title: Multiple isotope effect study of the acid-catalyzed hydrolysis of formamide.
abstract: Multiple isotope effects were measured at the reactive center of formamide during acid-catalyzed hydrolysis in water at 25 degrees C. The mechanism involves a rapid pre-equilibrium protonation of the carbonyl oxygen, followed by the formation of at least one tetrahedral intermediate, which does not appreciably exchange its carbonyl oxygen with the solvent (kh/kex = 55). The pKa for formamide was determined by 15N NMR and found to be about -2.0. The formyl-hydrogen kinetic isotope effect (KIE) is indicative of a transition state that is highly tetrahedral (Dkobs = 0.79); the carbonyl-carbon KIE (13kobs = 1.031) is in agreement with this conclusion. The small leaving-nitrogen KIE (15kobs = 1.0050) is consistent with some step prior to breaking the C-N bond as rate-determining. The carbonyl-oxygen KIE (18kobs = 0.996) points to attack of water as the rate-determining step. On the basis of these results, a mechanism is proposed in which attachment of the nucleophile to a protonated formamide molecule is rate determining.
authors: Department of Chemistry and Biochemistry, California Polytechnic State University, San Luis Obispo, California 93407, USA. jmarlier@calpoly.edu
authors: John F
authors: JF
authors: Marlier
authors: Erica
authors: E
authors: Campbell
authors: Catherine
authors: C
authors: Lai
authors: Michael
authors: M
authors: Weber
authors: Laurie A
authors: LA
authors: Reinhardt
authors: W W
authors: WW
authors: Cleland