Modelling multiple chemical equilbria in chiral partition systems

Ligand-exchange chiral extraction (LEXCEX) is an emerging technology for la rge-scale continuous resolution of enantiomers of amino acids and a wide ra nge of chiral therapeutics and drug precursors. LEXCEX is based on the abil ity of a chiral ligand (Li), solubilized in the non-aqueous phase of a wate r/alcohol two-phase system through complexation with a transition metal ion (i.e., Cu), to preferentially extract one enantiomer (En) into the organic phase through formation of a ternary Li: Cu: En electroneutral complex. He re we show that the efficiency of the extraction depends, often strongly, o n a number of process variables, including the selectivity of the ligand, t he solubility of the enantiomers and complexes containing them in the organ ic phase, pH and transition-metal ion (Cu) concentration. Phase-equilibria in LEXCEX systems is governed by the complex chemical equilibria in both th e aqueous and organic phases, To better understand this extraction process, we develop a model for ligand-exchange chiral extraction which couples a c omplete description of chemical equilibria in each phase with the overall p hase equilibria of the system. The model requires the complete set of proto nation constants and binary and ternary formation constants for each specie s present in either the aqueous or organic phase. When coupled with phase e quilibrium constraints, the model quantitatively predicts extraction perfor mance as a function of key operating parameters, thereby providing a simple computational approach to process optimization. Measured equilibrium forma tion constants for ternary complexes containing the N-decyl-L-hydropxy-prol ine ligand are found to depend strongly on solvent environment, with comple x stabilities in general decreasing when the complex is transferred from wa ter to n-octanol. The role of solvent in ternary complex stability is explo red through a series of molecular mechanics simulations. (C) 2001 Elsevier Science Ltd. All rights reserved.