KJM5220 - Heterocyclic chemistry

http://www.uio.no/studier/emner/matnat/kjemi/KJM5220/h09/

Rings containing one or more heteroatom (atom other than C)

Heteroatoms: N, O, S

Aromatic rings

5 and 6 membered rings + fused rings

Synthesis and reactivity

 Chapter 1

Structure (and spectroscopic) properties

of aromatic heterocycles
 Aromaticity
Hückel

4n + 2

Benzene
H H

H H

H H
All C-C bonds 1.39 Å

All C sp2

1.37 Å
Naphtalene

1.41 Å
 6-Membered heterocyclic rings
Heteroatom: N (or O)

Pyridine
lone pair
1.40 Å
H H

N H
1.39 Å
N N H H
2.2 D
1.34 Å sp2 N

N more electroneg. than C

C-2, C-4 and C-6

Electron defficient
N N N N
 6-Membered heterocyclic rings
Heteroatom: N (or O)

Pyridine as a base
Pyrylium cation

H H
+ H
N N O H
H O
H H
pKa 5.2

H H H H

N H H N H

H H H H

Still aromatic!
 5-Membered heterocyclic rings
Heteroatom: N, O, S
Cyclopentadienyl
Cyclopentadiene 6 π−electrons

H H H
H
H H H H
H H
H sp3 sp2
B

Pyrrole Thiophene Furan

1.43Å 1.42Å 1.44Å

1.37Å 1.37Å 1.35Å

N S O
H
1.38Å 1.71Å 1.37Å

H H H
H
H N H X
H
H H
Pyrrole Thiophene Furan

N S O
H

X X X

All C electron rich

 Tautomerism

H O OH
O O
H

Keto Enol

Pyridones (keto) - Hydroxypyridines (enol)

O HO

N N
As phenol
Pyridones (keto) - Hydroxypyridines (enol)

O OH

N O N O N OH
H H N N
H

N O N O

DMF

Summary taut. - 5 and 6-membered rings

O NH2

? HN N
O N O N
HX N X N H H
H
Uracil Cytosine
XH X X=O: one / hydroxy
? X=NR: imino / amino
X=S: thione (6-membered rings) /
N N thiol (5 membered)
H
 NMR
Benzene: 7.3ppm, 128ppm

7.5 ppm
136 ppm
H 7.1 ppm
H 124 ppm

N H 8.5 ppm
150 ppm

N N N N N

Inductive
effect

(15N NMR)
 6.2 ppm 7.1 ppm 6.3 ppm
H 108 ppm H 127 ppm H 110 ppm

N H 6.6 ppm S H 7.2 ppm O H 7.4 ppm

117 ppm 126 ppm 144 ppm
H
1.55 D 0.71 D
(sovent 0.52 D
dependent)

Electronegativity (Pauling)
C = 2.5
X X N = 3.0
X S = 2.5
O = 3.5
Inductive eff.

Only rel for X = S and Se

involved d-orbitals
X
 Chapter 2

Reactivity

of

aromatic heterocycles
We already know !!!!!

6-Membered rings - electron defficient on carbons

N N N N

5-Membered rings - electron rich on carbons

X X X
Electrophilic reactions Deprotonation
on Nitrogen of N-H
6-membered rings of C-H / C-metallation
5-membered rings C-Litiation
on Carbon Direct litiation
Metal-halogen exchange
6-membered rings C-metallation (Met not Li)
5-membered rings Transmetallation
Insertion

Nucleophilic reactions
on Carbon Reactions on metallated heterocycles
6-membered rings
Pd-cat. cross couplings
5-membered rings ipso-substitution

(Radical reactions) Metallation (deprotonation) in

alkyl side chains
Electrophilic reactions on Nitrogen

6-Membered rings 5-Membered rings

+ H
N N + H
H N N
pKa 5.23 H H H
pKa -0.27

RX H2O2

N N N
R O
RCOX
H
N N
+ H
N N
N H H
R O pKa 6.95
 Electrophilic reactions on Carbon
6-membered rings

N N N N

6-membered rings - electron defficient (at C) H

E
•Decreased reactivity E
•Both C (C-3 / C-5) and N may react
N N
•Diazines less reactive + res. forms
Electrophilic aromatic substitution

+ E
N

N
E
N-alkylation / acylation / protonation etc.
 Electrophilic reactions on Carbon
5-membered rings

X X X

Electron rich (on all C) - reactive in electrophilic Ar. subst

Selectivity (not always good) ?

+ E E E E
X X H X H X H X E

E E E
H H
+ E
X X X X
 Nucleophilic reactions on Carbon

Nucleophilic aromatic substitution (KJM4200)

X X X
X Nu Nu
•SNAr Nu Nu Nu

+X

•SN1: Via diazonuim salts and arylic cation

•Benzyne

•SRN1: Involves radicals

•VNS: Vicarious nucl. Subst.

 Nucleophilic reactions on Carbon
6-membered rings

N N N N

6-membered rings - electron defficient (at C-2 / C-4 / C-6)

Reactive in nucleophilic Ar subst

OMe
OMe
N Cl N N OMe
Cl

+ res. form

Nucleophilic reactions on Carbon

5-membered rings

electron rich (at C)

X X X
not reactive Nu Ar subst
 Deprotonation of N-H

H +
N N N N
H
pKa 17.5

N N
sp3 N Stabilization of
N neg. charge on N
N N
H H
pKa ≈44 pKa 4.8
 Deprotonation of C-H / C-metallation

C H C Met C X

X X X

C-Litiation: a) Direct litiation (C-H – C-Li)

(“Metal-Hydrogen exchange”)
b) Metal-Halogen exchange (C-X – C-Li)

C-Met a) Transmetallation (C-Li – C-Met)

(Me not Li) b) Insertion (C-X – C-Met-X cf Grignard)
 Deprotonation of C-H / C-metallation
C-Litiation: Direct litiation

R Li

X H X Li

H in α-position to heteroatom

•Reactivity / Acidity / Anion Stability

•Other subst - Directed ortho metallation
•R-Li: Alkyllithium and lithium amides

N N

X H X H X H X H

Li
 Deprotonation of C-H / C-metallation
C-Litiation: Metal halogen exchange

R Li
+ R-X
X Li
X: Br, I

R-Li: Alkyllithium, NOT LDA etc.

Metall - halogen exchange favored over direct litiation, low temp.
Formation of R-X may be avoided; 2 equivs. t-BuLi (cf react between RLi and RX)

Li

+ X
X Li

X + Li + H + LiBr
 Deprotonation of C-H / C-metallation
C-Litiation: Some ex. on 5-membered rings
N N
LDA or BuLi LDA or BuLi
X X Li X X Li

Li
BuLi BuLi
OLi O
X CO2H X X
Li
O O

Br Br Li
LDA BuLi
Li low temp. Li
X X X X

Br Br
BuLi

X Br X Li
 Deprotonation of C-H / C-metallation
C-Litiation: 6-membered rings

N N N N

R H

N R N

R H Met-halogen exchange
R substitution?

N H R3NLi: No add / subst

R

R
N
H N
 Deprotonation of C-H / C-metallation
C-metallation (Met not Li )
Transmetallation
Insertion

Met = MgX (Grignard reagents)

MgBr
Mg

MgBr Br MgBr

Metal - Halogen Exchange Insertion

Met = ZnX
Zn ZnX2

Br ZnBr Li
Insertion Transmetallation

Negishi coupling
Reformatski etc
 Deprotonation of C-H / C-metallation
C-metallation (Met not Li )
Transmetallation
Insertion

Met = B(OR)2, SnR3, SiR3

1) B(OMe)3 Suzuki coupling

2) H2O
B(OH)2

Bu3SnCl
Stille coupling
Ipso subst
Li
SnBu3
Me3SiCl

Ipso subst

SiMe3
Reactions on metallated heterocycles
Pd-cat. cross couplings (KJM4200)

Cat.
HetAr-Met + Ar-X HetAr-Ar + MetX

Pd(0)
Ar-X

HetAr-Ar

reductive
elimination Oxidative
addition

+II +II
HetAr-Pd-Ar Ar-Pd-X

Met-X HetAr-Met

transmetallation
 Reactions on metallated heterocycles
ipso-substitution

ipso
X
ortho
meta

para

Nu
SiMe3 E E
E SiMe3
+ Nu-SiMe3
X X X
+ res. form

Displacement of -SiR3, not H in E-fil Ar subst (also possible for SnR3)

Metallation (deprotonation) in alkyl side chains

H R1
R2 H
N
n R1
R2 X R2
N N R1 H
H N
Acidic H

Strong Base

N CH3 N CH2 N CH2

c.f. enolate anion

R Strong Base R
R
O CH3 O O CH2
CH2
Next time:

Chapter 3 - Synthesis of aromatic heterocycles

Chapter 4: Intro to pyridines and benzofused pyridines

Chapter 5: Pyridines