Racemization and hydrolysis of (S)-naproxen 2,2,2-trifluoroethyl ester in non-polar solvents by strong neutral bases: Implication for ion-pair kinetic basicity and hydrolysis

By using strong neutral bases as catalyst, a detailed investigation of the racemization of (S)-naproxen 2,2,2-trifluoroethyl ester was conducted in the non-polar solvents isooctane, cyclohexane and n-hexane. The second-order interconversion constant k_int* as representing the ion-pair kinetic basicity in isooctane was first estimated and correlated with the equilibrium ion-pair basicity pK_ip in tetrahydrofuran, giving slopes of 0.768 and 0.689 for non-phosphazene and phosphazene bases, respectively, in the Brønsted correlations. The result was further compared with that for (S)-naproxen 2,2,2-trifluoroethyl thioester, showing about a 1-2 orders of magnitude enhancement of k_int* for the corresponding thio-containing analogue. A smaller influence of non-polar solvents (i.e. isooctane, n-hexane and cyclohexane) on k_int* was found. Kinetic analysis of the racemization and hydrolysis of (S)-naproxen 2,2,2-trifluoroethyl ester in isooctane and n-hexane containing 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene and water suggests nucleophilic hydrolysis by the base, where the breakdown of tetrahedral intermediates I _R1 and I_S1 is the rate-limiting step and the hydrolysis constant k_hy is in proportion to the product of base and ion-pair concentrations.