1

Chemistry II (Organic)

Heteroaromatic Chemistry

LECTURES 4 & 5

Pyrroles, furans & thiophenes – properties,

syntheses & reactivity

Alan C. Spivey a.c.spivey@imperial.ac.uk

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been replaced by the iso-electronic NH, O and S units respectively: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