Page 665 - Advanced Organic Chemistry Part A - Structure and Mechanisms, 5th ed (2007) - Carey _ Sundberg

+ 647
RCH NR' + H + RCH NHR' (1)
SECTION 7.3
+ +
RCH NHR' + H O RCHNHR' RCHNH R' (2) Condensation Reactions
2
2
of Aldehydes and
+OH TI OH+ OH TI NH+ Ketones with Nitrogen
2
or Nucleophiles
+
RCH NHR + – OH RCHNHR' (3)
OH TI 0
+
RCHNHR' + H + RCHNH R' (4)
2
OH OH TI NH+
+ +
RCHNH R' + – OH RCHNH 2 R' + H 2 O RCH O + H 2 NR' (5)
2
OH O – TI +/-
The rates of the various steps are a function of the pH of the solution, the basicity
of the imine, and the reactivity of the aldehyde. Imine protonation enhances reactivity
toward either water or hydroxide ion as nucleophiles. N-Protonation in the tetrahedral
intermediate makes the amine a better leaving group. The zwitterionic intermediate
TI +/− is more reactive toward elimination of the amine than TI NH+ because of the
assistance of the anionic oxygen. In the alkaline range, the rate-determining step is
usually nucleophilic attack by hydroxide ion on the protonated C=N bond (Step 3).
At intermediate pH values, water replaces hydroxide as the dominant nucleophile
(Step 2). In acidic solution, the rate-determining step is the breakdown of the tetrahedral
intermediate (Step 5). A mechanism of this sort, in which the observed rate is sensitive
to pH, can be usefully studied by constructing a pH-rate profile, which is a plot
of the observed rate constants versus pH. (See Section 3.7.1.4 to review pH-rate
profiles.) Figure 7.5 is an example of the pH-rate profile for hydrolysis of a series
of imines derived from substituted aromatic aldehydes and t-butylamine. The form
of pH-rate profiles can be predicted on the basis of the detailed mechanism of the
reaction. The value of the observed rates can be calculated as a function of pH if a
sufficient number of the individual rate constants and the acid dissociation constants of
the participating species are known. Agreement between the calculated and observed
pH-rate profiles serves as a sensitive test of the adequacy of the postulated mechanism.
Alternatively, one may begin with the experimental pH-rate profile and deduce details
of the mechanism from it.
Complete understanding of the shape of the curves in Figure 7.5 requires a kinetic
expression somewhat more complicated than we wish to deal with here. However,
the nature of the extremities of the curve can be understood on the basis of quali-
tative arguments. The rate decreases with pH in the acidic region because formation
of the zwitterionic tetrahedral intermediate TI +/− is required for expulsion of the
amine (Step 5). The concentration of the zwitterionic species decreases with increasing
acidity, since its concentration is governed by an acid-base equilibrium.

+
H TI +/−
K =
TI NH+
Note also that in the acidic region, EWG substituents accelerate the reaction,
owing to a more favorable equilibrium for the hydration step. In the alkaline region,
the rate is pH independent. In this region, the rate-controlling step is attack of the