The Dutch Resolution Method: Attempted ... - ACS Publications

Article pubs.acs.org/crystal

The Dutch Resolution Method: Attempted Enhanced Selectivity of 2-Butylamine with Mixed Diol Hosts Nikoletta B. Báthori*,† and Luigi R. Nassimbeni‡ †

Crystal Engineering Unit, Department of Chemistry, Faculty of Applied Sciences, Cape Peninsula University of Technology, P.O. Box 652, Cape Town, 8000, South Africa ‡ Centre for Supramolecular Chemistry Research, Department of Chemistry, University of Cape Town, Private Bag, Rondebosch 7701, South Africa S Supporting Information *

ABSTRACT: The Dutch resolution method was employed to resolve 2-butylamine. Four similar diol host compounds were utilized singly and in combination to obtain inclusion compounds that displayed partial enantiomeric selectivity. However, the combination of any pair of host compounds did not significantly improve the enantiomeric excess of the 2-butylamine over that given by single host compounds. We attribute the results to the constant packing patterns of the structures.

1. INTRODUCTION The announcement of the “Family” approach to the resolution of racemic modifications, the so-called “Dutch Resolution Method”, was a significant advancement in the efficient practice of chiral separation.1 The procedure employs a combination of two or three generally homochiral resolving agents, whose structures are closely related, and it was found to greatly improve the enantiomeric excess of the targeted racemate. The groups of resolving agents included dioxaphosphorinanes, dibenzoyltartaric acids, mandelic acids, ethylamines, and N-benzoyl phenylglycines, and they yielded very high enantiomeric excess of the final enantiomeric product, with values often exceeding 95%. The method has been reviewed,2,3 and Kellogg2 has pointed out the importance of single enantiomer drugs to the pharmaceutical industry and a recent estimate (2010) of the worldwide sales of single enantiomer drugs is about $300 billion. In our previous paper, published in this journal,4 we discussed aspects of the mechanism of the enantiomeric resolution of racemic 2-butylamine (rac-2-BUAM or 2-BUAM) by the chiral host compounds H1 (R,R)-(−)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspiro(4.5)decane and H2 (R,R)(−)-trans-4,5-bis-(hydroxydiphenylmethyl)-2,2-dimethyl-1,3-dioxolane. We obtained crystals of the host which had been dissolved in mixtures of (R)- and (S)-2-BUAM of different, known proportions, and we mapped the enantiomeric composition of the 2-BUAM entrapped in the crystals as a function of the torsion angles of the phenyl moieties of the host. This study is now extended by analyzing the crystal structures obtained from rac-2-BUAM with two additional related host compounds H3 (R,R)-(+)-trans-2,3-bis(hydroxydiphenylmethyl)© 2012 American Chemical Society

1,4-dioxaspiro(4.4)nonane and H4 (S,S)-(−)-trans-2,3-bis(hydroxydiphenylmethyl)-1,4-dioxaspiro(4.4)nonane as well as combinations of the hosts: H1 + H2, H2 + H3, H1 + H3, and H1 + H4. 1:1 mixtures of the host compounds were prepared for crystallization from 2-BUAM because this was found to be the most successful combination by Vries and co-workers.1 However, the resulting crystals did not reflect the stoichiometric Chart 1. Hosts and Guest Compounds Employed in This Work

Received: January 26, 2012 Revised: March 21, 2012 Published: April 16, 2012 2501

dx.doi.org/10.1021/cg300119n | Cryst. Growth Des. 2012, 12, 2501−2507

a

579.75 173(2) 0.50 × 0.50 × 0.40 triclinic P1 9.6099(19) 10.045(2) 17.095(3) 95.83(3) 95.94(3) 96.29(3) 1620.8(6) 2 1.188 0.076 2.05−25.67

Mr temperature (K) crystal size (mm3) crystal system space group a (Å) b (Å) c (Å) α (deg) β (deg) γ (deg) V (Å3) Z ρ (calcd) (Mg m−3) μ (Mo Kα) (mm−1) theta range for data collection (deg) reflections collected no. unique data no. data with I > 2σ(I) final R (I > 2σ(I)) final wR2 (all data) extinction coefficient

2502

27055 6214 5796 0.0462 0.1180 0.0109(17)

539.69 173(2) 0.43 × 0.41 × 0.32 triclinic P1 9.4560(12) 9.5766(12) 17.197(2) 79.130(3) 82.298(3) 79.182(3) 1494.3(3) 2 1.199 0.077 2.20−26.60

H2 C31H30O4·C4H11N

2a 3

13848 5955 5148 0.0414 0.0994 0.026(4)

565.72 173(2) 0.10x 0.10 × 0.10 triclinic P1 9.4990(19) 9.853(2) 17.227(3) 96.43(3) 96.01(3) 96.13(3) 1581.9(5) 2 1.188 0.076 2.17−25.73

H3 C33H32O4·C4H11N

4

51876 7907 6914 0.0435 0.1170

565.72 173(2) 0.20 × 0.20 × 0.20 triclinic P1 9.4910(18) 9.8633(18) 17.218(3) 96.364(3) 95.956(4) 96.117(4) 1581.8(5) 2 1.188 0.076 2.09−28.41

H4 C33H32O4·C4H11N

H1 and H2 structures are published in ref 4 and we included their parameters for clarity.

13584 9508 7899 0.0667 0.1763 0.054(7)

H1 C34H34O4·C4H11N

1a

host(s) moiety formula

structure

Table 1. Crystallographic Data and Structure Refinement Parameters 5

11102 5776 5332 0.0497 0.1418 0.011(4)

H1 + H2 C34H34O4·C31H30O4·2C4H11N 1119.44 173(2) 0.15 × 0.10 × 0.08 triclinic P1 9.5335(11) 9.7566(12) 17.279(2) 77.473(3) 82.389(2) 79.562(2) 1535.7(3) 1 1.211 0.078 2.18−25.72

6

10620 5244 4009 0.0636 0.1938 0.015(5)

H2 + H3 C31H30O4·C33H32O4· 2C4H11N 1105.42 173(2) 0.10 × 0.10 × 0.07 triclinic P1 9.5079(13) 9.7035(13) 17.333(2) 79.125(3) 82.499(3) 80.303(3) 1540.0(4) 1 1.192 0.077 2.16−24.86

7

21007 6589 6230 0.0429 0.1179 0.007(2)

H1 + H3 1.85C34H34O4· 0.25C33H32O4·2C4H11N 1153.18 173(2) 0.08 × 0.05 × 0.05 triclinic P1 9.5582(6) 9.9594(6) 17.1751(11) 96.1440(10) 95.9170(10) 96.1510(10) 1605.33(17) 1 1.193 0.076 2.07−26.45

8

13985 5939 5152 0.0360 0.0945 0.0072(13)

H1 + H4 C34H34O4·C33H32O4· 2C4H11N 1145.47 173(2) 0.10 × 0.10 × 0.08 triclinic P1 9.4984(10) 10.2547(11) 17.1794(18) 76.269(2) 74.228(2) 82.563(2) 1560.5(3) 1 1.219 0.078 2.17−25.80

Crystal Growth & Design Article


Crystal Growth & Design

Article

composition in all experiments. The solubility of these compounds in 2-BUAM has been found to be similar. The host compounds are illustrated in Chart 1. The concept of the selectivity coefficient5 was adopted when analyzing the preference of a host for a given enantiomer: KR : S = (KS : R )−1 = ZR /ZS*XS /XR , (XR + XS = 1)

where XR, XS are the mole fractions of the (R) and (S) enantiomer in the liquid, and ZR, ZS are their mole fraction in the crystal.

2. STRUCTURE ANALYSIS Table 1 contains the crystal data and experimental and refinement parameters. We have included the data for 1 and 2, the inclusion compounds with H1 and H2 crystallized from 2-BUAM, for the sake of completion. 3 (H3·2-BUAM) crystallizes in the space group P1 with Z = 2. Figure 1 shows one of

Figure 2. Packing of structure 3 (red - site A, blue - site B).

Figure 1. One host−guest pair in the asymmetric unit of 3.

the host−guest pairs in the asymmetric unit. We note the intramolecular H-bond O1−H1···O2A which locks the host molecule in this conformation, with the torsion angle O1−C1−C5−O2 = −6.4°. There is a second H-bond interlinking O2 to the guest. These three parameters remain practically constant in all the reported structures, and their metrics are given in the Supporting Information (Table 1S). Aspects of the packing of 3 are shown in Figure 2. There are two sites that accommodate the BUAM guest molecules, which refined to 100% (R) at site A and 62% (R) at site B (overall 81% R). In our previous publication,4 we showed that X-ray diffraction was a robust and accurate method of determining the composition of mixed guests. This was carried out by measuring the selectivity curve for the system H1·(pyridine/morpholine) and demonstrated that the proportion of entrapped guest, as measured by NMR, correlated with that obtained from structure refinement. However, as a double check on our methodology, crystals were grown from the enantiomerically opposite host H4 and 2-BUAM. The resulting crystal structure 4 yielded 100% (S) at site A and 58% (S) at site B (overall 79.2% S). It was concluded that the overall precision of the method was high, with the error in the estimated enantiomeric percentage being less than 2%. The structure of 5, (H1 + H2)·2-BUAM crystallizes in P1 with Z = 1. Thus there is one molecule of H1, one of H2, and two BUAM guests in the unit cell. Aspects of the packing are

Figure 3. Aspects of structure 5, (H1 + H2)·2-BUAM packing (red site A, blue - site B).

shown in Figure 3. The guest at site A, hydrogen bonded to H2 and henceforth abbreviated to (···H2), is disordered and is 100% (R), while the guest at site B, (···H1) is disordered and is 100% (S). Thus the overall result is 50% (R). A similar situation arises with structure 6, (H2 + H3)·2-BUAM which again crystallizes in P1 with Z = 1. Here the guest at site A (···H3) is 65% (R) and at site B (···H2) is 100% (R), yielding an overall 82% (R). Structure 7, (H1 + H3)·2-BUAM is interesting in that the guest at site A (···H1) is 100% (R). However site B shows that the host is disordered, comprising 71% H1 and 29% H3. The guest was 58% (R), and the overall result was 79% (R). Finally 2-BUAM was crystallized with an equimolar mixture of host H1 and H4. We used these similar but not identical hosts with opposite chirality because in certain cases the application of host compounds with the reverse chirality unexpectedly can enhance the selectivity.6 A pseudo-centrosymmetric structure resulted in 8 with the E-statistics of the intensity data verging on centrosymmetry, although the structure was solved in P1. Aspects of the packing are shown in Figure 4, in which we note two hosts and two guests related by a pseudo 2503



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are two crystallographically independent molecules A and B and the sites in which the guests are located are named after the host molecule to which the guest is hydrogen-bonded. We note a pattern for structures 1−7, in that the torsion angles for host molecule A are closely related but are different from those of host molecule B. Their average values are given as well as their absolute differences. Structure 8 does not conform to the pattern, being pseudo-centrosymmetric. Structures 1−7 can be divided into two groups. The first group, comprising structures 1, 3, 4, and 7, have packing features which are subtly different from those of the second group, comprising structures 2, 5, and 6. For the first group, not all the phenyl moieties have close contacts with the guest, and this can be seen by inspection of Figure 5, which shows a projection of structure 5 viewed along [100] and is representative of this group. For clarity, all H atoms have been omitted, and host molecules A and B are colored in red and blue respectively. The BUAM guest at site A lies between a pair of phenyl rings of molecule B which are related by translation and whose torsion angle τ2 is −68°. By contrast, the BUAM molecule at site B has close contacts with one of the methyl groups of H2, the phenyl moiety of molecule B with τ4 = −60° and the phenyl ring of molecule A with τ1 = −28°. We note in Table 2 that the packing factors for site A () are consistently higher than for site B (). Figure 6 shows the packing of structure 7, (H1 + H3)·2BUAM, representative of the second group. The molecules are again coded as molecules A in red and molecules B in blue. As before the BUAM guest at site A lies between two phenyl moieties of molecule B, related by translation, with torsion angle τ2 = −62°. The difference lies with site B, where the BUAM molecule now has close contacts with the phenyl groups of molecule B with τ1 = −10° and τ4 = −59° as well as the cyclohexyl group of molecule A and the phenyl group of molecule A with τ1 = −27°.

Figure 4. Aspects of structure 8, (H1 + H4)·2-BUAM packing with pseudo center of symmetry.

center of symmetry. The guest at site A (···H4) is 77% (S) and at site B (···H1) is 72% (R), yielding an overall 53% (S). We have proposed that the torsional flexibility of the phenyl moieties of the hosts gives rise to the enantiomeric selectivity of the guest. The four torsion angles τ1 (O1−C1−C11−C12), τ2 (O1−C1−C17−C18), τ3 (O2−C5−C51−C56), and τ4 (O2− C5−C57−C62) as well as the volume which accommodates the guest were measured. The guest accessible space was mapped employing the program MSRoll,7 using a spherical probe of radius of 1.4 Å. This allowed us to evaluate the packing factors of the guest molecules at their respective sites. Table 2 shows the torsion angles of the phenyl moieties, estimated to the nearest degree, for all structures 1−8. In each structure there Table 2. Results of the Selectivity Experiments structure

host(s)

host ratio host ratio in in solution the crystal XR‑BUAM

1

H1a

0.5

2

H2a

0.5

3

H3

0.5

4

H4

0.5

5

H1 + H2

1:1

1H1:1H2

0.5

6

H2 + H3

1:1

1H2:1H3

0.5

7

H1 + H3

1:1

0.77H1:0.23 H3

0.5

8

H1 + H4

1:1

1H1:1H4

0.5

molecules

ZR, site

A (H1) B (H1) A (H2) B (H2) A (H3) B (H3) A (H4) B (H4) A (H2) B (H1) A (H2) B (H3) A (H1)

0.94 0.28 0.90 0.60 1.00 0.62 0.00 0.42 1.00 0.00 1.00 0.65 1.00

B (0.55H1 + 0.45H3) A (H4) B (H1)

0.58 0.22 0.71

overall ZR

% e.e.

0.60

22(R)

0.76

50(R)

0.81

62(R)

0.20

58(S)

0.50

0

0.82

65(R)

0.77

58(R)

0.47

49(R)

for 1−7 |Δ| a

τ1 (°)

τ2 (°)

τ3 (°)

τ4 (°)

Vvoid (Å3)

PF (%)

(%)

−26 −10 −28 −4 −25 −8 +26 +9 −28 −3 −28 −4 −27

−57 −63 −57 −66 −59 −63 +57 +63 −53 −68 −53 −68 −57

−9 −10 −3 −6 −7 −12 +7 +11 −4 −10 −4 −10 −8

−70 −58 −69 −61 −70 −61 +70 +61 −70 −60 −69 −62 −70

170 195 159 172 163 181 161 180 147 161 151 178 163

50.2 43.8 53.7 49.7 52.3 47.1 52.9 47.4 58.1 52.9 56.5 48.1 52.3

47.0

−10

−62

−11

−59

180

47.6

+13 −15

+50 −45

+23 −24

+59 −58

142 137

60.2 62.5

−27 −7 20

−56 −65 9

−6 −10 4

−70 −60 10

51.7 49.7 50.1 55.5 52.3 49.9

61.3

53.7 48.1 5.6

H1 and H2 structures are published in ref 4 and we included their parameters for clarity. 2504



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Figure 5. (a) Projection of structure 5 viewed along [100] and (b) [001] showing guest in site A (red) surrounded by phenyl moieties of molecule B (blue).

for (H2 + H3) 65% (R) and for (H1 + 0.79H1/0.21H3) 58% (R). We note that individual sites display a distinct increase in enantiomeric selectivity. Thus site A for H1 yields 94% (R) and 100% (R) for (H1 + H2). However, there is an internal compensation effect as site B is 28% (R) for H1 and 0% (R) for (H1 + H2). The best combination is for (H2 + H3) which yield an overall 83% (R), a marginal improvement on H3 which results in 81% (R). The important result is that site A, which has the smaller guest-available space (higher packing factor) invariably selects the (R)-enantiomer to a high percentage, averaging 98% (R) for structures 1−7. However site B, where the packing is looser, is a poor enantiomeric discriminator. It is confirmed, therefore, that the guest available space, which is controlled by the torsional flexibility of the phenyl moieties, is responsible for the enantiomeric selectivity of the host. The rigidity of the packing, controlled by the host···host interactions, did not allow any significant change in chiral discrimination. It is interesting to note that host H2 was employed to resolve both 1-phenylethanol (Cambridge Structural Databank reference code: NEMBOX)8 and 1-phenylethylamine (LATCOY).9 We analyzed the host−guest packing interactions using the program CrystalExplorer10 which yields the percentage of nonbonded interactions between the selected guest and the host molecules. It was observed that the structure with the 1-phenylethanol guest displayed C···H interactions that amounted to 29.1%, while that with 1-phenylethylamine yielded 33.2%. However in the case of 2-butylamine this amounted to 19.8% at site A (a weighted average of the values obtained for minor and major disorders) and 12.6% at site B, averaging to 16.8%, a significantly lower figure. We surmise that the host H2 was better able to resolve the 1-phenylethanol and 1-phenylethyamine guests due to the enhanced host−guest interactions (C···H) afforded by the phenyl moieties in the latter guests (Figure 7). In structure 6, which is built from both H2 and H3 and shows the best overall selectivity, we found that the host molecules are partially interdigitated, showing an increase in the host−host interactions (Figure 8), an additional reason for the obtained selectivity.

Figure 6. Structure 7 viewed along [100].

The salient point is that the smaller available guest volume of site A, with the higher packing factor, is associated with high enantiomeric discrimination, favoring the (R)-enantiomer. By contrast, site B, with lower packing factor, tends to yield poor discrimination with a wide range of enantiomeric enrichment. Only three or four of the phenyl moieties and their associated torsion angles form close contacts with the BUAM guests. The remaining phenyl torsion angles result from the packing requirements of the host−host interactions in the structures.

3. CONCLUSION No significant improvement in the overall enantiomeric excess of a single enantiomer was achieved by mixing pairs of host compounds (H1 + H2), (H2 + H3), and (H1 + H3). This is because the crystal structures all display a constant packing arrangement with two crystallographically distinct positions for the host molecules and the concomitant sites where the guests are located. Thus the e.e. values for H1 (22% (R)), for H2 (50% (R)), and H3 (62% (R)) become for (H1 + H2) 0% (R), 2505



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Figure 7. Hirshfeld surfaces and fingerprint plots for H2·1-phenylethanol (NEMBOX), H2·1-phenylethylamine (LATCOY), and H2·2-BUAM with highlighted C···H interactions.

Figure 8. Host−host interaction between molecule A (red) and molecule B (blue) in structure 6.

4. EXPERIMENTAL SECTION

173 K using an Oxford Cryostream 700. Data reduction and cell refinement were performed using SAINT-Plus,12 and the space groups were determined from systematic absences by XPREP13 and further justified by the refinement results. In all cases, the structures were solved in the aid of X-Seed14 by direct methods using SHELXS-9715 and refined using full-matrix least-squares/difference Fourier techniques using SHELXL-97. The hydrogen atoms bound to carbon atoms were placed at idealized positions and refined as riding atoms with Uiso (H) = 1.2Ueq (Ar−H, CH2) or 1.5Ueq (CH3). Diagrams and publication material were generated using PLATON16 and X-Seed. Experimental details of the X-ray analyses are provided in Table 1. Cif files for each structure have been deposited with the Cambridge Structural Database (CCDC 864367−864372).

4.1. Materials. Host compounds were obtained from Prof Fumio Toda and used without further purification. 2-Butylamine purchased from Aldrich were of ACS (≥99%) quality. 4.2. Preparation of Inclusion Compounds. The hosts (H1−H4) were then employed to measure the enantiomeric proportion of 2-butylamine. We dissolved a fixed quantity of host in racemic-2butylamine, and in the case of the Dutch Resolution experiment the hosts’ ratio was 1:1. The ensuing crystals (four) were all subjected to X-ray structure analysis at 173 K. 4.3. Single Crystal X-ray Diffraction. Diffraction data for all compounds were collected on a Bruker DUO APEX II diffractometer11 with graphite-monochromated Mo Kα1 radiation (λ = 0.71073 Å) at 2506



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Article

ASSOCIATED CONTENT

S Supporting Information *

Hydrogen bond metrics of all the reported structures. Crystallographic data structures 3−8 are available free of charge via the Internet at http://pubs.acs.org.

■

AUTHOR INFORMATION

Corresponding Author

*Fax: +27 21 460 3854. Tel: +27 21 460 8354. E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

REFERENCES

(1) Vries, T.; Wynberg, H.; van Echten, E.; Koek, J; ten Hoeve, W.; Kellogg, R. M.; Broxterman, Q. B.; Minnaard, A.; Kaptein, B.; van der Sluis, S.; Hulshof, L.; Kooistra, J. Angew. Chem. In. Ed. 1988, 37, 2349− 2354. (2) Kellogg, R. M.; Nieuwenhuijzen, J. W.; Pouwer, K.; Vries, T. R.; Broxterman, Q. B.; Grimbergen, R. F. P.; Kaptein, B.; La Crois, R. M.; de Wever, E.; Zwaagstra, K.; van der Laan, A. C. Synthesis 2003, 10, 1626−1638. (3) Kozma, D., Ed. Optical Resolution via Diastereomeric Salt Formation; CRC Press: New York, 2002. (4) Báthori, N. B.; Nassimbeni, L. R. Cryst. Growth Des. 2010, 10, 1782−1787. (5) Pivovar, A. M.; Holman, K. T.; Ward, M. D. Chem. Mater. 2001, 13, 3018−3031. (6) Dalmolen, J; Tiemersma-Wegman, T. D.; Nieuwenhuijzen, J. W.; van der Sluis, M.; van Echten, E.; Vries, T. R.; Kaptein, B.; Broxterman, Q. B.; Kellogg, R. M. Chem.Eur. J. 2005, 11, 5619−5624. (7) Connolly, M. L. J. Mol. Graph. 1993, 139−141. (8) Ghazali, N. F.; Ferreira, F. C.; White, A. J. P.; Livingston, G. Tetrahedron Asym. 2006, 17, 1846−1852. (9) Toda, F.; Tanaka, K.; Ootani, M.; Hayashi, A.; Miyahara, I.; Hirotsu, K. J. Chem. Soc. Chem. Commun. 1993, 1413−1415. (10) (a) McKinnon, J. J.; Spackman, M. A.; Mitchell, A. S. Acta Crystallogr. 2004, B60, 627. (b) Spackman, M. A.; McKinnon, J. J. CrystEngComm 2002, 4, 378. (11) APEX2, Version 1.0-27; Bruker AXS Inc., Madison, Wisconsin, USA 2005. (12) SAINT-Plus (including XPREP), Version 7.12; Bruker AXS Inc.: Madison, Wisconsin, USA, 2004. (13) XPREP2, Version 6.14; Bruker AXS Inc.: Madison, Wisconsin, USA, 2003. (14) Barbour, L. J. J. Supramol. Chem. 2001, 1, 189−191. (15) Sheldrick, G. M. SHELXS-97 and SHELXL-97, Programs for Crystal Structure Determination and Refinement; University of Göttingen, 1997. (16) Spek, A. L. J. Appl. Crystallogr. 2003, 36, 7−13.

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