Modeling the reaction mechanisms of the amide hydrolysis in an N-(o-carboxybenzoyl)-L-amino acid.
Reaction mechanisms of the amide hydrolysis from the protonated, neutral, and deprotonated forms of N-(o-carboxybenzoyl)-l-amino acid have been investigated by use of the B3LYP density functional method. Our calculations reveal that in the amide hydrolysis the reaction barrier is significantly lower in solution than that in the gas phase, in contrast with the mechanism for imide formation in which the solvent has little influence on the reaction barrier. In the model reactions, the water molecules function both as a catalyst and as a reactant. The reaction mechanism starting from the neutral form of N-(o-carboxybenzoyl)-l-amino acid, which corresponds to pH 0-3, is concluded to be the most favored, and a concerted mechanism is more favorable than a stepwise mechanism. This conclusion is in agreement with experimental observations that the optimal pH range for amide hydrolysis of N-(o-carboxybenzoyl)-l-leucine is pH 0-3 where N-(o-carboxybenzoyl)-l-leucine is predominantly in its neutral form. We suggest that besides the acid-catalyzed mechanism the addition-elimination mechanism is likely to be an alternative choice for cleaving an amide bond. For the reaction mechanism initiated by protonation at the amidic oxygen (hydrogen ion concentration H(0) < -1), the reaction of the model compound with two water molecules lowers the transition barrier significantly compared with that involving a single water molecule.
Wu
Zhijian
Z
Contribution from the Department of Chemistry, Dalhousie University, Halifax, Nova Scotia, B3H 4J3, Canada.
Ban
Fuqiang
F
Boyd
Russell J
RJ
D000577:Amides / Q000737:chemistry*; D000596:Amino Acids / Q000737:chemistry*; D005998:Glycine / Q000031:analogs & derivatives*; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008956:Models, Chemical; D013816:Thermodynamics
D000577:Amides; D000596:Amino Acids; D005998:Glycine