1
Chemistry II (Organic)
Heteroaromatic Chemistry
LECTURES 4 & 5
Pyrroles, furans & thiophenes – properties,
syntheses & reactivity
Alan C. Spivey [email protected]
Mar 2012
2
Format & scope of lectures 4 & 5
• Bonding, aromaticity & reactivity of 5-ring heteroaromatics:
– cf. cyclopentadienyl anion
– pyrroles, furans & thiophenes:
• MO and valence bond descriptions
• resonance energies
• electron densities
• Pyrroles:
– structure & properties
– syntheses
– reactivity
• Furans:
– structure & properties
– syntheses
– reactivity
• Thiophenes:
– structure & properties
– syntheses
– reactivity
• Supplementary slides 1-2
– revision of SEAr mechanism
Pyrroles, Furans & Thiophenes – Importance
Natural products:
Pharmaceuticals:
O
rosefuran(component of rose oil)
FURAN
NH
HO2C
CO2H
H2N
porphobilinogen(biosynthetic precursor to
tetrapyrrole pigments)
PYRROLE
O
OMeO2CO
N N
NN
Mg2+
chlorophyll(green leaf pigment)
~ 4 PYRROLES
Cyclopentadienyl anion → pyrrole, furan & thiophene
The cyclopentadienyl anion is a C5-symmetric aromatic 5-membered cyclic carbanion:
Pyrrole, furan & thiophene can be considered as the corresponding aromatic systems where the anionic CH unit has
been replaced by the iso-electronic NH, O and S units respectively:
They are no longer C5-symmetric and do not bear a negative charge but they retain 6p electrons and are still aromatic
H H
cyclopentadiene
NaOEt
sp3 HEtOH
= H
H
H
etc.
Na
=Na
=
sp2
cyclopentadienyl anion
4 electron
diene
6 electron
aromatic
Na
NH
O S
sp2 hybrid O sp
2 hybrid Ssp
2 hybrid NHsp
2 hybrid CH
C CC
HC N
C
HC O
CC S
C
H
MO Description ↔ Resonance Energies: pyrrole, furan & thiophene
The MO diagram for the cyclopentadienyl anion can be generated using the Musulin-Frost method (lecture 1). The
asymmetry introduced by CH → NH/O/S ‘replacement’ → non-degenerate MOs for pyrrole, furan & thiophene:
Moreover, the energy match and orbital overlap between the heteroatom-centered p-orbital and the adjacent C-centered
p-orbitals is less good and so the resonance energies are lower:
Consequently, the resonance energies (~ ground state thermodynamic stabilities) loosely reflect the difference in the
Pauling electronegativities of S (2.6), N (3.0) & O (3.4) relative to C (2.5):
The decreasing resonance energies in the series: thiophene > pyrrole > furan → increasing tendancy to react as
dienes in Diels-Alder reactions and to undergo electrophilic addition (cf. substitution) reactions (see later)
cyclopentadienylanion
6 e's
E
0
E
0
pyrrole, furan& thiophene
6 e's
Heteroatoms are more electronegative than carbon and so their
p-orbitals are lower in energy. The larger the mismatch in energy
(Ei) the smaller the resulting stabilisation (ESTAB) because:
E
carboaromatic
Ei = 0; ESTAB = 'BIG'
heteroaromatic
Ei > 0; ESTAB = 'SMALL'
ESTABpc
ESTAB
pcpx
pc
ESTAB S
2
Ei
S2 = overlap integral
ESTAB = stabilisation energy
Ei = interaction energy
Ei
S NH
O
152 kJmol-1resonance energies: 122 kJmol
-190 kJmol
-168 kJmol
-1
MOST
resonance
energy
LEAST
resonance
energy
Calculated Electron Densities ↔ Reactivities: pyrrole, furan & thiophene
However, relative resonance energies are NOT the main factor affecting relative reactivities with electrophiles...
Pyrrole, furan & thiophene have 6 -electrons distributed over 5 atoms so the carbon frameworks are ALL inherently
ELECTRON RICH (relative to benzene with 6 -electrons over 6 atoms) – all react quicker than benzene with E+
Additionally, the distribution of -electron density between the heteroatom and the carbons varies considerably between
the 3 ring-systems. The overall differences are manifested most clearly in their calculated -electron densities
NB. many text books highlight dipole moments in this regard – but the sp2 lone pairs of furan and thiophene (cf.
N-H of pyrrole) complicate this analysis
The calculated -electron densities reflect the relative REACTIVITIES of the 3 heterocycles towards electrophiles:
SNH
Odipole moments:
1.55-2.15 D
dipole moment is
solvent dependent
0.72 D 0.52 D
-electron densities:
dipole moment dominated by sp2 lone pair
1.087
1.647
1.090
1.078
1.710
1.067
1.071
1.760
1.046
0 D
all 1.000
MOST
electron
rich Cs
LEAST
electron
rich Cs
SNH
O
relative rates: 5.3 x 107 1.4 x 10
2 1 no reaction
X
F3C
O
O
O
CF3
75 °C X
O
CF3
MOST
reactive
LEAST
reactive
Valence Bond Description ↔ Electron Densities: pyrrole, furan & thiophene
The calculated -electron densities reflect a balance of ~opposing factors:
INDUCTIVE withdrawl of electron density away from the carbons (via s-bonds):
this mirrors Pauling electronegativities: O (3.4) > N (3.0) > S (2.6) as revealed by the dipole moments of the
saturated (i.e. non-aromatic) heterocycles:
RESONANCE donation of electron density towards the carbons (via -bonds):
the importance of this depends on the ability of the heteroatom to delocalise its p-lone pair
this mirrors the basicities of the protonated saturated heterocycles (i.e. ability of X atom to accommodate
+ive charge:
RESONANCE is the dominant factor pushing electron density onto the carbons and hence affecting REACTIVITY
SNO
dipole moments: ~1.6 D~1.7 D ~0.5 D
H
STRONG
electron
withdrawl
(C to X)
WEAK
electron
withdrawl
(C to X)
Pyrrole – Structure and Properties
A liquid bp 139 °C
Bond lengths, 1H and 13C NMR chemical shifts and coupling constants as expected for an aromatic system:
Resonance energy: 90 kJmol-1 [i.e. lower than benzene (152); intermediate cf. thiophene (122) & furan (68)]
→ rarely undergoes addition reactions & requires EWG on N to act as diene in Diels-Alder reactions
Electron density: electron rich cf. benzene & higher than furan & thiophene
→ very reactive towards electrophilic substitution (SEAr), unreactive towards nucleophilic substitution (SNAr)
NH-acidic (pKa 17.5). Non-basic because the N lone pair is part of the aromatic sextet of electrons & protonation leads
to a non-aromatic C-protonated species:
NH
1.42 Å
1.38 Å
1.37 Å
cf. ave C-C 1.48 Å
ave C=C 1.34 Å
ave C-N 1.45 Å
bond lengths:
NH
13C and
1H NMR:
6.6 ppm
6.2 ppm109.2 ppm
118.2 ppm
3.4 Hz
2.6 Hz
Pyrroles – Syntheses
Paal-Knorr (Type I): 1,4-dicarbonyl with NH3 or 1º amine
Knorr (Type II): b-ketoester or b-ketonitrile with -aminoketone
Hantzsch (Type II): -chloroketone with enaminoester
Commercial synthesis of pyrrole:
NH
R R'R R'
O O
R'RO
pt
H
NH
R'R
pt pt
H2O
NH
R R'
OH2H
N NH2HO
NH3
HO HO
NH
R'R
H2O
H
pt
H2O
pt
NC
R O
R'
H2N CO2R''
O
NH
R CO2R''
R'NC
NH
O R'
CO2R''
NC
RH2O H2O
NH
O R'
CO2R''
NC
R
H
N
O R'
CO2R''
NC
R
H
NR CO2R''
R'NCOH2pt pt pt pt
Hpt
H2OH
+H
N
Cl
R O
CO2R''
O R' NH
R R'
CO2R''
H2O
pt pt pt+
N NH3
Cl
R O
CO2R''
R'
+H2N
HO
H Cl
R O
CO2R''
R'
+
H2N R O
CO2R''
R'HN
HCl H2O
NH3O
+Al2O3
gas phase NH
Pyrroles – Reactivity
Electrophilic substitution: via addition-elimination (SEAr) (see supplementary slides 1-2)
reactivity: extremely reactive towards many electrophiles (E+); >furan, thiophene, benzene; similar to aniline
regioselectivity: the kinetic product predominates; predict by estimating the energy of the respective Wheland
intermediates → 2-substitution is favoured:
e.g. nitration: (E+ = NO2+)
Pyrroles – Reactivity cont.
Electrophilic substitution (SEAr) cont.
e.g. halogenation: (E+ = Hal+)
reacts rapidly to give tetra-halopyrroles unless conditions are carefully controlled
e.g. acylation: (E+ = RCO+)
comparison with analogous reactions of furan & thiophene
Vilsmeyer formylation: (E+ = chloriminium ion)
Pyrroles – Reactivity cont.
Electrophilic substitution (SEAr) cont.
e.g. Mannich reactions (aminomethylation): (E+ = RCH=NR’2+, iminium ion)
e.g. acid catalysed condensation with aldehydes & ketones: (E+ = RCH=OH+, protonated carbonyl compound)
→ tetrapyrroles & porphyrins
Pyrroles – Reactivity cont.
Metallation: (NH pKa = 17.5) NB. For an overview & mechanistic discussion see LECTURE 7 (also: Joule & Smith (5th
Ed) chapter 4).
Reaction as a Diels-Alder diene:
only possible with EWG on N to reduce aromatic character (i.e. reduce resonance energy):
N N E
R R
1) lithium base
(e.g. BuLi or LDA)
2) E
NH-pyrroles:(N-metallation)
NR pyrroles:(C-metallation)
NH
N
NaNH2 Na
N
MgBr
RMgBr
NH3
RHcovalent
ionicE
E
NH
E
N
E
E X = MeI, RCOCl etc.
metallated pyrrole is anambident nucleophile
hard
soft2
1
2E X = MeI, RCOCl etc.
E
E
N
CO2Me
CO2Me
MeO2C
OO
hv, CH2Cl2
N
OO
N
MeO2C
CO2Me
CO2Me
MeO2C
AlCl3, CH2Cl2, 0 ºC
Furan – Structure and Properties
A liquid bp 31 °C
Bond lengths, 1H and 13C NMR chemical shifts and coupling constants as expected for an aromatic system:
Resonance energy: 68 kJmol-1 [i.e. lower than benzene (152), thiophene (122) & pyrrole (90)]
→ tendency to undergo electrophilic addition as well as substitution
→ a good diene in Diels-Alder reactions
Electron density: electron rich cf. benzene (& thiophene) but less so than pyrrole
→ fairly reactive towards electrophilic substitution (SEAr), unreactive towards nucleophilic substitution (SNAr)
O
1.44 Å
1.35 Å
1.37 Å
cf. ave C-C 1.48 Å
ave C=C 1.34 Å
ave C-O 1.43 Å
bond lengths:
O
13C and
1H NMR:
7.3 ppm
6.2 ppm110 ppm
142 ppm
3.3 Hz
1.8 Hz
Furans – Syntheses
Paal-Knorr (Type I): dehydration of 1,4-dicarbonyl
Feist-Benary (Type II): 1,3-dicarbonyl with -haloketone
Commercial synthesis of furan:
Cl
R O CO2R''
O R' O R'
CO2R''pt pt
+
O Cl
R O CO2R''
R'+
CO2R''
R'O
H2O
HO
O
H
Cl
ROH R
O R'
CO2R''OHR
Cl
pt
oatsmaize
Hpentoses
H
steam distill O OO
furfuraldehyde
CO
Furans – Reactivity
Electrophilic substitution: via addition-elimination (SEAr) (see supplementary slides 1-2)
reactivity: reactive towards many electrophiles (E+); <pyrrole, but >thiophene & benzene
regioselectivity: as for pyrrole the kinetic 2-substituted product predominates
e.g. nitration: (E+ = NO2+)
e.g. sulfonylation: (E+ = SO3)
e.g. halogenation: (E+ = Hal+) like pyrrole – mild conditions to avoid poly-halogenation
e.g. acylation: Vilsmeyer formylation (E+ = chloriminium ion) as for pyrrole
O
AcONO2
O
NO2
H
OAcO H
NO2
AcO
pyridine O NO2
2
an isolableaddition product
substitution product
O O SO3H2
NSO3
HO3S5
O O
Me2NH + HCl
O
DMF
POCl3 (1eq)ON
Me
Me
Cl H2O
2
Furans – Reactivity cont.
Metallation: NB. For an overview & mechanistic discussion see LECTURE 7 (also: Joule & Smith (5th Ed) chapter 4).
Reaction as a Diels-Alder diene: NB. reversible reactions → exo (NOT endo) products
Reaction as an enol ether – electrophilic addition:
usually achieved by use of an electrophile in a nucleophilic solvent at low temperature
O H O Li O E
sBuLi, Et2O
2 EE X = MeI, RCOCl etc.
O
O
O
O
O
+ O
O
O
exothermodynamic product
ONOT
endokinetic product
OO
O
O
Br2, MeOH
O BrMeOH
O BrMeO
HBr
OMeOMeOH
HBrO OMeMeO
25
addition product
H3O
OO
Thiophene – Structure and Properties
A liquid bp 84 °C
Bond lengths, 1H and 13C NMR chemical shifts and coupling constants as expected for an aromatic system:
Resonance energy: 122 kJmol-1 [i.e. lower than benzene (152); but high cf. pyrrole (90) & furan (68)]
→ rarely undergoes addition reactions
→ does not act as a diene in Diels-Alder reactions
Electron density: electron rich cf. benzene but less so than pyrrole & furan
→ fairly reactive towards electrophilic substitution (SEAr), unreactive towards nucleophilic substitution (SNAr)
S
1.42 Å
1.37 Å
1.71 Å
cf. ave C-C 1.48 Å
ave C=C 1.34 Å
ave C-S 1.82 Å
bond lengths:
S
13C and
1H NMR:
7.0 ppm
6.9 ppm127 ppm
126 ppm
3.3 Hz
5.0 Hz
Thiophenes – Syntheses
Paal-Knorr (Type I): 1,4-dicarbonyl with P2S5 or Lawesson’s reagent (lecture 1)
Hinsberg: 1,2-dicarbonyl with thiodiacetate
NB. Z = CO2R’’
Commercial synthesis of thiophene:
S Z
R'
+
R
S
O O
R'R
S ZZ
tBuO
H +O O
R'R
S ZZ S Z
O
O
R''O S
O
Z
R' R'
R''O
H
OR O R O
HO2CS Z
R'R
O2C
O
R''OHtBuOH
tBuO
H
tBuO + HO
S
S8
600 °C
Thiophenes – Reactivity
Electrophilic substitution: via addition-elimination (SEAr) (see supplementary slides 1-2)
reactivity: reactive towards many electrophiles (E+); <<pyrrole & <furan, but >benzene
regioselectivity: as for pyrrole/furan the kinetic 2-substituted product predominates
e.g. halogenation: (E+ = Hal+) like pyrrole/furan – mild conditions to avoid poly-halogenation
Metallation: as for furan but -protons more acidic – easier to deprotonate
NB. For an overview & mechanistic discussion see LECTURE 7 (also: Joule & Smith (5th Ed) chapter 4).
NO reactivity as a Diels-Alder diene – high resonance energy
NO reactivity as a thioenol ether (i.e. addition reactions, cf. furan) – high resonance energy
Reactions at sulfur:
oxidation/reduction chemistry:
S H S Li S E
sBuLi, Et2O
2E
E X = MeI, RCOCl etc.
S S I2
I2, aq HNO3
90 °C
S
m-CPBA (Xs.)
SO O
Raney Ni, H2
R R' R R'R R'
Supplementary Slide 1 – Electrophilic Aromatic Substitution: SEAr
Mechanism: addition-elimination
e.g. for benzene: notes
• Intermediates: energy minima
• Transition states: energy
maxima
• Wheland intermediate is NOT
aromatic but stabilised by
delocalisation
• Generally under kinetic control
TS#1
EHH
TS#
2
EG
reaction co-ordinate
Supplementary Slide 2 – Electrophiles for SEAr
nitration:
c.HNO3:c.H2SO4 (1:1) or c.HNO3 in Ac2O
halogenation:
molecular halide ± Lewis acid (LA) catalyst in the dark
acylation:
acid chloride or anhydride ± LA promoter:
sulfonylation:
oleum (c.H2SO4 saturated with SO3)
O NO
O
H H2SO4 O NO
O
H
H
HSO4
O
N
O
H2O
nitronium ion = E
FeBr3Br2 Halogen-Lewis acid complex = EBr...FeBr4
AlCl3R Cl
O O
R
AlCl4 acylium ion = E+
S
O
O O H2SO4+ HSO4S
O
O OH
protonated sulfur trioxide = Esulfurtrioxide
= H2S2O7