O-18 EXCHANGE ACCOMPANYING THE BASIC HYDROLYSIS OF PRIMARY, SECONDARY, AND TERTIARY TOLUAMIDES .2. THE IMPORTANCE OF AMINE LEAVING ABILITIES FROM THE ANIONIC TETRAHEDRAL INTERMEDIATES

A series of primary, secondary, and tertiary toluamides (CH3(C6H4)C=ONRiR2) was studied with respect to their hydrolysis and C=0, 180 exchange rate constants in basic media at 100 °C. For the primary amides (R1 = R2 = H) the kex/khyd ratio is 3.7 ± 0.2 and is independent of [OH-]. For the secondary toluamides R1 = H, R2 = Et, iPr, or zBu, the kex/khyd ratio is constant at 0.4-0.75, despite the fact that fchyd drops from 1.0 to 0.22 to 0.02 in passing through the series. The tertiary toluamides R1 = R2 = CH3, R1 R2 = (CH2)4 have kex/khyd = 0.01-0.02 in H2O, and that ratio increases somewhat in D2O. Analysis of the energetics of the various possible intermediates, and their barriers for interconversion and breakdown, produces a mechanism consistent with presently known experimental data. The reaction proceeds stepwise via the addition of OH- to produce an anionic intermediate (T). Breakdown of T- to product involves a water-mediated proton switch to give an anionic zwitterion followed by rate-limiting C-N cleavage. By study of the partitioning of unsymmetrical amidines in base at 100 °C, an order of leaving ability from an anionic intermediate is established where R2NH (130-180) > RNH2 (15-20) > NH3 (1.0). These data account for the observed kex/khyd ratios for the corresponding amides and indicate that amine leaving ability determines whether a given amide will exhibit significant 180 exchange. © 1990, American Chemical Society. All rights reserved.