A heavy-atom isotope effect study of the hydrolysis of formamide

Isotope effects were measured for all the atoms at the reactive center of f ormamide during hydrolysis in dilute alkaline solution. Most of the reactio n proceeds by a pathway that is first-order in hydroxide, although a small amount proceeds by a pathway that is second-order in hydroxide. For alkalin e hydrolysis at 25 degrees C the carbonyl carbon isotope effect is (13)k(ob s) = 1.0321, the carbonyl oxygen isotope effect is (18)k(obs(C=O)) = 0.980, the formyl hydrogen isotope effect is (D)k(obs) = 0.80, and the nitrogen l eaving group isotope effect is (15)k(obs) = 1.0040. The ratio of the rate o f hydrolysis to the rate of exchange for the alkaline hydrolysis of formami de was shown to be linearly dependent on the hydroxide concentration, rangi ng from an extrapolated value of k(h)/k(ex) = 2.1 at very low hydroxide con centrations to k(h)/k(ex) = 8.4 at 1.5 M hydroxide. This is consistent with a mechanism in which an increasing fraction of the tetrahedral intermediat e pool is trapped as a dianion at high pH, effectively lowering the rate of exchange. These results also indicate that the transition states leading i nto and out of the tetrahedral intermediate are of comparable energy for th e pathway which is first-order in hydroxide. The solvent nucleophile isotop e effect is (18)k(obs(nuc)) = 1.022 for water as the attacking nucleophile or (18)k(obs(nuc)) = 0.982 for hydroxide as the attacking nucleophile. Thes e results strongly suggest that one of the water molecules hydrating the hy droxide ion is the actual attacking nucleophile instead of hydroxide ion it self.