N-Alkyl-N-methylacetamidinium Ions. Isomerization and Water Catalyzed Exchange Rates in D₂O

Previously we had reported results on the rate of stereoisomerization (see figure) in D₂O of N-benzyl-N´-methyllacetamidinium ion in an ample pD range (D₂O is used as a solvent).

We found that the sigmoided-type profile of kobs. vs. pD plot, fits the rate expression : kobs = (k₁[D⁺] + k₂Ka)/ (Ka + [D⁺]), where k₁ and k₂ are the rates of isomerization of the acetamidinium ion and the acetamidine respectively and Ka is the acidity equilibrium constant of the acetamidinium ion. These constants were evaluated by measuring the rates at each pD using dynamic NMR(H) (line shape analysis and saturation transfer). Based on the low barrier of 19.7 Kcal/mol at 25°C (k₁ = 0.02 s^-1) it was suggested that the isomerization (EZ-ZE) of the acetamidinium form procceds throw rotation of the C-N partial double bond. We argued that this relatively low barrier is due the steric repulsion of the N-benzyl group that destabilizes the ground state (planar amidinium) relative to its twisted transition state. On the other hand, our result supports that the E-syn-Z-anti isomerization of the acetamidine form proceeds via rotation about a C-N single bond as it had been proposed previously. We stated that the proposed mechanism was in agreement with the measured low barrier of 14.7 Kcal/mol at 25°C (k₁= 126 s^-1). In order to test the proposed mechanisms and in view of the biological importance of the acetamidines we have undertaken a systematic study on the isomerization of N´-alkyl-N-methylacetamidines as a complementary support to our previous results on the N-benzyl.N´-methylacetamidine. Therefore we have prepared the following acetamidines: N-allyl-N´-methylacetamidine (R=CH₂-CH=CH₂), N-trifluoroethyl-N´-methylacetamidine (R=CH₂CF₃) and N-methoxiethyl-N´-methylacetamidine (R=CH₂OCH₃). The purpose of this study is to measure the isomerization rates under pD conditions in which both forms, acetamidinium ion and acetamidine, participate. Therefore, the rates k₁ and k₂ and the equilibrium, Ka of each of these compounds was determined. We then explore the existence of a structure-reactivitity relationship for each parameter. Finally we search on the rate of proton exchange, at low pD, were the D₂O acts as a base and we found the relative acidity between the –NH sites at the acetamidinium ions.