Crystal Engineering with Alicyclic Î²-Amino Acids: Construction of

CRYSTAL GROWTH & DESIGN

Crystal Engineering with Alicyclic β-Amino Acids: Construction of Hydrogen-Bonded Bilayers Fa´biań,†

Ka´lmań,*,†

La´szlo´ Alajos Zsuzsanna Cs. Gyarmati‡

Gyula

Argay,†

Ga´bor

Berna´th,‡

2005 VOL. 5, NO. 2 773-782

and

Institute of Chemistry, Chemical Research Center of the Hungarian Academy of Sciences, P.O. Box 17, H-1525 Budapest, Hungary, Research Group for Heterocyclic Chemistry, Hungarian Academy of Sciences and University of Szeged, Szeged, Hungary, and Institute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary Received June 21, 2004;

Revised Manuscript Received September 17, 2004

ABSTRACT: The crystal structures of four homologous cis-alicyclic β-amino acids present a new recurring layer pattern of hydrogen bonds. This pattern was derived from two one-dimensional patterns observed in related alicyclic 2-hydroxycarboxylic acid structures. Its robustness is demonstrated by the isostructurality of the four crystals. The hydrogen bonds arrange the molecules in bilayers in the solid phase. The pattern was stressed by variations of the molecules, i.e., by the introduction of a double bond, by the change between stereoisomers, and by the replacement of the simple alicyclic ring with a bicyclic one. These variations gradually weaken the correspondence of the actual structure to the original design. Introduction engineering1-3

Crystal has the aim of the production of crystalline materials with predefined patterns of molecular organization. It may find practical applications via the identification of structural features that lead to a desired physical or chemical property. The molecules then need to be arranged in the crystal so that the required features are present.4 Crystal growth is a self-recognition process governed by the intermolecular interactions among the molecules that form the solid. These interactions are complex and mostly nondirectional, and the prediction of crystal structures from molecular structures therefore remains an unresolved problem.5 Crystal engineering overcomes this problem by utilizing supramolecular synthons to organize molecules into a predefined arrangement.1,4 This approach has been successfully applied for the construction of, for example, materials for nonlinear optics,6 nanoporous structures,7 and magnetic materials.8 In general, supramolecular synthons are identified as common hallmarks present in the crystal structures of a series of related compounds. However, it is possible to deduce new patterns from known ones. In the present paper, we demonstrate the derivation of a two-dimensional hydrogen bond pattern that leads to the formation of molecular bilayers9 in the crystal. The isostructurality10 of the crystals of four homologous compounds suggest that the pattern is robust. To test this robustness, derivatives of the homologous molecules were tested. Similar bilayer aggregation is exhibited by all these compounds in the solid phase. The resulting hydrogen bond patterns demonstrate gradually relaxed versions of the original design. * To whom correspondence should be addressed. Phone: +36-1-3257547. Fax: +36-1-325-7554. E-mail: [email protected]. † Institute of Chemistry, Chemical Research Center of the Hungarian Academy of Sciences. ‡ Research Group for Heterocyclic Chemistry, Hungarian Academy of Sciences and University of Szeged, and Institute of Pharmaceutical Chemistry, University of Szeged.

Experimental Section Preparations. Alicyclic cis-1,2-dicarboxylic acid anhydrides were earlier used as starting materials for the preparation of alicyclic cis-2-aminocarboxylic acids via monoamide formation and Hofmann degradation.11 This method is suitable for the synthesis of cis-2-aminocyclohexanecarboxylic and cis- and trans-2-aminocyclohex-4-enecarboxylic acids, as the starting dicarboxylic anhydrides are readily available. There is a more suitable general method for the preparation of the cis isomers: chlorosulfonyl isocyanate addition to cycloalkenes and hydrolysis of the resulting azetidione.12 General Procedure. (a) Chlorosulfonyl Isocyanate Addition to a Cycloalkene. Cycloalkene (0.27 mol) and 250 mL of abs CH2Cl2 were added to a four-necked flask, and the mixture was cooled to 0 °C. Chlorosulfonyl isocyanate (25.8 mL in 80 mL of CH2Cl2) was added dropwise to the stirred reaction mixture during 1.5 h. The mixture was then heated to 45 °C and refluxed for 2 days. The reaction mixture was cooled to 0 °C, and a solution of 54.5 g (0.43 mol) of Na2SO3 in 150 mL of H2O was cautiously added dropwise. The pH was held at 8-9 by parallel addition of 10% aqueous KOH. The organic phase was separated, and the aqueous layer was extracted twice with CH2Cl2. The combined organic phase was dried over Na2SO4 and CaCl2. After filtration, the solvent was distilled off. The β-lactam was recrystallized from ethyl acetate. (b) Hydrolysis. β-Lactam (20 mmol) was dissolved in 60 mL of concentrated aqueous HCl, and the solution was stirred at room temperature for 5 h. The white crystals that separated out were filtered off and washed with diethyl ether. The cis2-aminocarboxylic acid hydrochloride was recrystallized from water/acetone. cis-2-Aminocyclopentane- and Cycloheptanecarboxylic Acid (4, 6). The amino acid hydrochlorides were prepared from the corresponding cycloalkenes and chlorosulfonyl isocyanate by the general method. The amino acids were obtained by ion-exchange chromatography on Varion KSM resin. 4: yield, 65%; mp, 219-220 °C; lit. mp,11 223-224 °C. 6: yield, 68%; mp, 245-246 °C; lit. mp,13 242-243 °C. cis- and trans-2-Aminocyclohexanecarboxylic Acid (5, 9). The corresponding (cis- or trans-) hexahydrophthalic anhydride was transformed to the monoamide with NH4OH, and Hofmann degradation afforded 5 and 9. 5: yield, 70%; mp, 240-241 °C; lit. mp,14 235-236 °C. 9: yield, 55%; mp, 278279 °C; lit. mp,14 274-275 °C.

10.1021/cg0497997 CCC: $30.25 © 2005 American Chemical Society Published on Web 12/14/2004

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Table 1. Crystallographic Data formula formula weight crystal system space group color unit cell dimensions (Å, deg) a b c R β γ volume Z temperature (K) R [I > 2σ(I)] GOF on F2

4

5

6

7

8

9

10

11

C6H11NO2 129.16 triclinic P1 h colorless




C7H11NO2 141.17 monoclinic P21/c colorless



C8H13NO2 155.19 orthorhombic Pbcn colorless

5.123(2) 6.374(1) 10.931(2) 97.90(1) 99.08(2) 110.49(2) 322.93(15) 2 293(2) 0.0660 1.423

5.160(1) 6.383(1) 12.281(1) 95.11(1) 100.51(1) 108.97(1) 371.29(10) 2 293(2) 0.0486 0.856

5.134(1) 6.317(1) 13.468(1) 101.50(1) 96.17(1) 106.25(2) 404.68(11) 2 293(2) 0.0581 1.262

5.397(1) 6.338(1) 13.743(1) 94.49(1) 98.66(1) 105.94(2) 443.31(11) 2 293(2) 0.0374 1.015

11.757(1) 5.159(1) 12.075(1) 90 110.27(1) 90 687.04(16) 4 293(2) 0.0357 1.305

11.597(2) 5.640(1) 13.011(1) 90 111.07(1) 90 794.1(2) 4 293(2) 0.0353 1.370

10.961(1) 5.448(1) 12.994(1) 90 110.97(1) 90 724.55(16) 4 293(2) 0.0382 1.039

23.387(1) 6.654(1) 10.007(1) 90 90 90 1557.3(3) 8 293(2) 0.0526 1.044

cis-2-Aminocyclooctanecarboxylic Acid (7). The synthesis of cis-2-aminocyclooctanecarboxylic acid hydrochloride from cyclooctadiene was described earlier.12d We used the above general method for the preparation of the β-lactam, starting from cyclooctene. Yield, 55%; mp, 73-74 °C; lit. mp,15 71-72 °C. The amino acid hydrochloride was prepared by the reaction of the β-lactam and concentrated HCl. Yield, 85%; mp, 215-216 °C; lit. mp,12d 214-216 °C. cis-2-Aminocyclooctanecarboxylic acid was obtained from the hydrochloride by ionexchange chromatography on Varion KSM resin. 7 was recrystallized from water/acetone: yield, 71%; mp, 226-227 °C. 1H NMR (400 MHz, D2O) δ (ppm): 1.51-1.95 (m, 12H), 2.78-2.82 (m, 1H), 3.60-3.64 (m, 1H). IR (KBr, cm-1): 1403, 1502, 1573, 1639. Anal. Calcd for C9H17NO2: C, 63.13%; H, 10.01%; N, 8.18%. Found: C, 62.97%; H, 9.86%; N, 8.08%. cis- and trans-2-Amino-cyclohex-4-ene-1-carboxylic Acid (8, 10). A previously described method16 was used for the synthesis of 8 and 10 from cis- and trans-1,2,3,6-tetrahydrophthalic anhydride. 8: yield, 71%; mp, 210-214 °C; lit. mp,16 216-218 °C. 10: yield, 65%; mp, 269-271 °C; lit. mp,16 267-269 °C. 3-exo-Aminobicyclo[2.2.1]heptane-2-exo-carboxylic Acid (11). 3-exo-Aminobicyclo[2.2.1]hept-5-ene-2-exo-carboxylic acid was prepared from norbornadiene by chlorosulfonyl isocyanate addition.17 11 was prepared from this compound by reduction with Pd/C, in a yield of 91%; mp, 260-262 °C; no mp was given in the literature. 1H NMR (400 MHz, D2O) δ (ppm): 1.2681.765 (m, 6H); 2.406 (s, 1H); 2.517 (s, 1H); 2.578-2.599 (d, 1H, J ) 4 Hz); 3.377-3.397 (d, 1H, J ) 4 Hz). IR (KBr, cm-1): 1405, 1502, 1616, 1641. Anal. Calcd for C8H13NO2: C, 61.91%; H, 8.44%; N, 9.02%. Found: C, 62.16%; H, 8.46%; N, 8.99%. Crystallography. Crystal data and data collection parameters are listed in Table 1. The crystals were mounted on glass fibers. Each data set was collected on an Enraf-Nonius CAD4 diffractometer with graphite-monochromated Cu KR or Mo KR (for 5) radiation. Lattice parameters were determined by a least-squares fit for 25 reflections. The intensities of three standard reflections were monitored every hour, and the indicated decay was corrected for. All reflections were corrected for Lorentz and polarization effects.18 Absorption correction was applied by using ψ-scan data.19 Space groups were determined from the unit cell parameters, intensity statistics, and systematic absences. The structures were solved by direct methods (SHELXS-9720). All non-hydrogen atoms were modeled anisotropically in the structure refinement (SHELXL9721). Hydrogen atoms attached to nitrogen atoms were located in difference Fourier maps; the others were placed in calculated positions. Hydrogen atoms were refined isotropically in riding mode.

Results and Discussion Association of Hydrogen-Bonded Dimers. We have recently been investigating the hydrogen bond

patterns generated by vicinal cis and trans OH and COX (X ) OH or NH2) groups attached to alicyclic rings in racemic crystals.22-25 It was found that most of the

Figure 1. The two types of dimer units observed in the crystal structures of the alicyclic 2-hydroxycarboxylic acids. They are held together by COOH‚‚‚OH (a) and OH‚‚‚OdC (b) hydrogen bonds, respectively. Schematic representations of the dimer units are shown at the bottom. Since the dimer units are centrosymmetric, the two molecules are enantiomers. This is shown by black and white circles.

observed hydrogen bond patterns can be constructed by the self-assembly of helices25 or centrosymmetric dimer units.24 The dimer units are of two types, which differ in the role of the hydrogen bonds. They are held together by either COOH‚‚‚OH (a) or OH‚‚‚OdC (b) hydrogen Chart 1.

Molecular Formulas

Crystal Engineering with Alicyclic β-Amino Acids

Figure 2. Crystal structure of (1R*,2S*,4R*)-cis-4-tert-butyl2-hydroxycyclopentanecarboxylic acid (1). Each centrosymmetric dimer unit is held together by a pair of COO3H‚‚‚O1H hydrogen bonds, while O1H‚‚‚O2dC hydrogen bonds link coplanar dimer units and, between pairs of translation-related dimers, generate hydrogen-bond-containing rings that hold four molecules together.

bonds (Figure 1), which join rings with the R22(12) graph set notation.26 It was found that the self-assembly of dimer units may occur in two independent directions. The hydrogen bonds between adjacent dimer units may be either within the best plane of the dimer units or perpendicular to the plane of the dimer units. The former possibility is exemplified by the crystal structure of (1R*,2S*,4R*)-cis-4-tert-butyl-2-hydroxycyclopentanecarboxylic acid (1, Chart 1), and the latter by that of (1R*,2R*)-trans2-hydroxycyclooctanecarboxylic acid (2). When the dimer units are linked by hydrogen bonds lying within the plane, hydrogen-bond-containing R44(12) rings that link four molecules are formed between each pair of dimer units (Figure 2). If the bonds connecting the dimer units are perpendicular to the plane, then the rings formed between them connect only two molecules. These rings are the same as those in the dimer units. Rings containing OH‚‚‚OdC hydrogen bonds are formed between two COOH‚‚‚OH-linked dimer units, and vice versa. Thus, the resulting hydrogen bond pattern is the same no matter which bonds join the initial dimer units (Figure 3). Derivation of a Combined Hydrogen Bond Pattern. It has been pointed out that the packing pattern of 2 can be deduced topologically from that of 1 by a rearrangement of the hydrogen bonds.24 In both structures, COOH‚‚‚OH-linked dimer units (a) are repeated infinitely in three dimensions. From a topological point of view, they differ only in the connectivity of the dimer units (Figure 4). In 1, the O1H‚‚‚O2dC bonds connect the dimer units in a lateral manner to form hydrogenbond-containing rings that join four molecules, whereas the corresponding linking bonds are perpendicular to the dimer units in 2, and thus they form rings that join two molecules (b). Since both 1 and 2 crystallize with space group P1 h, this similarity is reflected by the arrangement of the molecules. In 1, a pattern resembling the infinite rows

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Figure 3. Crystal structure of (1R*,2R*)-trans-2-hydroxycyclooctanecarboxylic acid (2). The connection of dimer units held together by CO-O3H‚‚‚O1H hydrogen bonds leads to the formation of dimer units that are joined by O1H‚‚‚O2dC hydrogen bonds and vice versa. This gives rise to an infinite row of molecules held together by hydrogen-bond-containing rings joined alternately by COOH‚‚‚OH and OH‚‚‚OdC hydrogen bonds. Only two molecules are involved in the formation of each ring.

of hydrogen-bonded molecules in 2 can be identified. This observation suggested that the one-dimensional hydrogen bond patterns in 1 and 2 (Figure 4) could be combined to give a two-dimensional grid by modifying the molecular structure of 1 appropriately. Exchange of the O1H group in 1 for NH2 may provide an additional hydrogen bond between the dimer units, while maintaining the original ladder pattern of 1 (Figure 2), and may lead to the superposed pattern shown in Figure 4c. This exchange was suggested by the isostructurality of the carboxylic acid 2 and its carboxamide analogue, 3.25 In the latter structure, the chains of dimers are linked into two-dimensional networks without an alteration of the overall packing arrangement. The trial compounds were free from the bulky tert-butyl group, and the extent of steric repulsion between the dimer units was therefore reduced. Crystal Structures of 4-7. The alicyclic cis-β-amino acids with 5-8-membered alicyclic rings (Chart 1, 4-7) were synthesized and crystallized from water with the aim of testing whether the molecules associate with the expected hydrogen bond pattern in their crystals. All these compounds crystallize with space group P1 h, in similar unit cells (Table 1). The four crystals are isostructural; the molecules are located at the same positions in their respective unit cells (Figure 5). The hydrogen bond connectivity is the same in each crystal (Table 2), even though the orientation of the molecules of 7 in the unit cell is rotated by 180° as compared with that in 4-6, and thus the positions of the COO- and NH3+ substituents are interchanged. This may be attributed to slight differences in hydrophobic interactions due to the enlargement of the alicyclic rings. The reorientation hardly influences the degree of crystal structure similarity as measured by the volumetric

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Figure 4. Schematic representations of the hydrogen bond networks formed in the crystal structures of (a) (1R*,2S*,4R*)cis-4-tert-butyl-2-hydroxycyclopentanecarboxylic acid (1) and (b) (1R*,2R*)-trans-2-hydroxycyclooctanecarboxylic acid (2) and (c) the superposition of the two patterns expected for the crystals of the alicyclic β-amino acids (4-7). For the meanings of the symbols, see Figure 1.

isostructurality index.21 It is 72% for the identically oriented 5 and 6, in comparison with 70% for 6 and the flipped 7. Each molecule is part of two chemically indistinguishable centrosymmetric dimer units. They are joined by pairs of N1-H1b‚‚‚O3 and N1-H1c‚‚‚O3 hydrogen bonds, respectively. The third hydrogen of the ammonium ion is donated to the O2 atom of a translated molecule, leading to chains of N1-H1a‚‚‚O2 hydrogenbonded molecules. The overall pattern in Figure 6 exhibits the expected network topology (Figure 4c). Beside the hydrogen bond topology, these alicyclic cisβ-amino acids inherit patterns of molecular arrangement from the parent structures 1 and 2 (Figure 7). The ladder pattern of 1 (Figure 2) can be recognized in their crystal packing (Figure 7a,b). Each molecule is part of two such patterns. These patterns share their N-H1a‚ ‚‚O2-C-O3 fragments, but the hydrogen-bond-containing rings in them are closed by either N1-H1b‚‚‚O3 or N-H1c‚‚‚O3 bonds. (Table 2 reveals that the molecules connected by H1b and H1c are related to each other by

Fa´biań et al.

translation along the crystallographic a axis, which is approximately perpendicular to the plane of the dimer units.) The hydrogen bonds forming the dimer units are reversed in 4-7 as compared with 1, since the donor function is transferred from the acid to the amino function during zwitterion formation. The geometrical distortion of the original pattern (Figure 2 vs Figure 7a,b) is presumably related to the presence of the other hydrogen bonds. The infinite row of dimer units observed in 2 (Figure 3) is also present in the alicyclic β-amino acid structures 4-7 (Figure 7c). The conformations of the hydrogenbond-containing rings joined alternately by the N-H1b‚‚‚O3 and N-H1c‚‚‚O3 hydrogen bonds along the rows differ, but the torsion angles calculated for these rings vary by at most 10° among the homologous structures 4-7 (Table 3). Neither of the ring conformations corresponds to that of the planar or folded dimers observed in related 2-hydroxycarboxylic acids and 2-hydroxycarboxamides.25 This is not surprising, since both the dimer units and their mutual connections undergo change. In the parent structure 2, the hydrogen-bondcontaining rings are formed alternately by COOH‚‚‚OH and OH‚‚‚OdC hydrogen bonds, i.e., the donor and acceptor roles of the two functional groups are exchanged in adjacent rings (Figure 3). In contrast, the functional groups of the zwitterionic amino acids can only be either donors or acceptors. The NH3+ moiety must be a donor, while the COO- group must be an acceptor in each ring. Geometrically, the simplest arrangement that fulfills this requirement involves the incorporation of the same nitrogen and oxygen atoms in two adjacent rings (Figure 7c). This arrangement excludes one of the oxygen atoms (O2) from the pattern, which is involved only in the ladder patterns shown in Figure 7a,b. The formation of the zwitterions does not influence the graph set representation of the hydrogenbond-containing rings. Similarly to 1 and 2, R22(12) and R44(12) rings are formed in 4-7. All the hydrogen bonding groups are located in infinite hydrophilic layers in the crystal structures of 4-7 (Figure 6). The alicyclic rings are located above and below these layers, forming hydrophobic regions in the crystal (Figure 8). Overall, the hydrogen-bonded bilayers are self-assembled. The bilayers stack with only weak van der Waals interactions between them. This arrangement suggests that derivatives of alicyclic cis-βamino acids may be utilized in crystal engineering for the construction of two-dimensional arrays. Crystal Structure of an Unsaturated Analogue. To test the viability of the above hypothesis, further β-amino acids were examined (Chart 1). First, cis-2aminocyclohex-4-enecarboxylic acid (8) was synthesized and crystallized from a 2:1:1 ethanol/chloroform/acetone solvent mixture. This compound can be regarded as a minimally modified derivative of 5. The double bond reduces the flexibility of the alicyclic ring, but it may only be involved in weak intermolecular interactions, which cannot compete with the strong hydrogen bonds. Consequently, a structure similar to that in 4-7 was expected. It was found that 8 crystallizes with space group P21/c, so that the symmetry of the original pattern is evidently broken (Table 1). However, an analysis of the



Figure 5. Crystal structures of the homologous alicyclic β-amino acids: (a) cis-2-aminocyclopentanecarboxylic acid (4), (b) cis2-aminocyclohexanecarboxylic acid (5), (c) cis-2-aminocycloheptanecarboxylic acid (6), and (d) cis-2-aminocyclooctanecarboxylic acid (7).

hydrogen bond interactions (Table 2) reveals that the patterns of molecular self-assembly in 8 remain similar to those in 4-7. Similarly to its saturated analogue, each molecule of 8 is part of two dimer units. The symmetry of these dimer units is different for the unsaturated compound (8) and the saturated ones (47). In 4-7, the two dimer units are centrosymmetric and are not related to each other by symmetry. In 8, each dimer unit is formed by screw-related molecules. Thus, the two bonds (N1-H1b‚‚‚O3 and N1-H1c‚‚‚O3) that join a dimer unit are symmetry-independent, while the two molecules which form dimer units with a given molecule are related by a crystallographic translation (Table 2). The role of the third hydrogen bond (N1H1a‚‚‚O2) remains similar: it links the molecules into infinite chains. The molecules forming the chains are related by translation in 4-7 and by a glide plane in 8.

Irrespective of the differences in symmetry relationships between the molecules, the topology of the hydrogen bond network in 8 (Figure 9) remains the same as in 4-7 (Figure 6). Only the orientation of every second molecule is different; otherwise, the two patterns are identical. Accordingly, molecular arrangements resembling those observed in the parent structures 1 and 2 can also be identified in 8 (Figure 10). The similarity of these arrangements to those in Figure 7 is striking. Again, the difference in symmetry is shown by the different orientation of every second molecule (Figures 7c and 10b). The crystal packing of the molecules of 8 is characterized by hydrogen-bonded bilayers which stack with only weak van der Waals interactions between them (Figure 11). The unit cell of 8 can be derived from the unit cell of its saturated counterpart by the use of a glide plane to double the original cell.

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Table 2. Hydrogen Bond Dimensions structure

D-H

A

d(H‚‚‚A)/Å

d(D‚‚‚A)/Å

(D-H‚‚‚A)/deg

4

N1-H1b N1-H1c N1-H1c N1-H1a N1-H1b N1-H1c N1-H1c N1-H1a N1-H1b N1-H1c N1-H1c N1-H1a N1-H1b N1-H1c N1-H1c N1-H1a N1-H1b N1-H1c N1-H1c N1-H1a N1-H1b N1-H1c N1-H1c N1-H1a N1-H1b N1-H1c N1-H1a N1-H1a N1-H1b N1-H1c

O3 [1 - x, 1 - y, -z] O3 [-x, 1 - y, -z] O2 [-x, 1 - y, -z] O2 [x, y - 1, z] O3 [1 - x, 1 - y, -z] O3 [-x, 1 - y, -z] O2 [-x, 1 - y, -z] O2 [x, y - 1, z] O3 [1 - x, 1 - y, -z] O3 [-x, 1 - y, -z] O2 [-x, 1 - y, -z] O2 [x, y - 1, z] O3 [-x, 1 - y, -z] O3 [1 - x, 1 - y, -z] O2 [1 - x, 1 - y, -z] O2 [x, y + 1, z] O3 [-x, -1/2 + y, 1/2-z] O3 [-x, 1/2 + y, 1/2-z] O2 [-x, 1/2 + y, 1/2-z] O2 [x, 3/2 - y, 1/2 + z] O2 [-x, -1/2 + y, 1/2 - z] O3 [-x, 1/2 + y, 1/2 - z] O2 [-x, 1/2 + y, 1/2 - z] O2 [x, 1/2 - y, -1/2 + z] O2 [-x, -1/2 + y, 1/2 - z] O3 [-x, 1/2 + y, 1/2 - z] O2 [x, 1/2 - y, -1/2 + z] O3 [x, 1 - y, 1/2 + z] O3 [1/2 - x, 1/2 - y, 1/2 + z] O2 [1/2 - x, 1/2 + y, z]

1.95 2.05 2.56 1.86 1.95 2.11 2.54 1.89 1.97 2.03 2.59 1.90 1.93 2.21 2.44 1.91 2.12 1.94 2.58 1.84 2.03 1.95 2.65 1.88 2.17 1.97 1.85 1.92 1.96 1.90

2.8008(18) 2.9267(18) 3.1494(18) 2.7220(14) 2.8167(13) 2.9721(14) 3.1893(14) 2.7316(12) 2.8227(18) 2.9049(18) 3.200(2) 2.7600(16) 2.8064(16) 3.0496(16) 3.0976(14) 2.7893(16) 2.9544(14) 2.8020(14) 3.3036(15) 2.7252(13) 2.8130(11) 2.7975(11) 3.4147(13) 2.7363(9) 2.8395(14) 2.8190(14) 2.7104(12) 2.7819(16) 2.8111(16) 2.7428(15)

160.6 168.9 124.5 162.3 162.8 164.2 130.8 157.0 160.7 168.6 126.3 160.8 166.3 156.7 131.4 168.7 155.6 164.2 138.8 171.7 146.5 158.9 145.4 161.6 131.8 158.1 160.8 162.8 158.4 156.7

5

6

7

8

9

10 11

From the above discussion, it is evident that the crystals of 8 retain the hydrogen bond network and the basic molecular arrangements observed for 4-7. Thus, the combined hydrogen bond pattern proved robust enough to tolerate the change from saturated to unsaturated molecules. Crystal Structures of Two Trans Stereoisomers. To stress the pattern further, the crystal structures of two trans-β-amino acids, trans-2-aminocyclohexane-1carboxylic acid (9) and trans-2-aminocyclohex-4-ene-1carboxylic acid (10), were analyzed (Chart 1). Single crystals of 9 and 10 were obtained from solutions in methanol and ethanol, respectively. Both compounds crystallize with space group P21/c. Their structures exhibit a high degree of isostructurality. The volumetric isostructurality index for 9 and 10 is 86%. Despite the

Figure 6. Hydrogen bond network in the crystal structure of cis-2-aminocyclooctanecarboxylic acid (7). The alicyclic ring is omitted for clarity. The same pattern is formed in the crystals of the lower homologues 4-6. This pattern is a topological combination of the patterns observed in the crystal structures of 1 and 2 (Figure 4).

similarity of their unit cell parameters and symmetry, 9 and 10 are scarcely isostructural with 8. This can be explained by differences between the molecular conformations and the dimer units. The carbocycle exhibits a distorted half-chair/envelope conformation in 8, while it assumes a chair form in 9 and a half-chair form in 10. Additionally, the orientations of the molecules in the unit cell differ in these structures (Figures 11 and 12). The hydrogen bond connectivity is similar in all structures with space group P21/c (Table 2). Each molecule of 9 and 10 is involved in two dimer units. These dimer units, just like those in 8, are assembled from screw-related molecules and are joined by two symmetry-independent hydrogen bonds. In contrast with 8, one of these bonds (Table 2) is formed with O2 as the acceptor. This means that the shape of the dimer units in the trans stereoisomers is strongly bent (Figure 13). Nevertheless, the self-assembly of the dimer units shows the same patterns as those observed for the cis isomers. The ladder pattern inherited from 1 is retained with a minor modification: the hydrogen-bond-containing rings that link four molecules are alternately 8- and 12membered [R44(8) and R44(12)] in 9 and 10, while they are all 12-membered in 4-8. The 8-membered rings are formed because the two sides of the dimer units are not equivalent. On one side the carboxylate moiety is included in the ring, while on the other side it is excluded (Figure 13a). An infinite row of dimer units, resembling the structure of 2, is also formed. Again, this pattern differs from the corresponding pattern of the cis analogues in the bent shape of the dimer units and in the presence of both carboxylate oxygen atoms as acceptors. The overall hydrogen bond networks in 9 and 10 (Figure 14) reflect the above differences but are still accurately represented by the combined topological


Crystal Growth & Design, Vol. 5, No. 2, 2005 779 Table 3. Symmetry-Independent Endocyclic Torsion Angles in the Hydrogen-Bond-Containing Rings Joining Two Molecules of 4-7a dimer 4 (H1b) 5 (H1b) 6 (H1b) 7 (H1b) K&P (H1b)c 4 (H1c) 5 (H1c) 6 (H1c) 7 (H1c) K&P (H1c)c

C2-C1 C1-CXb CXb-O3 O3‚‚‚N1 45 52 54 52 +sc 45 52 54 52 +sc

-74 -72 -81 -81 -sc -74 -72 -81 -81 -sc

-45 -51 -49 -45 -sc 158 154 155 157 +ap

162 164 163 162 +ap -155 -161 -157 -157 -ap

N1-C2 -66 -59 -57 -62 -sc (-gauche) 76 83 86 84 +sc

a They are calculated for non-hydrogen atoms only. b CX denotes the carboxylate carbon atom. c Classification of the torsion angles according to Klyne and Prelog (ref 27).

Figure 8. Packing arrangement in the crystal structure of 4. The layout of the molecules of 5-7 is the same in their crystals.

Figure 7. Hydrogen bond patterns in the crystal structure of 4. The same patterns were observed in structures 5-7. Two symmetry-independent ladder patterns are formed by antiparallel chains of N-H1a‚‚‚O2 hydrogen bonds cross-linked by (a) N-H1b‚‚‚O3 and (b) N-H1c‚‚‚O3 hydrogen bonds, respectively. (c) The dimer units joined by the latter two bonds are fused into rows by common O3 donor and NH3+ acceptor moieties.

pattern in Figure 4c. This means that the designed network survived the transition from cis to trans stereoisomers, with small alterations in its topology at the atomic level but without change at the molecular level. Structure of the cis-β-Amino Acid with Norbornane as the Alicyclic Fragment. To subject the hydrogen-bonded grid to a different stress, the alicyclic ring in 5 was replaced by the bridged norbornane moiety. The resulting compound, 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (11), was recrystallized from methanol. The crystals obtained possess Pbcn

symmetry, and their packing arrangement differs from that in the previous compounds. It was found that the molecules of 11 do not form dimer units in the crystal. Molecular modeling28 revealed that the formation of dimer units and molecular ladders, like those in 1, is sterically permitted for 11. But, the protrusion of the bridging CH2 link would block the further association of these ladders to give a twodimensional network, and thus it would exclude one of the ammonium hydrogen atoms from hydrogen bonding. Consequently, a different network is self-assembled, in which all possible donors are involved (Table 2). The hydrogen-bond-containing rings link three molecules in this network (Figure 15) in contrast with the rings formed between two and four molecules in the previous structures. This means that the intended topology (Figure 4c) is not maintained. An excerpt from the crystal structure (Figure 16) shows that the ladder pattern is distorted so that its sidepieces are shifted relative to each other, and the steps (the hydrogen bonds) become slanted. This zigzag arrangement leaves

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Figure 9. Hydrogen bond network in the crystal structure of cis-2-aminocyclohex-4-enecarboxylic acid (8). The alicyclic ring is omitted for clarity. Except for the relative chirality of the molecules, the topology of this pattern is represented by Figure 4c. Figure 11. Packing arrangement in the crystal structure of cis-2-aminocyclohex-4-enecarboxylic acid (8).

Figure 12. Packing arrangement in the crystal structure of trans-2-aminocyclohexanecarboxylic acid (9).

Figure 10. Hydrogen-bonded molecular assemblies in the crystal structure of cis-2-aminocyclohex-4-enecarboxylic acid (8). (a) Ladder patterns are formed by antiparallel chains of N-H1a‚‚‚O2 hydrogen bonds cross-linked alternately by N-H1b‚‚‚O3 and N-H1c‚‚‚O3 hydrogen bonds. (b) The dimer units joined by the latter two bonds are fused into rows by common O3 acceptor and NH3+ donor moieties.

more space for the approach of a neighboring ladder than does the original ladder pattern in 1. Despite the extensive changes in hydrogen bonding interactions, the crystals of 11 are still built up from bilayers (Figure 17). A fundamentally altered hydrogen bond network leads to similar overall packing arrangements for 11 and 4-7, because both networks are infinite in two dimensions and they link the hydrophilic parts of the molecules. In turn, the hydrophobic parts of the molecules isolate the two-dimensional network from further interactions, and only weak van der Waals forces may exist between the bilayers. Conclusions The derivation of a two-dimensional hydrogen bond grid pattern from two one-dimensional ladder patterns



Figure 15. Hydrogen bond network in the crystal structure of 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (11). The norbornane moiety sterically prevents the formation of a network similar to the pattern in Figure 4c.

Figure 13. Hydrogen-bonded molecular assemblies in the crystal structure of trans-2-aminocyclohexanecarboxylic acid (9). (a) Ladder patterns are formed by antiparallel chains of N-H1a‚‚‚O2 hydrogen bonds cross-linked alternately by N-H1b‚‚‚O2 and N-H1c‚‚‚O3 hydrogen bonds. (b) The dimer units joined by the latter two bonds are fused into rows through common carboxylate and NH3+ moieties.

Figure 16. Ladderlike hydrogen bond pattern in the crystal structure of 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (11) formed with alternating 10- and 12-membered hydrogen-bond-containing rings.

Figure 14. Hydrogen bond network in the crystal structure of trans-2-hydroxycyclohexanecarboxylic acid (9). The topology of the network is the same as that in Figure 9, but the roles of the hydrogen bond donor and acceptor atoms are different.

with the same symmetry has been demonstrated. Although the original patterns did not prove robust,13 their combination yielded a recurring pattern. Its stability, underscored by the exceptional isostructurality of four homologues, stems from the advantageous accumulation of the individual interactions present in the parent structures. Additionally, the zwitterions add a favorable electrostatic component to the strength of the hydrogen bonds. The robustness of the pattern was probed via three different variations of the homologous compounds, which gradually weaken the correspondence of the

observed structures to the original design. The introduction of a double bond changes the symmetry of the original pattern but has no influence on the topology of the hydrogen bond network. The change between stereoisomers alters the roles of the donor and acceptor atoms in addition to the change in symmetry. On the other hand, it leaves the network topology the same at the molecular level. Extension of the alicyclic ring with a methylene bridge generates a steric barrier that prevents the formation of the original pattern but still allows the formation of hydrogen-bonded bilayers. Since the different molecular modifications all exhibit some aspects of the original design, we believe that derivatives of the presented compounds may be utilized in the crystal engineering of layered materials. The stability of the hydrogen bond pattern may allow the presence of other intermolecular interactions and supramolecular synthons without a significant perturbation of its structure. The structure of the norbornane derivative demonstrates the limit of this approach: the

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Figure 17. Crystal structure of 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (11).

network topology will change if it cannot satisfy all donors and acceptors for steric reasons. Acknowledgment. We thank OTKA (Grants T034985, T030647, and T034422) for financial support. We are grateful to Ms. Gyo¨rgyi To´th-Csa´kva´ri and Mr. Csaba Kerte´sz for technical assistance. Supporting Information Available: X-ray crystallographic data for 4-11 (CIF). This material is available free of charge via the Internet at http://pubs.acs.org.

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CG0497997

Crystal Engineering with Alicyclic Î²-Amino Acids: Construction of

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