Structural Studies of Enantiomers, Racemates, and Quasiracemates. 2

Oct 1, 2008 - Department of Chemistry, Eastern Illinois UniVersity, Charleston, Illinois 61920, Bristol-Myers. Squibb, New Brunswick, New Jersey 08903...
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Structural Studies of Enantiomers, Racemates, and Quasiracemates. 2-(3-Bromophenoxy)propionic Acid and 2-(3-Methoxyphenoxy)propionic Acid Meghan E. Breen,† Shella L. Tameze,‡ William G. Dougherty,⊥ W. Scott Kassel,⊥ and Kraig A. Wheeler*,†

CRYSTAL GROWTH & DESIGN 2008 VOL. 8, NO. 10 3863–3870

Department of Chemistry, Eastern Illinois UniVersity, Charleston, Illinois 61920, Bristol-Myers Squibb, New Brunswick, New Jersey 08903, and Department of Chemistry, VillanoVa UniVersity, VillanoVa, PennsylVania 19085 ReceiVed May 1, 2008; ReVised Manuscript ReceiVed August 5, 2008

ABSTRACT: The quasiracemate approach for constructing molecular assemblies has provided a fertile ground in which to exploit the crystal packing tendencies of quasienantiomeric components. The present study of quasiracemic behavior reveals that cocrystallization of (S)-3-(2-bromophenoxy)propionic acid and (R)-3-(2-methoxy)propionic acid generates supramolecular motifs organized in space group C2 with near inversion symmetry. This quasiracemic system, first investigated by J. and I. L. Karle in 1966, consists of carboxyl · · · carboxyl heterodimers that mimic those observed for (()-Br and (()-OCH3. These racemates crystallize to give four distinct phases (two polymorphic forms for each Br and OCH3 compound); two of which, (()-Br-I and (()-OCH3-I, are isostructural with the quasiracemate. This collection of structures, including those of the enantiopure (S)-Br and (R)-OCH3 compounds, underscores the importance of molecular shape to the construction of supramolecular assemblies. Introduction Jerome and Isabella Karle’s 1966 crystal structure determination of the cocrystal of (R)-2-(3-bromophenoxy)propionic acid and (S)-2-(3-methoxyphenoxy)propionic acid (1) provided a

historical contribution to the field of single-crystal X-ray crystallography and one of the first glimpses of the packing motifs of quasiracemic materials.1 The body of work compiled by early practitioners of crystallography, including the Karles, examined an assortment of mathematical constructs for solving the phase problem. Over the course of several decades of study, these efforts bridged the gap between theoretical considerations and practical procedures for solving light-atom structures by deriving structure factor phases directly from the observed amplitudes of diffracted X-rays. The collection of these methods is now commonly referred to as the direct method for structure solution. The symbolic addition procedure is one such direct method approach that traces its roots to Zachariasen in the early 1950s2 that was later extensively developed for noncentrosymmetric cases by the Karle laboratory.3 Given that one component of quasiracemate 1 contains a bromine atom, comparison of the results obtained from both symbolic addition and the classical * Corresponding author. Fax: [email protected]. † Eastern Illinois University. ‡ Bristol-Myers Squibb. ⊥ Villanova University.

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heavy-atom (Patterson function) procedures offered important insights to the utility of this direct method approach. Although symbolic addition remains a viable tool for crystallographers,4 current multisolution methods5 provide the combined benefit of automation and the processing of a large number of solutions, and thus it is not surprising this approach is almost exclusively used today for the solution of small-molecule light-atom structures. While many properties of quasiracemic materials were established prior to 1966, the spatial arrangement of the two chemically dissimilar components of these materials remained largely undiscovered until the Karle’s investigation.6 The crystal structure of quasiracemate 1 showed components organized in supramolecular assemblies described by approximate inversion relationships. Although the close correlation between crystal packing of quasiracemates and their racemic counterparts is now well established, the initial assessment of 1 provided one of the first opportunities to inspect crystallographic evidence of this near inversion relationship that has since become a fundamental tenet observed in all known quasiracemic structures. We have been interested for some time in the quasiracemic approach as a means to understand shape-based molecular recognition processes and were naturally drawn to the Karle’s investigation of quasiracemate 1.7 In the Karle’s study, X-ray intensity data of 1 were collected by use of the multiple-film Weissenberg technique (θmax ) 40°) to give a structure that refined to R ≈ 10%. The level of refinement of 1 is not surprising given the inherent limitations of this data collection strategy and the objectives of the study: “Further refinement with anisotropic temperature factors was not attempted since the main purpose of this investigation was to establish the conformation of a quasi-racemate, and precise values for bond distances were of secondary importance.”1 We report here our effort to reexamine the crystal chemistry of Karle’s quasiracemate by determining the crystal structure of 2, an enantiomorph of 1, and extending the 1966 Karle study to include assessment of the structures of the enantiopure and racemic compounds of 3 and 4. As depicted in Scheme 1, the key design element of

10.1021/cg800449r CCC: $40.75  2008 American Chemical Society Published on Web 10/01/2008

3864 Crystal Growth & Design, Vol. 8, No. 10, 2008 Scheme 1. Molecular Projections of (S)-3 and (R)-4 Showing Chemical Frameworks and Br/OCH3 Groups with Near Isometric Relationships

this investigation includes chemical systems that possess near molecular isometry with the features of chirality and the Br/ OCH3 substitutions as the imposed structural differences. Experimental Section General Considerations. All chemicals and solvents were purchased from the Aldrich Chemical Co. or Acros Chemicals and used as received without further purification. 1H and 13C NMR spectral data were recorded using a 400 MHz Bruker Avance spectrometer. Melting point data were determined using a Melt-Temp apparatus and are uncorrected. Recrystallization experiments were conducted by slow evaporation at room temperature using spectroscopic grade solvents. Quasiracemate of (S)-2-(3-Bromophenoxy)propionic Acid/ (R)-2-(3-Methoxyphenoxy)propionic Acid, 2. Equimolar amounts of (S)-2-(3-bromo-phenoxy)propionic acid, (S)-3, and (R)-2-(3-methoxyphenoxy)propionic acid, (R)-3, were dissolved in 2:1 CH2Cl2/hexanes and allowed to crystallize by slow evaporation to give 2 as colorless plates; mp 111-113 °C. (()-2-(3-Bromophenoxy)propionic Acid and (()-2-(3-methoxyphenoxy)propionic acid, (()-3 and (()-4. The synthesis of racemic 3 and 4 was carried out using the general procedure described by Zhao et al.8 In a round-bottom flask, 0.058 mol of the appropriate phenol and 8.86 g of NaOH (0.22 mol) were dissolved in deionized water (25 mL) to form a pale yellow solution. The solution was stirred at room temperature for 0.5 h then (()-2-chloropropanoic acid (9.02 mL, 0.098 mol) was added portionwise over an hour. The reaction mixture was heated at reflux for 1 h, during which time the solution became opaque. Deionized water (40 mL) was added, and the solution was acidified to pH 2 with concentrated HCl to give a brown oil. The oil was extracted with Et2O (3 × 30 mL), and the combined organic extracts were treated and extracted with 5% Na2CO3 (50 mL). The aqueous layer was acidified to pH 2 with concentrated HCl to give a tan solid. The off-white solid was isolated by vacuum filtration and dried in a vacuum desiccator to give a colorless solid. The solid was purified by recrystallization from 50% formic acid, isolated by vacuum filtration, washed with deionized water (2 × 10 mL), and dried in a vacuum desiccator to give the racemic product as colorless needles. (()-3 (73% yield): recrystallized from CH2Cl2/hexanes to give crystals with two distinct morphologies that were mechanically separated [(()3-I, colorless plates, mp 110-114 °C and (()-3-II, colorless needles, mp 111-114 °C]. 1H NMR (400 MHz, CDCl3): 7.12-7.17 (m, 2 H, Ar-H), 7.07 (dd, J ) 2.5 and 1.5 Hz, 1 H, Ar-H), 6.82 (dt, J ) 6.7 and 2.5 Hz, 1 H, Ar-H), 4.78 (q, J ) 6.8 Hz, 1 H, CH), 1.66 (d, J ) 6.9 Hz, 3 H, CH3). 13C NMR (100 MHz, CDCl3): δ 177.8, 158.1, 130.4, 125.2, 123.1, 118.5, 113.6, 72.4, 18.1. (()-4 (45% yield): recrystallized from CH2Cl2/hexanes [(()-4-I, colorless plates, mp 91-93 °C] and methanol [(()-4-II, colorless plates, mp 90.5-92 °C]. 1H NMR (400 MHz, CDCl3): δ 7.21 (t, J ) 8.4 Hz, 1 H, Ar-H), 6.58-6.46 (m, 3 H, Ar-H), 4.80 (q, J ) 6.8 Hz, 1 H, CH), 3.78 (s, 3 H, OCH3), 1.65 (d, J ) 6.8 Hz, 3 H, CH3). 13C NMR (100 MHz, CDCl3): δ 176.9, 160.5, 158.4, 129.8, 107.4, 106.4, 101.6, 71.8, 55.2, 18.2. (S)-2-(3-Bromophenoxy)propionic Acid, (S)-3. (()-2-(3-Bromophenoxy)propionic acid (0.2470 g, 1.01 mmol) and strychnine (0.3034 g, 0.91 mmol) were dissolved in ethanol (7 mL) and deionized water (4.3

Breen et al. mL), and the solution was allowed to crystallize by slow evaporation at 0 °C for several days. The resulting colorless crystals were isolated by vacuum filtration and treated with saturated Na2CO3 (10 mL) then extracted with CH2Cl2 (2 × 15 mL). The aqueous layer was acidified to pH 2 with 6 M HCl then extracted with CH2Cl2 (2 × 15 mL). The organic extracts were combined, dried over anhydrous MgSO4, and concentrated to give a colorless solid that was recrystallized by slow evaporation from 3:1 CH2Cl2/hexanes to yield (S)-3 as colorless plates; mp 97-101 °C. 1H NMR (400 MHz, CDCl3): 7.14 (m, 2 H, Ar-H), 7.07 (d, J ) 1.8 Hz, 1 H, Ar-H), 6.82 (m, 1 H, Ar-H), 4.77 (q, J ) 6.8 Hz, 1 H, CH), 1.65 (d, J ) 6.8 Hz, 3 H, CH3). 13C NMR (100 MHz, CDCl3): δ 177.43, 157.93, 130.73, 125.06, 122.93, 118.74, 113.73, 72.13, 18.34. (R)-2-(3-Methoxyphenoxy)propionic acid, (R)-4. Anhydrous K2CO3 (3.31 g, 24.0 mmol) and 3-methoxyphenol (1.10 mL, 10.0 mmol) were dissolved in acetonitrile (50 mL) in a 3-neck round-bottom flask and stirred at 0 °C with a mechanical stirrer. Ethyl (S)-(-)-2[(methylsulfonyl)oxy]propionate9 (1.65 mL, 10.2 mmol) was added dropwise over 1 h. The reaction was allowed to slowly warm to room temperature and stirring was continued for 24 h at room temperature then for 20 h at 60 °C. The bulk solids were collected by vacuum filtration and washed with CH2Cl2 (2 × 10 mL). The filtrate and washings were treated with saturated NaHCO3 (15 mL) and extracted. The organic extract was dried over anhydrous MgSO4 and concentrated to give a brown oil. The oil was purified by flash chromatography using 5:1 hexanes/acetone as the eluant (Rf 0.54) and concentrated to give a clear oil. The oil was dissolved in methanol (6 mL) and treated with 2 M NaOH (6.4 mL) at 0 °C for 2 h. The reaction was acidified to pH 2-3 with 6 M HCl then extracted with CH2Cl2 (3 × 10 mL). The extracts were dried over anhydrous MgSO4 and concentrated to give a mixture of pale yellow oil and crystals (0.2810 g, 15.6% yield). A portion of the solid (0.0279 g) was recrystallized via slow evaporation from a CH2Cl2/pentane solution to give two distinct crystal morphologies that were isolated from the mother liquor and mechanically separated as colorless plates [(()-4, mp 90-91 °C] and colorless needles ((R)-4, mp 52-56 °C). The remaining mother liquor was allowed to crystallize by slow evaporation to give (R)-4 as colorless needles (0.0169 g, 60.6% yield), overall yield 9.5%; mp 52-57 °C. 1 H NMR (400 MHz, CDCl3): δ 7.21 (t, J ) 8.2 Hz, 1 H, Ar-H), 6.60-6.48 (m, 3 H, Ar-H), 4.81 (q, J ) 6.9 Hz, 1 H, CH), 3.80 (s, 3 H, OCH3), 1.68 (d, J ) 6.9 Hz, 3 H, CH3). 13C NMR (100 MHz, CDCl3): δ 177.2, 160.9, 158.3, 130.1, 107.7, 106.8, 101.8, 72.0, 55.3, 18.4. Crystallography. Crystallographic details for compounds 2-4 are summarized in Table 1. The X-ray data for compounds 2, (()-4-I, (()4-II, (S)-3,and (R)-4 were collected on a Siemens P4 diffractometer using the XSCANS software package.10 Data collection, integration, scaling, and absorption corrections for (()-3-I and (()-3-II were carried out on a Bruker Kappa APEXII CCD diffractometer equipped with an Oxford Cobra low-temperature device using the Bruker APEXII software.11 The X-SEED software platform,12 equipped with SHELXS and SHELXL modules13 on a PC computer, was used for all structure solution and refinement calculations and molecular graphics. Structures were solved by direct methods and refined by anisotropic full-matrix least-squares for all non-hydrogen atoms. The function ∑w(|Fo|2 |Fc|2)2 was minimized where w ) [σ2(Fc2) + (aP)2 + bP + d + e sin θ] and P ) f[max(0 or Fo2)] + (1 - f)Fc2. Scattering factors for neutral atoms and f′ and f′′ were taken from ref 14, Tables 4 2.6.8 and 6.1.1.4. Hydrogen atom positions for 2-4 were located in difference density maps or calculated using C-H distance criteria. Hydrogen atoms were refined isotropically using a riding model with fixed thermal parameters set to uij ) 1.2Uij(eq) for the atom to which they are bonded (1.5Uij(eq) for methyl hydrogen atoms). Calculated methyl hydrogen atoms were allowed to rotate freely during refinement using the AFIX 137 command of SHELXL. Where possible, the HO hydrogen atoms were located in difference density maps and refined isotropically. Molecular configurations were compared with both the known chirality of the phenoxypropionic acid components and estimated Flack parameters15 and where applicable, atomic coordinates were inverted to achieve correct structural configurations.

Results and Discussion Crystal Structures. Single-crystal structure determinations were carried out on seven homologous phenoxypropanoic acid

Enantiomers, Racemates, and Quasiracemates

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Table 1. Crystallographic Data for Racemic and Quasiracemic Phenoxypropionic Acids 2-4 2

(()-3-I

(()-3-II

(S)-3

(()-4-I

(()-4-II

(R)-4

Crystal Data chemical formula Mr solvent crystal system, space group a, Å b, Å c, Å β, deg V, Å3 Z, Z′ Dx, mg · m-3 F(000) µ (mm-1), radiat. type temp, K crystal form, color crystal size, mm3

C19H21BrClO7 441.27 CH2Cl2/hexanes monoclinic, C2

C10H12O4 196.20 CH2Cl2/hexanes orthorhombic, Pbca 33.191(3) 32.252(3) 6.5305(5) 6.620(2) 33.735(9) 13.9238(13) 5.0850(5) 4.9983(4) 4.7954(3) 4.911(1) 5.188(2) 8.0603(5) 11.303(1) 11.4878(9) 29.301(2) 15.332(4) 11.172(3) 17.796(1) 90.605(7) 90.346(3) 91.773(1) 101.158(13) 93.149(2) 90 1907.6(3) 1851.9(3) 917.16(11) 489.0(2) 1955.3(1) 1997.2(3) 4, 1 8, 1 4, 1 2, 1 8, 1 8, 1 1.536 1.758 1.775 1.664 1.333 1.305 904 976 488 244 832 832 2.193, Mo KR 5.844, Cu KR 4.451, Mo KR 4.174, Mo KR 0.103, Mo KR 0.101, Mo KR 213(2) 173(2) 173(2) 298(2) 298(2) 298(2) plate, colorless needle, colorless plate, colorless plate, colorless plate, colorless plate, colorless 0.84 × 0.24 × 0.06 0.34 × 0.22 × 0.16 0.29 × 0.20 × 0.03 0.76 × 0.16 × 0.03 0.86 × 0.20 × 0.04 0.65 × 0.43 × 0.06

diffractometer

Bruker P4

C9H9BrO3 245.07 CH2Cl2/hexanes monoclinic, C2/c

C9H9BrO3 245.07 CH2Cl2/hexanes monoclinic, P21/n

C9H9BrO3 245.07 CH2Cl2/hexanes monoclinic, P21

C10H12O4 196.20 95% methanol monoclinic, C2/c

C10H12O4 214.21 CH2Cl2/pentane monoclinic, P21 7.832(2) 6.1604(7) 11.563(2) 96.18(2) 554.6(2) 2, 1 1.283 228 0.876, Cu KR 298(2) tablet, colorless 0.73 × 0.23 × 0.05

Data Collection

Tmin 0.23 Tmax 0.88 no. of reflns 2442, 1882, 1619 (meas, uniq, and obs) Rint 0.0494 θ scan range, deg 2.2-27.5

Bruker Kappa APEXII 0.24 0.45 6235, 1642, 1635

Bruker Kappa APEXII 0.28 0.85 6178, 1643, 1641

Bruker P4 0.14 0.89 1870, 1249, 1026

0.0224 2.7-67.8

0.0259 1.4-25.3

0.0529 2.7-27.5

0.0239/0.0639 0.0240/0.0640 1.24 1642 123 0.35/-0.67

0.0256/0.0672 0.0260/0.0676 1.07 1643 120 0.64/-0.51

Bruker P4

Bruker P4

Bruker P4

2326, 1784, 1057

2415, 1823, 1105

0.53 0.96 1366, 921, 894

0.0370 2.4-25.3

0.0216 2.3-25.3

0.0943 5.7-61.9

0.0565/0.127 0.111/0.157 1.03 1784 131 0.18/-0.36

0.0474/0.0933 0.0943/0.110 1.02 1823 131 0.14/-0.15

0.0535/0.132 0.0542/0.134 1.08 921 150 0.19/-0.37

Refinement R/Rω2 (obs data) R/Rω2 (all data) S no. of reflns no. of params ∆Fmax/min (e · Å-3)

0.0365/0.0842 0.0476/0.0889 1.08 1882 247 0.55/-0.35

0.0433/0.0929 0.0582/0.0990 1.04 1249 120 0.65/-0.53

Table 2. Hydrogen Bond Distances (Å) and Angles (deg) for 2-4 compound 2 (()-3-I (()-3-II (S)-3 (()-4-I (()-4-II (R)-4

O-H · · · O O1A-H · · · O2B O1A-H · · · O2B O1-H · · · O2 O1-H · · · O2 O1-H · · · O2 O1-H · · · O2 O1-H · · · O2 O1-H · · · O5 O5-H · · · O2 O5-H · · · O4

∠OO-H H · · · O O · · · O H · · · O (Å) (Å) (Å) (deg) 0.83 0.83 0.71(4) 0.63(3) 0.82 0.96(7) 0.95(4) 0.88(5) 0.89(2) 0.88(2)

1.83 1.82 1.95(4) 2.05(4) 1.89 1.69(7) 1.72(4) 1.73(5) 1.93(2) 1.95(3)

2.662(5) 3.132(3) 2.652(2) 2.673(2) 2.706(6) 2.653(3) 2.668(2) 2.590(4) 2.819(3) 2.797(3)

174 175 176(4) 170(4) 177 178(6) 174(3) 166(4) 175(5) 162(6)

symmetry operation x, y, z x, y, z 1 - x, 1 - y, 1 - z -x, -y, -z -x, 1/2 + y, 1 - z 1 - x, 1 - y 1 - z -x, -y, -z x, y, z 2 - x, 1/2 + y, -z x, y, z - 1

samples that differ by Br and OCH3 substitutions. The relevant crystallographic data are displayed in Table 1, with hydrogenbond geometries for each structure provided in Table 2. An overlay plot consisting of the eight symmetry-independent molecules included in this study shows several variations in conformational patterns (Figure 1). One noteworthy feature of this plot is a rotation about the O3-C4 bond for the racemic and enantiopure bromo structures [(()-3-I, (()-3-II, and (S)-3] to give two conformationally distinct arylbromide fragments. Additional examination of this data also indicates that the position of the methoxy group is evenly distributed over the syn [(()-4-II and (R)-4]) and anti [2 and (()-4-I] positions. Although significant to the overall supramolecular organization of these structures, the observed conformational differences, whether subtle or obvious, do not seem to inhibit formation of quasiracemate 2. Inspection of the crystal structure of 2 reveals a 1:1 binary cocrystal assembled from a blend of nonbonded contacts. As shown in Figure 2a, the asymmetric unit of 2 consists of molecules of (S)-2-(3-bromophenoxy)propionic acid, (S)-3, and

Figure 1. Overlay plot of eight phenoxypropanoic acid molecules showing both bromo (gold) and methoxy (gray) derivatives. For comparison, molecular geometries were inverted to R configurations where appropriate.

(R)-2-(3-methoxyphenoxy)propionic acid, (R)-4, positioned on a pseudoinversion center. As previously reported by Karle and Karle, these components assemble in space group C2 to give heteromeric head-to-head dimers linked by carboxyl O-H · · · O hydrogen bonds.1 These dimeric motifs are further stabilized in the crystal by Br · · · Br contacts with L-geometry16 [3.5889(6) Å, C-Br · · · Br 93.9(2)° and 173.3(2)°] that propagate along the b axis to give molecular tapes (Figure 2b). Although the analogous methoxy groups of 1 arrange in a similar fashion, these chemical functions are separated by >3.4 Å and thus seem an unlikely source of additional crystal cohesion. Crystal growth studies of racemates (()-3 and (()-4 from methanol and methylene chloride/hexane solutions resulted in four unique crystalline phases. In the case of (()-3, crystalline samples were mechanically retrieved as concomitant polymorphs [(()-3-I and (()-3-II]. As shown in Figures 3-6, each racemate

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Figure 2. Crystal structure of quasiracemate (S)-2-(3-bromophenoxy)propionic acid/(R)-2-(3-methoxyphenoxy)propionic acid, 2: (a) asymmetric unit and labeling scheme (50% probability) showing approximate centrosymmetric alignment; (b) packing diagram showing Br and OCH3 groups as space filling models. Hydrogen atoms are removed for clarity.

Figure 3. Crystal structure of racemic 2-(3-bromophenoxy)propionic acid, (()-3-I. Packing diagram showing labeling scheme, asymmetric unit (70% probability), and hydrogen bond scheme. Hydrogen atoms partially deleted for clarity.

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Figure 4. Crystal structure of racemic 2-(3-bromophenoxy)propionic acid, (()-3-II. Packing diagram showing labeling scheme, asymmetric unit (70% probability), and O-H · · · O and Br · · · O contacts. Hydrogen atoms partially deleted for clarity.

Figure 5. Crystal structure of racemic 2-(3-methoxyphenoxy)propionic acid, (()-4-I. Packing diagram showing labeling scheme, asymmetric unit (50% probability), and hydrogen bond scheme. Hydrogen atoms partially deleted for clarity.

in this study forms discrete patterns as carboxyl · · · carboxyl homodimers with comparable geometries to quasiracemate 2. Because the contents of these racemic materials include equimolar portions of chemically identical components that differ in handedness (i.e., enantiomers), the alignment of these hydrogenbonded dimers follows the expected centrosymmetric alignment. Closer inspection of the structures of racemates (()-3-I and (()4-I shows molecules assembled in space group C2/c with supramolecular patterns and unit cell parameters that are

isostructural to 2 (Figures 3 and 5). Similar to 2, (()-3-I forms close Br · · · Br contacts [3.5075(3) Å, C-Br · · · Br 89.90(6)° and 168.78(6)°] that offer additional crystal stabilization. The remaining polymorphs of racemates 3 and 4 [i.e., (()-3-II and (()-4-II], both grown from methylene chloride/hexane solutions, assemble with markedly different packing patterns and space groups (Table 1, Figures 4 and 6). Beyond the formation of the homodimers, the only additional intermolecular contacts observed with (()-3-II were short directional Br · · · O3 interactions

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Figure 6. Crystal structure of racemic 2-(3-methoxyphenoxy)propionic acid, (()-4-II. Packing diagram showing labeling scheme, asymmetric unit (50% probability), and hydrogen bond scheme. Hydrogen atoms partially deleted for clarity.

Figure 7. Crystal structure of (S)-2-(3-bromophenoxy)propionic acid, (S)-3. Packing diagram showing labeling scheme, asymmetric unit (50% probability), and O-H · · · O and Br · · · O contacts. Hydrogen atoms partially deleted for clarity.

[3.125(1) Å, Car-Br · · · O3 174.79(6)°] that occur between neighboring molecules.17 Similar to the structures of other known homochiral carboxylic acids, the components of (S)-3 and (R)-4 favor the formation of catemeric assemblies rather than carboxyl · · · carboxyl dimers as seen in the racemic structures.18 As shown in Figure 7, molecules of (S)-3 are linked by syn-syn O-H · · · O interactions that result in catemeric motifs that extend along the b-axis. This motif is further linked by Br · · · O3 contacts [3.248(4) Å, Car-Br · · · O3 173.4(2)°] similar to those observed for (()-3II. Crystals of (R)-4 form as the monohydrate via strong Ocarboxyl-H · · · Owater contacts (Figure 8). This motif propagates along the c-axis via additional Owater-H · · · Omethoxy interactions

that are further stabilized by Owater-H · · · Ocarbonyl from a neighboring chain to give a molecular tape. Quasiracemate Behavior. Materials that exhibit quasiracemic behavior experienced intense study in the 1960s and 1970s by A. Fredga and co-workers.6 These studies helped to establish the consequence of molecular chirality and degree of shape mimicry to quasiracemate formation through the construction of melting point phase diagrams. Although data retrieved using this approach offered an important contribution to understanding the structural complementarity of quasiracemic components, it was not until the use of single-crystal X-ray diffraction methods that important supramolecular trends of quasiracemates began to emerge. To our knowledge, the earliest crystallographic reports of quasiracemates appeared in the 1960s. In partnership with Fredga, Husebye19 investigated the crystal structure of a binary compound consisting of (-)-1,2-dithiane-3,6-dicarboxylic acid/(+)-1,2-diselenane-3,6-dicarboxylic acid with Karle and Karle1 pursuing the quasiracemic system of (R)-3-(2-bromophenoxy)propanoic acid/(S)-3-(2-methoxyphenoxy)propanoic acid. The principal conclusions from each of these studies emphasized that Fredga’s samples consisted of equimolar portions of components spatially arranged with pseudoinversion symmetry. Extending beyond inspection of the quasiracemate structure, Husebye’s work also included a comparative assessment of the unit cell parameters and space groups of the corresponding racemic compounds that suggested a high degree of isostructurality to the quasiracemate. Karle and Karle’s 1966 report provides the backdrop for the current investigation. Their original study, and others during that era,20 probed the range of utility of the symbolic addition method for structure solution. In addition to validating this method, X-ray data collected for quasiracemate 1 and subsequent data solution and refinement supplied crucial structural information that helped to establish the crystal packing features of this quasiracemic material. One far-reaching implication of this early study rests with its contribution to supramolecular chemistry. While reports that describe the construction of molecular

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Figure 8. Crystal structure of (R)-2-(3-methoxyphenoxy)propionic acid, (R)-4. Packing diagram showing labeling scheme, asymmetric unit (50% probability), and hydrogen bond scheme. Hydrogen atoms partially deleted for clarity.

assemblies using various supramolecular synthons are commonplace today, this 1960s study of quasiracemate 1 represents one of the few early crystallographic studies that offered insight into engineered molecular crystals. Given the historical importance of this work and its connection to quasiracemic materials, we were interested in investigating the complete family of crystal structures of 1 and the related racemic and chiral counterparts. We recently explored the crystal chemistry of a family of similar structures derived from 3-bromo, 3-chloro, and 3-methylphenoxylpropionic acids.7a As with this previous study, we anticipated that additional comparative assessments of homologous families could offer important insight to the structural features responsible for quasiracemic behavior and contribute to the current understanding of molecular shape-based supramolecular assembly that has since emerged from the pioneering work of A. I. Kitaigorodski.21 Our initial pursuit of 1 experienced several obstacles related to the diastereomeric resolution of (()-4 and thus our attention then turned to enantioselective manipulations using the available chiral precursor ethyl (S)-(-)-2-[(methylsulfonyl)oxy]propionate9 to give enantiomer (R)-4. Although this synthetic route provided a facile method for obtaining the methoxy component for quasiracemate formation, the handedness of this building block required that we modify our initial design strategy to include quasiracemate 2 rather than 1, a significant distinction of chirality but inconsequential in terms of quasiracemic supramolecular behavior. We have shown that cocrystallization of an equimolar mixture of (S)-3 and (R)-4 readily forms crystals of quasiracemate 2. The unit cell parameters, space group, and packing motifs observed in this study for 2 are nearly indistinguishable from the crystal structure cited in the 1966 Karle report. The driving force for the formation of this quasiracemic material rests with molecular shape, where the complementary properties of chirality and the topological similarity of Br and OCH3 functions offer key structural features for supramolecular assembly (Scheme 1). While it is true that compounds included in the current work participate in noncovalent interactions, the presence of such attractive forces does not sufficiently account for the formation of 2 since analogous contacts of comparable strength exist in the corresponding homomeric crystals. One indication of the affect of molecular shape on crystal packing may be seen in the structure of 2, where quasiracemate components assemble in space group C2 with molecular alignment that is isostructural

to (()-3-I and (()-4-I (space group C2/c). Each of these structures form “classic” carboxyl · · · carboxyl head-to-head dimers. In the case of 2, crystal motifs are constructed from chemically unique components [i.e., (S)-3 and (R)-4] and thus, unlike the structure of (()-3-I and (()-4-I, can only at best approximate centrosymmetry. The propensity of organic racemic compounds to crystallize with inversion symmetry is well documented in the literature and estimated at >92%.22 The diversity of chemical frameworks and functional groups represented by the entire collection of known racemic structures implies that molecular shape, rather than electrostatic contacts, serves as the primary steering influence for crystal construction that may be directly applied to the molecular assembly process of quasiracemates such as 2. A second polymorph of each racemate, (()-3-II and (()-4II, was also determined in our studies. Although these compounds form hydrogen-bonded dimers similar to quasiracemate 2 and racemates (()-3-I and (()-4-I, self-assembly and molecular conformations of these building-blocks differ markedly (Figures 2-6). The observed structural variations for the racemic and quasiracemic phases are significant. These described differences for the methoxy racemates (()-4-I and -II likely arise from the lack of additional electrostatic contacts beyond dimer formation, while the discrepancy in structures of the Br adducts originates from use of energetically similar Br · · · Br [2 and (()-3-I] or Br · · · O [(()-3-II] contacts.17 Beyond dimer formation, the consequence of insufficient crystal cohesion and the presence of competitive intermolecular contacts offers an interesting opportunity to study a homologous family of compounds that demonstrate supramolecular flexibility by adopting one of several energetically favorable packing modes. Our study also included crystallographic assessment of the quasienantiomers (S)-3 and (R)-4. These compounds, the building blocks for quasiracemate construction, crystallize individually to give molecular assemblies far removed from that observed for 2. These anticipated differences range from hydrogen-bond schemes to packing patterns lacking even a remote suggestion of near centrosymmetric alignment. Inclusion of the structures of such enantiomorphic compounds in this body of work helps establish important structural benchmarks for understanding the recognition profile of 2. A detailed crystal structure of quasiracemate 2 and its racemic and enantiopure counterparts allows for a comparative assess-

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ment of the structural trends of this homologous family. Cocrystals of 2 were successfully prepared by exploiting the crystal packing tendencies of racemic compounds and the complementarity feature of molecular shape of (S)-3 and (R)4. Conclusions from this study emphasize the importance of molecular shape to the organization of local and extended crystal environments. To date, only limited aspects of molecular recognition as related to assembling quasienantiomers to give quasiracemic compounds exist in the literature. Although it is generally accepted that successful construction of quasiracemates originates from best-fit scenarios involving the topologies of the quasienantiomeric components, several important questions persist. Is it possible to construct quantitative descriptors of molecular shape to account for its effects on supramolecular assemblies? Can successful quasiracemate formation take place using two quasienantiomers that differ considerably in shape and size? Suitable answers to such questions are not likely to emerge without the concerted effort of investigators and a blend of innovative approaches that involve synthetic manipulations, crystal growth applications, computational methods, and X-ray diffraction. Insight into the fundamental details of quasiracemate formation is not limited to applications directed at the assembly of quasienantiomers as such information will also contribute to the growing set of principles that describe the spatial control of molecular associations. Acknowledgement is made to the donors of the American Chemical Society Petroleum Research Fund Type B, the National Science Foundation (Grant 9414042 to K.A.W. and Grant 0521062 to W.S.K.), and institutional support from Eastern Illinois University. Supporting Information Available: X-ray crystallographic information files (CIF) for compounds 2, (()-3-I, (()-3-II, (S)-3, (()-4-I, (()-4-II, and (R)-4. This material is available free of charge via the Internet at http://pubs.acs.org.

Breen et al.

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