PREDOMINANT O-18 EXCHANGE ACCOMPANYING BASE HYDROLYSIS OF A TERTIARY TOLUAMIDE - N-ETHYL-N-(TRIFLUOROETHYL)TOLUAMIDE - ASSESSMENT OF THE FACTORS THAT INFLUENCE PARTITIONING OF ANIONIC TETRAHEDRAL INTERMEDIATES

The hydrolysis of N-ethyl-N-(trifluoroethyl)toluamide (III) in basic media at 100-degrees-C (mu = 1.0 (KCl) is reported. O-18 exchange in III recovered from the hydrolytic medium is observed ; k(ex)/k(hyd) = 33.4 +/- 1.6 and is independent of [OH-]. The low basicity of the amine in III (pK(a)(H-2+N(Et)CH2CF3) = 6.3) leads to 2300-3500-fold more exchange in III relative to N,N-dimethyltoluamide (I) or N-toluoylpyrrolidine (II). These findings indicate that amine leaving ability controls whether a tertiary amide will exhibit O-18 exchange and that restriction of conformational mobility in the manner required by the Deslongchamps' stereoelectronic theory is of little importance in the exchange process. Solvent deuterium kinetic isotope data for III indicate that (k(ex)H/D = 0.90 +/- 0.08 and (k(hyd)H/D = 1.05 +/- 0.04. These respective solvent kinetic isotope effects (SKIE) refer essentially to isolated kinetic processes k1 (the attack of OH- to form T0-) and k2 (the breakdown of the anionic intermediate to product). The small observed SKIE on exchange and hydrolysis is analyzed in terms of the fractionation factors for species involved in the transition states leading to the anionic tetrahedral intermediate T0- and away from it, respectively. The mechanism consistent for the SKIE on k(hyd) is suggested to involve rate-limiting breakdown of one or both of two anionic forms having a protonated N, an anionic zwitterion T(ZW-) or a neutral zwitterion with an encounter complex associated OH-. On the basis of SKIE, O-18 exchange, and hydrolysis data for a series of tertiary toluamides having an amine portion varying in basicity by approximately 14 pK units, a unified mechanism for base-promoted hydrolysis is presented.