The kinetics of amide bond cleavage of isatin and N-methylisatin in the presence of N,N-dimethylacetamide (DMA) was followed spectrophotometrically in the range of solvent composition (0–48.53wt.%) and temperatures (40–70°C) using piperidine as a nucleophile. The reaction was studied under pseudo-first-order kinetics. The rate of the reaction decreases largely with increasing organic solvent content. The thermodynamic activation parameters were calculated and discussed in terms of solvation of the activated complex. No linearity was observed between log rate constant and the reciprocal dielectric constant for the solvent used suggesting that there is a selective solvation by higher polar solvent (water). Finally, a mechanism for the ring opening for isatin and N-methylisatin was proposed.