Organic Crystal Engineering with 1,4-Piperazine-2,5-diones. 7. Crystal

Organic Crystal Engineering with 1,4-Piperazine-2,5-diones. 7. Crystal Packing of Piperazinediones Derived from 2-Amino-7-nitro-4-methoxyindan-2-carboxylic Acid Deogratias Ntirampebura,† Bhumasamudram Jagadish,† Gary S. Nichol,† Michael D. Carducci,† Alice Dawson,† Asha Rajapakshe,† Allen G. Oliver,‡ William Clegg,§ Ross W. Harrington,§ Larry Layne, Jr.,† Jason I. Margolis,† and Eugene A. Mash*,†

CRYSTAL GROWTH & DESIGN 2008 VOL. 8, NO. 9 3257–3270

Department of Chemistry, The UniVersity of Arizona, Tucson, Arizona 85721-0041, Department of Chemistry and Biochemistry, UniVersity of California, Santa Cruz, Santa Cruz, California 95064, and School of Natural Sciences (Chemistry), Newcastle UniVersity, Newcastle upon Tyne, NE1 7RU, U.K. ReceiVed December 17, 2007; ReVised Manuscript ReceiVed June 3, 2008

ABSTRACT: 1,4-Piperazine-2,5-diones derived from 2-amino-7-nitro-4-methoxyindan-2-carboxylic acid were prepared in meso, racemic, and enantiomerically pure forms, crystallized from DMSO or DMF, and the supramolecular organization in the crystals determined by X-ray crystallography. These molecules were designed to bear two strongly dipolar p-nitroanisole groups, aligned in the enantiomeric stereoisomers and opposed in the meso stereoisomer. Consistent with piperazinediones of similar size and shape bearing nonpolar or weakly dipolar arene groups, these compounds engage in R22(8) hydrogen bonding, most often forming onedimensional tapes. However, the preference for arene perpendicular edge-to-center interactions seen in the former is replaced by a preference for parallel edge-to-center arene interactions. While the dipoles of parallel edge-to-center associated arenes are often opposed, this is not a requirement in the solid state. Introduction The field of crystal engineering1–5 seeks an understanding of weak intermolecular associative forces and strives for rational development of materials useful for a wide range of applications, for example, nonlinear optical materials6–9 for use in devices for optical communication or computing. While it is clear that bulk materials with net dipoles display valuable properties, the design of such materials from first principles remains elusive.10 We consider the molecular framework of pentacyclic molecules 1 suitable for use in an exploration of structural effects on weak intermolecular associative forces and an appropriate scaffold for the design of compounds that could possess useful bulk properties.11–16 Conformational freedom of such molecules is restricted,17 limiting the number of possible packing options. At the same time, attachment of functional groups to the scaffold can provide structural variability. For example, incorporation of electron donor (D) and acceptor (A) groups as in 2 renders the molecule chiral and dipolar (see Figure 1). The central 1,4piperazine-2,5-dione ring is known to favor formation of supramolecular “one-dimensional” tapes through reciprocal amide-to-amide R22(8) hydrogen bonding.18 This was the case for piperazinediones 3 and 4.19,20 Formation of tapes from enantiomerically pure 2 requires that the groups D and A reside on opposite sides of the tape. Such tapes must necessarily possess aligned dipoles that are perpendicular to the long axis (z-axis, Figure 1) of the tape. Control of order in the second and third dimensions (Figure 1, x-axis and y-axis) for tapes of 2 depends on harnessing van der Waals interactions, arene interactions, Coulombic interactions, and/or additional hydrogen bonding interactions. van der Waals attractive interactions almost always contribute significantly to stabilization of the crystal structure as evidenced by

Figure 1. Intermolecular R22(8) hydrogen bonding interactions for piperazinedione 2.

* To whom correspondence should be addressed. Phone: (520) 621-6321. Fax: (520) 621-8407. E-mail: [email protected]. † The University of Arizona. ‡ University of California. § Newcastle University.

the tendency of organic compounds to achieve closest packing in the solid state.21–25 Various arene interaction types have been recognized as important, from the packing of small molecules to the stabilization of protein tertiary structures.26,27 The terms

10.1021/cg701240m CCC: $40.75  2008 American Chemical Society Published on Web 07/23/2008

3258 Crystal Growth & Design, Vol. 8, No. 9, 2008

“parallel center-to-center”, “parallel edge-to-center”, and “perpendicular edge-to-center” will be used to describe arene interaction types herein.28 Parallel center-to-center association is favored for arene rings that possess very different electron densities, as in cocrystals of arenes and perfluoroarenes.29–31 Parallel edge-to-center association also is responsive to changes in π electron density due to substituent effects.32,33 Perpendicular edge-to-center interactions are often observed for unsubstituted arenes, as in the crystal structures of benzene,34 naphthalene,35 and anthracene,36 among others. Both the nature and magnitude of perpendicular edge-to-center interactions have been questioned, but there is agreement that such interactions are stabilizing.37–41 Perpendicular edge-to-center associations of neighboring arene rings were observed in crystals of 3, meso4, rac-4, and (S,S)-4.19,20 The importance of dipolar interactions in determining crystal packing is less clear.10,42–48 In crystals of (S,S)-4, dipoles due to the p-bromoanisole groups of perpendicular edge-to-center associated neighboring tapes were opposed.20 However, in crystals of meso-4 and rac-4 the dipoles were randomly distributed as aligned or opposed along perpendicular edge-to-center-associated neighboring tapes. Thus, the observed dipole opposition in (S,S)-4 was considered a consequence of enantiomeric purity, and not a structural determinant. Rather, hydrogen bonding, arene perpendicular edge-to-center, and van der Waals interactions were thought to control crystal packing of molecules 3, meso-4, rac-4, and (S,S)-4.19,20

One might postulate that piperazinediones related to 3 and 4, but bearing stronger dipoles, would pack similarly. Pentacyclic scaffold 2 thus affords an opportunity to study the effect of local and molecular dipoles on crystal packing. Previously we reported the syntheses and crystal structures of the more strongly polar compounds (R,R)-5, (S,S)-5, and rac-5, which contain two aligned p-methoxybenzonitrile dipoles, and meso5, which contains two opposed p-methoxybenzonitrile dipoles.49 In crystals of these compounds, polar crystallization solvents such as DMSO were included as ordered components of the

Ntirampebura et al.

hydrogen bonding network and in some cases as disordered objects. Thus, 1D “ladder-like” tapes and perpendicular edgeto-center associations were absent. Instead, parallel edge-tocenter interactions with p-methoxybenzonitrile dipoles approximately aligned were observed in crystals of (R,R)-5, (S,S)-5, and rac-5. We report herein the syntheses and crystal structures of the even more strongly dipolar compounds (S,S)-6 and rac6, which contain two aligned p-nitroanisole dipoles, and meso6, which contains two opposed p-nitroanisole dipoles. The syntheses and crystal structures of the related (S)-phenylalaninecontaining compounds (R,S)-9 and (S,S)-9 are also presented and discussed. Experimental Section All reactions were performed under argon. Reaction mixtures were stirred magnetically. Hygroscopic liquids were transferred via syringe and were introduced into reaction vessels through rubber septa. Solutions were concentrated using a rotary evaporator at 30-150 mmHg. Analytical thin-layer chromatography was performed on glassbacked, precoated plates (0.25 mm, silica gel 60, F-254). Visualization of spots was effected by exposure to a UV lamp. Gravity driven column chromatography was performed using silica gel 60 (70-230 mesh). Proton magnetic resonance spectra were recorded at 300 or 500 MHz and were referenced to the residual proton signal of trifluoroacetic acid-d (TFA-d, 11.5 ppm). Carbon-13 magnetic resonance spectra were recorded at 75 or 125 MHz and were referenced to the center of the TFA-d quartet (162.4 ppm). Mass spectra were obtained from the Mass Spectrometry Laboratory in the Department of Chemistry at the University of Arizona. X-ray crystallographic analyses were carried out at the X-ray Diffraction Facility, Department of Chemistry, University of Arizona; on beamline 11.3.1 at the Advanced Light Source, Berkeley, CA; and at Newcastle University, Newcastle upon Tyne, UK. Details of the crystallographic analyses are reported in Supporting Information. Elemental analyses were performed by Desert Analytics, Tucson, AZ. 2,3-Dibromomethyl-4-nitroanisole (11).50 To a mixture of 2,3dimethyl-4-nitroanisole51 (10, 5.00 g, 27.6 mmol) and N-bromosuccinimide (NBS, 10.8 g, 61 mmol) in CCl4 (50 mL) was added benzoyl peroxide (BPO, 67 mg, 0.28 mmol). The mixture was heated to reflux for 4 days. Additional BPO (134 mg, 0.56 mmol) was added after 1, 3, 24, 48, and 72 h. The solvent was then removed under reduced pressure and the yellow solid residue chromatographed on silica gel 60 using 10% EtOAc/hexanes as eluent to give 8.43 g (24.9 mmol, 90%) of 11 as a light yellow solid, mp 96-98 °C. 1H NMR (CDCl3) δ 3.99 (s, 3H), 4.73 (s, 2H), 4.90 (s, 2H), 6.94 (d, 1H, J ) 9.3 Hz), 8.07 (d, 1H, J ) 9.3 Hz); 13C NMR (CDCl3) δ 22.1, 23.4, 56.6, 110.8, 127.4, 127.9, 133.6, 142.1, 161.1; HRGCMS (EI+) calcd for C9H9Br2NO3 336.8949, found 336.8956. rac-Ethyl 7-methoxy-4-nitro-2-isocyanoindan-2-carboxylate (rac12). The method of Kotha was employed.52 To a solution of ethyl isocyanoacetate51 (2.60 mL, 23.6 mmol) in acetonitrile (400 mL) were added finely ground potassium carbonate (19.5 g, 142 mmol), tetrabutylammonium hydrogen sulfate (3.20 g, 9.44 mmol) and 11 (8.00 g, 23.6 mmol). The resulting heterogeneous mixture was heated to reflux for 8 h. The reaction mixture was then cooled and filtered through a sintered glass funnel to remove the salts. Volatiles were removed in Vacuo and the residue taken up in ether, washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated to give a pale yellow solid. This material was chromatographed on silica gel 60 using 30% EtOAc/hexanes as eluent to give 3.6 g (12.4 mmol, 53%) of rac12 as a pale yellow solid, mp 108-109 °C. IR (cm-1) 2137, 1747, 1588, 1519; 1H NMR (CDCl3) δ 1.35 (t, 3H, J ) 7.2 Hz), 3.50 (d, 1H, J ) 17.1 Hz), 3.62 (d, 1H, J ) 17.1 Hz), 3.94 (s, 3H), 4.09 (s, 2H), 4.33 (q, 2H, J ) 7.2 Hz), 6.86 (d, 1H, J ) 9.3 Hz), 8.2 (d, 1H, J ) 9.3 Hz); 13C NMR (CDCl3) δ 13.8, 43.1, 48.2, 56.0, 63.3, 67.0, 109.7, 126.7, 128.3, 136.5, 138.4, 159.3, 160.2, 167.8. Anal. Calcd for C14H14N2O5: C, 57.93; H, 4.86; N, 9.65. Found: C, 57.65; H, 4.66; N, 9.49. rac-Ethyl 2-amino-7-methoxy-4-nitroindan-2-carboxylate (rac13). To a solution of rac-12 (3.6 g, 12.4 mmol) in ethanol (80 mL) was added conc HCl (3 mL). The reaction mixture was stirred at room temperature for 2 h. Ethanol was evaporated under reduced pressure

Crystal Engineering with 1,4-Piperazine-2,5-diones and the resulting hydrochloride salt was dissolved in water. The aqueous solution was extracted with ether (100 mL) and the ether layer was discarded. The aqueous layer was brought to pH 9-10 by addition of NH4OH solution and then extracted with EtOAc (2 × 100 mL). The combined ethyl acetate extracts were washed with water and brine and dried over anhydrous MgSO4. Removal of volatiles in Vacuo gave 3.05 g (10.9 mmol, 88%) of rac-13 as a light yellow solid, mp 120-121 °C. IR (cm-1) 3374, 2975, 2350, 1728, 1584, 1514; 1H NMR (CDCl3) δ 1.28 (t, 3H, J ) 7.2 Hz), 1.99 (s, 2 H), 2.91 (d, 1H, J ) 16.3 Hz), 3.41 (d, 1H, J ) 16.3 Hz), 3.47 (d, 1H, J ) 18.3 Hz), 3.89 (s, 3H), 3.90 (d, 1H, J ) 18.3 Hz), 4.22 (q, 2H, J ) 7.2 Hz), 6.79 (d, 1H, J ) 9.3 Hz), 8.13 (d, 1H, J ) 9.3 Hz); 13C NMR (CDCl3) δ 14.1, 42.7, 48.1, 55.8, 61.6, 64.1, 108.9, 126.0, 130.9, 139.0, 139.5, 160.5, 176.2; HRMS (FAB) calcd for C13H17N2O5 281.1137, found 281.1138. (S,S)-N-[(2-Carboethoxy)-4-methoxy-7-nitroindan-2-yl]-2-[(Ncarbo-2,2-dimethylethoxy)amino]-3-phenylpropanamide [(S,S)-14] and (R,S)-N-[(2-carboethoxy)-4-methoxy-7-nitroindan-2-yl]-2-[(Ncarbo-2,2-dimethylethoxy)amino]-3-phenylpropanamide [(R,S)-14]. The method of Castro was employed.53 To a solution of rac-13 (2.50 g, 8.93 mmol), N-carbobenzyloxy-L-phenylalanine51 (3.55 g, 13.4 mmol), and triethylamine (2 mL) in DMF (40 mL) was added BOP reagent51 (5.92 g, 13.4 mmol). The reaction mixture was stirred at room temperature for 12 h and then diluted with EtOAc (500 mL) and water (100 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (3 × 50 mL). The organic extracts were combined and sequentially washed with 2 N aqueous HCl (2 × 200 mL), water (200 mL), saturated NaHCO3 (2 × 200 mL), water (200 mL), brine (200 mL), and were then dried over anhydrous MgSO4. Volatiles were removed in Vacuo and the residue was chromatographed on silica gel 60 eluted with 20% EtOAc/benzene to give 14 as a mixture of diastereoisomers (4.54 g, 8.61 mmol, 96%). Repeated chromatography on silica gel 60 eluted with 10% EtOAc/benzene achieved separation of the diastereoisomers. Data for the less polar diastereomer: [R]25D -47.3 (c ) 0.54, CH2Cl2), mp 212-213 °C; IR (cm-1) 3311, 2966, 2386, 135, 1675, 1517, 1282;1H NMR (CDCl3) δ 1.22 (t, 3H, J ) 7.2 Hz), 1.38 (s, 9H), 3.03 (m, 2H), 3.27 (d, 1H, J ) 17.7 Hz), 3.54 (d, 1H, J ) 17.7 Hz), 3.67 (d, 1H, J ) 18.6 Hz), 3.87 (d, 1H, J ) 18.6 Hz), 3.93 (s, 3H), 4.20 (q, 2H, J ) 7.2 Hz), 4.30 (m, 1H), 5.01 (m, 1H), 6.61 (s, 1H), 6.81 (d, 1H, J ) 9.3 Hz), 7.20-7.26 (m, 5H), 8.16 (d, 1H, J ) 9.3 Hz); 13C NMR (CDCl3) δ 14.0, 28.2, 38.3, 40.3, 46.0, 55.9, 62.1, 64.3, 80.2, 109.0, 126.1, 126.9, 128.3, 128.6, 129.3, 130.9, 136.5, 138.4, 138.6, 160.1, 170.8, 172.5; HRMS (FAB) calcd for C27H34N3O8 528.2346; found 528.2340. Data for the more polar diastereomer: [R]25D +16.2 (c ) 0.53, CH2Cl2), mp 148-149 °C; IR (cm-1) 3737, 3312, 2985, 2360, 2340, 1742, 1677, 1517, 1280; 1H NMR (CDCl3) δ 1.22 (t, 3H, J ) 7.2 Hz), 1.37 (s, 9H), 3.01 (m, 2H), 3.23 (d, 1H, J ) 17.5 Hz), 3.46 (d, 1H, J ) 17.5 Hz), 3.69 (d, 1H, J ) 18.6 Hz), 3.89 (s, 3H), 3.97 (d, 1H, J ) 18.6 Hz), 4.20 (q, 2H, J ) 7.2 Hz), 4.33 (m, 1H), 5.14 (m, 1H), 6.78(d, 1H, J ) 9.0 Hz), 6.83 (s, 1H), 7.16-7.23 (m, 5H), 8.12 (d, 1H, J ) 9.0 Hz); 13C NMR (CDCl3) δ 13.9, 28.1, 38.2, 40.4, 45.7, 55.8, 62.0, 64.3, 80.3, 108.9, 126.0, 126.8, 128.2, 128.5, 129.2, 130.4, 136.5, 138.4, 138.8, 160.0, 170.7, 172.4; HRMS (FAB) calcd for C27H34N3O8 528.2346; found 528.2349. Anal. Calcd for C27H33N3O8: C, 61.46; H, 6.30; N, 7.96. Found: C, 61.22; H, 6.50; N, 7.96. (S,S)-Cyclo[(2-amino-4-methoxy-7-nitroindan-2-carboxylic acid)(phenylalanine)] [(S,S)-9]. The less polar diastereomer of dipeptide 14 (200 mg, 0.380 mmol) was dissolved in TFA (6 mL) and the mixture stirred at room temperature overnight. TFA was removed in Vacuo and MeOH added to the residue. Methanol was removed in Vacuo and the process repeated twice more to give a white solid. This solid was then dissolved in DMSO (6 mL) and DABCO (426 mg, 3.80 mmol) was added. The reaction mixture was stirred in an oil bath at 65 °C for 24 h. The solution was then cooled to room temperature, MeOH (20 mL) was added, and the mixture heated at reflux for 1 h. The precipitate was collected by filtration to give 100 mg (0.36 mmol, 94%) of 9 as a white solid, mp 312-313 °C, [R]D25 -63.2 (c 0.29, TFA). The stereochemistry of this compound was established as (S,S) by single crystal X-ray diffraction analysis. IR (cm-1) 3193, 2895, 2542, 2380, 1686, 1507; 1H NMR (DMSO-d6) δ 1.88 (d, 1H, J ) 17.1 Hz), 2.33 (d, 1H, J ) 17.7 Hz), 2.89 (dd, 1H, J ) 4.5 Hz, J ) 13.5 Hz), 3.16 (dd, 1H, J ) 3.5 Hz, J ) 13.7 Hz), 3.33 (d, 1H, J ) 18 Hz), 3.80 (d, 1H, J ) 18.0 Hz), 3.85 (s, 3H), 4.29 (s, 1H), 6.98 (d, 1H, J ) 9.1 Hz), 7.17-7.19 (m, 2H), 7.32-7.34 (m, 3H), 8.05 (d, 1H, J ) 9.1 Hz), 8.36 (s, 1H), 8.51 (s, 1H); 13C NMR (DMSO-d6) δ 38.5, 43.5, 48.1,

Crystal Growth & Design, Vol. 8, No. 9, 2008 3259 55.9, 56.2, 63.0, 109.8, 125.7, 127.0, 128.2, 129.9, 130.4, 135.9, 137.6, 139.0, 159.5, 165.8, 169.5. Anal. Calcd for C20H19N3O5: C, 62.99; H, 5.02; N, 11.02. Found: C, 62.92; H, 4.69; N, 11.09. (R,S)-Cyclo[(2-amino-4-methoxy-7-nitroindan-2-carboxylic acid)(phenylalanine)] [(R,S)-9]. The more polar diastereomer of dipeptide 14 (200 mg, 0.380 mmol) was similarly deprotected and cyclized to give 95 mg (0.34 mmol, 89%) of 9 as a white solid, mp 282 °C (dec), [R]D25 +31.3 (c 0.4, TFA). The stereochemistry of this compound was established as (R,S) by single crystal X-ray diffraction analysis. IR (cm-1) 3280, 2941, 2391, 1670, 1528, 1452; 1H NMR (DMSO-d6) δ 2.48 (d, 1H, obscured), 2.86 (m, 3H), 3.17 (m, 1H), 3.31 (d, 1H, obscured), 3.87 (s, 3H), 4.28 (s, 1H), 7.01 (d, 1H, J ) 9.0 Hz), 7.18 (m, 2H), 7.32-7.33 (m, 3H), 8.05 (d, 1H, J ) 9.0 Hz), 8.34 (s, 1H), 8.53 (s, 1H); 13C NMR (DMSO-d6) δ 38.4, 43.6, 48.2, 55.6, 56.2, 62.8, 109.9, 125.6, 127.3, 128.1, 130.3, 130.4, 135.6, 137.5, 138.5, 159.4, 165.6, 169.7; HRMS (FAB) calcd for C20H20N3O5, 382.1403; found, 382.1391. Thiourea (S,S)-15. To a solution of the less polar diastereomer of 14 (1.70 g, 3.22 mmol) in CH2Cl2 (20 mL) was added TFA (20 mL). After 1 h at room temperature, the mixture was made basic by addition of 2N NaOH and was extracted with ether (3 × 75 mL). The organic extracts were combined, dried over anhydrous MgSO4, filtered, and concentrated in Vacuo to give a white solid. This solid was dissolved in ethanol (20 mL) and triethylamine (1 mL) and phenylisothiocyanate (2.0 mL, 14.4 mmol) were added. After 2 h at room temperature, volatiles were removed in Vacuo to afford an off-white solid. The solid was chromatographed on silica gel 60 using 50% EtOAc/hexanes as eluent to give 1.61 g (2.86 mmol, 89%) of (S,S)-15, mp 119-120 °C, [R]25D – 36.6 (c 0.39, CH2Cl2). IR (cm-1) 3319, 1717, 1636, 1588, 1516; 1H NMR(CDCl3) δ 1.20 (t, 3H, J ) 7.2 Hz), 2.98 (dd, 1H, J ) 8.4 Hz, J ) 13.8 Hz), 3.23 (d, 1H, J ) 18.0 Hz), 3.29 (dd, 1H, J ) 6.4 Hz, J ) 13.8 Hz), 3.50 (d, 1H, J ) 17.4 Hz), 3.65 (d, 1H, J ) 17.4 Hz), 3.92 (s, 3H), 4.18 (q, 2H, J ) 7.2 Hz), 5.19 (m,1H), 6.62 (s, 2H), 6.81 (d, 1H, J ) 9.0 Hz), 7.0 (d, 2H, J ) 7.5 Hz), 7.21-7.27 (m, 6H), 7.31-7.39 (m, 3H), 7.63 (s, 1H), 8.2 (d, 1H, J ) 9.0 Hz); 13C NMR (CDCl3) δ 14.0, 37.9, 40.2, 45.8, 55.9, 59.3, 62.1, 64.6, 75.7, 98.6, 109.0, 124.9, 126.2, 127.1, 127.5, 128.7, 130.2, 130.6, 135.4, 136.2, 138.6, 160.1, 169.9, 172.3, 179.8; HRMS (FAB) calcd for C29H31N4O6 563.1964; found 563.1967. Anal. Calcd for C29H30N4O6S: C, 61.91; H, 5.37; N, 9.96; S, 5.70. Found: C, 62.27; H, 5.73; N, 9.30; S, 5.08. (S)-Ethyl 2-Amino-4-methoxy-7-nitroindan-2-carboxylate [(S)13]. A solution of (S,S)-15 (840 mg, 1.49 mmol) in TFA (8 mL) was heated to reflux for 45 min. Volatiles were removed in Vacuo and the residue was taken up in 2 N aqueous HCl (25 mL). The solution was extracted with hexanes (3 × 30 mL) and these extracts discarded. The aqueous phase was made basic to pH paper by addition of NaHCO3 and was extracted with EtOAc (3 × 30 mL). The EtOAc extracts were combined, dried over anhydrous MgSO4, filtered, and concentrated in Vacuo to give 365 mg of a yellow solid. This material was chromatographed on silica gel 60 using 60% EtOAc/hexanes as elutant to give 312 mg (1.11 mmol, 74%) of (S)-13 as a yellow solid, mp 97-98 °C, [R]D25 -100.6 (c 0.4, CH2Cl2). IR (cm-1) 2921, 1728, 1585, 1514, 1481; 1H NMR (CDCl3) δ 1.31 (t, 3H, J ) 7.2 Hz), 2.97 (d, 1H, J ) 16.8 Hz), 3.46 (d, 1H, J ) 16.8 Hz), 3.53 (d, 1H, J ) 18.0 Hz), 3.92 (s, 3H), 3.94 (d, 1H, J ) 18.0 Hz), 4.25 (q, 2H, J ) 7.2 Hz), 6.81 (d, 1H, J ) 9.0 Hz), 8.16 (d, 1H, J ) 9.0 Hz); 13C NMR (CDCl3) δ 14.2, 42.6, 47.9, 55.9, 61.8, 64.2, 109.0, 126.1, 130.7, 139.0, 139.3, 160.5, 176.2; MS (FAB) 281 (MH+); HRMS calcd for C13H17N2O5 281.1137, found 281.1134. (S)-Ethyl 2-[(N-carbo-2,2-dimethylethoxy)amino]-4-methoxy-7nitroindan-2-carboxylate [(S)-16]. To a solution of (S)-13 (300 mg, 1.07 mmol), NaHCO3 (68 mg), and NaCl (204 mg) in water (2 mL) and CH2Cl2 (2 mL) was added di-tert-butyldicarbonate (210 mg, 1.07 mmol). The resultant biphasic mixture was heated to reflux. After 2 h, the mixture was cooled to room temperature, the organic layer was separated, and the aqueous layer was extracted with CH2Cl2 (3 × 30 mL). The organic extracts were combined, dried (MgSO4), filtered, and concentrated. The resulting solid was chromatographed on silica gel 60 eluted with 40% EtOAc/hexanes to yield 330 mg (0.87 mmol, 81%) of (S)-16 as a white solid, mp 148-149 °C, [R]D25 -44.6 (c 0.4, CH2Cl2). IR (cm-1) 3366, 2978, 2930, 2359, 2247, 1739, 1578, 1479; 1 H NMR (CDCl3) δ 1.26 (t, 3H, J ) 7.2 Hz), 1.42, (s, 9H), 3.35 (m, 1H), 3.56 (d, 1H, J ) 17.7 Hz), 3.77 (d, 1H, J ) 18.6 Hz), 3.92 (s,

3260 Crystal Growth & Design, Vol. 8, No. 9, 2008 3H), 3.98 (d, 1H, J ) 18.6 Hz), 4.23 (q, 2H, J ) 7.2 Hz), 5.50 (s, 1H), 6.82 (d, 1H, J ) 9.0 Hz), 8.12 (d, 1H, J ) 9.0 Hz); 13C NMR (CDCl3) δ 14.0, 28.1, 40.5, 46.0, 55.8, 61.8, 64.7, 80.0, 108.9, 125.9, 130.6, 138.5, 138.7, 154.7, 160.1, 173.2; MS (FAB) 381 (MH+). rac-Ethyl 2-[(N-Carbo-2,2-dimethylethoxy)amino]-4-methoxy-7nitroindan-2-carboxylate (rac-16). To a solution of rac-13 (900 mg, 3.21 mmol), NaHCO3 (270 mg), and NaCl (560 mg) in water (10 mL) and CH2Cl2 (10 mL) was added di-t-butyl dicarbonate (700 mg, 3.21 mmol). The resultant biphasic mixture was heated to reflux. After 24 h, the mixture was cooled to room temperature, the organic layer was removed, and the aqueous layer was extracted with CH2Cl2 (3 × 30 mL). The organic extracts were combined, dried (MgSO4), filtered, and concentrated to give a white solid. Flash chromatography on silica gel 60 eluted with 40% EtOAc/hexanes afforded 1.11 g (2.92 mmol, 91%) of rac-16 as a white solid, mp 187-188 °C. IR (cm-1) 3365, 2979, 1728, 1702; 1H NMR (CDCl3) δ 1.26 (t, 3H, J ) 7.5 Hz), 1.42 (s, 9H), 3.34 (m, 1H), 3.57 (d, 1H, J ) 17.1 Hz), 3.77 (d, 1H, J ) 18.3 Hz), 3.92 (s, 3H), 3.99 (d, 1H, J ) 18.6 Hz), 4.23 (q, 2H, J ) 7.2 Hz), 5.29 (s, 1H), 6.81 (d, 1H, J ) 8.7 Hz), 8.14 (d, 1H, J ) 8.7 Hz); 13C NMR (CDCl3) δ 14.0, 28.2, 40.6, 46.2, 55.8, 61.9, 64.7, 80.2, 108.9, 126.0, 130.8, 138.6, 138.8, 154.7, 160.1, 173.2. HRMS (ESI, MNa+) calcd for C18H24N2O7Na 403.1481, found 403.1473. (S)-2-[(N-Carbo-2,2-dimethylethoxy)amino]-4-methoxy-7-nitroindan-2-carboxylic Acid [(S)-17]. To a solution of (S)-16 (130 mg, 0.34 mmol) in water (2 mL) and ethanol (10 mL) was added 2 M NaOH (5 mL). After stirring at room temperature for 18 h, the solution was concentrated, diluted with water (5 mL), treated with sufficient 2 M HCl to produce an acidic solution to pH paper, and extracted with EtOAc (3 × 10 mL). The organic extracts were combined, dried, filtered, and concentrated to give a light tan solid. This material was recrystallized from EtOAc/EtOH to give 78 mg (0.22 mmol, 65%) of (S)-17 as a white solid, mp >280 °C, [R]D25 -53.4 (c 0.4, CH2Cl2). IR (cm-1) 3552, 2570, 2466, 1719, 1642; 1H NMR (acetone-d6) δ 1.38 (s, 9H), 3.37 (d, 1H, J ) 17.2 Hz), 3.58 (d, 1H, J ) 17.2 Hz), 3.83 (d, 1H, J ) 18.0 Hz), 3.98 (d, 1H, J ) 18.0 Hz), 3.99 (s, 3H), 6.78 (s, 1H), 7.07 (d, 1H, J ) 9.1 Hz), 8.12 (d, 1H, J ) 9.1 Hz); 13C NMR (acetone-d6) δ 28.5, 40.8, 46.1, 56.4, 65.9, 79.8, 110.5, 126.3, 128.3, 131.76, 139.6, 140.0, 161.6, 174.8; HRMS (FAB) calcd for C16H21N2O7: 353.1349, found: 353.1341. rac-2-[(N-Carbo-2,2-dimethylethoxy)amino]-4-methoxy-7-nitroindan-2-carboxylic Acid (rac-17). To a solution of rac-16 (1.0 g, 2.63 mmol) in water (10 mL) and ethanol (60 mL) was added 2 M NaOH (6.6 mL, 13.16 mmol). After stirring at room temperature for 18 h, the solution was concentrated to ca. 5 mL, diluted with water (5 mL), and treated with 2 M HCl to produce a solution acidic to pH paper. The aqueous mixture was extracted with EtOAc (3 × 30 mL). The organic extracts were combined, dried (MgSO4), filtered, and concentrated to give 842 mg (2.39 mmol, 91%) of rac-17 as a white solid, mp 266-268 °C. IR (cm-1) 3314, 2973, 1716, 1642; 1H NMR (DMSO-d6) δ 1.36 (s, 9H), 3.17 (d, 1H, J ) 17.1 Hz), 3.35 (d, 1H, J ) 17.4 Hz), 3.61 (d, 1H, J ) 18.0 Hz), 3.80 (d, 1H, J ) 18.0 Hz), 3.90 (s, 3H), 7.06 (d, 1H, J ) 9.3 Hz), 7.57 (s, 1H), 8.10 (d, 1H, J ) 9 Hz); 13C NMR (DMSO-d6) δ 28.1, 38.2, 44.9, 56.2, 64.3, 78.3, 110.0, 125.7, 130.2, 138.1, 139.0, 155.1, 160.0, 174.6. HRMS (ESI, MNa+) calcd for C16H20N2O7Na 375.1168, found 375.1156. (S,S)-N-[2-(Carboethoxy)-4-methoxy-7-nitroindan-2-yl]-2-[(Ncarbo-2,2-dimethylethoxy)amino]-4-methoxy-7-nitroindan-2-carboxamide [(S,S)-18]. To a solution of (S)-13 (150 mg, 0.54 mmol), (S)-17 (207 mg, 0.59 mmol), and triethylamine (1.0 mL) in DMF (5 mL) was added BOP reagent (250 mg, 0.57 mmol). After stirring at room temperature 72 h, the mixture was diluted with EtOAc (50 mL) and water (30 mL). The organic layer was removed and the aqueous layer extracted with EtOAc (3 × 50 mL). The organic extracts were combined and sequentially washed with 2 M HCl (3 × 50 mL), water (50 mL), saturated NaHCO3 (2 × 50 mL), and water (50 mL), then dried (MgSO4), filtered, and concentrated to give 150 mg (0.24 mmol, 45%) of (S,S)-18 as a light tan solid, mp 225-226 °C, [R]D25 -45.3 (c 0.3, CH2Cl2). IR (cm-1) 3335, 2969, 2360, 2337, 1725, 1515; 1H NMR (CDCl3) δ 1.14 (t, 3H, J ) 7.2 Hz), 1.25 (s, 9H), 3.31 (d, 1H, J ) 17.7 Hz), 3.49 (d, 1H, J ) 17.4 Hz), 3.59 (d, 1H, J ) 17.7 Hz), 3.78 (d, 1H, J ) 17.4 Hz), 3.82 (s, 3H), 3.85 (s, 3H), 3.91-4.03 (m, 4H), 4.12 (q, 2H, J ) 7.2 Hz), 6.74 (d, 2H, J ) 9.0 Hz), 7.50 (s, 1H), 8.07 (d, 2H, J ) 9.0 Hz); 13C NMR (CDCl3) δ 14.0, 28.0, 40.4, 45.8, 55.8, 55.9, 62.0, 65.9, 108.9, 109.1, 126.0, 126.2, 130.3, 138.5, 138.7, 138.8,

Ntirampebura et al. 154.8, 160.2, 160.4, 172.5. HRMS (FAB) calcd for C29H35N4O11 615.2302, found 615.2302. A racemic mixture of (R,S)-N-[2-(Carboethoxy)-4-methoxy-7nitroindan-2-yl]-2-[(N-carbo-2,2-dimethylethoxy)amino]-4-methoxy7-nitroindan-2-carboxamide [(R,S)-18] and (S,R)-N-[2-(Carboethoxy)4-methoxy-7-nitroindan-2-yl]-2-[(N-carbo-2,2-dimethylethoxy)amino]4-methoxy-7-nitroindan-2-carboxamide [(S,R)-18] Plus a Racemic Mixture of (S,S)-N-[2-(Carboethoxy)-4-methoxy-7-nitroindan-2yl]-2-[(N-carbo-2,2-dimethylethoxy)amino]-4-methoxy-7-nitroindan2-carboxamide [(S,S)-18] and (R,R)-N-[2-(Carboethoxy)-4-methoxy7-nitroindan-2-yl]-2-[(N-carbo-2,2-dimethylethoxy)amino]-4-methoxy7-nitroindan-2-carboxamide [(R,R)-18]. To a solution of rac-13 (517 mg, 1.84 mmol), rac-17 (650 mg, 1.84 mmol), and triethylamine (0.3 mL) in DMF (15 mL) was added BOP reagent (814 mg, 1.84 mmol). After stirring at room temperature for 24 h, the solution was diluted with EtOAc (100 mL) and washed with water (3 × 50 mL), brine (50 mL), then dried (MgSO4), filtered, and concentrated to give a light yellow solid. Flash chromatography on silica gel 60 eluted with 20% EtOAc/benzene afforded 960 mg (1.56 mmol, 85%) of a mixture of (R,S)-18, (S,R)-18, (S,S)-18, and (R,R)-18 as a white solid. Gravity column chromatography on silica gel 60 eluted with 20% EtOAc/ benzene achieved the separation of a mixture of (S,S)-18 and (R,R)18, mp 256-257 °C, from a mixture of (R,S)-18 and (S,R)-18, mp 240-242 °C. Spectral data for the mixture of (S,S)-18 and (R,R)-18: IR (cm-1) 3323, 2927, 1724, 1701, 1669; 1H NMR (DMSO-d6) δ 1.02 (t, 3H, J ) 6.9 Hz), 1.08 (s, 9H), 3.01 (d, 1H, J ) 17.7 Hz), 3.32 (m, 2H), 3.45 (m, 3H), 3.81 (m, 2H), 3.90 (s, 6H), 3.98 (q, 2H, J ) 6.9 Hz), 7.05 (d, 2H, J ) 8.7 Hz), 7.24 (s, 1H), 8.09 (d, 2H, J ) 9.3 Hz), 8.57 (s, 1H); 13C NMR (DMSO-d6) δ 13.7, 27.6, 44.4, 56.1, 56.2, 60.7, 64.4, 64.7, 78.3, 109.8, 109.9, 125.6, 125.8, 130.1, 130.4, 138.2, 138.8, 139.2, 154.3, 160.0, 160.2, 172.4, 172.7. HRMS (ESI, MNa) calcd for C29H34N4O11Na 637.2122, found 637.2147. Spectral data for the mixture of (R,S)-18 and (S,R)-18: IR (cm-1) 3362, 3320, 2976, 1719, 1706, 1667;1H NMR (DMSO-d6) δ 1.03 (t, 3H, J ) 6.9 Hz), 1.08 (s, 9H), 2.99 (d, 1H, J ) 17.1 Hz), 3.34-3.55 (m, 5H), 3.79 (m, 2H), 3.90 (s, 6H), 4.00 (q, 2H, J ) 6.9 Hz), 7.05 (d, 2H, J ) 9.3 Hz), 7.24 (s, 1H), 8.09 (d, 2H, J ) 9.0 Hz), 8.56 (s, 1H); 13C NMR (DMSO-d6) δ 13.7, 27.6, 44.3, 44.4, 56.1, 56.2, 60.7, 64.4, 64.7, 78.3, 109.8, 109.9, 125.6, 125.7, 130.2, 130.4, 138.1, 138.2, 138.7, 139.1, 154.3, 160.0, 160.1, 172.4, 172.7. HRMS (ESI, MNa+) calcd for C29H34N4O11Na 637.2122, found 637.2111. (S,S)-Cyclo-bis(2-amino-4-methoxy-7-nitroindan-2-carboxylic acid) (S,S)-6. The peptide (S,S)-18 (100 mg, 0.163 mmol) was dissolved in TFA (3 mL) and the mixture stirred at room temperature overnight. Volatiles were removed under reduced pressure and MeOH was added to the residue. Methanol was removed under reduced pressure and the process repeated twice to give a foamy substance. This foam was dissolved in DMSO (3 mL) and DABCO (183 mg, 1.63 mmol) was added. The reaction mixture was stirred in an oil bath at 65 °C for 12 h. The solution was cooled to room temperature, diluted with MeOH (10 mL), and the mixture heated for 1 h. The precipitate was filtered to give 48 mg (0.10 mmol, 63%) of piperazinedione (S,S)-6 as a tan solid, mp > 300 °C, [R]D25 -77.2 (c 0.25, TFA). IR (cm-1) 3220, 3060, 1674, 1589; 1H NMR (DMSO-d6) δ 3.15 (d, 2H, J ) 16.8 Hz), 3.50 (d, 2H, J ) 16.8 Hz), 3.59 (d, 2H, J ) 18.1 Hz), 3.94 (s, 6H), 4.06 (d, 2H, J ) 18.1 Hz), 7.10 (d, 2H, J ) 9.1 Hz), 8.15 (d, 2H, J ) 9.1 Hz), 8.87 (s, 2H); 13C NMR (DMSO-d6) δ 43.9, 47.4, 56.3, 63.8, 110.1, 126.1, 129.5, 137.9, 138.9, 159.8, 169.8. HRMS (FAB) calcd for C22H21N4O8, 469.1359, found, 469.1355. rac-Cyclo-bis(2-amino-4-methoxy-7-nitroindan-2-carboxylic Acid) (rac-6). A mixture of (R,R)-18 and (S,S)-18 (240 mg, 0.39 mmol) was dissolved in TFA (5 mL) and stirred at room temperature overnight. TFA was removed under reduced pressure and methanol added to the residue. Methanol was removed under reduced pressure and the process repeated twice to give a foamy substance. This was then dissolved in DMSO (5 mL) and DABCO (437 mg, 3.9 mmol) was added. The reaction mixture was stirred in an oil bath at 65 °C. After 12 h, the solution was cooled to room temperature and methanol (20 mL) was added to precipitate a tan solid. The suspension was heated to reflux for 1 h and the precipitate was collected by filtration and washed with methanol. The yield of rac-6 was 110 mg (0.23 mmol, 60%), mp > 300 °C. IR (cm-1) 3233, 3099, 2954, 1674, 1616, 1588;1H NMR (DMSO-d6) δ 3.14 (d, 2H, J ) 17.1 Hz), 3.50 (d, 2H, J ) 16.8 Hz), 3.59 (d, 2H, J ) 18 Hz), 3.94 (s, 6H), 4.05 (d, 2H, J ) 18 Hz), 7.10 (d, 2H, J ) 9.3 Hz), 8.15 (d, 2H, J ) 9.3 Hz), 8.8 (s, 2H); 13C NMR

Crystal Engineering with 1,4-Piperazine-2,5-diones

Crystal Growth & Design, Vol. 8, No. 9, 2008 3261 Scheme 1. Synthesis of (S)-13

Scheme 2. Synthesis of (S,S)-6

(DMSO-d6) δ 43.9, 47.3, 56.2, 63.8, 110.1, 126.0, 129.4, 137.8, 138.9, 159.8, 169.7. HRMS (ESI, MNa+) calcd for C22H20N4O8Na 491.1179, found 491.1163. (R,S)-Cyclo-Bis(2-amino-4-methoxy-7-nitroindan-2-carboxylic Acid) (meso-6). A mixture of (R,S)-18 and (S,R)-18 (100 mg, 0.162 mmol) was dissolved in TFA (2.5 mL) and stirred at room temperature overnight. TFA was removed under reduced pressure and methanol added to the residue. Methanol was removed under reduced pressure and the process repeated twice to give a foamy substance. This was then dissolved in DMSO (3 mL) and DABCO (182 mg, 1.62 mmol) was added. The reaction mixture was stirred in an oil bath at 65 °C. After 12 h, the solution was cooled to room temperature and methanol (20 mL) was added to precipitate a tan solid. The suspension was heated to reflux for 1 h and the precipitate was collected by filtration and washed with methanol. The yield of meso-6 was 53 mg (0.113 mmol, 70%), mp > 300 °C. IR (cm-1) 3219, 3100, 2936, 1662, 1615, 1587;1H NMR (DMSO-d6) δ 3.13 (d, 2H, J ) 17.1 Hz), 3.51 (m, 2H), 3.60 (d, 2H, J ) 19.5 Hz), 3.94 (s, 6H), 4.00 (d, 2H, J ) 19.2 Hz), 7.10 (d, 2H, J ) 8.7 Hz), 8.14 (d, 2H, J ) 9 Hz), 8.8 (s, 2H); 13C NMR (DMSO-

d6) δ 43.2, 48.1, 56.2, 63.7, 110.1, 126.0, 129.9, 137.8, 138.5, 159.7, 169.7. HRMS (ESI, MNa+) calcd for C22H20N4O8Na 491.1179, found 491.1167.

Results Synthesis of Compounds 6 and 9. Compound (S,S)-6 was prepared as depicted in Schemes 1 and 2. Commercially available 2,3-dimethyl-4-nitroanisole51 (10) was brominated under free radical conditions to give o-xylene dibromide derivative 1150 in 90% yield (Scheme 1). Condensation of dibromide 11 with ethyl isocyanoacetate by the method of Kotha52 produced rac-12 in 52% yield. Hydrolysis of rac-12 under acidic conditions gave the amino ester rac-13 in 88% yield. Coupling of rac-13 with N-t-butoxycarbonyl-L-phenylalanine51 using benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate51,53 (BOP reagent) afforded a 1:1


Ntirampebura et al.

Scheme 3. Synthesis of (S,S)-9 and (R,S)-9

Table 1. Crystallographic Data for Piperazinediones 6 and 9 a

formula form weight (g mol-1) temp (K) radiation cryst syst space group a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) V (Å3) Z R1 (obs data) wR2 (all data) GOF on F2 mp (°C)

(S,S)-6

rac-6b

rac-6c

meso-6

(R,S)-9

(S,S)-9

C22H20N4O8 · C3H7NO C25H27N5O9 541.52 150(2) Mo ΚR orthorhombic P212121 6.341(3) 19.275(10) 20.483(10) 90 90 90 2503(2) 4 0.1083 0.2989 1.062 >300 (dec)d

3C22H20N4O8 · 6C3H7NO · 2H2O C84H106N18O32 1879.87 150(2) Mo ΚR triclinic P1j 14.721(4) 15.416(5) 20.197(4) 93.42(2) 100.887(15) 94.46(2) 4474(2) 2 0.0624 0.1527 1.057 >300 (dec)d

2C22H20N4O8 · 5C2H6SO C54H70N8O11S5 1327.48 170(2) Mo ΚR triclinic P1j 9.603(2) 11.614(3) 14.295(3) 82.504(4) 79.188(4) 82.969(4) 1544.8(6) 2 0.0596 0.1325 1.032 >300 (dec)d

C22H20N4O8

C20H19N3O5

C20H19N3O5

468.42 120(2) synchrotron monoclinic C2/m 17.149(7) 6.368(3) 9.310(4) 90 106.207(6) 90 976.3(7) 2 0.0598 0.1715 1.046 >300 (dec)

381.38 173(2) Mo ΚR monoclinic P21 11.872(5) 6.262(3) 12.819(6) 90 111.215(12) 90 888.4(7) 2 0.0537 0.1702 1.052 >280 (dec)

381.38 170(2) Mo ΚR monoclinic P21 10.6551(10) 6.0480(6) 13.9914(13) 90 91.171(2) 90 901.45(15) 2 0.0599 0.1091 1.030 >300 (dec)

a A 1:1 solvate of piperazinedione (S,S)-6 and DMF. b A 3:3:12:4 cocrystal of the enantiomers (R,R)-6, (S,S)-6, DMF, and water. c A 1:1:5 cocrystal of the enantiomers (R,R)-6, (S,S)-6, and DMSO. d Melting point of solvent-free material.

mixture of dipeptides (R,S)-14 and (S,S)-14 in 96% yield. These diastereomers were separated by repeated cycles of gravitydriven column chromatography on silica gel 60 eluted with 10% ethyl acetate/benzene. Structures were assigned to the separated diastereomers by means of X-ray crystallographic analyses of piperazinediones (R,S)-9 and (S,S)-9 (Vide infra). Application of the Edman degradation to (S,S)-14 afforded (S)-13 via the intermediate thiourea (S,S)-15 in 66% yield over three steps (Scheme 1). Treatment of (S)-13 with Boc anhydride produced (S)-16 in 81% yield (Scheme 2). Ester hydrolysis was effected using aqueous sodium hydroxide to give (S)-17 in 65% yield. Coupling of (S)-17 with (S)-13 using BOP reagent gave dipeptide (S,S)-18 in 44% yield. Following removal of the Boc group with TFA, treatment of the resulting dipeptide aminoester with DABCO in DMSO at 65 °C produced the cyclic dipeptide (S,S)-6 in 61% yield. The N-Boc acid rac-17 was prepared from amino ester rac13 in a manner similar to that described above for the preparation of (S)-17 (see the Experimental Section for details). Coupling of rac-13 with rac-17 using the BOP reagent afforded a 1:1:1:1 mixture of dipeptides (R,S)-18, (S,R)-18, (R,R)-18, and (S,S)-18 in 85% yield. The (R,S) and (S,R) stereoisomers in this mixture were separated from the (R,R) and (S,S) stereoisomers by gravity-driven column chromatography on 70-230 mesh silica gel 60 eluted with 5% ethyl acetate/benzene. Structures were assigned to the separated pairs of enantiomers by comparison of their spectroscopic and chromatographic properties with those of (S,S)-18 derived from (S)-13 and (S)-17. Treatment of the mixture of (R,R)-18 and (S,S)-18 with TFA to

remove the Boc groups, followed by reaction of the resulting dipeptide aminoesters with DABCO in DMSO at 65 °C produced rac-6, a 1:1 mixture of the enantiomers (S,S)-6 and (R,R)-6, in 60% yield. A similar treatment of the mixture of (R,S)-18 and (S,R)-18 produced the cyclic dipeptide (R,S)-6, or meso-6, in 70% yield. Compounds (S,S)-9 and (R,S)-9 were prepared from (S,S)14 and (R,S)-14 in 94% and 89% yields, respectively, by removal of the Boc protecting groups with TFA followed by reaction of the resulting dipeptide aminoesters with DABCO in DMSO at 65 °C as depicted in Scheme 3. Crystallizations of Compounds 6 and 9. Compound (S,S)-6 was crystallized by slow cooling of a hot saturated solution in DMF. Compound rac-6 also crystallized from a saturated solution in DMF, but crystals that included water molecules were deposited months after the solution was made. Compounds rac-6, meso-6, (R,S)-9, and (S,S)-9 were crystallized by slow cooling of hot saturated solutions in DMSO. Crystal Structures. NMR spectra of compounds 6 and 9 were consistent with the expected point group symmetries for these molecules in solution: C2 for (R,R)-6 and (S,S)-6; i for meso-6; and C1 for (R,S)-9 and (S,S)-9. Crystal structure data are given in Table 1. Geometric (conformational) data and the calculated dipoles for the conformers resident in the crystals are given in Table 2.54,55 Compound (S,S)-6 crystallized from DMF with inclusion of solvent in space group P212121. One conformer of (S,S)-6 (see Figure 2, conformer A) lacking C2 symmetry was present in


Crystal Growth & Design, Vol. 8, No. 9, 2008 3263

Table 2. Conformational Data for Piperazinediones 6 and 9a

compound

conformer

dipole moment (D)b

φc

Ψc

ωc

Rd

βd

χe

δf

-38.0 -40.9 16.9 20.5 -0.8 13.3 -11.7 -7.8 -10.2 -12.8 3.5 -3.5 -13.5 -19.7 21.0 16.5

25.7 27.6 -17.2 -13.8 -17.3 -4.6 7.9 11.4 6.4 4.0 3.5 -3.5 12.7 7.1 -8.3 -12.3

10.3 13.7 -0.8 -4.7 -2.6 12.4 -2.2 2.0 7.5 4.8 4.0 -4.0 9.6 3.0 -5.6 -10.4

153

125

167

152

169

165

172

164

173

166

180

180

171

158

178 175 169 174 162 178 164 178 174 160 180 180 172

179 177 -179 179 -175 178 -178 175 -174 -178 180 180 178

169

156

144

-175

(S,S)-6g

A

12.5

rac-6h

B

12.8

ent-C

11.1

D

11.0

rac-6i

E

11.2

meso-6

F

0.0

(R,S)-9

G

5.8

(S,S)-9

H

7.0

a Values are in degrees and are given for each substructural element. b The dipole moment of each conformer was calculated from the crystal structure coordinates (single point energy) at the semiempirical AM1 level using Spartan ‘02 v1.0.4e.54 c The dihedral angles φ, Ψ, and ω are the torsion angles defined for conformational analysis of amide bonds in peptides.55 d The dihedral angles R and β were previously defined12 and are measures of the degree of nonplanarity of the piperazinedione ring (for flat rings R ) β ) 180°). e The dihedral χ was previously defined19 and is a measure of the degree of nonplanarity of the cyclopentene ring component of the indane system (for flat rings χ ) 180°). f The C6-C9-O3-C13 torsion angle, δ, measures the twist of the methoxy substituent relative to the plane of the benzene ring. g A 1:1 solvate of (S,S)-6 with DMF. h A 3:3:12:4 cocrystal of the enantiomers (R,R)-6, (S,S)-6, DMF, and water. Data for the ent-B, C, and ent-D conformers is omitted. i A 1:1:5 cocrystal of the enantiomers (R,R)-6, (S,S)-6, and DMSO. Data for the ent-E conformer is omitted.

the crystal along with disordered DMF in a 1:1 ratio. In the crystal, the piperazinedione ring of (S,S)-6 adopts a pseudotwistboat conformation (see Table 2, RΑ ) 153°, βΑ ) 125°) that brings the methoxy groups of each molecule into closer proximity than the nitro groups. The cyclopentene subunits of the indane rings are nearly flat (χΑ ) 178°, 175°). In this and in all subsequent cases, the methoxy groups are at most only slightly torsionally displaced from the plane of the arene to which they are attached with the methyl pointed away from the piperazinedione unit (174° e |δ| e 180°). Compound rac-6 crystallized from wet DMF with included solvent and water in space group P1j. Three conformers of (S,S)-6 (conformers B, C, and D) and the enantiomeric conformers of (R,R)-6 (ent-B, ent-C, and ent-D), all lacking C2 symmetry, along with 12 ordered DMF molecules and 4 ordered water molecules, were present in the unit cell. In conformer B the piperazinedione ring adopts a shallow pseudoboat conformation (RΒ ) 167°, βΒ ) 152°) that brings the methoxy groups into closer proximity than the nitro groups. The cyclopentene subunits of the indane rings are folded, one slightly and the other more substantially, toward the proximal oxygen atoms of the piperazinedione ring (χΒ ) 174°, 169°). In conformer C the piperazinedione ring adopts a shallow pseudotwist-boat conformation (RC ) 169°, βC ) 165°) that brings the nitro groups into slightly closer proximity than the methoxy groups. One cyclopentene subunit is nearly flat and the other is bent toward the proximal oxygen atom of the piperazinedione ring (χC ) 178°, 162°). In conformer D the piperazinedione ring adopts a shallow pseudoboat conformation (RD ) 172°, βD ) 164°) that brings the nitro groups into slightly closer proximity than the methoxy groups. One cyclopentene subunit is nearly

flat and the other is bent toward the proximal oxygen atom of the piperazinedione ring (χD ) 178°, 164°). Compound rac-6 also crystallized from DMSO with included solvent in space group P1j. One molecule each of (S,S)-6 (conformer E) and (R,R)-6 (ent-E) lacking C2 symmetry, along with four ordered DMSO molecules and one disordered DMSO molecule, were present in the unit cell. In conformer E the piperazinedione ring adopts a shallow pseudotwist-boat conformation (RE ) 173°, βE ) 166°) that brings the nitro groups into slightly closer proximity than the methoxy groups. The cyclopentene subunits of the indane rings are bent, on one side only slightly and on the other more substantially, toward the proximal oxygen atoms of the piperazinedione ring (χE ) 174°, 160°). Compound meso-6 crystallized from DMSO without inclusion of solvent in space group C2/m. The conformer observed in the crystal (conformer F) exhibited inversion symmetry. The piperazinedione ring is flat (RF ) 180°, βF ) 180°) as are the cyclopentene subunits of the indane rings (χF ) 180°, 180°). L-Phenylalanine-containing compounds (R,S)-9 and (S,S)-9 both crystallized from DMSO in space group P21 without inclusion of solvent. Conformation H observed for (S,S)-9 is very similar to conformations previously observed for Lphenylalanine-containing compounds (S,S)-7, (R,S)-7, (S,S)-8, and (R,S)-8.20,49 The piperazinedione ring exhibits a shallow pseudotwist-boat conformation (RH ) 169°, βH ) 156°). The indane cyclopentene ring is folded toward the proximal nitrogen atom of the piperazinedione ring (χH ) 144°). The phenylalanine side chain is folded over the piperazinedione such that an intramolecular van der Waals contact occurs between the arene


Ntirampebura et al.

Figure 2. Two views of hydrogen-bonded “1D tapes” and “islands” from the crystal structures of compounds 6 and 9. Included DMF and hydrogen atoms are usually omitted for clarity. Left: A view parallel to the hydrogen-bonding axis. Right: A view perpendicular to the hydrogen-bonding axis. These views serve to illustrate the conformations A-H of piperazinediones 6 and 9 observed in the crystals. Conformers B-D (and the enantiomers) are found in crystals of rac-6 grown from wet DMF. In this depiction, conformer B is blue, ent-C is red, and D is green. Conformer E (and the enantiomer) are found in crystals of rac-6 grown from DMSO. Table 3. Intermolecular Structural Parameters for Self-Association of Piperazinediones 6 and 9: Hydrogen Bondinga

N-O distances compound (S,S)-6 rac-6e rac-6f meso-6 (R,S)-9 (S,S)-9 CSD average

ε1 (Å)b

ε2 (Å)b

τp (deg)c

2.98 2.92 2.92 2.97 3.03 2.91 2.84

3.03 2.95 2.96 2.97 3.03 2.93 2.85

0.00 1.38 2.86 0.00 0.00 0.00 0.00 0.00

2.88

ηp (Å)d 0.14 na na 0.61 0.00 0.21 0.54 0.29

a

Values are listed for each unique substructural element. b The distances ε1 and ε2 lie between the amide nitrogen and oxygen atoms involved in hydrogen bonding. c The dihedral angle τp is formed by the intersection of the average planes defined by the atoms of adjacent piperazinedione rings in a tape. d The distance ηp lies between parallel average planes defined by the atoms of adjacent piperazinedione rings in a tape. e Crystallized from wet DMF. The water oxygen to amide nitrogen distances are 2.80 and 2.82 Å and the water oxygen to amide oxygen distances are 2.77 and 2.78 Å. f Crystallized from DMSO. The sulfoxide oxygen to amide nitrogen distance is 2.82 Å.

of the side chain and one hydrogen of the indanyl unit. The arene centroid-to-hydrogen distance is 2.69 Å. Conformation G observed in crystals of (R,S)-9 (Figure 2) is dissimilar to conformation H observed for (S,S)-9 and conformations previously observed for (S,S)-7, (R,S)-7, (S,S)-8, and (R,S)-8.20,49 The piperazinedione ring of (R,S)-9 exhibits a shallow pseudotwist-boat conformation (RG ) 171°, βG ) 158°) but is ring flipped relative to (S,S)-9. The indane cyclopentene

ring is bent slightly toward the proximal oxygen atom of the piperazinedione ring (χG ) 172°). These changes increase the distance between the arene of the “scorpion tail” phenylalanine and the proximal hydrogen atoms of the indanyl unit. No intramolecular van der Waals contacts are observed between the indane and phenylalanine components of (R,S)-9. The expectation that ladder-like 1D tapes would form via reciprocal amide hydrogen bonding was realized for (S,S)-6,



Figure 3. Tape assembly in the crystal structures of compounds 6 and 9. In some figures DMF molecules and hydrogen atoms are omitted for clarity. Left: A view of lateral neighbor tapes (LNTs) perpendicular to the hydrogen bonding axis illustrating intratape reciprocal hydrogen bonding and intertape arene interactions. Right: A view of sets of LNTs parallel to the hydrogen bonding axis illustrating intertape arene interactions and assembly of sheets principally through the development of van der Waals interactions.

meso-6, (R,S)-9, and (S,S)-9 (Figure 2). Structural parameters for such hydrogen-bonded networks (see Table 3) include the N-O interatomic distances, ε1 and ε2, which are indicative of the length of the N-H · · · O hydrogen bonds, the angle from

intersection of the average planes of adjacent piperazinedione rings, τp, and the distance between the average planes of adjacent piperazinedione rings when these planes are parallel (i.e., when τp ) 0). Values of these structural parameters are in close


Ntirampebura et al.

Table 4. Intermolecular Structural Parameters for Self-Association of Piperazinediones 6 and 9: Arene Interactionsa

centroid-to-centroid distances (κ), angles (τ) or distances (η) between arene rings, and centroid-to-closest arene hydrogen distances (γ) p-nitroanisole rings compound (S,S)-6b(O)c rac-6e ent-D + D (O) D + C (A)c C + B (A) B + ent-B (O) ent-B + ent-C (A) ent-C + ent-D (A) rac-6f E + E (A) E + ent-E (O) ent-E + ent-E (A) meso-6 F + ent-F (O) (R,S)-9 (O) (S,S)-9 (O)

γ1 (Å)

κ2 (Å)

τ2 (deg)

γ2 (Å)

3.52 3.55

1.5 1.5

nad na

3.51,3.69 3.45,3.49

nad

nad

nad

3.67 3.76 3.55 3.72 3.55 3.76

0.0 14.75 4.59 0.0 4.59 14.75

3.44 na na 3.26 na na

3.60,3.60 3.31,3.81 3.42,3.50 3.39,3.39 3.42,3.50 3.31,3.81

3.51 3.63 3.51

9.14 0.0 9.14

na 3.29 na

3.44,3.79 3.46,3.46 3.44,3.79

3.49 3.58

0.0 ∼0

3.18 ∼3.13

5.10

34

3.20

4.76

78

na

3.47,3.47 3.45 3.46 2.59

5.39

34

3.53

κ1 (Å)

τ1 (deg)

η1 (Å)

phenylalanine rings

For optimal parallel edge-to-center interactions, κ ≈ 3.8 Å and τ ≈ 0°.56–59 For optimal perpendicular edge-to-center interactions, κ ≈ 5.0 Å and τ ≈ 90°.56–59 b A 1:1 solvate of (S,S)-6 with DMF. c (O) indicates that the p-nitroanisole dipoles of interacting arenes are opposed, while (A) indicates these dipoles are aligned. d na ) not applicable. e A 3:3:12:4 cocrystal of the enantiomers (R,R)-6, (S,S)-6, DMF, and water. f A 1:1:5 cocrystal of the enantiomers (R,R)-6, (S,S)-6, and DMSO. a

agreement with the CSD averages for 1D tapes formed by R22(8) associations of 1,4-piperazine-2,5-diones.18 In the crystal of (S,S)-6 grown from DMF solution, lateral neighbor tapes (LNTs) are related by screw symmetry (see Figure 3). Parallel edge-to-center arene interactions are developed. Opposition of the associated p-nitroanisole dipoles, required by screw symmetry, is presumably energetically preferred over other possible alignments. The centroid-tocentroid distances (κ) for these arenes are 3.52 and 3.55 Å (data are listed in Table 4), the planes containing these rings are very nearly parallel (τ ) 1.5°), and the arene centroid-to-closest arene hydrogen distances (γ) are 3.51, 3.69, 3.45, and 3.49 Å, values consistent with parallel edge-to-center association.56–59 Sheets of (S,S)-6 molecules formed by association of LNTs appear in Figure 3 to have sharp contours when viewed parallel to the hydrogen bonding axis. However, a disordered DMF molecule, omitted for clarity in Figures 2 and 3, occupies space above the reciprocal hydrogen bond array proximal to the methoxy substituents. As shown in Figure 4, sheets of (S,S)-6 + DMF have a shallow grooved topography. These sheets associate through van der Waals interactions of complementary surfaces with the p-nitroanisole dipoles of vertical neighbor tapes in register. This second type of head-to-tail alignment presumably is also energetically favorable. In the crystal of meso-6, LNTs are related by screw symmetry (see Figure 3). Parallel edge-to-center associated arenes with opposed p-nitroanisole dipoles are observed. The centroid-tocentroid distance (κ) is 3.49 Å, the planes containing the p-nitroanisole rings are parallel (τ ) 0°), and the arene centroidto-closest arene hydrogen distance (γ) is 3.47 Å. Sheets formed from meso-6 by association of LNTs have sharp contours when viewed parallel to the hydrogen bonding axis (Figures 3 and

4). These sheets associate through van der Waals interactions of deeply ridged, complementary surfaces. Positional disorder (3:1) was observed for the nitro and methoxy groups. This disorder can be explained as follows. First, hydrogen bonding along each tape must be substantially uninterrupted; that is, carbonyl oxygen rarely points at carbonyl oxygen and NH at NH (Figure 2). Reorientation of the hydrogen-bonding pattern every fourth residue is unlikely. Second, LNTs are substantially related by screw symmetry (Figure 3). Given that arene parallel edge-to-center interactions are thus developed, the requirement for centrosymmetry in the crystal, and assuming that opposition of the associated p-nitroanisole dipoles is energetically preferred, a regular orientation, rather than a random orientation, of these dipoles along each edge of the hydrogen-bonded tape must exist. Thus, the structure of a given sheet of meso-6 formed by association of LNTs is highly ordered (Figure 3). In this case, positional disorder of the nitro and methoxy groups can be attributed to the more random manner in which sheets associate. “Peaks” of “bundled” alternating methoxy and nitro groups fill “valleys”, at the bottom of which lie piperazinedione rings (Figures 3 and 4). On average, every fourth sheet is “flipped over” relative to the bulk of the sheets. Alternatively, every fourth sheet is translated by half a period (ca. 3.2 Å) along the hydrogen bonding axis. Either of these operations exchange the positions of the nitro and methoxy groups, while maintaining an ordered hydrogen bonding pattern. In the crystal of (R,S)-9, LNTs are related by screw symmetry. As with (S,S)-6 and meso-6, parallel edge-to-center associations of p-nitroanisole groups with opposed dipoles are observed on one tape edge where LNTs meet (Figure 3). The centroid-tocentroid distance (κ) is 3.58 Å, the planes containing these rings are very nearly parallel, and the arene centroid-to-closest arene



Figure 4. Sheet topography and association from the crystals of (S,S)-6, meso-6, (R,S)-9, and (S,S)-9.

hydrogen distances (γ) are 3.45 Å and 3.46 Å. LNTs associate on the phenylalanine edge by interleaving of antiparallel “scorpion tails”. The centroid-to-centroid distance (κ) for interacting phenylalanine arenes is 5.10 Å, the angle between planes containing these rings (τ) is 34°, and the arene centroidto-closest arene hydrogen distance (γ) is 3.20 Å. These values are consistent with nonoptimal perpendicular edge-to-center association.56–59 Hydrogen atoms of methoxy groups contact the opposite face of the phenylalanine arene ring, where the centroid-to-closest methyl hydrogen distances are 3.35 Å and 3.46 Å. Sheets thus formed from (R,S)-9 possess shallow ridged contours when viewed parallel to the hydrogen bonding axis (Figures 3 and 4). These sheets assemble through close approach of parallel piperazinedione rings, producing van der Waals contacts between methylene hydrogen atoms on the cyclopentene rings and the R and benzylic H atoms of the phenylalanine groups (the closest hydrogen-to-hydrogen distances are 2.53 Å and 2.30 Å, respectively). As with (S,S)-6, the p-nitroanisole dipoles of vertical neighbor tapes (VNTs) are in register and are aligned head-to-tail, though here separated by ca. 4 Å. van der Waals interactions are observed between methoxy groups, where the closest hydrogen-to-hydrogen distance is 3.37 Å. In the crystal of (S,S)-9, LNTs are also related by screw symmetry. However, perpendicular edge-to-center associations of p-nitroanisole groups with dipoles opposed are observed on one tape edge where LNTs meet (Figure 3). Consistent with this observation, the centroid-to-centroid distance (κ) for interacting dipolar arenes is 4.76 Å, the angle between planes containing these rings (τ) is 78°, and the arene centroid-to-closest arene hydrogen distance (γ) is 2.59 Å. LNTs associate on the phenylalanine edge by close approach of noninterleaved anti-

parallel “scorpion tails”. This produces contacts between methylene H atoms on the phenylalanine side chains of one tape and the “outside” face of the phenylalanine arene rings in the neighboring tape. These hydrogen-to-arene centroid distances are 3.22 Å and 3.75 Å. Nonoptimal perpendicular edge-to-center interactions are also observed between arenes on the phenylalanine edges of LNTs. The centroid-to-centroid distance (κ) for these arenes is 5.39 Å, the angle between planes containing these rings (τ) is 34°, and the arene centroid-to-closest arene hydrogen distance (γ) is 3.53 Å. Sheets thus formed from (S,S)-9 have very shallow ridged contours when viewed parallel to the hydrogen bonding axis (Figures 3 and 4). These sheets associate through van der Waals interactions involving contacts between methoxy groups (the closest hydrogen-to-hydrogen distance is 2.74 Å), nitro group oxygen atoms and the meta and para hydrogens of the phenylalanine arene (the oxygen-to-closest hydrogen distances are 2.52 Å and 2.74 Å, respectively), and the R-hydrogens of the phenylalanine side chain and hydrogens on the indane cyclopentene ring (where the closest hydrogento-hydrogen distance is 2.64 Å). When crystallized from wet DMF, rac-6 formed enantiomeric “islands” consisting of one molecule of (R,R)-6 and two molecules of (S,S)-6 (an island containing conformers ent-C, B, and D is depicted in Figure 2) or alternatively of one molecule of (S,S)-6 and two molecules of (R,R)-6 (conformers C, ent-B, and ent-D, not shown in Figure 2) that engage in R22(8) reciprocal amide hydrogen bonding. The N-O distances (ε1 and ε2) are in agreement with the CSD averages for R22(8) associated piperazinediones, but deviation from a parallel alignment of the average planes of neighboring piperazinediones (i.e., τpip * 0) is unusual (Table 3). Two molecules of water “link” neighboring


Figure 5. Sheet structure in the crystal of rac-6 grown from wet DMF. Symmetry-related objects are color-coded: conformers B and ent-B are blue, C and ent-C are red, and D and ent-D are green. DMF molecules and hydrogen atoms are omitted for clarity. Hydrogen bonding with water links piperazinedione “islands” of like composition to produce 1D tapes. Neighbor tapes are related by inversion symmetry and engage in parallel edge-to-center interactions.

islands (which are related by translational symmetry) via hydrogen bonding to produce a 1D-tape structure (Figure 5). Lateral neighbor tapes are related by inversion symmetry. Parallel edge-to-center arene interactions are developed, twothirds of which involve p-nitroanisole dipoles that are approximately aligned. The structural parameters for these arene interactions are listed in Table 4 by pairwise interactions of the conformers. Sheets formed by development of orthogonal hydrogen bonding and arene interactions stack in such a way that contacts are made between rows of methoxy groups and nitro groups, producing a solid with channels (Figure 6). These channels are filled with ordered DMF molecules that hydrogen bond with the water molecules in the 1D tapes. These crystals were unstable in air at room temperature, presumably due to loss of solvent from these channels. When crystallized from DMSO, rac-6 formed “islands” with inversion centers in which one molecule of (S,S)-6 and one molecule of (R,R)-6 associate by R22(8) hydrogen bonding (Figure 2). The distances and geometries of these interactions are in agreement with the CSD averages for R22(8) associated piperazinediones (Table 3). Two molecules of DMSO “cap” these islands via sulfoxide-to-amide hydrogen bonding. Islands are connected by parallel edge-to-center association of pnitroanisole rings, which forms 1D tapes (Figure 7). There are twice as many aligned edge-to-center associated p-nitroanisole dipoles as there are opposed dipoles in this crystal (see Table 4). These tapes are insulated by DMSO on all sides. The closest interisland contact is made by methoxy hydrogen atoms (3.09 Å, not shown). Discussion In prior work with compounds 3, 4, and other nonpolar piperazinediones,19 DMSO had proven to be a useful solvent for growing crystals suitable for single-crystal analysis. However, efforts to grow solvent-free crystals of compounds 5 from

Ntirampebura et al.

Figure 6. Sheet assembly in the crystal of rac-6 grown from wet DMF. Symmetry-related objects are color-coded: conformers B and ent-B are blue, C and ent-C are red, and D and ent-D are green. DMF molecules and hydrogen atoms are omitted for clarity. Top view perpendicular to 1D tape axis: sheets stack and engage in C-HsO interactions involving rows of methoxy hydrogens and rows of nitro group oxygens. Bottom view parallel to 1D tape axis: sheet stacking produces channels which are filled with ordered DMF molecules.

DMSO failed.49 In the present study, solvent-free crystals of meso-6, (R,S)-9, and (S,S)-9 were obtained from DMSO. Crystals of rac-6 grown from DMSO or DMF included solvent as a component of the hydrogen bonding array. Crystals of (S,S)-6 grown from DMF also included solvent, although not as a component of the hydrogen bonding array. Solvent is undoubtedly associated with compounds 3-9 when in solution through hydrogen bonding and, in cases such as 5 and 6 where strong molecular and/or local dipoles are present, through dipole-dipole interactions. In the solvent-free crystal of (S,S)-4, the p-bromoanisole dipoles (ca. 1.8 D)60 of perpendicular edge-to-center associated arenes were opposed. Because (S,S)-4 is enantiomerically pure, dipoles must be aligned along both edges of the hydrogenbonded 1D tape. If two such tapes related by screw symmetry interact via perpendicular edge-to-center association, the pbromoanisole dipoles of associated arenes must be opposed. However, in crystals of rac-4 and meso-4, these dipoles were randomly distributed as aligned or opposed while the other packing features of (S,S)-4 were maintained, producing very similar 1D tapes, 2D sheets, and 3D solids. Thus, dipole opposition in (S,S)-4 was considered a consequence of enantiomeric purity, and not a structural determinant.20 In the crystal of (S,S)-5, R22(8) hydrogen bonding was replaced by hydrogen bonding with included DMSO molecules.49 Surprisingly, the p-methoxybenzonitrile dipoles (ca. 3.3 D)60 of parallel edge-to-center associated arenes were approximately aligned, leading to a crystal that exhibited NLO properties. In the crystal of rac-5 parallel edge-to-center arene association with aligned p-methoxybenzonitrile dipoles was also observed, while in the crystal of meso-5 parallel edge-to-center arene association with opposed p-methoxybenzonitrile dipoles was observed.



meso-6 as well. However, aligned p-nitroanisole dipoles outnumbered opposed dipoles in these crystals. Conclusion From studies of piperazinediones 3-9, we conclude: (1) despite the thermodynamic favorability of 1D tape formation that results from R22(8) reciprocal amide hydrogen bonding, solvents capable of competing for amide hydrogen bonds frequently intercede when the arene rings are strongly dipolar, leading to less stable (i.e., lower melting) crystals that include solvent; (2) arenes bearing larger dipoles (g3 D) favor parallel edge-to-center alignments; (3) in spite of this preference, arenes bearing large dipoles (up to 6 D) can adopt perpendicular edgeto-center motifs when other factors encourage this; (4) arene associations involving dipole opposition are favored, but arene associations involving dipole alignment are not uncommon. These findings will be employed in future attempts to engineer crystals and polymers that possess significant NLO properties based on scaffold 1.

Figure 7. Sheet structure in the crystal of rac-6 grown from DMSO. Hydrogen atoms are omitted for clarity. Top: view perpendicular to tape axis. Parallel edge-to-center arene interactions link piperazinedione “islands” to produce 1D tapes (two are shown) that run from side to side. Bottom: view parallel to tape axis. Tapes are isolated by ordered and disordered DMSO molecules included in the crystal. Neighboring tapes are related by translation.

In the present work, incorporation of the p-nitroanisole group (ca. 6.0 D)60 in compounds 6 and 9 extends the study of the effects of local and net molecular dipoles on crystal packing with minimal structural perturbation.61 From prior work with piperazinediones (S,S)-7, (R,S)-7, (S,S)-8, and (R,S)-8,20,49 it was anticipated that in crystals of (S,S)-9 and (R,S)-9, 1D tapes would form via R22(8) hydrogen bonding, and that screw-related ”herringbone” motifs between neighboring tapes would lead to a sheet structure stabilized by intermolecular perpendicular edgeto-center arene interactions in which the dipoles of the associated arenes were opposed. While expectations were met in the case of (S,S)-9, parallel edge-to-center arene associations with opposed p-nitroanisole dipoles were observed in the crystal of (R,S)-9. Given that compound (S,S)-9 packs similarly to compounds (S,S)-7, (R,S)-7, (S,S)-8, and (R,S)-8, it seems reasonable to assume that the molecular topography of (S,S)-6 does not preclude solvent-free crystal packing similar to that observed for (S,S)-4. Such packing, which would result in opposition of the p-nitroanisole dipoles on adjacent neighboring tapes engaged in perpendicular edge-to-center arene interactions, was not observed. Instead, neighboring 1D tapes formed via R22(8) hydrogen bonding associate via parallel edge-to-center arene associations with opposed p-nitroanisole dipoles similar to the packing observed in the crystal of (R,S)-9. Parallel edge-tocenter arene associations were observed in crystals of rac-6 and

Acknowledgment. This work was supported in part by the Office of Naval Research through the Center for Advanced Multifunctional Nonlinear Optical Polymers and Molecular Assemblies, by the University of Arizona Office of the Vice President for Research, and by the Donors of the Petroleum Research Fund, administered by the American Chemical Society. The diffractometer used for data collection for (S,S)-6 + DMF, rac-6 + DMSO, (R,S)-9, and (S,S)-9 was purchased with funds from NSF grant CHE 9610374. Sample meso-6 was submitted through the SCrALS (Service Crystallography at Advanced Light Source) program. Crystallographic data were collected at Beamline 11.3.1 at the Advanced Light Source (ALS), Lawrence Berkeley National Laboratory. The ALS is supported by the U.S. Department of Energy, Office of Energy Sciences, under contract DE-AC02-05CH11231. Supporting Information Available: X-ray crystallographic information files (CIFs) for (S,S)-6 + DMF, rac-6 + DMF + water, rac-6 + DMSO, meso-6, (R,S)-9, and (S,S)-9, and the results of an October, 2007 CSD search for reciprocal hydrogen bonding interactions involving 1,4-piperazine-2,5-diones. This information is available free of charge via the Internet at http://pubs.acs.org.

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CG701240M

Organic Crystal Engineering with 1,4-Piperazine-2,5-diones. 7. Crystal

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