Racemic Triarylmethanol Derivative Crystallizes as ... - ACS Publications

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Racemic Triarylmethanol Derivative Crystallizes as a Chiral Crystal Structure with Enantiomeric Disorder, in the Sohncke Space Group P21 Katherine Chulvi, Ana M. Costero,* Luis E. Ochando, and Pablo Gaviña Centro de Reconocimiento Molecular y Desarrollo Tecnológico (IDM), Unidad Mixta Universidad Politécnica de Valencia-Universidad de Valencia, C/Doctor Moliner 50, 46100, Burjassot, Valencia, Spain S Supporting Information *

ABSTRACT: The X-ray crystal structure of a racemic triarylcarbinol derivate ((±)-1) was determined. Compound (±)-1 crystallizes as a chiral structure in the noncentrosymmetric Sohncke space group P21 and the crystals show a special case of enantiomeric disorder with two molecules of opposite handedness sharing many of the atomic positions in the asymmetric unit. The corresponding (R)- and (S)-enantiomers of 1 were separated by chiral HPLC, and crystallized independently yielding single crystals of both of them. The X-ray diffraction analysis of the crystals allowed the determination of the absolute configuration of both enantiomers (R)-1 and (S)-1. Both enantiomers establish intermolecular hydrogen bonds in the solid state, which induce significant differences in their molecular arrangement when compared to racemic crystal (±)-1.

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INTRODUCTION Racemic mixtures of chiral molecules can crystallize as racemic compounds (the most common situation, a single crystalline phase with both enantiomers in a 1:1 ratio in the elementary cell), as conglomerates of chiral crystals (mechanical mixture of enantiomerically pure crystals; about 10% of the time), or as pseudoracemates (or racemic solid solutions). Racemic compounds can yield either chiral or achiral crystal structures, and can theoretically be arranged in any one of the 230 space groups,1 although around 95% of the known racemic compounds crystallize as centrosymmetric achiral crystal structures.2 In this paper, we report the structural study of (4(dimethylamino)phenyl)(phenyl)(thiophen-2-yl)methanol (1, see Figure 1), a chiral molecule which was synthesized as a racemic mixture from achiral precursors in the course of ongoing research. This compound was designed by our group to be used as an OFF/ON optical chemodosimeter for nerve agent mimics, due to the changes in its optical properties in the presence of these toxic compounds.3 We have found that (±)-1

crystallizes as an ordered racemic crystal structure in the noncentrosymmetric space group P21. This space group is one of 65 Sohncke space groups, which are the groups allowed for chiral crystal structures, containing only symmetry operations of the first kind (rotations and translations).4 Actually, around of 5.2% of the CSD structures (of a total of 682 999) belong to a P21 space group.5 Racemic mixtures that happen to crystallize as chiral crystal structures in Sohncke space groups are a very unusual case, and few examples have been reported in the literature.6−9 Furthermore, the corresponding R and S enantiomers of 1 were separated by chiral HPLC, and crystallized independently yielding single crystals of both of them suitable for X-ray diffraction.

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X-ray Diffraction Analysis. Appropriate colorless acicular crystals of compound (±)-13 were grown from heptane/2-propanol as solvent at 4 °C by means of liquid−liquid diffusion and analyzed by X-ray diffraction technique. The crystallization of the enantiomers, (S)-1 (1a) and (R)-1 (1b), was carried out at 4 °C by the slow evaporation method from heptane/2-propanol. The crystals were mounted in a fine nylon loop assisted by of Fomblin Y lubricant. The loop was attached to the copper mounting pin held on by a magnetic base. Crystal sections with approximate dimensions 0.30 × 0.25 × 0.20 mm3, 0.20 × 0.10 × 0.08 mm3, and 0.13 × 0.11 × 0.10 mm3 of (±)-1, 1a, and 1b, respectively, were measured. Data collection for the three single crystals was carried out at 120 K on the Oxford Diffraction Gemini S Ultra equipped with a graphite-monochromated Mo Kα Received: April 14, 2015 Revised: May 15, 2015

Figure 1. (a) (S)-1 (1a) and (b) (R)-1 (1b). © XXXX American Chemical Society

EXPERIMENTAL SECTION

A

DOI: 10.1021/acs.cgd.5b00515 Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

Article

radiation (λ = 0.71073 Å) source and a CCD detector at 120 K. The structures were solved using direct methods and refined with full matrix least-squares on |F|2 for all data, performed with the WINGX package software.10 The hydrogen atoms of (±)-1 and 1a structures were placed in calculated positions, while in the case of the 1b structure the H atoms were located in the Fourier map and their parameters were freely refined. All molecular graphics were created using MERCURY11 and ORTEP-III software.12 The monoclinic system is common for the three crystal structures (±)-1, 1a, and 1b. The systematic absences show the P21 space group. Thus, the three crystals of (±)-1, 1a, and 1b are noncentrosymmetric with an estimated centrosymmetric probability of 18.1%, 28.0%, and 7.8% for 1, 1a, and 1b, respectively. Crystal data are listed in Table 1. The

Table 1. Crystal Data and Structure Refinement 1 (R,S) Formula Crystal color Data collection temperature (K) Crystal system Space group Cell parameters a (Å) b (Å) c (Å) β (deg) Volume (Å3) Z Calculated density (Mg/ m3) Reflections collected Unique reflections Rint Final R indices [I > 2σ(I)] R indices (all data) Flack Parameter

1a (S)

1b (R)

C19H19NOS Colorless 120(2)



Monoclinic P21

Monoclinic P21

Monoclinic P21

9.0500(1) 6.0800(1) 15.1000(1) 101.670(1) 813.69(17) 2 1.263

6.5672(6) 14.5638(13) 8.2949(8) 91.341(8) 793.14(13) 2 1.296

6.5739(6) 14.5868(12) 8.3126(7) 91.506(8) 796.84(12) 2 1.290

3034 2047 0.0255 R1 = 0.0509 wR2 = 0.1172 R1 = 0.0691 wR2 = 0.1224 −0.08(17)

3096 2144 0.0971 R1 = 0.0915 wR2 = 0.2556 R1 = 0.1188 wR2 = 0.3402 −0.1(3)

2972 2083 0.0232 R1 = 0.0300 wR2 = 0.0741 R1 = 0.0317 wR2 = 0.0758 0.03(8)

Figure 2. ORTEP diagram of the asymmetric unit with 15% thermal ellipsoids and part of the numbering scheme of compound (±)-1. Hydrogen atoms have been omitted for clarity.

enantiomerically pure crystals also have similar unit cell parameters to those of the racemate but in different order. Therefore, a axes of enantiomers 1a and 1b (about 6.6 Å) are similar to the b axis of racemic crystal (ca. 6.1 Å), and the b axes of the enantiomers (ca. 14.6 Å) are similar to the c axis of 1 (15.1 Å). The absolute configuration was determined for the enantiomerically pure crystals 1a and 1b, being S for 1a and R for 1b, resulting values of Flack parameter of −0.1(3) for 1a and 0.03(8) for 1b. Chiral HPLC Separation of 1a and 1b. Chiral HPLC was performed with a Hitachi series HPLC system equipped with L-2130 pump and L-7450 diode array monochrome detector monitoring the wavelength 300 nm. The HPLC column used was a normal chiral column CHIRALPAK IC size 5 μm from Agilent technologies. The mobile phase was 90:10 (v/v) mixture of heptane/2-propanol. The sample, racemic crystals of 1 were dissolved in the same mixture of solvents than the mobile phase at a concentration of 2 mM for the preparative chiral column. Both enantiomers were collected in separate vials. The experiment was carried out at room temperature using flow rate of 3 mL/min after injecting 250 μL of the racemate.

Figure 3. HPLC profiles of compound (±)-1, using a CHIRALPAK IC column of 5 μm, using heptane/2-propanol (90:10) (v/v) as mobile phase at flow rate of 3 mL/min.

acicular crystals of (±)-1 suitable for X-ray diffraction were grown in the fridge from heptane/2-propanol by means of liquid−liquid diffusion. Several difficulties were observed in the structural resolution process. Thus, in a first attempt, two thiophene rings appeared in the unit cell with a residual factor value of R = 0.1519, suggesting an incorrect solution. In addition, the corresponding anisotropic displacement parameters were too high, showing systematic and significant differences where the sulfur atoms in the thiophene rings present bulky thermal ellipsoids. Q peaks from the difference electron density map demonstrated the existence of phenyl rings, as expected for molecule 1, but superimposed over the thiophene rings. In conclusion, a remarkable case of disorder seemed to be present. The number of reported organic crystals that present disorder in its resolution is increasing in the literature. Disorder

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RESULTS AND DISCUSSION Crystallization of racemate (±)-1 was challenging due to the high reactivity of triarylcarbinol compounds. The tertiary hydroxyl group can easily undergo dehydroxylation, causing different crystallization techniques such as liquid−vapor diffusion or sited drop to yield unsatisfactory results. Colorless B



Article

Figure 4. ORTEP diagram of the crystal structure of compounds: (i) (S)-(−)-1 (1a), (ii) (±)-1, and (iii) (R)-(+)-1 (1b) with 15% thermal ellipsoids.

Table 2. Torsion Angles of the Aromatic Rings in the Racemic Crystal (±)-1 and in Both Enantiomersa racemic

enantiomers

(S) C7-C10-(C4a5, C1b6)-(S5a5, C6b6) C7-C10-(C4a5,C1b6)-(C3a5,C2b6) C7-C10-(C1a6,C1b5)-(C2a6, C2b5) C7-C10-(C1a6, C1b5)-(C6a6, S5b5) a

(R)

173.7(8)° −3.5(15)° 112.8(14)° −67.2(15)°

ap -sc +ac -sc

172.4(16)° −8.8(14)° 104.6(18)° −71.6(10)°

(S)-1a ap sp +ac -sc

78.3(11)° −101.6(14)° 62.8(12)° −119.4(11)°

(R)-1b +sc -ac +sc -ac

−78.7(3)° 101.1(4)° −59.5(4)° 119.6(3)°

-sc +ac -sc +ac

ap: antiperiplanar; ac: anticlinal; sc: synclinal; sp: synperiplanar.

Table 3. Torsion Angles, Atomic Bond Distances, and Angles for the Dimethylamino Group in Compounds (±)-1, 1a, and 1b torsion angles (deg) (±)-1 S-1a R-1b

atomic bond distances (Å)

C1-N3-C4-C5

C2-N3-C4-C9

C4-N3

C1-N3-C4

C2-N3-C4

0.9(7) 60.4(13) −59.6(4)

−4.9(6) 2.6(15) −3.9(4)

1.409(6) 1.432(14) 1.435(4)

120.5(4) 113.6(10) 113.9(3)

121.5(4) 114.5(9) 115.1(3)

among different unit cells (static disorder), which is related to the normal atomic vibration. However, when different types of atoms, with similar binding properties and equivalent occupancy factors, occupy the same site in two unit cells the structure presents substitutional disorder. Enantiomeric disorder, which is a class of substitutional disorder, occurs when in a racemic crystal the superimposition of both enantiomers takes place. Compound 1 provides an ordered racemic crystal structure which presents enantiomeric disorder in its crystalline structure,14,15 conferring to this compound high structural interest. There are very few examples of disorder related to the presence of a position shared by two different types of atom, like the description of the tripivaloylmethane16 or a free neutral form of nicotine derivate.17 In order to fix the problem, the rigid-body constraint AFIX 66 on the phenyl ring was used, generating the two phenyl rings from three assigned carbon atoms. In addition, command PART1 and PART2 were needed to split disordered atoms. In some cycles of refinement, it was possible to define the occupation of 50% for enantiomers, with crystal 1 being a racemate crystal. The model obtained seemed to refine successfully yielding a R index of 0.0509 for 3034 reflections collected. Crystals of (±)-1 contain one molecule in the asymmetric unit, where the two enantiomers are superimposed in the same molecule, in equal amounts, sharing many of the atomic

Figure 5. Hydrogen bond interactions in (i) 1a and (ii) 1b.

Table 4. Hydrogen Bond Geometry (Å, °) for 1a and 1b D−H···A

D−H

angles (deg)

H···A

D−H···A

D···A

(1a) O1− H1···N3

0.84

2.06

173.3

2.900(12)

(1b) O1− H1···N3

0.85(4)

2.05(4)

176(4)

2.906(4)

symmetry codes N3 [−x+1, y−1/ 2, −z+1] N3 [−x+1, y+1/ 2, −z+2]

in crystallography can be classified in two large groups: positional disorder and substitutional disorder.13 The positional disorder occurs when one atom occupies more than a single site in a single unit cell (dynamic positional disorder) or distributed C



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Figure 6. Packing diagram of (i) 1, along b axis, and (ii) 1a and (iii) 1b, along a axis. Diagrams were created using Mercury software.

experimental error, the values of the angles of (±)-1 in the racemic structure are clearly different. This fact can be justified by the absence of disorder in the enantiomerically pure structures (S)-(−)-1 (1a) and (R)-(+)-1 (1b). Another important structural difference appears in the dimethylamino group that adopts different dispositions in the racemic compound (±)-1 and in the enantiomers (S)-(−)-1 and (R)-(+)-1 (see Figure 4). Thus, the torsion angles C1-N3-C4-C5 and C2-N3-C4-C9 in the racemic crystal are close to zero. The planarity of the dimethylamino group, the bond angles close to 120°, and the distance of the bond C4−N3 of 1.409 Å (see Table 3) in the racemate suggest a sp2 hybridization of the N atom. This fact is corroborated by the comparison with the values found in the literature, dCar-N(C#)2 = 1.371 Å for a planar sp2 N,20 with values around 1.384−1.400 Å for other carbinol compounds such as Sunset Orange (SO), Malachite Green (MG), and Crystal Violet (CV).21 On the contrary, both enantiomerically pure structures show a clear tendency toward pyramidal disposition of the N with C−N−C angle values near 114° and distances of the C4−N3 bond slightly larger than before, with values of 1.432 and 1.435 Å. The C1-N3-C4-C5 torsion angle was found to be 60.4° for (S)-(−)-1 and the same value but opposite direction (−59.6°) for the R enantiomer. The pyramidal conformation for the dimethylamino group in both enantiomerically pure crystals could be explained by an intermolecular hydrogen bond that plays a key role in determining the crystal packing. Whereas hydrogen bonding is present in the two enantiomers (Figure 5), it is not present in the racemic structure. As a result, the packing diagram differs also between enantiomers and the racemic compound. The atoms involved in this moderate intermolecular hydrogen bond are the N atom of the dimethylamino group and the O atom of the hydroxyl group of an adjacent molecule (Table 4). The arrangement of the molecules for both enantiomers can be described as a tail-to-head association, being defined as zigzag chains between the molecule layers. However, in the racemate the absence of hydrogen bond interactions and the need to completely fill all the space cause a tail-to-tail molecular disposition, as a herringbone22 (Figure 6). Finally, if we compare the density of the packing of the racemic crystal (1.263 g/cm3) with that of the two enantiomers 1a and 1b (1.296 and 1.290 g/cm3, respectively), the average density of the enantiomerically pure crystals is approximately 2.4% greater

positions by different types of atoms and having bonds in common (Figure 2). In the framework of 1, the dimethylaniline ring and the OH group unit over the central C atom preserve their position, while the thiophene ring and the phenyl ring are subjected to the enantiomeric disorder. Atom numbering in Figure 2 is labeled with the character a in the case of the (S)enantiomer and the character b for the case of the (R)enantiomer. Additionally, labels 5 and 6 stand for thiophene and phenyl ring, respectively. Therefore, it is possible to see the four rings disordered in the structure: S enantiomer: thiophene ring (C1a5, C2a5, C3a5, C4a5, and S5a5) and phenyl ring (C1a6, C2a6, C3a6, C4a6, C5a6, and C6a6); R enantiomer: thiophene ring (C1b5, C2b5, C3b5, C4b5, and S5b5) and phenyl ring (C1b6, C2b6, C3b6, C4b6, C5b6, and C6b6). Moreover, the unit cell volume of the racemic crystal (813.69 Å3) was higher than the volumes of 1a and 1b (793.14 and 796.84 Å3, respectively), due to the effect of the superimposition of the two enantiomers in the same unit cell. In order to completely understand the characteristics of this racemic compound and to confirm the structural disposition and the superposition of the atomic sites, its resolution was carried out using HPLC with a chiral stationary phase. The retention time for each enantiomer was 14 min (1a) and 16 min (1b). Both peaks had the same integration area (see Figure 3). The observed optical activity was measured, using enantiomerically pure solutions, in a PerkinElmer 343 polarimeter equipped with a sodium lamp of 589 nm, and the specific rotation was determined. Thus, the enantiomer 1a was levorotatory with [α]25 D − 17° and the enantiomer 1b was dextrorotatory with [α]25 D + 16°. X-ray crystallography is the most reliable method to assign the absolute configuration of a molecule. Thus, the structure of both enantiomers was elucidated by X-ray diffraction analysis (Figure 4). Compound (−)-1a was identified as the S enantiomer and (+)-1b as the R enantiomer. In reference to the geometrical features, the three aromatic rings that define the triarylcarbinol moiety are placed in a three-blade propeller configuration.18,19 As can be deduced from Table 2, in the racemic compound the torsion angles of both enantiomers are very similar. Thus, the torsion angle corresponding to the phenyl ring of the S part, 173.7°, is similar to the torsion angle of the thiophene ring in the R part, 172.4°, for the superposition effect. The same occurs in the rest of the aromatic rings. Nevertheless, even though the values of torsion angles of (S)-(−)-1 and (R)-(+)-1 are similar within D



Article

(5) http://www.ccdc.cam.ac.uk/Lists/ResourceFileList/2014_stats_ sgnumorder.pdf. (6) Fábián, L.; Brock, C. P. Acta Crystallogr., Sect. B 2010, 66, 94− 103. (7) Dalhus, B.; Görbitz, C. H. Acta Crystallogr., Sect. B 2000, 56, 715−719. (8) Kostyanovsky, R. G.; Kostyanovsky, V. R.; Kadorkina, G. K. Mendeleev Commun. 2009, 19, 17−18. (9) Steinberg, A.; Ergaz, I.; Toscano, R. A.; Glaser, R. Cryst. Growth Des. 2011, 11, 1262−1270. (10) Farrugia, L. J. J. Appl. Crystallogr. 1999, 32, 837−838. (11) Macrae, C. F.; Bruno, I. J.; Chisholm, J. A.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Rodriguez-Monge, L.; Taylor, R.; van de Streek, J.; Wood, P. A. J. Appl. Crystallogr. 2008, 41, 466−470. (12) Farrugia, L. J. J. Appl. Crystallogr. 1997, 30, 565−566. (13) Mü ller, P. et al. in Crystal Structure Refinement: A Crystallographer’s Guide to SHELXL; IUCr monographs on crystallography; Oxford Science Publications: Oxford, 2006. (14) Hayashi, N.; Mori, T.; Matsumoto, K. Chem. Commun. 1998, 1905−1906. (15) Tessler, L.; Goldberg, I. Acta Crystallogr. 2005, C61, o707− o710. (16) Kaitner, B.; Slinovic, V. Acta Crystallogr. 2005, C63, o353−o354. (17) Evian, M.; Felpin, F.; Laurence, C.; Le Breton, J.; Le Questel, J. Z. Kristallogr. 2003, 218, 753−760. (18) Keum, S. R.; Roh, S. J.; Kim, Y. N.; Im, D. H.; Ma, S. Y. Bull. Korean Chem. Soc. 2009, 30, 2608−2612. (19) Ochando, L. E.; Rius, J.; Louër, D.; Claramunt, R. M.; Lopez, C.; Elguero, J.; Amigó, J. M. Acta Crystallogr. 1997, B53, 939−944. (20) Allen, F. H.; Kennard, O.; Watson, D. G.; Brammer, L.; Orpenv, A. G.; Taylor, R. J. Chem. Soc., Perkin Trans. 2 1987, S1−S19. (21) Bacci, A.; Bosetti, E.; Carcelli, M.; Pelagatti, P.; Pelizzi, G.; Rogolino, D. Cryst. Eng. Comm. 2006, 8, 233−244. (22) Aitipamula, S.; Thallapally, P. K.; Thaimattam, R.; Jaskólski, M.; Desiraju, G. R. Org. Lett. 2002, 4, 921−924.

than that of the racemic crystal. This difference in packing efficiency can be explained by the intermolecular hydrogen bonding interactions observed in the crystal structures of both enantiomers.

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CONCLUSIONS The crystal structures of racemic (±)-1, and the enantiomers (S)-(−)-1 and (R)-(+)-1, were solved by X-ray diffraction analysis. Unexpectedly, compound (±)-1 crystallized as a chiral crystal structure in a noncentrosymmetric Sohncke space group P21. This is one of the rare cases of racemic mixtures crystallizing as chiral crystals in a Sohncke space group. The surprising disorder present in the racemate and the superposition of two enantiomeric forms in the same crystal was exhaustively studied, as well as the sharing of the same atomic positions for different kinds of atoms. Resolution of compound (±)-1 using chiral HPLC was performed, allowing the crystallization of both enantiomers separately. The crystal structures of both enantiomers were solved by X-ray diffraction analysis, and their absolute configurations could be determined. Hydrogen bond intermolecular interactions were observed in the pure enantiomers but not in the racemic compound, resulting in zigzag chains between the layers, and possibly in a higher density of the packing compared to that of the racemic crystal.

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ASSOCIATED CONTENT

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AUTHOR INFORMATION

S Supporting Information *

CIF file of 1, 1a, and 1b. Tables with crystal data and structure refinement, nonhydrogen atomic coordinates and equivalent isotropic displacement parameters, bond lengths and angles, anisotropic displacement parameters, torsion angles, and figures of the asymmetric unit and the unit cell of (±)-1, 1a, and 1b. Crystallographic information files are also available from the Cambridge Crystallographic Data Centre (CCDC) upon request (http://www.ccdc.cam.ac.uk CCDC deposition numbers 1057142−1057144). The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.cgd.5b00515. Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge the MINECO and European FEDER funds (MAT2012-38429-C04-02 project) and FPU scholarship for financial support. We also want to express our gratitude to ICMOL and University of Valencia for the instrumental used and especially to Prof. Duane Choquesillo-Lazarte and coworkers of the Laboratory for Crystallographic Studies (University of Granada−CSIC) for fruitful discussions.

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REFERENCES

(1) Flack, H. D. Helv. Chim. Acta 2003, 86, 905−921. (2) Dupray, V. in Recrystallization of Enantiomers from Conglomerates; Recrystallization, Sztwiertnia, K., Ed.; InTech, 2012; ISBN: 978−953− 51−0122−2. (3) Costero, A. M.; Parra, M.; Gil, S.; Gotor, R.; Martínez-Máñez, R.; Sancenón, F.; Royo, S. Eur. J. Org. Chem. 2012, 26, 4937−4946. (4) Dryzun, C.; Avnir, D. Chem. Commun. 2012, 48, 5874−5876. E


Racemic Triarylmethanol Derivative Crystallizes as ... - ACS Publications

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