Inclusion complexation chiral recognition mechanisms

Although the chiral recognition mechanism of these cyclodexttin-based phases is not entirely understood, thermodynamic and column capacity studies indicate that the analytes may interact with the functionalized cyclodextrins by either associating with the outside or mouth of the cyclodextrin, or by forming a more traditional inclusion complex with the cyclodextrin (122). As in the case of the metal-complex chiral stationary phase, configuration assignment is generally not possible in the absence of pure chiral standards. 

The chiral recognition mechanisms that operate on the cellulosic CSPs have been studied by Wainer and co-workers (49,50). In one study, the chiral recognition of amides on the OB CSP was examined (49), The results indicated that the solute/CSP complexes formed between the OB CSP and the amide solutes were based on attractive hydrogen bonding, ti-tt, and dipole-dipole interactions. Chiral recognition within the solute/CSP complex was due to the differential inclusion (or fit) of the solute into a chiral cavity or ravine on the CSP However, studies with aromatic alcohols... 

Most chiral HPLC analyses are performed on CSPs. General classification of CSPs and rules for which columns may be most appropriate for a given separation, based on solute structure, have been described in detail elsewhere. Nominally, CSPs fall into four primary categories (there are additional lesser used approaches) donor-acceptor (Pirkle) type, polymer-based carbohydrates, inclusion complexation type, and protein based. Examples of each CSP type, along with the proposed chiral recognition mechanism, analyte requirement(s), and mode of operation, are given in Table 3. Normal-phase operation indicates that solute elution is promoted by the addition of polar solvent, whereas in reversed-phase operation elution is promoted by a decrease in mobile-phase polarity. 

Enantiomeric resolution of solutes that fit within the molecular cavity, which is chiral, results in the formation of an inclusion complex (Ref. 169 and Fig. 4). In general, the enantiomers are separated on the basis of formation constants of the host-guest complexes. The enantiomer that forms the more stable complex has a greater migration time because of this effect. The chiral recognition mechanism for cyclodextrin enantioseparation has been discussed in several works (163-168). 

One of the most recently reported CCC chiral separations where chiral recognition occurs in the aqueous phase involves the separation of gemifloxacin enantiomers using (-(-)-(18-crown-6)-tetracarboxylic acid (I8C6H4) as CS [37]. This CS has been previously used in CE to resolve the enantiomers of chiral primary amines. The macrocyclic polyether ring in ISCeHq structure forms stable inclusion complexes with protonated primary amines. This interaction is the basis of the chiral recognition mechanism. 

Several studies demonstrated that the chiral recognition mechanism of CTB was based on the formation of inclusion complexes and, simultaneously, of hydrogen bonds between alcoholic hydrogen of the analyte and the carbonyl group of the CTB [33]. The type and shape of substituents attached to the stereogenic center strongly affected the permeability of the enantiomers into chiral cavities and, therefore, resolution. 

Mechanism of Separation. There are several requirements for chiral recognition. (/) Formation of an inclusion complex between the solute and the cydodextrin cavity is needed (4,10). This has been demonstrated by performing a normal-phase separation, eg, using hexane—isopropanol mobile phase, on a J3-CD column. The enantiomeric solute is then restricted to the outside surface of the cydodextrin cavity because the hydrophobic solvent occupies the interior of the cydodextrin. (2) The inclusion complex formed should provide a rdatively "tight fit" between the hydrophobic species and the cydodextrin cavity. This is evident by the fact that J3-CD exhibits better enantioselectivity for molecules the size of biphenyl or naphthalene than it does for smaller molecules. Smaller compounds are not as rigidly held and appear to be able to move in such a manner that they experience the same average environment. (5) The chiral center, or a substituent attached to the chiral center, must be near to and interact with the mouth of the cydodextrin cavity. When these three requirements are fulfilled the possibility of chiral recognition is favorable. 

Reaction of rac-1 -tert-buty l-3-chloroazetidin-2-one (28) with 25 gave the rac-phthalimide derivative (29). Optical resolution of rac-29 was accomplished efficiently by complexation with 15. When a solution of 15b and two molar equivalents of rac-29 in benzene-hexane (1 1) was kept at room temperature for 12 h, a crystalline 1 1 inclusion complex of 15b and (-)-29 was obtained. After one recrystallization from benzene-hexane, the crystals were chromatographed on silica gel to give pure complex consisting of (-)-29 of 100% ee in 63% yield. Decomposition of the complex with hydrazine gave optically pine (-)-3-amino- l-/m-butylazetidin-2-onc (30) in 44% yield.15 Mechanism of the precise chiral recognition between 15b and (-)-29 in their 1 1 complex was clarified by X-ray crystal structural analysis.15... 

In the optical resolution of bicyclo[2.2.1]heptanones (87a, 88-90), bicyclo[2.2.2]- octanones (91-94) and bicyclo[3.2.1]octanone (95) by complexation with various chiral host compounds, some best host-guest combinations were found. Resolutions of 88, 89, 90, and 92 were accomplished efficiently by complexation with 3 to give (+)-88 (100% ee, 33%), (-)-89 (100% ee, 16%), (+)-90 (100% ee, 60%), and (-)-92 (100% ee, 41%), respectively, in the optical and chemical yields indicated.36 However, resolutions of 93 and 95 were accomplished efficiently by complexation with 8a to give optically pure (-)-93 and (-)-95 in 56 and 48% yields, respectively. On the other hand, resolution of 94 can be accomplished only by complexation with 15c to give finally (-)-94 of 100% ee in 31% yield.36 Mechanism of these chiral recognition in the inclusion complex crystal has been studied by X-ray analysis.36 Nevertheless, none of 3,8a and 15c is applicable to the resolution... 

Pantolactone, dihydro-3-hydroxy-4//-dimethyl-2(3//)-furanone (103) which is an important starting material of the synthesis of pantothenic acid, was also easily resolved by complexation with 10a. When a solution of 10a (5.5 g, 9.93 mmol) and rac-103 (2.6 g, 20 mmol) in 1 1 benzene-hexane (20 ml) was kept at room temperature for 1 h, a 1 1 complex of 10a and (.S)-(-)- 03 was obtained, after two recrystallizations from 1 1 benzene-hexane, as colorless needles (2.05 g), which upon heating in vacuo gave (S)-(-)-103 of 99% ee (0.39 g, 30%).40 In order to clarify the mechanism of the precise chiral recognition between 10a and (S)-(-)-103, their inclusion complex crystal was studied by X-ray analysis40 and by AFM technique.41... 

Fig. 9.16. Simplified schematics illustrating two different molecular recognition mechanisms exemplified for native (i-CD and propranolol. Case A is the polar-organic phase mode where the solvent molecules occupy the cavity and the SA is bound to the outer surface of the CD via polar interactions (hydrogen bonding and/or dipole-dipole interactions) which contribute to chiral recognition in combination with steric interactions. In the reversed-phase mode, the primary binding mechanism is similar to case B SO-SA association may be driven by inclusion type complexation into the hydrophobic cavity of the CD macrocycle (reprinted with permission from Ref. [27. ]).

The primary mechanism of chiral recognition in CE in aqueous conditions seems to be inclusion complexation [464] as discussed above for CD-based CSPs under reversed-phase conditions. Moreover, one of the main advantages of CDs and CD-derived chiral selectors is that they do not carry chromogenic groups, thus being quasi-UV transparent. Therefore, there is no interference regarding detection sensitivity. 

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