Pyrimidines nucleophilic displacement, mechanism

Brill et al.16 confirmed earlier observations that for the substitution on the C2 of pyrimidines the less nucleophilic anilines are actually more reactive than aliphatic amines, presumably because of an auto-acid-catalyzed mechanism. In turn, less reactive centers like the C6 chloro group of pyrimidines could be displaced with anilines in the presence of tm-butoxide as a base (see the experimental section). 

Leucine aminopeptidase is interesting in that its active site contains two zinc atoms which together bind and activate the water molecule [74]. Despite this enzyme containing a dinuclear metal center at its active site, its mechanism, and specifically its mode of proton transfers reactions, appear to follow the general theme established by thermolysin and carboxypeptidase Adenosine deaminase and other members of the family of nucleoside and nucleotide deaminases utilize zinc-bound water as the catalytic nucleophile to displace ammonia from the 6-position of purines or the 4-position of pyrimidines and in all cases display inverse solvent deuterium isotope effects ranging from 0.3 to 0.8 on fec/Kni [75-80]. These effects are reminiscent of those observed for metallopro-teases and have their origins, like those of the proteases, in fractionation factors for the protons of the bound water that are less than one. 

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