Reduction of 3,5,7,7,10,12,14,14-octamethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene (Me8[14]diene) with sodium borohydride yields three diastereomeric Me8[14]anes. These diastereomers can be separated through fractional crystallization from xylene. The structure of these isomers has been established on the bseis of their NMR spectra. The structure of one isomer has been confirmed by X-ray crystallography.
Rate constants have been obtained for the hydrolysis of the trifluoroethyl, phenyl, and p-nitrophenyl esters of 2-aminobenzoic acid at 50 degrees C in H(2)O. The pseudo-first-order rate constants, k(obsd), are pH independent from pH 8 to pH 4 (the pK(a) of the amine group conjugate acid). The 2-aminobenzoate esters hydrolyze with similar rate constants in the pH-independent reactions, and these water reactions are approximately 2-fold slower in D(2)O than in H(2)O. The most likely mechanism involves intramolecular general base catalysis by the neighboring amine group. The rate enhancements in the pH-independent reaction in comparison with the pH-independent hydrolysis of the corresponding para substituted esters or the benzoate esters are 50-100-fold. In comparison with the hydroxide ion catalyzed reaction, the enhancement in k(obsd) at pH 4 with the phenyl ester is 10(5)-fold. Intramolecular general base catalyzed reactions are assessed in respect to their relative advantages and disadvantages in enzyme catalysis. A general base catalyzed reaction can be more rapid at low pH than a nucleophilic reaction that has a marked dependence on pH and the leaving group.
The plot of log k
obsd
vs pH for
the hydrolysis of o-carboxybenzaldehyde
trans-1,2-cyclohexanediyl acetal
at 50 °C in H2O has four unit changes of slope in the pH
range 2−9. The plot is here described by proceeding
from
low pH to high pH. The observed hydronium ion- and water-catalyzed
reactions at pH < 6 have rate constants that
are similar, but not identical, to those for hydrolysis of the acylal
3-[(trans-2-hydroxycyclohexyl)oxy]phthalide,
which
was isolated from the reaction at pH 3, and synthesized independently.
The pH−log rate constant profile for hydrolysis
of the acetal bends downward near pH 6 to give a slope of −1.0.
Oxocarbonium ion hydrolysis is then a water
reaction. At pH 7 the mechanism of the reaction changes to attack
of OH- on the oxocarbonium ion intermediate.
A change in rate-determining step takes place at pH 8 to hydronium
ion-catalyzed ring opening of the anionic species
of the acetal, or the kinetically equivalent intramolecular general
acid catalysis in ring opening of the neutral species.
The mechanism involving general acid catalysis by the neighboring
carboxyl group is strongly supported by the
D2O solvent isotope effect. The o-carboxyl
group enhances the rate of the acetal ring-opening reaction by a
factor
of 220 in comparison with the exactly analogous
p-carboxyl-substituted acetal. In contrast, the
analogous p-OCH3-,
p-NO2-, o- and
p-COOCH3-, and p-COOH-substituted
derivatives have uncomplicated linear pH−log rate
constant
profiles with slopes of −1.0. A neighboring carboxyl group can
participate in the hydrolysis of an acetal of an
aliphatic alcohol if the C−O bond breaking process is facilitated by
the release of steric strain. The implications of
these results for the mechanism of lysozyme-catalyzed reactions are
discussed.
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