In Silico Prediction of Medium Effects on Esterification Equilibrium Using the COSMO-RS Method

Abstract

This paper presents a new approach for predicting solvent effects on esterification reactions of industrial importance in the field of biocatalysis. The COSMO-RS method has been used to calculate the activity coefficients of the chemical species involved in various reactions, carried out in different solvents. For comparison we also used the traditional UNIFAC method. Three lipase-catalyzed esterifications were considered: (1) 1-dodecanoic acid with menthol in n-hexane, n-heptane, cyclohexane, 2,2,4-trimethylpentane, toluene, acetonitrile, and 2-methyl-2-butanol; (2) 1-dodecanoic acid and 1-dodecanol in n-hexane, n-heptane, cyclohexane, 2,2,4-trimethylpentane, and toluene; and (3) glycerol and n-octanoic acid in acetonitrile, benzene, and toluene and in the neat reaction mixture (without any solvent). Predicted activities were used to calculate the thermodynamic equilibrium ratio. This should be independent of medium, and the variation in COSMO-RS values is at most 9-fold (corresponding to a DeltaG degrees of about 5.5 kJ/mol, which would still be a very useful prediction) and often only 2-fold (corresponding to less than 2 kJ/mol or 0.5 kcal/mol, therefore comparable with experimental error). UNIFAC is weaker, especially when important roles are played by conformational freedom, intramolecular interactions, strong polar effects, and charge distribution of molecules in the mixture. The relative percent deviations from the mean of equilibrium constants in different solvents range between 17 and 49 for COSMO-RS versus 32 to 65 for UNIFAC. The COSMO-RS method opens up new perspectives for the development of theoretical models for solvent selection with general applicability.

Thermodynamical Methods for the Optimization of Lipase-Catalyzed Reactions

“…This method, combining ab initio quantum chemical calculations of solutes and solvents with an effi cient statistical thermodynamics, results in a powerful predictive tool for estimating many thermodynamic properties ( 25 ) . The control of the thermodynamic equilibrium position in biocatalytic processes has been used as a model for evaluating COSMO-RS and comparing it with classical UNIFAC contribution group method ( 4 ) . In this sense, three different lipase-catalyzed esterifi cations were evaluated in different media.…”

“…Actually, thanks to the remarkable properties and useful applications of enzymatic catalysis in nonconventional media, this area of modern biotechnology has turned into a valuable tool for the industrial production of fi ne chemicals ( 4 ) . Among other interesting advantages, the use of nonconventional media in biocatalysis facilitates the solubility of nonpolar substrates and the recovery of products, reduces water-dependent side reactions, and promotes the shift of thermodynamic equilibria favoring the synthesis over the hydrolysis ( 5 ) .…”

“…It is worth mentioning that, when hydrolases are used as biocatalysts in organic media, the position of thermodynamic equilibria may be altered not only favoring synthesis, but also inhibiting sequential reactions or side reactions (i.e., hydrolysis, degree of acylation, and chemoselectivity) ( 11,(13)(14)(15)(16) . In other words, contrary to kinetically controlled chemical transformations, most of these enzymecatalyzed processes carried out at mild conditions are generally controlled by the position of thermodynamic equilibrium ( 4 ) .…”

“…The control of the position of thermodynamic equilibrium in lipasecatalyzed reactions has resulted as a very useful tool for enhancing the yields of esterifi cation and transesterifi cation reactions, controlling the degree of acylation or regioselectivity on polyfunctional molecules, and handling chemoselectivity ( 4,11,(13)(14)(15)(17)(18)(19)(20)(21)(22)(23) . In this sense, it has been a common practice in nonaqueous biocatalysis to associate some general properties of solvents with the thermodynamic equilibrium position of different reactions.…”

Measurement and prediction of solvent effect on enzymatic esterification reactions

“…As a result COSMO-RS does not depend on experimental data or any parametrization for the solvent so it efficiently enables the calculation of the chemical potential of almost any solute is almost any solvent. Fermeglia et al [22] have evaluated COCMO-RS and UNIFAC in the prediction of solvent effect on the equilibrium position for a series of lipase-catalyzed esterification reactions concluded that COSMO-RS method is very accurate and superior to UNIFAC.…”