The Influence by Substituents on the Intermolecular Hydrogen

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The Influence by Substituents on the Intermolecular Hydrogen-Bonding Interactions in Imidazole-4,5-dicarboxylic Acid Derivatives Paul W. Baures,*,⊥ Adam W. Caldwell,†,§ Chris R. Cashman,†,§ Marie T. Masse,†,§ Ethan B. Van Arnam,†,§ and Rebecca R. Conry‡

CRYSTAL GROWTH & DESIGN 2006 VOL. 6, NO. 9 2047-2052

Department of Chemistry and Biochemistry, 600 College AVenue, The UniVersity of Tulsa, Tulsa, Oklahoma 74104, Department of Chemistry, 6600 College Station, Bowdoin College, Brunswick, Maine 04011, Department of Chemistry, 5764 Mayflower Hill, Colby College, WaterVille, Maine 04901 ReceiVed February 1, 2006; ReVised Manuscript ReceiVed June 20, 2006

ABSTRACT: A series of chiral imidazole-4,5-dicarboxylic acid derivatives was prepared in order to test the significance that stereochemistry and substitution have on the preferred intermolecular associations of the compounds in solution and the solid state. Solution 1H NMR spectroscopy provided evidence for racemic associations by enantiomeric imidazole-4,5-dicarboxamides (I45DCs) but not for enantiomeric imidazole-4-carboxylic acid ester-5-carboxamides (I45EAs). Melting point phase diagrams illustrate that enantiomeric and dissymmetrically disubstituted imidazole-4,5-dicarboxamides (I45DCs) preferably form racemic compounds in the solid state. It is anticipated that the aggregation occurs through intermolecular hydrogen-bonding interactions identified for similar compounds in this class. In contrast, imidazole-4-carboxylic acid ester-5-carboxamides (I45EAs) form intermolecular hydrogenbonded tapes, and equimolar mixtures of enantiomeric I45EAs yield solid solutions. Introduction Intermolecular hydrogen-bonding interactions between complementary functional groups on molecular scaffolds is an oftenutilized means for the assembly of molecules, and utilizing multiple intermolecular hydrogen-bonding interactions is a common theme in the design of molecular associations.1 These multiple interactions may arise through the self-association of one compound or through the cocrystallization of two or more compounds. Regardless, the directing interactions must be reliable even in the presence or alteration of other functional groups in the structure in order to be useful and described as supramolecular synthons.2 Imidazole-4,5-dicarboxamides (I45DCs) and imidazole-4carboxylic acid ester-5-carboxamides (I45EAs) both form intramolecular and intermolecular hydrogen bonds in the solid state.3 Previous single-crystal X-ray analysis of 16 I45DCs and I45EAs identified multiple intermolecular hydrogen-bonding motifs in the solid state, including hydrogen-bonded C(5) and R22(8) chains, as well as a NH‚‚‚O R22(10) dimer and a NH‚‚‚N R22(10) dimer (Figure 1a). The NH‚‚‚O R22(10) dimer was the most common intermolecular association observed in the crystalline I45DCs and considered the strongest intermolecular interaction. Indeed, there were few exceptions to this interaction (aside from an analogous nonplanar interaction) in crystalline I45DCs also containing an intramolecular hydrogen bond. The hydrogen-bonded chains were observed in I45DCs with benzylamine as the substituents. The NH‚‚‚N hydrogen-bonded C(5) chain was observed for the benzylamine symmetrically disubstituted I45DC, whereas the chain interconnected by repeating R22(8) interactions also utilizes the acidic C2-H in a CH‚‚‚O hydrogen bond and formed for the R-R-methylbenzylamine symmetrically disubstituted I45DC. In contrast to the I45DC * E-mail: [email protected]. Tel: 918-631-3024. Fax: 918-6313404. ⊥ The University of Tulsa. † Bowdoin College. § These four students contributed equally to this project. ‡ Colby College.

Chart 1.

Dissymmetrically Disubstituted I45DCs (1-6) and I45EAs (7-12) Employed in This Study

structures, I45EAs formed NH‚‚‚N and CH‚‚‚O hydrogenbonded R22(8)R22(8) tapes in the solid state (Figure 1b). It is reasonable to expect a shift from monomer to dimer to higher aggregates en route to crystallization, regardless of whether the monomer in solution is an I45DC or I45EA. In addition, we can expect solutions to contain multiple aggregate forms at any given concentration. The benzyl group was chosen for this work in part to further investigate the role that this substituent has on the aggregation behavior and crystallization motif in I45DCs and I45EAs. In addition, stereochemistry was included as another variable that may impact the intermolecular hydrogen-bonding associations for enantiomers of the benzylsubstituted compounds. Specifically, this study employs dissymmetrically disubstituted I45DCs (1-6, Chart 1) bearing R-methylbenzylamines in

10.1021/cg060057i CCC: $33.50 © 2006 American Chemical Society Published on Web 08/02/2006

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Figure 1. Common intermolecular hydrogen-bonding associations observed in the X-ray crystal structures of (a) imidazole-4,5-dicarboxamides (I45DCs) and (b) imidazole-4-carboxylic acid ester 5-amides (I45EAs) as formed in solution from the monomer.3

order to examine the aggregation behavior of the resulting compounds in both solution and the solid state. Evidence of different chemical shifts in the aggregation of enantiopure versus racemic solutions of these compounds was obtained by 1H NMR spectroscopy. Melting point phase diagrams with varying percentages of enantiomeric I45DCs were used to provide evidence of aggregation behavior for the solids obtained from racemic solutions. A series of I45EAs (7-12, Chart 1) were studied in similar fashion, although we also investigated one pair of enantiomers without benzylamine substitution in order to address results discovered in the course of this work. Our results are consistent with the formation of heterochiral (racemic) intermolecular hydrogen-bonded NH‚‚‚O or NH‚‚‚N R22(10) dimers for the I45DCs and with homochiral intermolecular hydrogen-bonded R22(8)R22(8) tape formation in I45EAs with a benzylamine substituent. In addition, our data suggests the formation of a solid solution for an I45EA without an aromatic substituent. This work represents a step in our longterm goal of engineering the I45DCs or I45EAs or both to selfassemble into interesting and potentially useful supramolecular architectures. Experimental Section Concentration-Dependent Solution 1H NMR Spectroscopy. A stock solution of each compound was prepared in CDCl3 at 10 mM. Serial dilutions were made to provide concentrations that include some or all of the following: 0.005, 0.003, 0.001, 0.0005, 0.0003, and 0.0001 M. The 1H NMR spectrum for each sample was recorded at 303 K with a minimum of 64 scans and a maximum of 512 scans as necessary in order to provide adequate signal-to-noise for identification of the amide and imidazole NH signals. Tetramethylsilane was included as a spectral reference (0.00 ppm). The 1H NMR spectra of the racemic solutions were obtained by making a 10 mM solution containing 5 mM

of each enantiomer. Serial dilutions from this stock gave all subsequent samples. Data collection was done analogously to the enantiomerically pure solutions. Melting Point Phase Diagrams. Stock solutions of compounds 1-12 in CDCl3 were used to make mixed solutions wherein the ratios of the two enantiomers were varied between 100:0 and 0:100. The solutions were placed in small test tubes with approximately 5-10 mg of total material in each tube. The solutions were allowed to evaporate to dryness at room temperature. The solids from evaporation were mixed with a spatula to homogeneous powders and packed into capillary tubes, and their melting points were determined in a capillary melting point apparatus. FT-IR Spectroscopy. The pure enantiomers and solids obtained from 50:50 solutions of enantiomer pairs for 1-12 were used to collect FTIR spectra as KBR pellets. In addition, the solids from other ratios of 11/12 were also collected. The instrument used for this work has 4 cm-1 resolution, and the spectra were an average of 32 scans. X-ray Crystallography. The X-ray intensity data were measured with φ and ω scans on a Bruker SMART4 APEX CCD-based X-ray diffractometer system equipped with a Mo target X-ray tube (λ ) 0.710 73 Å). The detector was placed at a distance of 5.00 cm from the crystal. A total of 1850 frames were collected (a hemisphere of data) with an exposure time of 30 s/frame (5) or 10 s/frame (7). The frames were integrated with the Bruker SAINT5 software package using a narrow-frame integration algorithm giving a total of 17 497 reflections (5, 8814 independent reflections) and 16 773 reflections (7, 4441 independent reflections) to a maximum 2θ angle of 57°. The structures were solved (direct methods) and refined using the Bruker SHELXTL,6 version 6.1, software package with literature scattering factors.7 No absorption correction was applied to either structure. The final anisotropic full-matrix least-squares refinement of F2 converged at R1 ) 5.82%, wR2 ) 12.93% (5) and R1 ) 6.80%, wR2 ) 19.88% (7) for data with intensities greater than 2σ(I). The goodness-of-fit is 0.905 (5) and 1.313 (7) for all data. All non-hydrogen atoms were modeled anisotropically. Hydrogens on carbons were placed at calculated distances and were refined with a riding model, whereas hydrogens on nitrogens were found in difference maps and isotropically refined. The

Substituent Influence on Hydrogen-Bonding Interactions

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Table 1. Concentration-Dependent Solution Chemical Shift Data for NHs in 1 and 1 + 2 (Racemic Solution) chemical shift (δ) as a function of concentration in CDCl3 compda 1

1+2

hydrogen

5 mM

3 mM

1 mM

0.5 mM

0.3 mM

aniline NH (hb) amide NH (hb) imidazole NH aniline NH (free) amide NH (free) aniline NH (hb) amide NH (hb) imidazole NH aniline NH (free) amide NH (free)

13.19 11.55 11.56/11.15 9.39 7.92 13.18 11.52 11.38/11.02 9.41 7.92

13.16 11.50 11.31/10.95 9.38 7.91 13.15 11.48 10.90 9.41 7.92

13.12 11.44 10.88/10.65 9.37 7.90 13.14 11.46 10.88 9.40 7.91

13.11 11.41 10.70/10.56 9.37 7.90 b b b b b

13.10 11.39 10.59/10.49 9.36 7.90 b b b b b

a Comparisons were also made between 3 and 3 + 4 (racemic solution). However, these enantiomersracemic solutions showed no significant chemical shift differences between comparable hydrogens. b The chemical shifts of the NH hydrogens in these solutions were broad in comparison with 1, and their locations were uncertain even after averaging numerous scans.

largest peak and hole in the final difference map for 5 are 0.194 and -0.191 e-/Å3, respectively, and those for 7 are 0.287 and -0.202 e-/Å3, respectively. Thermal ellipsoid drawings (25%) were generated with the Bruker SHELXTL software.

Results and Discussion Synthesis. The synthetic protocols used to prepare the compounds in this paper are given in the Supporting Information and are similar to those reported previously for related analogues.3,8 The dissymmetrically disubstituted imidazole-4,5dicarboxamides (1-6) were prepared by stoichiometric addition of an aniline to 5,10-dioxo-5H,10H-diimidazo[1,5-a:1′,5′-d]pyrazine-1,6-dicarbonyl dichloride,3 yielding an aniline-substituted pyrazine intermediate that is subsequently opened with the benzylamine derivative as described in ref 8. Data for the pyrazine intermediates substituted with p-toluidine and p-nitroaniline are reported in this same reference. The imidazole4-ester-5-carboxamides, 7-12, were prepared by reacting 5,10dioxo-5H,10H-diimidazo[1,5-a:1′,5′-d]pyrazine-1,6-dicarbonyl dichloride3 with the appropriate alcohol before addition of the amine to the same reaction vessel. Dissymmetrically Disubstituted I45DCs (1-6). In the 1H NMR spectrum, only the imidazole NH is different in the 1 + 2 racemic solution as compared with 1 alone, and this is most apparent only in the 5 mM solution (Table 1). At more dilute concentrations, the imidazole NH chemical shift is either observed to be similar for both pure enantiomer and racemate or simply unobservable in the racemic solutions. The imidazole NH has been used as a sensitive indicator of intermolecular aggregation in solution for an achiral I45DC.9 In this case, we reason that the differences at dilute concentrations are evidence of heterochiral aggregate interactions in the racemic solutions, although it is not possible to assign the differences to altered hydrogen-bonding interactions or specific heterochiral aggregate concentrations or combinations of both. We next investigated the intermolecular hydrogen-bonding interactions in the solid state by determining phase diagrams based on variations in the molar ratios of enantiomers. These phase diagrams were prepared by determining the melting point range for different sample mixtures in capillary tubes. As such, the diagrams are only useful qualitatively: that is, they distinguish whether the enantiomeric pairs yield racemic compounds, racemic mixtures (conglomerates), or solid solutions (pseudoracemates).10 Nonetheless, these phase diagrams are suitable for the purpose of comparing the molecular interactions in the solid state of the enantiomers versus mixed solids. This is particularly true since we did not observe any visual changes in the solids during the melting point determinations that would suggest solvation, hydration, or solid-state phase transformations

Figure 2. Melting point phase diagrams for molar ratios of (a) 1/2 and (b) 3/4. The dark squares and light squares represent the beginning and ending of the melt, respectively.

in the solids. Thus, the need for more accurate thermodynamic measurements from differential scanning calorimetry data, for example, was considered unnecessary for these examples and our purpose. The melting point phase diagrams for the dissymmetrically disubstituted I45DCs, 1 with 2 and 3 with 4, are shown in Figure 2. Both phase diagrams show broad melting point behavior on each side of the equimolar mixture of enantiomers but sharper melting points for the equimolar or nearly equimolar ratios. This phase behavior indicates that racemic compounds form preferentially by association in the solid state of the two enantiomers.10 We note that the melting point of the equimolar mixture for racemic compounds can be less than, equal to, or greater than the melting point of the enantiomers. Powder X-ray diffraction data for 1 versus the solid from a 1:1 stoichiometric mixture of 1 and 2 (see Supporting Information) confirms the uniqueness of the racemic compound 1:2 in the solid state. This is also the case for the powder X-ray diffraction data for 4 versus the 1:1 stoichiometric mixture of 3 and 4. We reason that these racemic compounds form pairwise intermolecularly hydrogen-bonded dimers in the solid state. Unfortunately, attempts to grow X-ray quality crystals of the pure enantiomers or the racemic compounds for 1-4 have failed to date.

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Figure 3. Melting point phase diagram for molar ratios of 5/6. The dark squares and light squares represent the beginning and ending of the melt, respectively.

Figure 4. Melting point phase diagrams for molar ratios of (a) 1/3 and (b) 1/4. The dark squares and light squares represent the beginning and ending of the melt, respectively.

The melting point phase diagram for the N-methylated dissymmetrically disubstituted I45DCs, 5 with 6, is shown in Figure 3 and similarly shows broad melting point behavior on each side of the equimolar mixture of enantiomers with sharper melting points for the equimolar or nearly equimolar ratios. Thus, this pair of enantiomers also forms a racemic compound in the solid state. Compound 5 has yielded an X-ray quality crystal, and details of the solid-state structure are reported below. This enantiomer forms NH‚‚‚O R22(10) interactions in the solid state. Attempts to grow X-ray quality crystals for the racemic compound have not yielded suitable crystals to date. Surprisingly, the dissymmetrically disubstituted I45DCs, 1-6, gave FT-IR spectra with no discernible differences between pure enantiomer and racemic compounds within the resolution of the instrument. Racemic compounds often have spectral differences, although it is possible for them to give identical spectra with their enantiomers either by coincidence or due to analogous intermolecular interactions in their solid states.11 The melting point phase diagrams for 1 with 3 and 1 with 4 (Figure 4) were also determined in order to investigate the comparative roles of stereochemistry versus the p-substituent on the observed solid-state packing. The phase diagram for 1/3 (Figure 4a) shows sharp melting point behavior continually throughout the molar ratios of the two compounds, thus indicating the formation of a solid solution.10 The phase diagram for 1/4 (Figure 4b) also has sharp melting points at the tested

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molar ratios of 1 with 4. However, the sample at the 8:2 ratio of 1/4 was observed at a lower melting point in comparison with 1, and the equimolar mixture of 1/4 also appears to fall below the range observed for the 6:4 ratio of 1/4. This phase diagram is consistent with that of a quasiracemate but is less obvious due to the significant difference in melting points between 1 and 4. Quasiracemate formation is reasonably expected between these two compounds given the known importance of molecular shape to crystal packing. In fact, the methyl and nitro functional groups are isosteric and have been used to form quasiracemates in other chiral amides.12 Powder X-ray diffraction data of 1 and 4 versus the solid obtained from the 1:1 stoichiometric mixture of 1/4 further supports quasiracemate formation. In this case, the stoichiometric mixture yields powder diffraction data that has similarities in part with 4 and 3/4 but with little resemblence to 1 (see Supporting Information). This behavior is consistent with recent X-ray crystal structures of enantiomers, racemates, and quasiracemates that indicate a quasiracemate may adopt both the intermolecular associations and the unit cell parameters found in either the enantiomers or the racemate of each component but may also differ completely in one or both of these features.12,13 This data supports the use of stereochemistry as a guide for the aggregation of dissymmetrically disubstituted I45DCs with different p-substituents in the design and assembly of supramolecular architectures with I45DCs. I45EAs (7-12). The solution 1H NMR spectra for 7 and 11 were identical at all concentrations with their racemic solutions 7 + 8 and 11 + 12, respectively. This is strong evidence for the preferred formation of homochiral intermolecular hydrogenbonding interactions in solution for the I45EAs, although we cannot rule out the presence of hetereochiral aggregates with chemical shift values that are identical by coincidence. The melting point phase diagrams for I45EAs, 7 with 8, 9 with 10, and 11 with 12, are shown in Figure 5. The phase diagram for 7/8 (Figure 5a) shows broad melting point behavior on each side of the equimolar mixture of enantiomers but sharper and lower melting points for the equimolar or nearly equimolar ratios. The phase diagram for 9/10 (Figure 5b) is similar except that the equimolar ratios melt at a higher temperature. These phase behaviors best fit the formation of solid solutions between these enantiomeric pairs, with type III behavior observed (lower melting point at the equimolar solution) for 7/8 and type II behavior observed for 9/10.10a We further investigated how the aryl f alkyl group change manifested such a significant change in the phase diagram behavior by examining 11 and 12 (Figure 5c), an enantiomeric pair that contains no substituent aryl rings. Interestingly, this phase diagram does not contain a eutectic at all but does otherwise appear to follow the trend for the I45EAs to yield solid solutions with broadened melting points at different molar ratios of the two enantiomers. The alternative interpretation of this phase diagram is that these enantiomers form a racemic mixture without eutectic formation or a broadly melting racemic compound. In either case, the lack of a sharper melting point at the equimolar mixture of enantiomers is an unanticipated result. As expected, I45EAs 7 and 9 had no differences in their FTIR spectra as compared with 7 + 8 and 9 + 10, respectively. On the other hand, a significant change in the amide stretching frequency was observed between 11 or 12 (1659 cm-1) and an equimolar mixture of these two enantiomers (1637 cm-1). The neopentyl ester is involved in the intramolecular hydrogen bond

Substituent Influence on Hydrogen-Bonding Interactions

Crystal Growth & Design, Vol. 6, No. 9, 2006 2051 Table 2. Selected Crystal Data Collection and Refinement Data for 5 and 7

Figure 5. Melting point phase diagrams for molar ratios of (a) 7/8, (b) 9/10, and (c) 11/12. The dark squares and light squares represent the beginning and ending of the melt, respectively.

and its carbonyl absorbance is observed at different frequencies (1693 cm-1 in 11 and 1685 cm-1 in 11/12), but this difference is only at 2 times the instrument resolution and therefore within the limits for experimental observation. The tert-butyl ester carbonyl is observed with even less of a difference in their stretching frequencies (1739 cm-1 in 11 and 1735 cm-1 in 11/12). An observed change in the amide carbonyl stretch is consistent with racemic compound formation and is not generally explained by formation of a racemic mixture of two homochiral phases.11b However, in the case of a racemic compound, the melting point phase diagram (Figure 5c) would be expected to have a sharp melting range for the equimolar mixture of enantiomers. Neither scenario in its traditional interpretation can satisfactorily explain this data. We offer the hypothesis that these enantiomers form a solid solution by intermolecular tape formation and that the carbonyl stretches of the intermolecular hydrogen-bonded tape are coupled to one another. In this manner, the random introduction of some percentage of an enantiomer into an otherwise homochiral tape could alter the observed stretching frequency linking the molecules together. This is known to occur in chains of intermolecularly hydrogen-bonded amides, where coupling influences both the observed frequencies and intensities of the absorbance.14 Thus, we think the amide stretch in 11 or 12 (1659 cm-1) is the coupled frequency observed in an intermolecular homochiral hydrogen-bonded tape, while an equimolar mixture of these two enantiomers yields a heterochiral tape with the amide carbonyl observed at 1637 cm-1. The fact that the frequency shift occurs

crystal

5

7

formula weight (g mol-1) crystal size (mm3) crystal system space group a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) Z temp (K) R/Rw2 (obsd data) S

C21H22N4O2 362.43 0.79 × 0.14 × 0.13 monoclinic P21 6.340(1) 25.017(3) 12.435(1) 90.0 102.64 (1) 90.0 4 296(2) 0.0582/0.1293 0.905

C20H19N3O3 349.38 0.51 × 0.10 × 0.07 orthorhombic P212121 9.874(1) 11.606(1) 16.244(2) 90.0 90.0 90.0 4 297(2) 0.0680/0.1988 1.313

all at once between samples in our analysis may be the way the coupling is manifested in the solid-state arrangement or that the change requires some minimal amount of enantiomeric impurity in order to alter the observed frequency or both. It could also be that we have not sampled the relative concentrations of the two enantiomers where the frequency shift occurs the most, and smaller relative concentrations changes along with the use of a higher resolution instrument may make it possible to measure the transition in the frequency shift. The solid solution of 11/12 is likely the result of random associations of the two enantiomers within a given intermolecular hydrogen-bonded tape in order to explain the broad melting temperature for the equimolar sample in the phase diagram. The randomness of the association in the heterochiral tapes would result in poor packing efficiencies, similar to those observed differences between atactic and syndiotactic polymers.15 X-ray Crystallography. Attempts to grow crystals of the enantiomers and the equimolar mixtures of enantiomer pairs in this study have produced quality single crystals for X-ray analysis only in the case of 5 and 7. Selected crystallographic information is given in Table 2. A representation of the solid-state arrangement in the X-ray crystal structure of 5 is shown in Figure 6. The intramolecular hydrogen bond direction is controlled by N-methylation and intermolecular hydrogen-bonded dimerization by the NH‚‚‚O R22(10) is the principal intermolecular association. There are two molecules in the asymmetric unit. Both NH‚‚‚O intramo-

Figure 6. X-ray crystal structure representation of 5 illustrating the intramolecular hydrogen bond and intermolecular hydrogen-bonded NH‚‚‚O R22(10) dimer observed in the solid state.

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Summer Research Fellowships) and the National Science Foundation (Grants NSF-MRI No. 0116416 and NSF-MRI No. 0115832). We thank Elizabeth A. Stemmler (Bowdoin College) for mass spectrometry assistance and Winton C. Cornell (U. Tulsa) for powder X-ray diffraction assistance. Supporting Information Available: Synthetic procedures, NMR spectra, HPLC traces, FT-IR spectra, X-ray crystallographic information files (CIF), and X-ray powder diffraction traces. This material is available free of charge via the Internet at http://pubs.acs.org.

References Figure 7. X-ray crystal structure representation of 7 illustrating the intramolecular hydrogen bond and intermolecular hydrogen-bonded R22(8)R22(8) tape observed in the solid state.

lecular hydrogen bond distances (2.66 and 2.68 Å) as well as the two intermolecular NH‚‚‚O hydrogen bond distances (2.71 and 2.76 Å) that yield the R22(10) dimer are within the observed values for the solid-state structures of other I45DCs.3 A representation of the solid-state arrangement in the X-ray crystal structure of 7 is shown in Figure 7. The intramolecular hydrogen bond direction in this case is controlled by functional group substitution, and R22(8)R22(8) hydrogen-bonded tape formation is the principal intermolecular association. The NH‚‚‚O intramolecular hydrogen bond distance (2.73 Å) and two intermolecular CH‚‚‚O hydrogen bond distances (CH‚‚‚Oamide ) 3.04 Å and CH‚‚‚Oester ) 3.35 Å) are within the observed values for the solid-state structures of other I45EAs.3 Conclusions The intermolecular hydrogen-bonding associations in the solid state for 5 and 7 are just as expected based on previous work3 and increase our confidence in the reliability of the solid-state packing interactions for individual enantiomers of I45DCs and I45EAs. Without crystal data, we are unable to definitively show that the NH‚‚‚O R22(10) is the solid-state arrangement for racemic compounds 1 + 2, 3 + 4, and 5 + 6 or that intermolecular hydrogen-bonded R22(8)R22(8) tapes are present in the solid solutions of 7/8 and 9/10 and the presumed solid solution for 11/12. On the other hand, the melting point phase diagrams provide a rationale for us to use stereochemistry in future endeavors to control the intermolecular hydrogen-bonded aggregation of chiral I45DCs in order to yield interesting and potentially useful supramolecular architectures. The use of stereochemical control in supramolecular assembly is illustrated by a peptide nucleic acid-based i-motif that assembles by preferred association of racemic oligomers.16 Acknowledgment. This study was supported by Bowdoin College (Faculty Research Award and James Stacy Coles

(1) For leading references on multiply hydrogen-bonded assembly, see the following: (a) Ikeda, M.; Nobori, T.; Schmutz, M.; Lehn, J.-M. Chem.sEur. J. 2005, 11, 662-668. (b) Mayer, M F.; Nakashima, S.; Zimmerman, S. C. Org. Lett. 2005, 7, 3005-3008. (c) Park, T.; Zimmerman, S. C.; Nakashima, S. J. Am. Chem. Soc. 2005, 127, 6520-6521. (d) Ligthart, G. B. W. L.; Ohkawa, H.; Sijbesma, R. P.; Meijer, E. W. J. Am. Chem. Soc. 2005, 127, 810-811. (e) Perron, M.-E.; Monchamp, F.; Duval, H.; Boils-Boissier, D.; Wuest, J. D. Pure Appl. Chem. 2004, 76, 1345-1351. (2) Aakero¨y, C. B.; Desper, J.; Leonard, B.; Urbina, J. F. Cryst. Growth Des. 2005, 5, 865-873. (3) Baures, P. W.; Rush, J. R.; Wiznycia, A. V.; Desper, J.; Helfrich, B. A.; Beatty, A. M. Cryst. Growth Des. 2002, 2, 653-664. (4) SMART, v5.060; Bruker Analytical X-ray Systems: Madison, WI, 1997-1999. (5) SAINT, v6.02; Bruker Analytical X-ray Systems: Madison, WI, 1997-1999. (6) SHELXTL, v6.1; Bruker Analytical X-ray Systems: Madison, WI, 1997. (7) Wilson, A. J. C., Ed. International Tables for Crystallography; Kluwer Academic Publishers: Dordrecht, The Netherlands, 1992; Vol. C. (8) Perchellet, E. M.; Perchellet, J.-P.; Baures, P. W. J. Med. Chem. 2005, 48, 5955-5965. (9) Rush, J. R.; Sandstrom, S. L.; Yang, J.; Davis, R.; Prakash, O.; Baures, P. W Org. Lett. 2005, 7, 135-138. (10) (a) Mitchell, A. G. J. Pharm. Pharm. Sci. 1998, 1, 8-12. (b) Li, Z. J.; Grant, D. J. W. J. Pharm. Sci. 1997, 86, 1073-1078. (11) (a) Eliel, E. L.; Kofron, J. T. J. Am. Chem. Soc. 1953, 75, 45854587. (b) Eliel, E. L.; Wilen, S. H.; Doyle, M. P. In Basic Organic Stereochemistry; Wiley-Interscience: New York, 2001; Chapter 6, pp 120-121. (12) Hendi, M. S.; Hooter, P.; Davis, R. E.; Lynch, V. M.; Wheeler, K. A. Cryst. Growth Des. 2004, 4, 95-101. (13) (a) Fomulu, S. L.; Hendi, M. S.; Davis, R. E.; Wheeler, K. A. Cryst. Growth Des. 2002, 2, 637-644. (b) Fomulu, S. L.; Hendi, M. S.; Davis, R. E.; Wheeler, K. A. Cryst. Growth Des. 2002, 2, 645-651. (14) (a) Kobko, N.; Dannenberg, J. J. J. Phys. Chem. A 2003, 107, 66886697. (b) Kobko, N.; Dannenberg, J. J. J. Phys. Chem. A 2003, 107, 10389-10395. (15) (a) Choi, P.; Mattice, W. L. J. Chem. Phys. 2004, 121, 8647-8651. (b) Cho, J. D.; Lyoo, W. S.; Chvulun, S. N.; Blackwell, J. Macromolecules 1999, 32, 6236-6241. (16) Diederichsen, U. Angew. Chem., Int. Ed. 1998, 37, 2273-2276.

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