Kinetic Analysis and Mechanism of the Hydrolytic Degradation of Squaramides and Squaramic Acids

Abstract

The hydrolytic degradation of squaramides and squaramic acids, the product of partial hydrolysis of squaramides, have been evaluated by UV spectroscopy at 37°C in the pH range 3-10. In these rather smooth conditions both squaramides and squaramic acids are kinetically stable for long time periods (>100 d). The rates of the hydrolytic degradation of squaramic acids, as squaramates, have been measured at pH > 10. The hydrolysis reactions are shown to be second-order, first-order both in the squaramic acid and OH–. At the same temperature and [OH–], the hydrolysis of the bis-squaramides usually displays biphasic spectral changes (A  B  C kinetic model) with observed rate constants k1obs and k2obs that fit to and . The measured rates of the first hydrolysis step k1 (c.a. 10–4 M–1s–1) are two to three orders of magnitude faster than the second one (k2, 10–6 M–1s–1), and k2 values agree well with expectations from the previously determined rates for squaramates. Experiments at different temperatures performed for both steps in selected cases reveal a mixed thermodynamic control of the hydrolysis with H‡ ~ 9 – 18 kcal mol-1 and S‡ ~ (-5) – (-30) cal K-1 mol-1. DFT calculations show that the mechanism for the alkaline hydrolysis of squaramic acids is similar to that of amides. Firstly, hydroxide attack results in the formation of a tetrahedral intermediate, and the cleavage of the CN bond takes place in the second and rate-determining step. Notably, this latter step is assisted by the solvent and its barrier decreases significantly upon inclusion of an explicit water molecule in the calculations. Studies on a model squaramide show that the hydrolysis of each CN bond follows the same biphasic mechanism, also confirming that the first hydrolysis is significantly faster than the second one.