Structural Studies of Enantiomers, Racemates, and Quasiracemates: N-(4-Methylbenzoyl)methylbenzylamine and N-(4-Nitrobenzoyl)methylbenzylamine Mukta S. Hendi,† Paul Hooter,† Raymond E. Davis,‡ Vincent M. Lynch,‡ and Kraig A. Wheeler*,†
CRYSTAL GROWTH & DESIGN 2004 VOL. 4, NO. 1 95-101
Department of Chemistry, Delaware State University, Dover, Delaware, 19901-2202, and Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas, 78712-1167 Received July 18, 2003;
Revised Manuscript Received September 9, 2003
ABSTRACT: Cocrystallization of equal portions of (R)-N-(4-methylbenzoyl)-R-methylbenzylamine and (S)-N-(4nitrobenzoyl)-R-methylbenzylamine yields bimolecular crystals that exhibit quasiracemic behavior. Derived from a slight chemical modification of one component of the “true” racemate, this quasiracemate compound extends the current knowledge base of structural features responsible for the construction of quasiracemic molecular arrays. A crystallographic comparison of the quasiracemate structure with its enantiomeric components and racemic counterpartssa total of five structuressdemonstrates the importance of molecular shape to the self-assembly of crystalline architectures. Inspection of the quasiracemate structure reveals local molecular packing that closely mimics the centrosymmetric alignment of the racemates. Unlike our prior investigations of the quasiracemate phenomena, however, the current set of enantiomeric, racemic, and quasiracemic compounds lacks any prominent long-range isostructural correlation as indicated by their relevant crystal structure information (i.e., space groups, unit cell parameters, and packing patterns). The absence of any clear preferences in crystal packing for this set of diarylamides emphasizes the practical importance of the quasiracemate approach, for which the generation of predictable molecular assemblies is not restricted by any single molecular feature as is often the case with design methods based solely (or nearly so) on hydrogen bonding patterns. Introduction In our recent investigations to understand the specificity and transferability of molecular shape to crystal packing, we described the crystal chemistry of several families of isosteric compounds.1-4 Unlike the vast majority of investigations that control the alignment of molecular crystals by use of functional group associations (e.g., hydrogen bonds), our approach utilizes the control feature of molecular topology to engineer molecular arrays. Conceptually, the self-assembly of molecules based on topological influences could result in a host of supramolecular architectures; however, in practice, molecular organization is often limited to energetically favorable closest-packed arrangements.5 An important structural consequence of such a best-fit scenario is the tendency for molecules to form centrosymmetric alignments. This bias for centrosymmetry is estimated to be 4:1 for all structures6 and from a search of the Cambridge Structural Database (version 5.24, ref 7), >90% for organic racemic compounds. The design strategy used in our studies exploits this well-known statistical preference for racemic materials to crystallize with centrosymmetric alignment. By synthesizing sets of isosteric compounds that are chemically unique and opposite in handedness, we have successfully generated molecular cocrystals that approximate centrosymmetry. A crystallographic study comparing such bimolecular compounds, termed quasiracemates, to the structures * Corresponding author. Fax: (302) 857-6539. E-mail: kwheeler@ dsc.edu. † Delaware State University. ‡ University of Texas at Austin.
of the individual components (i.e., the “true” racemates and enantiomers) allows evaluation of the structural preferences responsible for quasiracemate formation. The family of diarylamides 1-3 provides the basis of investigation for this study.
Our reports on the phenomenon of quasiracemate behavior follow a rational design that includes the synthesis and structural characterization of not just the structures of the quasiracemates, but also the individual enantiomers and the “true” racematessa total of five crystal structures. Such an approach promotes elucidation of key structural features for consideration in designing molecular alignment. Our previous studies of quasiracemates constructed from diarylamide (4)1 and propanoic acid (5 and 6)2,3 templates provided insight into the structural preferences of these quasiracemate systems. Despite the imposed functional group differences, a comparison of relevant crystal structure infor-
10.1021/cg0341353 CCC: $27.50 © 2004 American Chemical Society Published on Web 10/18/2003
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Hendi et al.
Table 1. Crystallographic Data for 1-3 crystal data
(R)-1
(()-1
(S)-2
(()-2
3
empirical formula MW (g mol-1) crystal size (mm) crystal system space group a, Å b, Å c, Å R, deg β, deg γ, deg V, Å3 Z Z′ Dcalc (g cm-3) F(000) µ(Mo KR) (mm-1) temp (K) 2θ scan range (°) reflns collected unique reflns data:param ratio Rint R/R2ω (obs data) R/R2ω (all data) ∆Fmax/min (e‚Å-3) S
C16H17NO 239.31 0.74 × 0.32 × 0.22 monoclinic P21 (No. 4) 8.2681(8) 5.2570(3) 15.7174(9) 90 99.097(8) 90 674.57(9) 2 1 1.178 256 0.073 293(2) 2.49-30.00 3038 2564 14.5 0.0134 0.0465/0.0987 0.0870/0.1158 0.116/-0.128 1.01
C16H17NO 239.31 0.79 × 0.36 × 0.32 orthorhombic Pca21 (No. 29) 12.332(1) 9.731(1) 22.926(1) 90 90 90 2751.2(4) 8 2 1.156 1024 0.081 293(2) 2.09-26.71 1350 1350 4.1 0.000 0.0336/0.0752 0.0488/0.0866 0.122/-0.129 1.11
C15H14N2O3 270.28 0.76 × 0.30 × 0.30 orthorhombic P212121 (No. 19) 8.554(1) 9.8900(7) 33.038(3) 90 90 90 2794.8(4) 8 2 1.285 1136 0.091 293(2) 2.15-27.50 4679 4417 11.9 0.0186 0.0613/0.1336 0.1188/0.1599 0.209/-0.294 1.06
C15H14N2O3 270.28 0.38 × 0.12 × 0.10 monoclinic P21/n (No. 14) 11.8850(1) 5.4550(1) 40.4438(6) 90 95.367(1) 90 2610.58(7) 8 2 1.375 1136 0.097 153(2) 2.92-27.48 10329 5920 16.0 0.0322 0.0448/0.0985 0.0817/0.1141 0.222/-0.319 1.02
C31H31N3O4 509.59 0.56 × 0.56 × 0.16 monoclinic P21 (No. 4) 9.4413(9) 5.9721(7) 23.394(3) 90 93.670(15) 90 1316.3(3) 2 2 1.286 540 0.086 173(2) 2.16 -27.50 3967 3426 9.8 0.0226 0.0467/0.0950 0.0823/0.1222 0.235/-0.259 1.04
mation (i.e., unit cell parameters, crystallographic data, and packing patterns) revealed that those quasiracemic systems exhibited a high degree of isostructurality with the corresponding “true” racemates. As a continuing effort to expand the database of known quasiracemic materials and our understanding of the key features that contribute to quasiracemate formation, this study examines the crystal structures of a family of diarylamides (1-3) that differ by CH3 and NO2 substitutions.
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 NMR spectral data were recorded using a JEOL FX90Q spectrometer equipped with the TECMAG computer interface. Melting point data were determined using a Melt-Temp apparatus and are uncorrected. Recrystallization experiments were conducted at room temperature using spectroscopic grade solvents. General Synthesis of Diarylamides 1-3. To a nitrogen purged 25 mL round-bottomed flask containing either 4-nitrobenzoic acid or 4-methylbenzoic acid (0.0060 mol) at 0 °C was added 2.2 mL of thionyl chloride (0.030 mol). Upon warming to room temperature, the reaction mixture was
stirred and refluxed for 3 h. Excess thionyl chloride was removed by washing the contents of the flask with 10 mL of hexane and subsequent reduction under reduced pressure to give the crude acid chloride as a light-yellow solid. The acid chloride was used without further purification. The acid chloride was dissolved in 10 mL of methylene chloride and allowed to stir at 0 °C for 20 min. A solution of the appropriate enantiomeric or racemic R-methylbenzylamine was dissolved in 5 mL of methylene chloride and then added to the reaction mixture and stirred for an additional 30 min. The homogeneous solution was then washed with 25 mL of water and the resulting organic layer was extracted with a succession of water saturated sodium bicarbonate, 4 M HCl, and water and finally dried with anhydrous magnesium sulfate. Reduction of the organic layer under vacuo gave solid products in > 70% yield. X-ray quality crystals of 1-3 were obtained by slow evaporation of 1:1 solutions of methylene chloride and hexane at room temperature. (R)-N-(4-Methylbenzoyl)-R-methylbenzylamine, (R)-1. mp 133-135 °C; 1H NMR (CDCl3): δ 7.67 (d, J ) 7.9, 2H), 7.35 (Br s, 5H), 7.19 (d, J ) 7.9, 2H), 6.36 (Br s, N-H), 5.245.40 (m, 1H), 2.37 (s, 3H), 1.58 (d, J ) 6.9 Hz, 3H), (()-N-(4-Methylbenzoyl)-R-methylbenzylamine, (()-1. mp 127-128 °C; 1H NMR (CDCl3): δ 7.63 (d, J ) 7.7, 2H), 7.39 (Br s, 5H), 7.14 (d, J ) 7.7, 2H), 6.36 (Br s, N-H), 5.245.40 (m, 1H), 2.36 (s, 3H), 1.55 (d, J ) 7.1 Hz, 3H). (S)-N-(4-Nitrobenzoyl)-R-methylbenzylamine, (S)-2. mp 120-121 °C; 1H NMR (CDCl3): δ 8.23 (d, J ) 8.6, 2H), 7.90 (d, J ) 8.6, 2H), 7.36 (Br s, 5H), 6.60 (Br s, N-H), 5.24-5.40 (m, 1H), 1.62 (d, J ) 6.7 Hz, 3H). (()-N-(4-Nitrobenzoyl)-R-methylbenzylamine, (()-2. mp 113-114 °C; 1H NMR (CDCl3): δ 8.17 (d, J ) 8.5, 2H), 7.85 (d, J ) 8.5, 2H), 7.29 (Br s, 5H), 6.61 (Br s, N-H), 5.23-5.41 (m, 1H), 1.59 (d, J ) 6.9 Hz, 3H). (R)-N-(4-Methylbenzoyl)-R-methylbenzylamine/(S)-N(4-Nitrobenzoyl)-R-methylbenzylamine - Quasiracemate 3. mp 128-129 °C; 1H NMR (CDCl3): δ 8.20 (d, J ) 8.5, 2H, 7.88 (d, J ) 8.5, 2H), 7.65 (d, J ) 7.7, 2H), 7.32 (Br s, 5H), 7.17 (d, J ) 7.7, 2H), 6.42 (Br s, 2 N-H), 5.22-5.45 (m, 2H), 2.36 (s, 3H), 1.58 (br d, 6H) Crystallography. Crystallographic details for compounds 1-3 are summarized in Table 1. The X-ray data for compounds (R)-1, (()-1, (S)-2, and 3 were collected on a Siemens P4 diffractometer using a graphite monochromatic Mo KR radiation (λ ) 0.71073 Å) and XSCANS software package.8 The data
Enantiomers, Racemates, and Quasiracemates
Crystal Growth & Design, Vol. 4, No. 1, 2004 97
Table 2. Hydrogen Bond Distances (Å) and Angles (°) for 1-3a cmpd (R)-1 (()-1 (S)-2 (()-2 3 a
D-H‚‚‚A (Å) N-H‚‚‚Oi N1A-H‚‚‚O1Bi N1B-H‚‚‚O1Aii N1A-H‚‚‚O1Biii N1B-H‚‚‚O1Aiii N1A-H‚‚‚O1Aii N1B-H‚‚‚O1Biv N1A-H‚‚‚O1Bv N1B-H‚‚‚O1Avi
N-H (Å)
H‚‚‚O (Å)
N‚‚‚O (Å)
N-H‚‚‚O (°)
0.80(3) 0.94(6) 0.86(6) 0.75(4) 0.86(3) 0.87(2) 0.82(2) 0.90(7) 0.87(4)
2.35(3) 1.99(6) 2.03(7) 2.17(4) 2.00(3) 2.47(2) 2.52(2) 2.05(7) 2.13(4)
3.132(3) 2.897(8) 2.871(8) 2.914(4) 2.828(4) 3.333(2) 3.282(2) 2.926(6) 2.983(6)
170(2) 161(4) 168(7) 170(5) 163(3) 171(2) 154(2) 162(6) 164(3)
Symmetry codes: (i) x, y, z; (ii) x, y - 1, -z; (iii) 1 - x, y - 0.5, 1.5 - z; (iv) x,1 + y, z; (v) -x, y - 0.5, 1 - z; (vi) 1 - x, y - 0.5, 1 -
z. Table 3. Selected Torsional Angles (°) for 1-3
cmpd (R)-1 (()-1 (S)-2 (()-2 3
molecule a b a b a b a (S-2) b (R-1)
C11-C10-C8-N (°)
C10-C8-N-C7 (°)
C8-N-C7-C4 (°)
N-C7-C4-C5 (°)
45.3(4) 103.7(7) -41.8(8) -49.2(5) -13.6(6) 48.7(2) 55.5(2) -49.5(6) 50.1(6)
79.9(3) 108.5(7) -94.6(7) -72.0(5) -83.2(5) 95.9(2) 82.2(2) -80.9(7) 81.2(7)
-177.2(2) 175.5(5) 177.2(5) 179.0(4) 168.4(3) 178.2(1) -171.5(1) 170.7(5) -170.2(5)
152.2(2) 155.7(6) 171.3(5) -159.1(4) 157.1(4) -153.9(1) -145.0(2) 151.3(5) -149.1(5)
set for (()-2 was collected on a Nonius Kappa CCD diffractometer equipped with an Oxford Cryostream low-temperature device using monochromatized MoKR radiation (λ ) 0.71073 Å). Data sets were collected at 25 °C [(R)-1, (()-1, and (S)-2], -120 °C [(()-2] and -100 °C [3] and corrected for Lorentz and polarization effects. No absorption corrections were applied since the absorption coefficient, µ, was low and crystal geometry was favorable in each case. Crystal stabilities were monitored by measuring three standard reflections every 97 reflections with no significant variations (
