Hydrogen-bond mediated catalysis: The aminolysis of 6-chloropyrimidine as catalyzed by derivatives of uracil

The aminolysis of 6-chloropyrimidine and 2-amino-6-chloropyrimidine has bee n examined by-using density functional theory. Relative to the aminolysis o f 6-chloropyrimidine, the addition of an electron-donating NH2 group to C-2 increases the barrier to aminolysis, indicating that the third hydrogen bo nd does not play a catalytic role but introduces additional rigidity into t he system. However, the computations suggest that there is an interesting c orrelation between the barrier to aminolysis and the proton affinity of the species that interacts with the incoming NH3. To extend the range of proto n affinities, the aminolysis of 6-chloropyrimidine was examined by using fl uoro, imine, and thioketo derivatives of the uracil-derived bases. The prot on affinity of the moiety that hydrogen bonds with NH3 is decreased by fluo ro substitution, and thus the aminolysis barriers are increased. Similarly, imine substitution enhances the PA of the moiety, which is reflected in a decrease in the aminolysis barriers. The same correlation exists for the th ioketo-derived bases, whose PA are intermediate between the fluoro and imin e derivatives. Thus, the aminolysis of 6-chloropryimidine and 2-amino-6-chl oropyrimidine demonstrates the importance of a well-chosen proton acceptor and the catalytic possibilities associated with the formation of multiple h ydrogen bonds.