Alkaline Hydrolysis of Amide Bonds:  Effect of Bond Twist and Nitrogen Pyramidalization

• Published in: The journal of physical chemistry. A, Molecules, spectroscopy, kinetics, environment, & general theory Vol. 107; no. 13; pp. 2304 - 2315
• Main Authors: Lopez, Xabier, Mujika, Jon Iñaki, Blackburn, G. Michael, Karplus, Martin
• Format: Journal Article
• Language: English
• Published: American Chemical Society 03.04.2003
• ISSN: 1089-5639; 1520-5215
• DOI: 10.1021/jp022014s

We present an ab initio study of the alkaline hydrolysis reaction of planar and pyramidal amides. The aim is to investigate the effect of C−N bond twisting and nitrogen pyramidalization on the rate of hydrolysis. The transition states, intermediates, and products for the two steps of the reaction (hydroxide attack and breaking of the C−N bond) were characterized in the gas phase using the B3LYP density functional quantum mechanical method with the 6-31+G* basis set. The energetics were then refined using the 6-311++G(d,p) basis set. The effect of the solvent was introduced by means of several methods:  Poisson−Boltzmann (PB) and polarizable continuum model (PCM) calculations at the gas-phase geometries; both allow for charge relaxation in solution. We found that the transition state corresponding to the second step of the reaction (TS2), breaking of the C−N bond, is the transition state of highest energy in the gas phase and in solution. However, calculation with formamide as a model showed that the inclusion of an explicit water molecule significantly decreases the TS2 barrier. The ΔΔG TS2 between the twisted and planar species is about 15 kcal/mol in solution, favoring the hydrolysis of the former. Our estimation for the value of the ΔΔG TS1 for the first step of the reaction, hydroxide addition, ranges between 7 and 9.7 kcal/mol. There are also significant differences between the planar and twisted forms in the thermodynamics of the reaction. In solution, the hydrolysis of the twisted amide is exothermic by −6.8 kcal/mol, whereas the hydrolysis of the planar amide is highly endothermic, 16 kcal/mol. Thus, twisting of the amide bond and nitrogen pyramidalization is found to be an effective way of accelerating the otherwise slow hydrolysis of planar amides. As much as 14.7 kcal/mol of acceleration could be expected if the rate-limiting transition state is the breaking of the C−N bond from the tetrahedral intermediate, and 7.0−9.7 kcal/mol could be expected if the rate-limiting step is hydroxide attack. The fact that experimental studies have demonstrated a rate enhancement of about 10 kcal/mol suggests that the latter step is rate-limiting in alkaline solution.