Selectivity and Enantiomeric Resolution in Inclusion Chemistry: A

Mar 17, 2010 - We then measured the enantiomeric selectivity of this host for ... by repeating the competition experiments with a related chiral host...
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DOI: 10.1021/cg901461k

Selectivity and Enantiomeric Resolution in Inclusion Chemistry: A Systematic Study of Chiral Discrimination through Crystallization

2010, Vol. 10 1782–1787

Nikoletta B. Bathori and Luigi R. Nassimbeni* Centre for Supramolecular Chemistry Research, Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7701, South Africa Received November 23, 2009; Revised Manuscript Received January 27, 2010

ABSTRACT: The mechanism of enantiomeric resolution of 2-butylamine has been elucidated by employing a chiral host which enclathrated (R)- and (S)-2-butylamine in different proportions. We first measured the selectivity curve for a mixture of pyridine and morpholine, whose proportions in the crystals were determined by the refinement of single crystal X-ray structure determination and independently by 1H NMR spectroscopy and showed that X-ray diffraction is a robust and accurate method for determining the composition of mixed guests. We then measured the enantiomeric selectivity of this host for 2-butylamine and found correlation between selectivity, the torsional flexibility of the phenyl moieties of the host, and the concomitant remaining volume that accommodates the guest. This mechanism was confirmed by repeating the competition experiments with a related chiral host.

1. Introduction Chirality is an important aspect of biological activity, because the process of molecular recognition between the receptor sites on a protein, which is homochiral, and a substrate molecule is stereochemically controlled. This phenomenon has wide applicability and is pertinent to the use of many bioactive substances such as drugs, herbicides, food additives, and insecticides. Thus, the methods of enantiomeric resolution have been studied extensively and involve the process of spontaneous resolution by crystallization, diastereomer formation, enzymatic transformations, and chromatographic methods.1-3 Inclusion chemistry using chiral host compounds has also proved to be a useful technique for resolving enantiomers, and cyclodextrins, deoxycholic acid, urea and triortho-thymotide are among the hosts that have been employed for this purpose.4 Cram has devised an enantiomer-resolving machine5 in which he employed chiral coronands to resolve amino acids. Bishop has shown that a bicyclononanediol can be crystallized as a conglomerate and the individual crystals dissolved, the optical rotation recorded, and the ensuing laevo- and dextro-rotatory solutions separately accumulated.6 There are many examples of structural studies of diastereomeric salts, such as those formed by the Chinchona alkaloids with mandelic acids.7-9 Dielectric controlled resolution has been employed to resolve amines.10,11 Price has employed thermal, solubility, and solution calorimetry measurements to determine the relative stabilities of diastereomeric salts and used lattice energies to formulate predictive models.12 Studies in solution and in the solid state were also carried out by Arnett, who studied ion pair formation by NMR spectroscopy.13 An important contribution to diastereomeric salt formation is the discovery by Vries et al. who used a combinatorial approach of related “families” of resolving agents to obtain improved resolution of racemates,14 and the announcement of the “Rule of Reversal” by Addadi and *Corresponding author. Tel: þ27(21)650 5893; fax: þ27(21)650 5419; e-mail: [email protected]. pubs.acs.org/crystal

Published on Web 03/17/2010

Scheme 1. Structural Formulas of the Host and Guest Molecules

Lahav15 who used tailor-made impurities to achieve successful resolutions. Paradoxically, one obtains more information regarding the resolution process when the selectivity is relatively poor and the targeted (R)- and (S)-enantiomers are both entrapped in the same crystal, although in different proportions. In this manner, one can assess the forces that impinge on both guests as they are entrapped in the crystal structure and the resultant conformation changes that occur in the host in order to best accommodate these guests. To our knowledge, no detailed study of the correlation between structure in the solid state and enantiomeric resolution has been carried out. We have therefore employed the two hosts, (R,R)-(-)-trans-2,3-bis(hydroxydiphenylmethyl)1,4-dioxaspiro(4.5)decane (H1) and (R,R)-(-)-trans-4,5-bis(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane (H2), to carry out a series of competition experiments in order to measure the selectivity between two similar guests, pyridine and morpholine, and for the enantiomeric resolution of 2-butylamine, in order to understand the mechanism of this process (Scheme 1). r 2010 American Chemical Society

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Figure 1. (a) Selectivity curve for the H1 3 (PYR)/(MOR) system (Series I). (b) View of structure 5, representative of the system. Note the intramolecular hydrogen bond and the two guests occupying the same site. (c) Correlation of guest mole fraction as measured by NMR and X-ray structure refinement.

Figure 2. Selectivity curves for Series II, H1 3 (R)/(S)BUAM, (a) overall selectivity, (b) and (c) selectivity for molecules 1 and 2, respectively.

When analyzing the preference of a host compound for a particular guest in a crystalline inclusion complex, it is convenient to use the idea of the selectivity coefficient, defined for a particular host and two guests A and B as ðXA þ XB ¼ 1Þ KA:B ¼ ðKB:A Þ -1 ¼ ZA =ZB XB =XA where XA, XB are the mole fractions of A and B in the

liquid mixture, and ZA, ZB are their mole fractions in the crystal.16 The selectivities are determined by competition experiments, in which the host compound is added to a series of guest mixtures of known composition, and the ensuing crystals are analyzed by a suitable analytical technique. Details of the method have been previously described.17

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Figure 3. Series II. (a) Variation of H1 torsion angles for molecule 1. (b) Conformation in 2-butylamine guests for molecule 1. (c) and (d) as above for molecule 2 (sp = synperiplanar, sc = synclinal, ac = anticlinal, ap = antiperiplanar).

2. Results and Discussion We have determined the selectivity profile of H1 in mixtures of pyridine and morpholine. The result is shown in Figure 1a, in which we note that the host preferentially enclathrates pyridine over morpholine for the whole competition range with a low selectivity coefficient KPYR:MOR = 1.4. We carried out a series of crystal structure analyses of the complete range of compounds H1 3 ZPYR 3 (1-Z)MOR (Series I). The crystals are isostructural with regard to the host atomic positions, while the two guests share the same site with varying occupancy factors. The host molecule displays a constant conformation which is governed

by an intramolecular O-H 3 3 3 O hydrogen bond, while the second hydroxyl moiety acts as a hydrogen bond donor to the guest, as shown in Figure 1b. The value of Z, the mole fraction of a given guest in the crystal, was measured by 1H NMR spectroscopy and independently by refinement of the crystal structures, all of which were carried out at 173 K. The two analytical methods of mole fraction determination are compared in Figure 1c, which shows a high correlation (rZMOR,XRD; ZMOR,NMR = 0.997) and established that single crystal structure refinement was a satisfactory method of determining mixed guest composition. Details of the competition experiments for Series I are given in tables in the Supporting Information.

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The host H1 was then employed to measure the enantiomeric proportion of 2-butylamine. We dissolved a fixed quantity of host H1 in mixtures of (R)- and (S)-2-butylamine of known composition, with the mole fraction of the (R)-enantiomer varying from 0 to 1. The ensuing crystals (10) were all subjected to structure analysis at 173 K (Series II). The structures crystallized in either P21 or P1 with similar unit cell dimensions and host/guest ratios of 1:1. We noted that the conformation of H1 was governed by the intramolecular hydrogen bond (O2-H2 3 3 3 N(H2)), the four torsion angles of the phenyl rings (τ1-τ4), and the torsion angle which describes the twist of the cyclohexyl moiety (τ5). The intramolecular hydrogen bond is virtually constant with dO 3 3 3 O ranging from 2.63 to 2.68 A˚. Similarly the O-H 3 3 3 N(H2) hydrogen bonds are practically invariant, with dO 3 3 3 N ranging from 2.66 to 2.85 A˚. In the case of the P1 structures, there are two crystallographically independent host molecules and two independent sites at which the mixtures of (R)- and (S)-2-butylamine guest are located. We have therefore represented the overall averaged selectivity curve in Figure 2a, which displays a concentration dependent selectivity, and note that the racemic guest mixture XR = XS = 0.5 yielded ZR = 0.60, which corresponds to an enantiomeric excess of 20%. The crystallographically independent molecules, however, display selectivities that are remarkably different, and are represented by Figure 2b,c. Molecule 1 (Figure 2b) shows increased discrimination beyond XR = 0.33, so that structures 5 and 6 have ZR = 0.85 and 0.94, respectively. Beyond XR = 0.67, ZR = 1, which represents total selectivity. Figure 3a shows the values of the five torsion angles that characterize the conformation of the host. We note practically no change in structures 1-4, but significant changes beyond structure 4. There are notable changes in τ1 (-8° to -26°), τ3 (-20° to -7°), and smaller changes in τ2 and τ4. There is a large change in τ5 (-70° to -175°), related to the flip of the cyclohexyl moiety. The corresponding torsion angles of the guests (alkyl backbone) are shown in Figure 3b, where the conformations of the entrapped guests are described for both the (S)- and (R)-enantiomer. The (R)-enantiomer, occurring in structures 3-10, is always in the trans-configuration, while for the (S)-enantiomer it is more variable, with the trans-configuration occurring in structures 1-4 and 7-10, and torsion angles of -152° and -140° in structures 5 and 6. The guest site for molecule 2, however, is a less efficient discriminator. Figure 2c shows that the selectivity curve is closer to the diagonal line, and shows a small preference for the (S)-enantiomer. The host torsion angle changes in Figure 3c display a significant change in τ3 (-20° to -8°), smaller changes for τ1, τ2, and τ4, but τ5 changes dramatically as before. The conformation of the 2-butylamine guest is now more variable (Figure 3d). Structures 1-4 are identical to those in molecule 1 (P21 structures, Z = 1), but the conformation of the 2-butylamine guest for structures 5-10 is now scattered. The (S)-enantiomer has a cluster of gaucheconformations with the torsion angle of the alkyl backbone ≈ þ60° (structures 5, 6, 7, and 8) and three structures with the alkyl backbone torsion angle at ≈ -120° (structures 5, 7, and 9), while structure 6 also displays a torsion angle ≈ -1.9°. The (R)-enantiomer is equally scattered, with large variabilities in structures 5, 6, and 8, and a cluster in the trans-conformation (structures 7-10). It is interesting to note that the space available for the guests, which are generally disordered, correlates with the

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Figure 4. Packing in structure 5, representative of Series II (structures 5-10). Guest accessible voids are represented in gray. View along [100].

selectivity of the host. We have mapped the guest accessible space employing the program MSRoll,18 using a spherical probe of radius 1.4 A˚, and found significantly different results for molecules 1 and 2. For structures 1-4, this has an averaged value of 178 A˚3, while for structures 5-10 it takes on values of 167 A˚3 for molecule 1. For molecule 2, the guest volume is 195 A˚3 for structures 5 and 6 and ≈187 A˚3 for structures 7-10. The details (Series II) are reported in the Supporting Information which also gives the selectivity data (overall and for molecules 1 and 2), the metrics of the hydrogen bonding, host torsion angles, volume of the voids, the site occupancies, and torsion angles of the guests. A typical structure is shown in Figure 4, which displays the skeleton of the host structure and the shape of the cavity which accommodates the guests. In a similar manner, we have analyzed the conformational and volume changes in the third series of structures which comprise host H2 with mixtures of the 2-butylamine guests (Series III). In this case, the cyclohexyl moiety has been replaced by two methyl groups, so that τ5 falls away. Structure 1, comprising only the (S)-enantiomer, crystallizes in the space group P212121 with Z = 4, so there is only one host and one guest in the asymmetric unit. However, structures 2-9 crystallize in P1 with Z = 2, so that we have a crystallographically independent host and guest molecules as occurred in Series II. The conformation of H2 is again governed by a practically constant intramolecular hydrogen bond, with dO 3 3 3 O ranging from 2.61 to 2.65 A˚, and the O-H 3 3 3 N(H2) hydrogen bonds show a small variation (2.64-2.67 A˚). The overall averaged selectivity is improved, however, and favors the (R)-enantiomer over the whole composition range (Figure 5a). The racemic mixture (structure 5) yielded ZR = 0.75, corresponding to an e.e. of 50%. However, the corresponding data for molecule 1 and molecule 2 are more emphatically different. For molecule 1, Figure 5b shows strong selectivity, with the racemic mixture yielding ZR = 0.90 (e.e. = 80%). The torsion angles only change after structure 1, after which they remain practically constant and the 2-butylamine displays clusters with the alkyl chain torsion angle ≈ -70° for the (S)-and þ80° for the (R)-enantiomer. Molecule 2 only displays selectivity in the range XR = 0-0.67, after which the curve follows the diagonal line. The host torsion angles follow the trend of molecule 1 and the guest torsion angles are clustered at approximately the trans-configuration. The guest accessible volume shows the same trend as before. It is 197 A˚3 for

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Figure 5. Selectivity curves for Series III, H2 3 (R)/(S)BUAM. (a) Overall selectivity, (b) and (c) selectivity for molecules 1 and 2, respectively.

structure 1 and averages 160 A˚3 for molecule 1 and 174 A˚3 for molecule 2. Details for Series III, figures of the host H2 torsion angles, and those of the entrapped guests are given in the Supporting Information. The precipitation of solid solutions in the formation of diastereomeric salts has been discussed.19 In this work, we note the formation of solid solutions in Series I for the H1 3 (PYR)/(MOR) system, which extends over the whole range of the guest mixtures. For Series II, however, the formation of the solid solutions is more subtle, because it is dependent on the two crystallographically independent sites that occur in the crystals. Thus, the solid solution of H1 3 (R)/(S)BUAM is restricted to a narrow range for XR-BUAM of 0.2-0.6 for molecule 1 but extends to practically the whole range for molecule 2. A similar result is obtained for Series III, where the solid solution of H2 3 (R)/(S)BUAM occurs in the range for XR-BUAM of 0 to 0.6 for molecule 1 and over the complete range for molecule 2. 3. Conclusion We conclude that the mechanism for enantiomeric differentiation is therefore due to the adjustment of the torsion angles and the concomitant space available for the 2-butylamine guest. The mechanism is subtle, however, and the overall selectivity profiles, although of practical significance, are not instructive in this regard. One must analyze the results given by the crystallographically independent molecules which arise from the P1 structures. In particular, in Series II for molecule 1, Figure 3a shows significant changes in τ1 and τ3 of ≈18° and 13°, smaller changes in τ2 and τ4 and a large

conformational change in the cyclohexyl moiety (τ5). These changes, which occur between structures 4 and 5, are accompanied by a decreased guest volume from 178 A˚3 to 167 A˚3. We note that this smaller volume for structures 5-10 is correlated with sharply increased enantiomeric resolution and modest variation in the conformational flexibility of the entrapped 2-butylamine. In contrast, for molecule 2, the variations in τ1 and τ4 are smaller, but the available guest volume is significantly larger, being 195 A˚3 for structures 5 and 6 and 189 A˚3 for structures 7-10. Here we note poor enantiomeric resolution and large variabilities in the conformation of the 2-butylamine guests. This phenomenon is repeated in Series III, where molecule 1 has torsion angles that are constant but different from those of molecule 2 for structures 2-9. However, the guest volume for molecule 1 is 160 A˚3 while for molecule 2 it increases to 174 A˚3, and the smaller volume gives rise to the good chiral discrimination shown in Figure 5b. Interestingly, the conformation of the guest 2-butylamine does not display large variations being ≈ -70° for (S)-butylamine and þ80° for the (R)-butylamine in molecule 1. For molecule 2, they are close to the trans-conformation for both enantiomers. 4. Methods The relative proportions of pyridine and morpholine were measured on a 400 MHz Varian NMR instrument by integrating the signal from the ortho protons around 8.6 and 3.6 ppm. The proportion of the host compound was measured by integrating the protons bonded to the chiral carbon atoms at 4.6 ppm. The results of the competition experiments are shown in Table 1S, Supporting Information.

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X-ray diffraction data for compounds of Series I-III were collected on a Nonius Kappa CCD diffractometer20 with graphitemonochromated Mo-KR1 radiation (λ = 0.71073 A˚) at 173 K using an Oxford Cryostream 600 and on a Bruker DUO APEX II diffractometer21 with graphite-monochromated Mo-KR1 radiation (λ = 0.71073 A˚) at 173 K using an Oxford Cryostream 700. Data reduction and cell refinement were performed using DENZO22 or SAINT-Plus.23 The space groups were determined from systematic absences by XPREP24 and further justified by the refinement results. The structures were solved using SHELXS-9722 and refined using full-matrix least-squares methods in SHELXL-9725 with the aid of the program X-Seed.26 The hydrogen atoms bound to carbon atoms were placed at idealized positions and refined as riding atoms with Uiso (H) = 1.2 Ueq (Ar-H, CH2) or 1.5 Ueq(CH3). The refinement of the hydroxyl hydrogen atoms was carried out by first locating them on a difference electron density map and subsequently imposing an appropriate O-H bond length constrain (Table 2S and 3S, Supporting Information). For the refinement of the 2-butylamine guest, we allowed free refinement of the heavy atoms, but if this proved unsatisfactory we imposed fixed isotropic temperature factors and bond length constraints, but ensuring that there was free torsional freedom around the C2-C3 bond of the 2-butylamine (Table 4S and 5S, Supporting Information). Diagrams and publication material were generated using PLATON27 and XSeed. Cif files for each series have been deposited with the Cambridge Structural Database (CCDC 752938-752964). Supporting Information Available: Crystallographic data and details of experimental preparations of Series I-III are available free of charge via the Internet at http://pubs.acs.org.

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