Substituent effects on the pK a values and rates of hydrolysis of arylmethylene-erythromycylamines

Abstract

The pK, values and rates of hydrolysis of a series of N-benzylidene derivatives of the macrolide antibiotic, erythromycylamine (I) have been measured. Anomalies in the correlations of the pK, values with the Hammett equation and of the mechanism of hydrolysis with that of an analogous series of N-benzylidene-I ,I -dimethylethylamines have been explained in terms of steric and electronic interactions involving the macrolide ring and the unusual effect of orth omet h oxys u bs ti t u e n ts.THE mechanism of hydrolysis of Schiff's bases has been well established and reviewed by Jencks.l For subst it ut ed N-benzylidene-1,l &met h ylet hylamines ,2 the rate of hydrolysis is independent of pH under basic conditions (pH >S), a consequence of rate-determining attack of hydroxide ion on the protonated Schiff's base 2-5 which is present in low concentration. Under inore acidic conditions, in which the Schiff's bases are predominantly protonated, rate-determining attack of water, rather than hydroxide, on the protonated Schiff's base becomes the major reaction path. In strongly acidic solution, a change in the rate-determining step to elimination from the carbinolamine intermediate occurs and the rate decreases with decreasing pH.2-6 A similar rate profile is found for the hydrolysis of substituted benzylideneanilines,6-l0 but attack of hydroxide on the free imine, competes with the pH-independent reaction at high pH (> 12),6 as is also the case for salicylaldehyde derivatives. l1, l2The dibasic amine, erythromycylamine (1) (ENH,) has pK, values of 8.7 and 9~9.l~ Consequently, the concentration of free base at physiological pH is extremely small. Conversion into a Schiff's base derivative would be expected to decrease the basicity of the primary amine group and to increase the concentration