Fundamentals of Medicinal Chemistry

Friedel-Crafts disconnections:

Ar = an aromatic system. The position of substitution will depend on the nature of the
substituents on the aromatic (Ar) ring system

Adjacent to a ketone:

Adjacent to an alcohol:

H

CH

C C CH 2 R^1

O

R

COOC 2 H 5

O

R

COOC 2 H 5

R^1 CH 2 −Br CH

C

O

R

COOC 2 H 5

R^1

Z

R

Z

R

− +

+CH

2 R

1

Ar

Ar−

R

O

C

R

O

+

Z is an electron withdrawing

group, eg. NO 2 , COOR, SOR,

SO 2 R, CN.

Base CH

+C Source of the

nucleophile

ArH

RCOCl

or

RCOOCOR

AlCl 3

ArCOR

RMgBr

R^1 COCl

C

O

Source of the RR^1

electrophile

Source of the

nucleophile

C R− +

O

RR^1

O

R^1

+C

+ R−

R

OH OH

R^1 R^1 R^1 R^1

R^2 R^2

R^2 R^2

Grignard

reagent

+

Source of the

electrophile

Aldehyde

or ketone

Source of the

nucleophile

R

OH

C

O

+ RMgBr

Carbanion

Source of the

electrophile

Carboxylic acids:

R COOH R− + +CO 2 H

RMgBr

CO 2

CO 2

RCO 2 MgBr

H 2 O

H 2 O

RCO 2 Li

H+

H+

RCO 2 H

RCO 2 H

RLi

Source of the

nucleophile

Source of the

electrophile Reaction work up

DESIGNING ORGANIC SYNTHESES 219