Inclusion complexes, modified cyclodextrins

Cyclodextrins are cyclic oligosaccharides forming inclusion complexes with a wide variety of organic and inorganic compounds. The formation of inclusion complexes modifies the physicochemical parameters of the guest molecule, resulting in modified retention behavior. The aims of this entry are to provide a short overview of the chemistry and physicochemistry of cyclodextrins and of their applicatiou for improving separatioD, with special emphasis on the separation of enantiomer pairs of pharmaceuticals and euvirou-meutal pollutauts. 

Immobilization. The abiUty of cyclodextrins to form inclusion complexes selectively with a wide variety of guest molecules or ions is well known (1,2) (see INCLUSION COMPOUNDS). Cyclodextrins immobilized on appropriate supports are used in high performance Hquid chromatography (hplc) to separate optical isomers. Immobilization of cyclodextrin on a soHd support offers several advantages over use as a mobile-phase modifier. For example, as a mobile-phase additive, P-cyclodextrin has a relatively low solubiUty. The cost of y- or a-cyclodextrin is high. Furthermore, when employed in thin-layer chromatography (tic) and hplc, cyclodextrin mobile phases usually produce relatively poor efficiencies. 

The theory and development of a solvent-extraction scheme for polynuclear aromatic hydrocarbons (PAHs) is described. The use of y-cyclodextrin (CDx) as an aqueous phase modifier makes this scheme unique since it allows for the extraction of PAHs from ether to the aqueous phase. Generally, the extraction of PAHS into water is not feasible due to the low solubility of these compounds in aqueous media. Water-soluble cyclodextrins, which act as hosts in the formation of inclusion complexes, promote this type of extraction by partitioning PAHs into the aqueous phase through the formation of complexes. The stereoselective nature of CDx inclusion-complex formation enhances the separation of different sized PAH molecules present in a mixture. For example, perylene is extracted into the aqueous phase from an organic phase anthracene-perylene mixture in the presence of CDx modifier. Extraction results for a variety of PAHs are presented, and the potential of this method for separation of more complex mixtures is discussed. 

These interesting results are attributed to the formation of an alkene/ cyclodextrin inclusion complex as well as the solubility of the chemically modified cyclodextrin in both phases. Prior to this study, hydroformylation in the presence of unmodified cyclodextrins had been studied by Jackson, but the results were rather disappointing.174... 

Monflier and co-workers recently described a new approach based on the use of chemically modified /3-cyclodextrins to peform efficiently the functionalization of water-insoluble olefins in a two-phase system. These compounds behave as inverse phase transfer catalysis, i.e., they transfer olefins into the aqueous phase via the formation of inclusion complexes.322... 

Decene was hydrocarboxylated with a [PdClaj/TPPTS catalyst in acidic aqueous solutions (pH adjusted to 1.8) in the presence of various chemically modified cyclodextrins (Scheme 10.11) [18]. As in most cases, the best results were obtained with DiOMe-P-CD. In an interesting series of reactions 1-decene was hydrocarboxylated in 50 50 mixtures with other compounds. Although all additives decreased somewhat the rate of 1-decene hydroformylation, the order of this inhibitory effect was 1,3,5-trimethylbenzene < cumene < undecanoic acid, which corresponds to the order of the increasing stability of the inclusion complexes of additives with p-CD, at least for 1,3,5-trimethylbenzene (60 M ) and cumene (1200 M ). These results clearly show the possible effect of competition of the various components in the reaction mixture for the cyclodextrin. 

The milder metal hydride reagents are also used in stereoselective reductions Inclusion complexes of amine-borane reagent with cyclodextrins reduce ketones to optically active alcohols, sometimes in modest enantiomeric excess [59] (equation 48). Diisobutylaluminum hydride modified by zmc broniidc-iV./V.A V -tetra-methylethylenediamine (TMEDA) reduces a,a-difluoro-(3-hydroxy ketones to give predominantly erythro-2,2-difluoro-l,3-diols [60] (equation 49). The threo isomers arc formed on reduction with aluminum isopropoxide... 

Electrostatic self-assembly was combined with supramolecular chemistry to obtain inclusion complexes of a polymeric nonlinear optical (NLO) active dye and modified [3-cyclodextrin with induced chromophore orientation [37], The polyanion is a N,N-diallyl-aniline and sodium-2-acrylamido-2-methylpropanesulfonate copolymer functionalized with pendant azo group. The modified /i-cyclodextrin oligo-cation was obtained by treatment of hcptakis(6-dco y-6-iodo-/i-cyclodcxtrin) with excess pyridine. A linear polyamine, chitosan, was also combined with the polyanion, for comparison. Films were deposited on glass slides by dipping them alternatively in aqueous solutions of the cation and the polyanion. UV-visible spectra indicate dye aggregation and suggest the formation of an inclusion complex of the dye with the cyclodextrin, thus isolating the chromophores. 

Inclusion properties of molecular nanotubes composed of crosslinked a-cyclodextrin was investigated [47], Induced circular dichroism was used to probe the formation and dissociation of complexes between the nanotubes and azobenzene modified polyethylene glycol), either with or without a hydrophobic alkyl chain. The inclusion complex between the nanotubes and polymers formed at room temperature, and the polymers dissociated from the nanotubes with increasing temperature. 

The inclusion complexation of spiropyrans in cyclodextrins has also been explored as a means to control photochromic reactions.1591 Distinct differences in complexation of sulfonic acid-modified spiropyrans to various cyclodextrins were observed and the closed spiropyran form bound to (3-cyclodextrin was stable towards photochemical ring-opening. 

Cyclodextrins have been covalently modified for catalytic oxidation, such as compounds 57, 62-65 (Schemes 3.14 to 3.16) [44, 45]. Enantioselective epoxidation of styrene derivatives, and carene using 20-100 mol% of the CD-ketoester 57 has been achieved. The inclusion-complex formation was confirmed by aH NMR titration experiments, confirming the 1 1 substrate catalyst stoichiometry under the reaction conditions. In the oxidation of carene, NOE and ROESY experiments showed different behavior according to the size of the R group (Scheme 13.14). Evidence was found for the formation of inclusion complexes with compounds 58 and 59. On the other hand, compounds 60 and 61 proved to interact with the catalyst via a tail inclusion vide infra). The increased diastereoselectivity observed with compounds 58 and 59 might be explained by a closer proximity to the covalently linked dioxirane. 

The rigid structure of the cyclodextrin host results in well defined but different inclusion and interaction patterns for any potential guest molecule. Treating a mixture of compounds with a dissolved or solid, immobilized CD, leads to the formation of inclusion complexes of different stability and solubility. Consequently separations can be based either on strongly modified solubility in water of the CD-complex of a certain component, or on the... 

The use of cyclodextrins as the mobile phase components which impart stereoselectivity to reversed phase high performance liquid chromatography (RP-HPLC) systems are surveyed. The exemplary separations of structural and geometrical isomers are presented as well as the resolution of some enantiomeric compounds. A simplified scheme of the separation process occurring in RP-HPLC system modified by cyclodextrin is discussed and equations which relate the capacity factors of solutes to cyclodextrin concentration are given. The results are considered in the light of two phenomena influencing separation processes adsorption of inclusion complexes on stationary phase and complexation of solutes in the bulk mobile phase solution. 

Cyclodextrins can form inclusion complexes with some drugs, modifying their physical and chemical properties. Because cyclodextrins are mainly used to increase the solubility of poorly soluble drugs, most investigations in this field focus on photostability of drugs in solution. Here, the positive effect of cyclodextrins on the photostability of colchicine (36), emetine and cephaeline (37) could be shown. However, these results show that the photoprotective effect depends on the particular cyclodextrin used. For some forms of cyclodextrin, an increase of the photodegradation rate can be obtained, as the example of molsidomine shows (13). 

The separation selectivity often can be modified by adding to the mobile phase reagents that form complexes with the separated solutes and affect the retention and the selectivity of separation as a result of competing complexing equilibria [68]. Addition of crown ethers to the mobile phase can be used to form selective complexes with molecules or ions whose dimensions correspond to the inner cavity in the crown ether molecule [69]. Similarly, formation of inclusion complexes with p- or y-cyclodextrin added to the mobile phase can be utilised to improve the separation of both geometric and optical isomers [70,71 ]. 

If an achiral ferrocene derivative is converted to a chiral one by chiral reagents or catalysts, this may be called an asymmetric synthesis. All asymmetric syntheses of ferrocene derivatives known so far are reductions of ferrocenyl ketones or aldehydes to chiral secondary alcohols. Early attempts to reduce benzoylferrocene by the Clemmensen procedure in (5)-l-methoxy-2-methylbutane as chiral solvent led to complex mixtures of products with low enantiomeric excess [65]. With (25, 3R)-4-dimethylamino-l,2-diphenyl-3-methyl-2-butanol as chiral modifier for the LiAlH4 reducing agent, the desired alcohol was formed with 53% ee (Fig. 4-9 a) [66]. An even better chiral ligand for LiAlH4 is natural quinine, which allows enantioselective reduction of several ferrocenyl ketones with up to 80% ee [67]. Inclusion complexes of ferrocenyl ketones with cyclodextrins can be reduced by NaBH4 with up to 84% enantioselectivity (Fig. 4-9 b) [68 — 70]. 

Table 1.1 shows a selection of catalysts developed in 2006-2007, which operate under biphasic aqueous conditions. For previous literature, readers are directed to an excellent review by List and co-workers.In terms of catalyst performance, since 2006 most of the best achievements have been reported for (9-modified Z/Y///A-4-hydroxy-i -prolinc derivatives 3-5, including the inclusion complex 6 of a proline derivative and a P-cyclodextrin, or catalysts consisting of chiral amines 7 and 8 or (thio)amides 9-14 derived from L-proline. The O-protected serine 15a, threonine 15b and threonine amide 16 complete the list of catalysts. 

The best results in terms of activity have been obtained with cationic surfactants such as octadecyltrimethylammonium bromide. The normal to branched (njiso) aldehydes ratio was found to be very dependent on the nature of the surfactant. For example, methyl 9-decenoate hydroformylation gave methyl 11-formylunde-canoate with an n/iso aldehydes ratio of 6.1 1, 4.0 1, 2.3 1 and with anionic, amphophilic, and cationic surfactants, respectively. Interestingly, hydroformylation of this substrate has also been achieved successfully with inverse-phase transfer catalysts such as chemically modified /l-cyclodcxtrins. In this approach, the cyclodextrin forms an inclusion complex with methyl 9-decenoate and transfers the alkene into the aqueous phase. Under optimal conditions, the aldehydes are obtained in a 100% yield and in an n/iso aldehydes ratio of 2.3 1 [10]. 

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