PROTONATION OF 2,4-DIAMINOPYRIMIDINES .I. DISSOCIATION CONSTANTS AND SUBSTITUENT EFFECTS
PROTONATION OF 2,4-DIAMINOPYRIMIDINES .I. DISSOCIATION CONSTANTS AND SUBSTITUENT EFFECTS
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DOI：
10.1021/jo01256a011
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发表时间：
1969-01-01
影响因子：
3.6
通讯作者：
STRELITZ, JZ
中科院分区：
文献类型：
--
作者：
ROTH, B;STRELITZ, JZ
The basic dissociation constants of a series of approximately 70 2, 4-diaminopyrimidines andcondensed pyrimi-dine derivatives havebeen obtained. The major effect of 5 substitution is inductive, but there is a greater resonance component than can be accounted for by correlation with Hammett am constants. Maximum cor-relation is achieved with theequation log (K/Ko)=[0.72+ 0.28], in which or-has been substituted for vR with the— R substituents. The effect of 6 substitution, on the other hand, is almost completely inductive. The equation log (K/Ko)=[0.96+ 0.04] best satisfies the data in this case. Similar relationships have been found with 4-amino-6-substituted pyrimidines. In some cases hydrogen bonding renders such correlations imprecise. Dissociation constants of 4-substituted pyrimidines can be correlated with constants, but 2-substituted derivatives appear to have a considerably greater inductive component. The shifts in ultraviolet maxima of 2, 4-diamino-6-substituted, but not 5-substituted, pyrimidines havebeen found to have a dependence on the+ R or— R character of the substituents. Ion pair formation between certain diaminopyrimidines and divalent ions in aqueous solution has been postulated on the basis of uv studies.The 2, 4-diaminopyrimidines haveassumed an important role in the chemotherapy of infectious disease, as a result of their strong preferential binding to the enzyme dihydrofolate reductase, in competition with the substrate, dihydrofolic acid. 1 A great many com-pounds of this type have been prepared. 2 We deemed it of importance to determine the basic dissociation constants of representative 5-and 6-substituted de-rivatives, in order to analyze electronicand steric effects upon the basicities of these molecules, and pos-sible relationships to enzyme binding. Although these are complicated polyfunctional systems, it seemed possible that a relation to the Hammett substituent con-stants for the benzoic acids would develop. A fairly large number of p values have been listed
