A Guidebook to Mechanism in Organic Chemistry

Nucleophilic Attack on Carboxylic Acid Derivatives

rule enunciated by Cram which has been found to forecast accur­

ately the major product from a large number of such addition reac­

tions.

NUCLEOPHILIC ATTACK ON CARBOXYLIC ACID DERIVATIVES

The observed sequence of reactivity, in general terms, of derivatives

of acids:

is in accord with the view that their characteristic reactions, e.g.

alkaline hydrolysis, can be looked upon as nucleophilic addition

followed by elimination:

C

o fo o

HI A II

R—C—Y -> R—C-i-Y -»• R—C + Y

C i i
^OH OH OH
It should be said that the difference between an addition/elimination
and a direct displacement reaction may be apparent rather than real
if the elimination follows sufficiently rapidly on the initial addition.
The observed reactivity sequence is due to the fact that although
chlorine, oxygen and nitrogen exert an electron-withdrawing induc­
tive effect on the carbonyl carbon atom/^they all have unshared
electron pairs which can interact to form a n orbital with the carbonyl
carbon atom (mesomeric effect) thus decreasing the positive char­
acter of this atom and, hence, the ease with which nucleophiles will
attack it. This effect increases as we go Cl-»-OEt->-NH 2 ->-NR 2 , the
difference between NH 2 and NR 2 being due to the inductive effect
of the two alkyl groups increasing electron-availability on the nitro­
gen atom. There njay also be a slight fall in the reactivity of any one
derivative as the R group of the acid is changed from methyl to an
alkyl-substituted methyl group as its slightly greater inductive effect
also reduces the positive nature of the carbonyl carbon atom.