Chapter 25:
Heterocycles
Heterocyles – Cyclic molecules that
contain at least 1 heteroatom (O, N, S)
• Oxacyloalkane: Oxygen-containing heterocycle
• Azacycloalkane: Nitrogen-containing heterocycle
• Thiacyloalkane: Sulfur-containing heterocycle
Numbering starts at heteroatom
Aromatics:
Preparation of Heterocloalkanes
1. Intramolecular SN2 reaction
CH2− L
:
X
(CH2)n
2. Special reaction for oxacyclopropanes
O
+ RCO3H
Reactions
Three- and four-membered rings open:
Usual conditions
are basic.
But, recall acidic opening of oxacyclopropanes:
For rings larger than four, ring strain driving force is absent:
Need strong acid:
+ HBr OH HBr Br
Br Br
O
For azaheterocycloalkanes: Acid just protonates the
nitrogen to ammonium salt. Ring opening can be done by
Hofmann degradation:
1. CH3I 1. CH3I
excess excess
2. Ag2O 2. Ag2O
N
N
H
Other chemistry is the same as for acyclic systems, e.g.:
H2O2
H2O2
HNO2 S S
O O O
N N S CH3I
H -
NO + I
S
CH3
Heterocyclopentadienes:
Pyrrole, Furan, and Thiophene
The lone pairs participate in the aromatic cyclic
six e system: Like the cyclopentadienyl anion
-
:
: :
: :
N O S
H
Furan Thiophene
The distribution of 6 π electrons
over five atoms makes these
systems relatively e-rich,
compared to benzene.
Cyclopentadienyl Pyrrole
anion
Orbitals
Resonance
Relative to benzene: Electron rich
δ-
:
N
H
δ-
:
N
H
m/z = 67 (M +)
:
N
H
M + - CN/HCN/HCNH
~
ν
N-H
Synthesis of Heterocyclopentadienes
Paal-Knorr synthesis of pyrroles and
its variations
:O:
: :
P2 O5 O
:O:
Mechanism:
H H H
:O
:
:O :O
-H+ H+
H :O: :O: :O
H
H
:
O OH OH2
: :
O
-H+ H+
:
: :
O
: :
-H2O
O -H+
H
Mechanism: Goes via thioketone and then enethiol
S S S H
:S
:
P P : S:
:O:
:S: S
H :O: :O:
:O:
Mechanism: (H3C)2HC
Goes via enamine
H
:
N
:O:
Reactions
1. Electrophilic Aromatic Substitution: Activated!
Attack at C2 is preferred generally
Good
But often also attack at C3
Good
Examples:
Relative reactivity: Benzene
B << thiophene < furan < pyrrole
Mixture
2. Basicity of pyrrole (and other
heterocyclopentadienes)
Relatively (cf. normal amines) nonbasic: Lone pair is tied up by resonance.
Protonation occurs on carbon!
pKa of normal
alkane-
ammonium
~ 10
Recall:
:
:O: :OH
+ +
H +
:
NH2 NH2
Or: CH3
+ +
H +
:
NH2 NH2
3. Pyrrole is quite acidic
Compare:
Reason is sp2-hybridization of attached carbons
and cyclic delocalization of charge.
Like cyclopentadienyl anion
4. Ring opening
General for all heterocyclopentadienes
Mechanism is the reverse of synthesis:
H
:
H+
: : H2O:
O
: :
O
-H+ H+
: :
:
H 2O O HO O
:
H
H
O: :O: :O:
-H+
O: O: :O:
H
:
H
:
Reductive desulfurization: Unique for thiophenes
5. Diels-Alder cycloadditions to furan: Not general
Needs a hot dienophile
6. Benzofusion: Indole
Cf. naphthalene
:
N
H
EAS at C3 allows for resonance forms which do
not disrupt the benzene ring:
Attack at C3: E H
+ H Etc.
Leaves
:
aromaticity N
H
Attack at C2: E
Etc.
Disrupts H
N+
aromaticity H
Pyridine: Azabenzene
Can be viewed as a cyclic aromatic imine:
The nitrogen is sp2-hybridized, the lone
pair is perpendicular to the aromatic π
Imine
system.
The N does not donate
e-density; rather, it
withdraws by induction
Cf. benzene
The inductive effect of nitrogen can be pictured by
dipolar resonance forms:
δ+
+ δ+
: :
N N-
:
Pyridine Spectral Data
H NMR
1
7.46
7.06
8.50
N
:
δ+
+ δ+
C NMR
: :
13 N N-
:
136.1
124.1
150.4
N
:
Mass m/z = 79 (M +)
-HCN
:
IR
wet
C-H
C=N
Pyridine is a (weak) base
+
+ H
N N+
:
H
Pyridine Pyridinium ion
pKa = 5.29
+
Compare pKa of R3NH ~ 9-10
Preparation of
Pyridines
(a condensation reaction) Arthur R. Hantzsch
(1857-1935)
Mechanism:
― = e pair
Reactions of Pyridine
Pyridine is relatively (to benzene) electron poor, therefore
EAS only under extreme conditions and only at C3
Activating substituents improve yields
Pyridine undergoes relatively easy
nucleophilic aromatic substitution
Leaving groups are typically halides;
2- and 4-halopyridines are particularly
reactive
Alexej J. Čičibabin
(1871-1945)
Think of the C=N bond as imine-like
Quinoline and
Isoquinoline:
Benzopyridines
N
N
Quinoline Isoquinoline
Preparation of Quinoline and
Isoquinoline
1. Friedländer Synthesis
O Aldol
CH O H2O, NaOH,
+ 50 ºC
H N
NH2 Imine
2-Aminobenzene- Enolizable
carboxaldehyde carbonyl 85%
compound
Paul Friedländer
(1857 - 1923)
2. Bischler-Napieralski Synthesis
POCl3, P2O5,
100 ºC
R NH -H2O N
O
+ Pd, 200 ºC, R
H - H2
R
Reactions
EAS away from heteroaromatic ring and α (for both quinoline
and isoquinoline); like naphthalene.
Chichibabin Reaction of Quinoline
and Isoquinoline
Alkaloids and Drugs
(Since the beginning of mankind.......)
LSD: Albert Hofmann
100 years old!
Allowable drug quantities
approved by Mexico,
April 28, 2006:
Opium: 5 g
Heroin: 25 mg
Marijuana: 5 g
Cocaine: 500 mg
LSD: 0.015 mg
MDA: 200 mg
Ecstasy: 200 mg
Mescaline: 1 g
Peyote: 1 kg
Psilocybin (pure): 100 mg
Mushrooms: 250 mg
Amphetamines: 100 mg
Dexamphetamines: 40 mg
Phencyclidine (PCP, or
Angel Dust): 7 mg
Methamphetamines: 200
mg
Nalbuphine (synthetic
opiate): 10 mg
