ORGN 42 |
| Although an elementary chemical reaction, the mechanism for alkaline formamide hydrolysis is still controversial, in particular the nature of the attacking species. Kinetic isotope effect measurements suggested a general base mechanism where a water molecule in the first solvation shell of hydroxide is the reactive nucleophile. More recent kinetic studies favored direct nucleophilic attack of hydroxide. In this contribution we present results of an ab-initio metadynamics simulation study carried out to compute a 2-dimensional free energy surface which allows to distinguish between the two mechanisms in question. We find that hydroxide either attacks the carbonyl bond directly via self diffusion, or accepts a proton transforming one of the water molecules into the reactive hydroxide ion (structural diffusion). In the latter hydrogen transfer is completed before the transition state is reached. The large free energy barrier in aqueous solution of about 21 kcal/mol, is related to the breaking of two strong hydrogen bonds formed between the solvent and hydroxide. Such an unfavorable activation process is effectively circumvented in an enzyme active site permitting a rate enhancement by several orders of magnitude. The free energy barrier obtained is in good agreement with experiment and the computed reaction paths support the interpretation of latest heavy-atom kinetic isotope effect measurements. |
|
Physical Organic Chemistry: Calculations, Mechanisms, Photochemistry, and High-Energy Species
8:00 AM-11:40 AM, Sunday, 10 September 2006 Moscone Center -- Room 133, Oral
Division of Organic Chemistry |