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

The pKa 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 pKa values with the Hammett equation and of the mechanism of hydrolysis with that of an analogous series of N-benzylidene-1,1-dimethylethylamines have been explained in terms of steric and electronic interactions involving the macrolide ring and the unusual effect of ortho-methoxy-substituents.