DOI: 10.1021/cg100208m
trans-β2,3-Amino Acid-Based Supramolecular Synthons for Probing the Interrelationships between Structure, Torsion-Directed Assembly, and Isomorphism
2010, Vol. 10 2460–2464
D. Balamurugan, V. Ramkumar, and K. M. Muraleedharan* Department of Chemistry, Indian Institute of Technology Madras, Chennai, 600 036 - India Received February 9, 2010; Revised Manuscript Received April 8, 2010
ABSTRACT: Variations in the lattice arrangement and the tendency toward isomorphic behavior in a group of trans-β2,3 amino acid
derivatives with Boc and oxazolidinone moieties at the N- and C-terminals are discussed. The substitution pattern at the R- and β positions in these systems was found to give different torsional preferences and hence different molecular organizations in their crystals. Analysis of such preferences in their azide analogs has unraveled the involvement of a relatively uncommon carbonyl-azide dipolar interaction in lattice stabilization. The study of conformational preferences in molecules, their tendency to exist in polymorphic crystalline states, and its effect on molecular properties is an expanding area of science that has importance in material science1 and pharmaceutics alike.2-5 Conformational isomers can organize into different crystalline forms to give conformational polymorphs or coexist in the same lattice as isomorphs.6,7 Understandably, apart from the energy state of the individual conformer, contributions from inter- and intramolecular interactions and overall molecular packing in the lattice dictate the preference for one crystalline form over the other.8 Despite a large number of reports and detailed investigations, our current ability to accurately predict the three-dimensional packing propensities of molecules is in its infancy.9,10 An analysis of the literature suggested that studies on structurepolymorphism relationships represent one of the hottest areas in crystal engineering and can be extremely important in building predictive models to foresee polymorphism and lattice arrangements.11-13 As part of a program aimed at developing membrane-active compounds from laterally amphiphilic β-peptide strands, we have synthesized a number of trans-β2,3-amino acid monomers in acceptable yields and stereoselectivities.14 The choice of these building blocks was mainly based on their known propensity to form extended structures upon oligomerization.15,16 The synthetic strategy toward these involved an anti-selective Evan’s Aldol reaction, inversion at the β-center through a mesylate intermediate to form an azide (e.g., 5-8, Figure 1), and subsequent reductive Boc-protection to get oxazolidinone derivatives of the N-Boc-protected β-amino acids (1-4). Compounds 1-4 possess one hydrogen bond donor (NH) at Cβ and three hydrogen bond acceptors: two at CR and one as part of the Boc group. Dipoles associated with the carbonyl groups of the N-acyloxazolidinone unit and the donor-acceptor sites from the Boc group provide multiple H-bonding possibilities. Studies on N-C(O) rotations in compounds with carbamate17-20 or oxazolidinone moieties21,22 have individually been carried out in the context of polymorphism and stereoinduction. Compounds in our hands seemed to provide a combination of possibilities of such rotations along with the expected torsion around the CR-Cβ bond and give different solid-state architectures. Thus, the relative orientations of donor-acceptor sites and hence the packing propensities of such molecules would depend on the torsion around the CR-Cβ bond and the rotational freedom associated with bonds connecting it to oxazolidinone and Boc-groups. The azides *To whom correspondence should be addressed. Telephone: (þ91)-44 2257 4233. Fax: (þ91)-44 2257 4202. E-mail:
[email protected]. pubs.acs.org/crystal
Published on Web 04/22/2010
Figure 1. β-Amino acid derivatives selected for the study. Carbonyl groups are numbered arbitrarily. Sites involved in secondary interactions are indicated by arrows.
5-8 lack a hydrogen bond donor, but intermolecular association through dipolar interaction between any one of the carbonyl oxygens and the central nitrogen atom of the azide unit could dictate their organization in the crystal.23 Our interest in the solidstate structures of these monomers stemmed from the finding that compound 1 contained two molecules—one gauche and anti conformer each—in its asymmetric unit, forming a R22(10) motif as shown in Figure 2. The solution-state NMR data of compounds 5-8 had indicated antiperiplanar orientations of azide, aryl, and CβH vs carbonyl, alkyl, and CRH groups, respectively.14 Since the crystal structure of 1 showed the possibility of having multiple conformers in the solid state, it seemed worthwhile to analyze this tendency by varying the substitution at the CR- and Cβ-positions, as this could lead to different supramolecular arrangements. Toward this end, crystals of compounds 1-8 were grown from an ethyl acetatehexane 1:4 mixture under identical conditions and their X-ray diffraction studies were carried out.24 Absence of solvent molecules in their lattices was gratifying and made their structural comparison more meaningful, as our focus was to develop crystal lattices useful for studying relationships between structure, torsional preferences, crystal packing, and polymorphism. Compound 1 crystallized from an ethyl acetate-hexane mixture in the orthorhombic form under the space group P212121 with Z = 8. A closer examination of the structure revealed that there are two types of molecules in the asymmetric unit, existing as a hydrogen bonded dimeric R22(10) motif, where the urethane -C(O)-NH- of the anti conformer adopts a nearly cis orientation and bridges the NH and C1dO of the second molecule r 2010 American Chemical Society
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Figure 2. Hydrogen bonded heterodimer of conformers I and II of compound 1. Xc denotes the (S)-4-benzyloxazolidin-2-one chiral auxiliary. H-bonding is indicated by dotted yellow lines.
(N-H 3 3 3 O=∼2.034 A˚). Such isomorphism was however absent in the case of its precursor—the azide 5. This molecule (5) crystallized in the orthorhombic form under the space group P212121 with Z = 4. The individual molecule had an antiperiplanar arrangement of substituents at CR- and Cβ- with a dihedral angle of -177.22(15)°. The observed C1-O 3 3 3 N distance of 3.113 A˚ and a consistent “T”-shaped arrangement of carbonyl and the azide units suggest a dipolar interaction, likely assisting the overall packing (Figure 4B). Compound 2 is a close structural analog of 1, with a 4-OMegroup at the Cβ phenyl ring. This compound crystallized as a monoclinic system under the space group P21 with Z = 2. In its crystal structure, 2 showed a synclinal arrangement of R- and β-substituents, and the conformation was more or less comparable to that of conformer II of compound 1. A notable feature in this case, however, was the involvement of the oxazolidinone carbonyl (C2) in propagating an interdigitating C(8) motif, as shown in Figure 4A (N-H 3 3 3 O = 2.484 A˚). Hydrophobic clustering between the layers through proper orientation of benzyl, anisyl, Boc, and alkyl groups (Supporting Information) was present and could be contributing to the overall stability of the arrangement. The azide of this molecule (6) interestingly showed isomorphism due to the presence of conformers that differ by just 0.9° around the CR-Cβ bond. The orthorhombic crystal of this compound, under the space group P212121, had Z = 8. Conformers I and II, respectively, had dihedral angles of -171.9(3)° and -171.0(3)°. In the lattice, they individually formed interdigitated layers with azide-carbonyl interactions, as shown in Figure 3. The network in the case of conformer I extended along axis a, whereas that of II showed propagation in the b axis. As in the case of 5, the azide-carbonyl dipolar interaction with a C1-O 3 3 3 N distance of 3.060 A˚ for I and 3.034 A˚ for II seemed to stabilize the lattice structure. Compounds 3 and 4 are analogs of 1 and 2, with an ethyl group instead of propyl at CR. Compound 3, the structurally simplest in this series, having ethyl and phenyl groups, respectively, at the CR- and Cβ-positions, crystallized as a monoclinic system under the P21 space group with Z = 2. They formed extended hydrogen bonded C(6) chains, as shown in Figure 4C. Unlike compound 2, this molecule showed an antiperiplanar arrangement of R- and β-substituents, and a torsion of 173.9(2)° across the CR-Cβ bond facilitated the formation of a C(6) motif with a N-H 3 3 3 O distance of 2.254 A˚. Its azide analog 7 gave orthorhombic crystals under the P212121 space group with Z = 4. A torsion of -172.8(2)° across the CR-Cβ bond positioned molecules to have an interdigitated arrangement with a C1-O 3 3 3 N distance of 3.179 A˚. A display when viewed along axis b is shown in Figure 4D. Compound 4 crystallized in the orthorhombic system under the space group P212121 with Z = 4. The decrease in the alkyl chain length compared to 2 did not alter the synclinal arrangement of
Figure 3. Separate interdigitated segments of conformers I and II in the crystal structure of compound 6. Dipolar interactions are indicated by dotted yellow lines.
R- and β-substituents, and an interdigitating C(6) type of hydrogen bonded network along axis a between molecules related by the operation of a screw axis formed the network, as shown in Figure 4E (N-H 3 3 3 O = 2.454 A˚). Evidently, the alkyl and benzyl groups from adjacent layers of molecules segregated to form a hydrophobic channel, which is flanked by four hydrogen bonded motifs (Supporting Information). Like 4, its azide analog 8 also gave orthorhombic crystals under the P212121 space group with Z = 4. The antiperiplanar arrangement of groups with a torsion of -179.9(3)° across a CR-Cβ bond facilitated an interdigitating arrangement akin to 7 to give the pattern shown in Figure 4F. A near “T” shaped arrangement of carbonyl and azide units with a C1-O 3 3 3 N distance of 3.022 A˚, indicating a dipolar interaction stabilizing the organization, is seen in this case as well. Comparison of X-ray crystallographic information and results from 1H NMR studies suggest that the anti-conformers of compounds 5-8, which are predominant in their CDCl3 solution, are the preferred ones in their solid states as well (under the present conditions of crystallization), and this preference may be due to the ability of these conformers to orient the dipoles for extended assembly, as seen. Comparisons of solution- and solidstate rotamer preferences of compounds 1-4 were however difficult, as signals due to CβH appeared broad in their 1H NMR spectra at room temperature. An important task at this juncture was to ascertain their rotamer preference, if any, in the solution state and see whether it is retained during crystallization, as was the case with 5-8. Toward this end, a variable temperature 1 H NMR study with compounds 1-3 was carried out in CDCl3 between 20 °C and -40 °C. As shown in Figure 5, the fine structure of the CβH signal at 5.22 ppm in compound 2 became clearer as the temperature was
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Figure 4. Organization of molecules in the lattices of Boc-derivatives 2-4 and azides 5, 7, and 8. Secondary interactions are represented by dotted yellow lines.
lowered to -10 °C, which is accompanied by the population of a new rotamer(s) whose percentage ratio reached approximately 10% by -30 °C (Y). Based on 2D-NMR data obtained at -30 °C, the peaks at 5.22, 5.12, and 4.23 in the major conformer(s) were assigned to CβH, NH, and CRH, respectively. The corresponding peaks of the minor conformer(s) appeared at 4.75, 4.91, and 4.43 ppm. Interestingly, the NH peak at 4.8 ppm (at 20 °C) for the minor conformer (Y) gradually shifted downfield with a decrease in temperature, likely due to hydrogen bonded associations.25 This effect was, however, not significant with the NH proton of the major conformer(s). A medium J value of 6.0 Hz for the coupling of the CRH to the CβH signal at 5.22 ppm in X suggests the coexistence of interconverting gauche-anti rotamers.26,27 A larger value of 9.2 Hz observed for this coupling in the case of the minor rotamer (Y, at 4.75 ppm) is indicative of the preference of the protons toward an anti-orientation. The stability difference between the minor more stable anti-form and the one undergoing exchange with a gauche conformation could
be due to an additional favorable orientation of Boc and(or) oxazolidinone moieties in the former. The results from variable temperature 1H NMR studies of compounds 1 and 3 were identical to those for 2, and the presence of gauche-anti exchange and a minor anti-rotamer was detected in both. Their preferences were, however, different in the solid state, as discussed above: anti in the case of 3, synclinal in the case of 2, and gauche-anti pair in the case of 1. It is true that the conformer populations in a hexane-EtOAc mixture (4:1)—the conditions during crystallization—could be different from those in CDCl3, but the information from NMR data definitely indicate significant torsional freedom across CR-Cβ. Reasonably, one of the factors that stabilizes the synclinal arrangement in 2 and the anti-orientation in 3 could be the possibilities for C(8) and C(6) motifs, respectively, in their lattices. Compound 1 represents a borderline case where both the conformers exist as a H-bonded heterodimer in the crystal. These examples thus provide information on how the characteristics of weak interactions from Boc and
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Figure 5. (a) Variable temperature 1H NMR (400 MHz, CDCl3) spectra of compound 2 between 20 and -40 °C; X and Y represent signals of major and minor rotamers, respectively. (b) Expanded CβH signals of major and minor rotamers at -30 °C.
oxazolidinone groups change with incremental variation in the nature of substituents at the CR- and Cβ-positions, and could be useful during the development of new predictive models. As mentioned, compounds 1-8 were crystallized from an ethyl acetate-hexane solvent system under identical conditions. The absence of solvent molecules or other guests in the lattice excluded the possibility of having pseudopolymorphism, and these compounds can serve as good candidates to study structure-conformationassembly polymorphism relationships. Among the Boc-protected derivatives, compound 3—the structurally simplest—has a phenyl group at Cβ and an ethyl group at CR. A near perfect antiperiplanar arrangement of these substituents placed the NH and C1dO groups in the correct orientation for an extended hydrogen bonded C(6) chain. Interestingly, introduction of a OCH3 group at the para position of the phenyl ring led to a synclinal conformation in 4 which remained unaffected even after the elongation of the CR-alkyl chain by one unit as seen in 2. Although both these compounds exhibited interdigitating extended hydrogen bonded patterns, a notable difference was the involvement of C1dO in the case of 4 and C2dO in the case of 2 in forming the network. Hydrophobic clustering through segregation of phenyl, benzyl, Boc, and aliphatic chains was seen in all these lattices and could be a stabilizing factor in the crystal structure. Variable temperature 1H NMR studies involving compounds 1-3 showed significant population of interconverting gauche-anti rotamers. All azides, irrespective of the nature of the groups at CR and Cβ, exhibited antiperiplanar arrangement of the substituents. A notable feature in their crystal structure was a consistent, near “T-shaped” arrangement of carbonyl and azide units with a C1-O 3 3 3 N distance of ∼3.08 A˚ suggestive of a dipolar interaction assisting the lattice arrangement. In order to assess the generality and importance of this type of interaction in organic crystals, we have carried out a CSD search with a CdO 3 3 3 N distance constraint of 2.8-3.4 A˚.28 Of the 92 organic carbonyl azides, 26 hits have the CdO 3 3 3 N interaction angle greater than 120°, having the type of interaction under consideration. There are 13 examples where groups such as amide, hydroxyl, etc. are present in addition, and in these cases, hydrogen bonding interactions are preferred over azide-carbonyl dipolar interaction in forming the supramolecular network. A cooperative effect from both of these interactions was, however, seen in two other examples from this class (see the Supporting Information for the list of CSD Refcodes). Among Boc-protected derivatives, compound 1 showed isomorphism by forming a gauche-anti heterodimeric R22(10) motif
in the lattice. Isomorphism due to the azide 6, however, was due to formation of separate interdigitated layers from conformers that differ by 0.9° across the CR-Cβ bond. It is important to mention here that the conformational preferences and arrangement of molecules in the lattice may vary widely as a function of crystallization condition, and hence, it is possible for the class of molecules analyzed here to show a different arrangement if it is varied. Nevertheless, identical solvent and crystallization conditions employed in the present case and absence of guests in their lattices could make them useful while developing predictive models for crystal packing and polymorphism. Acknowledgment. Financial support of this work by the Department of Science and Technology (DST), India (Grants SR/S1/OC-13/2007), is gratefully acknowledged. D.B. thanks DST for the research fellowship. We thank Professor Ashwini Nangia of the University of Hyderabad for helpful suggestions and for giving access to the CSD. Supporting Information Available: Crystallographic data, structure refinement parameters, ORTEP diagrams of compounds 1-5 and 7; variable temperature 1H NMR spectra of compounds 1 and 3; COSY spectrum of compound 2 at -30 °C; view of the crystal packing of compounds 1-8 along the a, b, and c axes; crystallographic information files. Results from a CSD search with reference codes and details of known examples having azide-carbonyl dipolar interactions. This information is available free of charge via the Internet at http:// pubs.acs.org.
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(9) Xu, Z.-T.; Lee, S.; Lee, A. J.; Lobkovsky, E. B.; Emmott, N. Jiegou Huaxue 2002, 21, 592. (10) Li, T.; Ayers, P. W.; Liu, S.; Swadley, M. J.; Aubrey-Medendorp, C. Chem.—Eur. J. 2009, 15, 361. (11) Das, D.; Desiraju, G. R. Chem.—Asian J. 2006, 1, 231. (12) Braga, D.; Maini, L.; Fagnano, C.; Taddei, P.; Chierotti, M. R.; Gobetto, R. Chem.—Eur. J. 2007, 13, 1222. (13) Ischenko, V.; Englert, U.; Jansen, M. Chem.—Eur. J. 2005, 11, 1375. (14) Balamurugan, D.; Muraleedharan, K. M. Tetrahedron 2009, 65, 10074. (15) Wu, Y.-D.; Han, W.; Wang, D.-P.; Gao, Y.; Zhao, Y.-L. Acc. Chem. Res. 2008, 41, 1418. (16) Seebach, D.; Abele, S.; Gademann, K.; Jaun, B. Angew. Chem., Int. Ed. 1999, 38, 1595. (17) Hersh, W. H.; Klein, L.; Todaro, L. J. J. Org. Chem. 2004, 69, 7355. (18) Ikonen, S.; Valkonen, A.; Kolehmainen, E. J. Mol. Struct. 2009, 930, 147. (19) Moraczewski, A. L.; Banaszynski, L. A.; From, A. M.; White, C. E.; Smith, B. D. J. Org. Chem. 1998, 63, 7258. (20) Smith, B. D.; Goodenough-Lashua, D. M.; D’Souza, C. J. E.; Norton, K. J.; Schmidt, L. M.; Tung, J. C. Tetrahedron Lett. 2004, 45, 2747.
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[email protected]. (25) Wang, W.; Weisz, K. Chem.—Eur. J. 2007, 13, 854. (26) Bifulco, G.; Dambruoso, P.; Gomez-Paloma, L.; Riccio, R. Chem. Rev. 2007, 107, 3744. (27) Riccio, R.; Bifulco, G.; Cimino, P.; Bassarello, C.; Gomez-Paloma, L. Pure Appl. Chem. 2003, 75, 295. (28) Cambridge Structural Database ver. 5.30, ConQuest 1.11, November 2009 release, Nov 2009 update. Molecules were analyzed using Mercury 2.2. Details of azide-carbonyl (CdO 3 3 3 N) dipolar interaction from a CSD search are provided in the Supporting Information.
