Crystallization of Supramolecular Complexes as an Alternative Route for the Separation of Racemic p-X-Phenylethanol By Arnaud Grandeury , SØverine Tisse, GØraldine Gouhier, ValØrie Agasse, Samuel Petit*, and GØrard Coquerel A partial chiral discrimination of racemic p-halogenated derivatives of phenylethanol is observed during the crystallization in water of host-guest supramolecular compounds with permethylated b-cyclodextrin. Enantioenrichment with this chiral host is however highly sensitive to crystallization durations and to the chemical nature of the halogenated substituent of the guest. Structural determinations performed for the complexes formed with (R) and (S) p-bromo-phenylethanol indicate that stereodifferenciation for this guest is associated to distinct inclusion features. The understanding of the underlying chiral recognition mechanisms, the careful design of suitable crystallization conditions, and the use of a procedure involving successive crystallizations allows to envisage a complete resolution of racemic mixtures by means of supramolecular complexations. 1 Introduction The two enantiomers of a chiral compound exhibit different vectorial properties and can present specific activities, in particular in the frame of interactions with biological systems. It is therefore necessary, for potential applications in fine chemicals or pharmaceutical industries, to obtain enantio- merically pure substances, either by performing asymmetric syntheses, or by resolving (separating) racemic mixtures [1]. However, asymmetric syntheses, performed by chemical or enzymatic procedures, have often difficulties, and resolutions by means of large scale chromatographic methods are usually expensive. Therefore, the most convenient and cheapest methods for preparative resolutions consist of crystallization procedures, either through the formation of diastereomeric salts or, in case of racemic mixture crystallizing as a conglomerate (i.e., a physical mixture of enantiomerically pure particles), by means of preferential crystallization [2±4]. An alternative route, which has not yet received the interest that deserves, consists of the crystallization of host-guest supramolecular complexes formed with a chiral host [5,6]. In order to use this method at a preparative scale, several conditions should be fulfilled: (i) sufficient quantities of the host should be available for crystallization experiments in routine conditions, (ii) the obtained supramolecular complex- es should present suitable stabilities and solubilities for an easy separation from the growth medium, i.e., the mother liquor, (iii) the specific interactions between the chiral host and the two guest enantiomers should induce significant differences in terms of physical properties (mainly solubi- lities) of the two diastereomeric compounds, so that separa- tion can be easily achieved, (iv) the release of the guest and the host should be easy to perform. The first of these four conditions is fulfilled in the case of b- cyclodextrin (b-CD) since the latter is easily produced by enzymatic degradation of starch [7,8]. As the other cyclodex- trins, this compound is made of the macrocyclic association of seven a (1®4)-linked glucopyranose units, and is therefore enantiomerically pure. Furthermore, the presence of numer- ous hydroxy groups induces that it can be chemically modified [9], and several derivatives of b-CD are widely used in the food and pharmaceutical industries for various applications such as protection against chemical degradation, enhancement of solubility, increase of bioavailability, protection against repulsive taste of drugs, etc. [10]. These properties are assumed to be a consequence of the ability of native or modified b-CDs to form supramolecular associations of the host-guest type in aqueous medium. Indeed, these macro- cycles have the shape of truncated cones and usually exhibit a hydrophobic cavity in which some organic compounds can be at least partially engulfed in order to avoid direct interactions with water. b-CD and several of its derivatives are also widely used as chiral selectors for analytical applications in chroma- tography and capillary electrophoresis [11,12]. One of the most famous b-CD derivatives is the trimethy- lated b-CD (heptakis(2,3,6-tri-O-methyl)-b-CD, TMb-CD hereafter, Fig. 1a, and is known to be an efficient selector in chiral gas chromatography [11]. As other permethylated CDs, this compound exhibits specific properties in terms of molecular conformation and solubility. Indeed, the macro- cyclic ring is strongly distorted because of steric hindrances induced by the methoxy groups and the inability to form 354 Ó 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim 0930-7516/03/0303-00354 $ 17.50+.50/0 Chem. Eng. Technol. 26 (2003) 3 ± [*] A. Grandeury, S. Tisse, V. Agasse, S. Petit (e-mail: samuel.petit@univ- rouen.fr), GØrard Coquerel, UnitØ de Croissance Cristalline, de Chroma- tographie et de ModØlisation MolØculaire (UC 3 M 2 ), Sciences et MØthodes SØparatives (SMS), UPRES EA 2659; G. Gouhier, Laboratoire des Fonctions AzotØes et OxygØnØes Complexes, UMR 6014, IRCOF ± UniversitØ de Rouen, F-76821 Mont Saint-Aignan Cedex, France. X = H, F, Cl, Br, I OH X * OMe OMe O O O OMe 7 a b Figure 1. Molecular structures of trimethylated b-cyclodextrin (TMb-CD, a) and p-halogenophenylethanol (b). 0930-7516/03/0303-0354 $ 17.50+.50/0 Full Paper