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

Abstract

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 $k^*_{\rm int}$ as representing the ion‐pair kinetic basicity in isooctane was first estimated and correlated with the equilibrium ion‐pair basicity pKip 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 $k^*_{\rm int}$ for the corresponding thio‐containing analogue. A smaller influence of non‐polar solvents (i.e. isooctane, n‐hexane and cyclohexane) on $k^*_{\rm int}$ 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 IR1 and IS1 is the rate‐limiting step and the hydrolysis constant khy is in proportion to the product of base and ion‐pair concentrations. Copyright © 2004 John Wiley & Sons, Ltd.

Rapid Base-Catalyzed Racemization of (R)-Ibuprofen Ester in Isooctane–Dimethyl Sulfoxide Medium with Improved Kinetic Model

“…In addition, a hydrolysis reaction also takes place in the presence of water and strong base, competing over the racemization reaction. 7 This result is in agreement with the investigation carried out by Chavez-Flores and co-worker, where in situ racemization was not observed in the presence of an aqueous buffer solution. 4 From Table 1, it can be observed that the racemization progresses slowly in both isooctane and isooctane−water media with interconversion rate, k int of less than 0.001 h −1 .…”

“…In the case of isooctane–water medium, the OH – ion could easily dissociate in the aqueous phase; however, a poor racemization rate of the ( R )-ibuprofen ester was still observed. In addition, a hydrolysis reaction also takes place in the presence of water and strong base, competing over the racemization reaction . This result is in agreement with the investigation carried out by Chavez-Flores and co-worker, where in situ racemization was not observed in the presence of an aqueous buffer solution …”

Lipase‐catalyzed dynamic hydrolytic resolution of (R,S)‐2,2,2‐trifluoroethyl α‐chlorophenyl acetate in water‐saturated isooctane

“…In comparison with k int = 0.362 h −1 for α‐chlorophenyl acetate at 35 °C, smaller interconversion constants 1.28 × 10 −2 h −1 for the racemization of ( R )‐2,2,2‐trifluoroethyl α‐phenylpropionic thioester and 7.47 × 10 −5 h −1 for that of ( R )‐2,2,2‐trifluoroethyl naproxen ester in isooctane containing ( B ) = 100 mmol dm −3 at 45 °C have been reported 19, 20. This implies that the electron‐withdrawing strength of α‐chloro moiety is much higher than that of 2,2,2‐trifluorothioethyl, 2,2,2‐trifluoroethyl or α‐methyl group in affecting rate‐limiting α‐proton abstraction to form a planar enolate for racemization.…”