a molecule has the greater the variety of acceptors a molecule has the greater the variety of structures that it can form, since they might be expected to structures that it can form, since they might be expected to combine in a multitude of different ways.combine in a multitude of different ways.

However, However, some donor-acceptor combinations are more some donor-acceptor combinations are more favorable than othersfavorable than others • Strong H-donorsStrong H-donors preferentially H-bond with preferentially H-bond with strong H-acceptorsstrong H-acceptors• This is a little like the soft/hard ligand and metal concept in OM This is a little like the soft/hard ligand and metal concept in OM

chemistrychemistry

Relies on the fact that H-bonds are both very strong and Relies on the fact that H-bonds are both very strong and directional. As a consequence patterns between functional directional. As a consequence patterns between functional groups tend to be consistent.groups tend to be consistent.

Graph set notation Graph set notation contd.contd. Preference for some H-bond patterns leads to H-bond Preference for some H-bond patterns leads to H-bond

patterns being patterns being retainedretained in the various polymorphs of a in the various polymorphs of a specific compound rather than the creation of a variety of specific compound rather than the creation of a variety of hydrogen bond patterns. (Look at the OETCA example)hydrogen bond patterns. (Look at the OETCA example)

The The understanding and characterization of hydrogen bonds understanding and characterization of hydrogen bonds is therefore very important in order to understand their is therefore very important in order to understand their effect on crystal structureeffect on crystal structure - allows one to have some idea of - allows one to have some idea of what kind of interactions will occur between molecules of a what kind of interactions will occur between molecules of a given compound.given compound.

Graph set notation has been introduced in order to Graph set notation has been introduced in order to simplify simplify this processthis process..

Graph set notation Graph set notation contd.contd.• The graph set approach to the analysis of H-bond patterns The graph set approach to the analysis of H-bond patterns

allows the most complicated networks can be reduced to allows the most complicated networks can be reduced to four basic patterns, each specified by a designator:four basic patterns, each specified by a designator:• chainschains ( (CC))• ringsrings ( (RR))• intramolecular hydrogen bonded patterns (intramolecular hydrogen bonded patterns (SS) () (selfself))• other finite patterns (other finite patterns (DD) () (discretediscrete))

• Graph set designators are given in the form Graph set designators are given in the form GGaabb(n)(n)

• GG is one of the four possible designators ( is one of the four possible designators (CC, , SS, , DD and and RR))• aa gives the number of H-bond acceptors gives the number of H-bond acceptors• bb gives the number of H-bond donors gives the number of H-bond donors• nn gives the number of atoms in the pattern and is called the gives the number of atoms in the pattern and is called the

degree of the pattern and is given in parenthesis degree of the pattern and is given in parenthesis

Graph set notation examplesGraph set notation examples

A pattern composed of only one type of H-bond pattern composed of only one type of H-bond is referred to as a Motif - each of the above is a motif

Extending Graph set notation – “levels”Extending Graph set notation – “levels”

• To simplify the analysis of complex H-bond networks the To simplify the analysis of complex H-bond networks the network is network is broken down into its component patternsbroken down into its component patterns and and given as a list of motifsgiven as a list of motifs

This list of component motifs is referred to as the unitary or This list of component motifs is referred to as the unitary or first level graph set and is noted as first level graph set and is noted as N1N1

These unitary graph sets can then be combined to give These unitary graph sets can then be combined to give higher level graph setshigher level graph sets

A network formed by two different H-bonds is referred to as A network formed by two different H-bonds is referred to as a binary level graph set (noted as a binary level graph set (noted as N2N2) while a network ) while a network composed of three different hydrogen bonds is referred to composed of three different hydrogen bonds is referred to as a tertiary level graph set (noted as as a tertiary level graph set (noted as N3N3), i.e. the more ), i.e. the more component hydrogen bonds in a specific pattern the higher component hydrogen bonds in a specific pattern the higher the level of the graph setthe level of the graph set

Extending Graph set notation – “levels”Extending Graph set notation – “levels”