Page 679 - Advanced Organic Chemistry Part A - Structure and Mechanisms, 5th ed (2007) - Carey _ Sundberg

In acidic solution, the protonated nitrogen is a better leaving group, and also loses its 661
ability to assist in the elimination of the alkoxide. Under these circumstances, nitrogen
elimination is favored. SECTION 7.4
Substitution Reactions of
OR' O R' OR' O Carboxylic Acid
+
H 2 O Derivatives
+ R +
R"N H 2 C OR' C + R C OH RCOR' + R"N H 3 + R'OH
H
OR'
R R'O
+ R" 2 NH
In analyzing the behavior of these types of tetrahedral intermediates, it should be
kept in mind that proton transfer reactions are usually fast relative to other steps. This
circumstance permits the possibility that a minor species in equilibrium with the major
species may be the kinetically dominant intermediate. Detailed studies of kinetics,
solvent isotope effects, and catalysis are the best tools for investigating the various
possibilities.
Recent computational work has suggested the existence of a mechanism for
aminolysis that bypasses the tetrahedral intermediates. Transition structures cor-
responding to both stepwise addition-elimination through a tetrahedral intermediate
and direct substitution were found for the reaction of methylamine with methyl acetate
and phenyl acetate. 45 There is considerable development of charge separation in the
direct displacement mechanism because proton transfer lags rupture of the C−O bond.

H O OH H O
R
N: C OR' NH C OR' CH N: C
CH 3 CH 3 3
R
H R H O R'
Addition-elimination Direct Substitution

The direct substitution reaction becomes progressively more favorable as the alcohol
becomes a better leaving group. According to the computations, the two mechanisms
are closely competitive for alkyl esters, but the direct substitution mechanism is favored
for aryl esters. These results refer to the gas phase.

Computed Activation Energy (kcal/mol)

Addition-elimination Direct substitution
35.5 36.2
CH 3 CO 2 CH 3
32.1 26.6
CH 3 CO 2 C 6 H 5
∼1 7
CH 3 CO 2 C 6 H 4 NO 2
A direct substitution mechanism was indicated for the 2-pyridone catalysis of
aminolysis of methyl acetate by methylamine. 46 This mechanism is represented in
Figure 7.9. It avoids a tetrahedral intermediate and describes a concerted displacement
process that is facilitated by proton transfer involving 2-pyridone. Two very closely
related TSs involving either the 2-hydroxypyridine or 2-pyridone tautomers were
found. These TSs show extensive cleavage of the C−O bond (2.0–2.2 Å) and formation

45 H. Zipse, L.-h. Wang, and K. N. Houk, Liebigs Ann., 1511 (1996).
46
L.-h. Wang and H. Zipse, Liebigs Ann., 1501 (1996).