We report the use of cross-linked enzyme aggregates (CLEAs 1 ) to catalyse the kinetic resolution of tetralol and 1-phenylethanol in a continuous supercritical carbon dioxide (scCO 2 ) system. We describe the performance of the CLEA from Candida antarctica lipase B (CALB) and compare this to the catalytic activity of Novozym 435 (CALB immobilised on a macroporous acrylic resin). In addition, we report a two-stage reaction with the kinetic resolution of 1-phenylethanol performed in series with the metal (Pd) catalysed hydrogenation of acetophenone. Reactions performed in series have a potential economic advantage as the second, and subsequent reactions do not require additional expenditure of energy for re-pressurization of solvent.

Continuous hydrogenation in supercritical fluids has been shown to be a technically viable alternative to traditional batch-wise methodologies. Clearly, the next stage of development of this technology is the application of immobilised enantioselective catalysis in the preparation of optically active products. Enantioselective hydrogenation has been successfully carried out in supercritical carbon dioxide using batchtype reactors but has yet to be efficiently carried out continuously. Here we examine an established method of catalyst immobilisation and demonstrate its suitability for application in continuous reactors using supercritical carbon dioxide as solvent.

Continuous flow supercritical carbon dioxide (scCO 2 ) has previously been shown (P. Stephenson, P. Licence, S. K. Ross, M. Poliakoff, Green Chem. 2004, 6, 521) to be a viable medium for conducting continuous asymmetric hydrogenation when it is combined with an appropriate enantioselective catalyst. Here we examine the use of a composite catalyst immobilisation system modified with several different types of asymmetric bisphosphine ligands in continuous flow scCO 2 . In particular, proprietary ligands from Solvias AG were found to be the most successful, with Josiphos 001 improving the enantiomeric excess (ee) to> 80 % in the asymmetric hydrogenation of dimethyl itaconate (DMIT); this ee is higher than that reported for the batch hydrogenation of DMIT using a homogeneous catalyst fully dissolved in scCO 2 (S. Lange, A. Brinkmann, P. Trautner, K. Woelk, J. Bargon, W. Leitner, Chirality 2000, 12, 450).

A new approach for optimization and monitoring of continuous reactions has been developed using 2D correlation methods for the analysis of GC data (2DCOR-GC). 2DCOR-GC maps are obtained following perturbation of the system that allow the effect of changing reaction parameters such as time, temperature, pressure, or concentration to be both monitored and sequenced with regard to changes in the raw GC data. In this paper, we describe the application of the 2DCOR-GC technique to monitoring the reverse water-gas shift reaction in scCO(2). 2DCOR-GC is combined with FT-IR data to validate the methodology. We also report the application of 2DCOR-GC to probe the mechanism of the alkylation of m-cresol with isopropyl alcohol in scCO(2) using Nafion SAC-13 as the catalyst. These results identify coeluting peaks that could easily be missed without exhaustive method development.