Engineering Crystalline Architecture with Supramolecular Tapes

CRYSTAL GROWTH & DESIGN 2002 VOL. 2, NO. 5 337-350

Symposium Delivered at the Crystal Engineering to Crystal Growth: Design and Function Symposium, ACS 223rd National Meeting, Orlando, Florida, April 7-11, 2002

Engineering Crystalline Architecture with Supramolecular Tapes: Studies on Secondary Donor-Acceptor Interactions in Cocrystals of the Cyclic Dipeptide of Glycine Tzy-Jiun M. Luo and G. Tayhas R. Palmore* Division of Engineering, Brown University, Providence, Rhode Island 02912 Received June 4, 2002;

Revised Manuscript Received July 23, 2002

ABSTRACT: In this study, we examine the noncovalent interactions that occur between the cyclic dipeptide of glycine (GLYDKP) and a carboxylic acid guest. This study complements our earlier studies on the cyclic dipeptide of aspartic acid by exploring further the possibility of using hydrogen-bonded tapes comprised of molecules of GLYDKP, as a scaffold with which to control the location of guest molecules in a crystalline lattice. On the basis of the 11 cocrystals of GLYDKP reported herein, we conclude that guest molecules will be positioned between tapes of GLYDKP if the guest molecules meet the following criteria. First, the width of the guest molecule should be between 4.5 and 8.5 Å. Second, interactions between adjacent guest molecules should be stronger than a van der Waals contact. Third, a hydrogen-bond donor (hydroxyl group) and a hydrogen-bond acceptor (carbonyl group) should be present in the structure of the guest with their separation no greater than two bonds between the carbon atom of the carbonyl group and the oxygen atom of the hydroxyl group. Fourth, the strength of interactions between molecules in the cocrystal should be of the following order: host-host > host-guest > guest-guest. This order ensures the tape superstructure dictates the location of guest molecules in the host lattice. Introduction To predict the pattern of packing that a molecule will adopt in the solid state is difficult.1-4 This task is made easier if the molecule is capable of interacting in a manner that reduces the symmetry of the pattern of packing.5-9 One such molecule is the cyclic dipeptide of glycine (GLYDKP), which forms a linear superstructure (i.e., tape)10,11 through an R22(8) motif of hydrogen bonds between adjacent amides.12,13 Crystallographic and kinetic studies of cyclic dipeptides with bulky substituents demonstrate that this linear superstructure dominates the pattern of packing adopted by cyclic dipeptides in the absence of other hydrogen-bond donors * To whom all correspondence [email protected].

should

be

addressed:

or acceptors.14,15 Even when other hydrogen-bond donors or acceptors are present, such as the carboxylic acid groups in the cyclic dipeptide of S-aspartic acid (ASPDKP), the R22(8) motif of hydrogen bonds between adjacent amides remains intact in the crystalline solid.16 Because carboxylic acid groups do not disrupt the R22(8) motif of hydrogen bonds between adjacent molecules of ASPDKP, the donor-acceptor properties of carboxylic acids can be used to position guest molecules between tapes of ASPDKP.17 In this paper, we explore further the possibility of using hydrogen-bonded tapes to control the assembly of guest molecules in a crystalline lattice by examining the noncovalent interactions that can occur between GLYDKP and a guest molecule. Our hypothesis is that if a strong interaction can occur between GLYDKP and

10.1021/cg025535d CCC: $22.00 © 2002 American Chemical Society Published on Web 08/16/2002

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Figure 1. In the cocrystal of GLYDKP and formic acid, molecules of GLYDKP assemble into hydrogen-bonded tapes, a superstructure commonly found in crystals of cyclic dipeptides. Tapes pack in parallel both within a single layer and in adjacent layers. Molecules of formic acid reside between adjacent tapes and form a strong hydrogen bond with the amide acceptor of GLYDKP.

a guest molecule, then these two molecules can be treated as a single unit or building block,18 similar to a cyclic dipeptide with a bulky substituent.14 Consequently, the pattern of packing of this unit, comprised of GLYDKP and guest, is more facile to predict than that of two separate molecules. Increasing our ability to predict how cyclic dipeptides and their guests will pack in the solid state improves our understanding of the limitations of the tape superstructure to organize guest molecules. In contrast to cyclic dipeptides with bulky substituents, the shape of this building block, and thus the lattice parameters, are modified easily by choice of guest. The ease by which one guest molecule can be interchanged for another provides a powerful and convenient method for manipulating the physical properties of these crystalline materials.19-22 We began this study by examining the published structure of the cocrystal of GLYDKP and formic acid (Figure 1).23 On the basis of our previous studies on the patterns of packing of cyclic dipeptides in the presence of a carboxylic acid functional group, this structure was chosen for two reasons. First, interactions between carboxylic acid donors and amide acceptors are known to be strong with reasonably predictable patterns of hydrogen bonds.24-27 Second, by studying carboxylic acid guests, the importance of a weaker hydrogen-bonding interaction,28 namely, the interaction between the methylene donor of GLYDKP and the carbonyl acceptor of the guest, could be examined for its role in the assembly of the tape superstructure. In the cocrystal of GLYDKP and formic acid, molecules of GLYDKP assemble into tapes via amideamide interactions. In addition, each molecule of GLYDKP interacts with two molecules of formic acid via the carboxylic acid donor of formic acid and the oxygen acceptor of GLYDKP. Tapes pack parallel to each other with molecules of formic acid on adjacent tapes in close contact. Two features of this cocrystal are noteworthy.

Figure 2. Four structural themes for guest molecules are generated by modifying the structure of formic acid in the cocrystal with GLYDKP: (a) elongation; (b) elongation with lateral expansion; (c) fusion; and (d) fusion with lateral expansion.

First, the interaction of formic acid with the carbonyl group of GLYDKP does not disrupt the R22(8) motif of hydrogen bonds between adjacent amides despite the fact that electron density has been reduced in the amide-amide interaction. Second, the R22(8) motif of hydrogen bonds does not occur between two molecules of formic acid despite the observation of this motif in some solids of carboxylic acids.29 Moreover, the more common motif observed in solids of carboxylic acids (i.e., chains) is not observed between adjacent molecules of formic acid in the cocrystal with GLYDKP.30 As a result, the carbonyl acceptor of formic acid is available to interact with the methylene group of GLYDKP (CdO‚ ‚‚H-C 2.63 Å). Note that this bond length is shorter than the distance between the carbonyl acceptor and

Crystalline Architecture with Supramolecular Tapes

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Table 1. Crystallographic Data of Cocrystals of GLYDKP formula FW temp crystal system space group a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) V (Å3) Z D (g cm-3) µ (mm-1) R1 Rw

formula FW temp crystal system space group a (Å) b (Å) c (Å) R (deg) β (deg) γ (deg) V (Å3) Z D (g cm-3) µ (mm-1) R1 Rw a

1

2aa

2ba

2c

3

4aa

C10H10N2O6 254.20 90 K monoclinic P21/c 9.3740(6) 29.318(2) 12.5881(9) 90 102.958(2) 90 3371.4(4) 12 1.50 0.127 0.042 0.12

C11H12N2O6 268.27 90 K orthorhombic Pna21 26.332(1) 6.3550(3) 12.9136(5) 90 90 90 2160.9(2) 8 1.81 0.136 0.060 0.178

C18H14N2O6Cl4 496.12 90 K monoclinic P21/n 3.8469(2) 6.1731(4) 40.630(3) 90 90.780(1) 90 964.8(2) 4 1.51 0.655 0.046 0.103


C8H10N2O6 230.18 90 K triclinic P-1 5.9359(9) 6.5936(9) 7.304(1) 109.262(3) 90.762(3) 116.527(2) 237.06(6) 1 1.61 0.140 0.041 0.115


4ba

5aa

5ba

6a

6b

C12H10N2O6Cl2 349.12 90 K triclinic P21/c 6.639(1) 6.991(1) 7.063(1) 100.371(4) 97.433(4) 92.838(4) 318.8(1) 1 1.82 0.544 0.042 0.106


C10H8N2O6Cl2 3223.08 90 K monoclinic P21/c 9.828(1) 6.1935(7) 10.646(1) 90 106.626(2) 90 621.1(1) 2 1.73 0.551 0.039 0.110

C10H12N2O4 224.22 90 K triclinic P1 5.4774(7) 6.4627(8) 7.5257(10) 94.196(2) 95.267(2) 114.939(2) 238.69(9) 1 1.56 0.122 0.038 0.113


Indicates cocrystals with tapes.

Figure 3. Seven compounds (1, 2a, 2b, 2c, 3, 4a, 4b) that cocrystallize with GLYDKP were identified from the four structural themes shown in Figure 2. Movement of the hydroxyl and carbonyl groups in 4 transforms this compound into 5a and 5b. Similarly, substitution of the carbonyl groups in 5 for hydrogen atoms produces 6a and 6b.

hydrogen atom on adjacent molecules of formic acid (Cd O‚‚‚H-C 2.68 Å). Our approach to identifying other guest molecules that would cocrystallize with GLYDKP is based on structural themes generated by modifying the geometry of formic acid in its cocrystal with GLYDKP using the four procedures outline below. These structural themes are illustrated in Figure 2 and are referred to as (a) elongation; (b) elongation with lateral expansion; (c) fusion; and (d) fusion with lateral expansion. Procedure 1. Increase the length of formic acid in the cocrystal of GLYDKP and formic acid (Figure 2a). The only functional group that will lengthen formic acid and maintain a spacing of 6.2 Å between molecules of GLYDKP is an alkyne group. Thus, formic acid can be elongated by the insertion of one triple bond to give propiolic acid. Procedure 2. On the basis of the results of procedure 1, search for carboxylic acid derivatives with lateral dimensions similar to GLYDKP that could pack with a periodicity of 6.2 Å. Thus, the benzene ring represents a lateral expansion of the results from procedure 1. Functional groups (shown as X and Y) on the benzene ring are considered for their ability to form guest-guest interactions (Figure 2b). In addition, these guest molecules lack a center of inversion. Procedure 3. Search for molecules that occupy the same volume of two adjacent formic acids. The geometry and volume of fumaric acid are similar to that of two adjacent formic acids in the cocrystal with GLYDKP,

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Figure 4. GLYDKP cocrystallized with 2a, 2b, 4a, 4b, 5a, or 5b exhibit the tape superstructure in the corresponding cocrystalline solids (C-2a, C-2b, C-4a, C-4b, C-5a, and C-5b). The R22(8) motif is highlighted in blue in C-2a and the R44(16) motif is highlighted in red in C-4b.

and thus represents a fusion of two formic acid molecules (Figure 2c). Procedure 4. On the basis of the results of procedure 3, search for carboxylic acid derivatives with lateral dimensions similar to GLYDKP that could pack with a periodicity of 6.2 Å (fusion with lateral expansion). Lateral expansion of fumaric acid produces a geometry that is best matched by terephthalic acid, which has a

packing periodicity approaching 6.2 Å in its pure crystal. Hydroxyl or halogen substituents at the 2 and 5 position of terephthalic acid can be used to increase the interactions between adjacent guest molecules and maintain the required spacing of ∼6.2 Å (Figure 2d). Molecules that were geometrically similar to one of the four structural themes in Figure 2 subsequently were selected for computer modeling studies. Modeling



Figure 5. Cocrystalline solids of GLYDKP and 1, 2c, 3, 6a, 6b (C-1, C-2c, C-3, C-6a, C-6b) do not exhibit the tape superstructure but instead form hydrogen-bonded networks.

studies were performed on a periodic array of minimized units consisting of GLYDKP and a guest molecule that was generated using the same symmetry as the cocrystal of GLYDKP and formic acid. Subseqently, the periodic array was minimized, and, if the tape remained intact, the guest molecule was selected for cocrystallization with GLYDKP and crystallographic analysis. Results Using the procedures described above, seven compounds (1, 2a, 2b, 2c, 3, 4a, and 4b) were identified that would cocrystallize with GLYDKP (Figure 3). Four additional compounds were identified as potential guests based on modifications to the molecular structure of compound 4 (Figure 3). For example, compounds 5a and 5b are derived from 4 by moving both the carbonyl and hydroxyl groups onto the aromatic ring. Similarly, the molecular structures of 6a and 6b are derived from 5 by substituting hydrogen atoms for the carbonyl groups located on the aromatic ring. Listed in Table 1 are the crystallographic and refinement data for the eleven cocrystals of GLYDKP examined in this study. Molecules of GLYDKP assemble into tapes when cocrystallized with 2a, 2b, 4a, 4b, 5a, and 5b (Figure 4),

whereas a network structure appears when molecules of GLYDKP are cocrystallized with 1, 2c, 3, 6a, and 6b (Figure 5). It should be noted that all guest molecules identified by the procedures described above possess an aromatic ring in their molecular structures with the exception of 1 and 3. In addition, the X and Y substituents of the guest molecules were chosen on the basis of the strength of guest-guest interactions relative to the strength of host-host or host-guest interactions. Specifically, the order of the strength of these three interactions should be host-host > host-guest > guest-guest. Thus, X and Y substituents on the guest molecules are hydroxyl or chloride groups. Discussion Requirements for Guest Molecules to Form a Cocrystal with GLYDKP. It is difficult to predict whether a molecule chosen arbitrarily can form a cocrystal with a host molecule such as GLYDKP. Therefore, we screened for molecules that would cocrystallize with GLYDKP on the basis of the pattern of packing observed in the published structure of GLYDKP cocrystallized with formic acid. Two additional criteria were used in the screening. First, the structure of the guest molecule should be such that intermolecular

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Figure 6. Illustration of how a guest molecule of length L and width W (determined from the calculated Connolly surface) can reduce its apparent size by twisting relative to the long access of the tape superstructure through the angle θ. Increasing θ thus enables guest molecules to acquire a packing periodicity, defined as Wcos(θ), to match that of GLYDKP in a tape.

interactions of moderate strength can occur between guest and host molecules and between adjacent guest molecules. Second, the host and guest molecules should be able to pack in a manner that minimizes void space, thus forming a stable crystalline lattice. It is well established that both carboxylic acids and hydroxyl groups can function as strong hydrogen-bond donors and strong hydrogen-bond acceptors.26 Assuming GLYDKP will form hydrogen-bonded tapes through strong amide-amide interactions, carboxylic acids or hydroxyl groups on a guest molecule have the potential to function as hydrogen-bond donors to the carbonyl oxygen acceptor of GLYDKP and to function as hydrogenbond acceptors to the hydrogen atoms on the methylene group of GLYDKP. It is also important to select guest molecules with the potential to form a noncovalent interaction with adjacent guest molecules. In each of the 11 cocrystalline solids studied, at least two of the three types of weak hydrogen-bonding interactions that could occur (i.e., C-O‚‚‚H-C, CdO‚‚‚H-C, and C-Cl‚ ‚‚H-C) were present. The spacing between adjacent molecules of GLYDKP within a tape ranges between 6.2 and 7.0 Å. Consequently, guest molecules with a lateral dimension greater than 7.0 Å have a high probability of preventing GLYDKP from assembling into tapes unless the guest molecule can reduce its apparent width by twisting relative to the long axis of the tapes (Figure 6). The 11 guest molecules identified by our screening procedures have lateral dimensions ranging from 4.5 to 8.5 Å. Several other compounds were identified as having a lateral dimension less than 7.0 Å (e.g., compounds 7-11 in Figure 7) but were not expected to cocrystallize with GLYDKP because they lack the ability to form guestguest interactions. This expectation was confirmed by

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experiment, thus demonstrating the importance of guest-guest interactions in a cocrystal of GLYDKP. In addition, there are several compounds (e.g., compounds 12-15 in Figure 7) with the potential to form good guest-guest interactions that did not cocrystallize with GLYDKP. Modeling studies of GLYDKP with compounds 12 or 13 indicate that the nonplanar conformations of 12 and 13 prevent efficient packing in parallel and thus leaves excess void space in the crystal structure. Exchanging the carboxylic acid donor for an amide donor prevents guest molecules such as compound 14 or 15 from cocrystallizing with GLYDKP, suggesting donor strength is important despite the planar conformation of these molecules or their potential to form guest-guest interactions. Patterns of Hydrogen Bonds in Cocrystalline Solids of GLYDKP that Exhibit the Tape Superstructure. On the basis of the molecular structures of GLYDKP and carboxylic acid guests, four patterns of hydrogen-bonding interactions (P-a, P-b, P-c, P-d) are possible (Figure 8). In patterns P-a and P-b, the carbonyl acceptor of the carboxylic acid is in a position to form a weak hydrogen bond with the hydrogen atoms of a methylene group on GLYDKP. Of the six cocrystals that exhibit tapes (C-2a, C-2b, C-4a, C-4b, C-5a, and C-5b), only chloranillic acid cocrystallized with GLYDKP (C-5b) exhibits the P-a pattern exclusively.31 The remaining five cocrystals that exhibit the tape superstructure are stabilized further by the additional interaction in the P-b pattern. In this pattern, the oxygen atom of the carboxylic acid guest interacts with the hydrogen atoms of the methylene group on an adjacent molecule of GLYDKP. Although the P-c pattern is the most stable pattern of hydrogen bonding (i.e., R22(8) motif), this pattern is not observed in any of the eleven structures examined in this study. The P-c pattern is observed, however, in the cocrystal of GLYDKP and salicyclic acid.32 A hydrogen bond between the donor of the carboxylic acid and the carbonyl acceptor of GLYDKP is observed in all 11 cocrystals. The structure of the cocrystal becomes increasingly more difficult to predict when the carboxylic acid of the guest can bridge two molecules of GLYDKP, as illustrated in pattern P-d. Of the 11 cocrystals examined in this study, only one exhibited polymorphism (C-5a). Two polymorphs of C-5a differ by the relative orientation of adjacent guest molecules. In one polymorph, adjacent guest molecules alternate in their relative orientation to the tape (cf. Figure 4). By contrast, adjacent guest molecules in the other polymorph are related by translation along the tape axis (not shown). Cocrystalline Solids that Exhibit Network Structures. All molecules identified by our method are able to form a cocrystal with GLYDKP because they fulfill the required geometry and size specified by our screening procedures. Not all of these cocrystals, however, have supramolecular tapes in their structures. For example, propiolic acid and fumaric acid could be pendant to supramolecular tapes when cocrystallized with GLYDKP and either interdigitate (as in the case of propiolic acid, Figure 9a) or cross-link adjacent tapes (as in the case of fumaric acid, Figure 9b). The crystal structures show, however, that the packing arrange-



Figure 7. Compounds that are similar to 3 and 4 but do not form a cocrystal with GLYDKP.

ments of the molecules in these two cocrystals are quite different from the other cocrystals. Analysis of GLYDKP tapes with pendant propiolic acids reveals that a parallel packing of propiolic acid does not permit the acidic acetylenic hydrogen atoms to participate in any hydrogen-bonding interaction. By rotating a pair of propiolic acids, the acetylenic hydrogen atoms are positioned closer to a carbonyl oxygen acceptor of GLYDKP in an adjacent crystalline layer (not shown) that results in a hydrogen-bonding interaction (e.g., C-H‚‚‚OdC 2.380 Å).33 At the same time, this rotation maintains the π-π interaction (3.5 Å) between two adjacent molecules of propiolic acid (Figure 9c). Analysis of GLYDKP tapes with pendant fumaric acids reveals that a parallel packing of fumaric acid results in a large void space between guest molecules when packed adjacent to each other at the periodicity of GLYDKP in the tape superstructure (Figure 9b). In fact, fumaric acid as a pure crystal maximizes the contact between vinylic hydrogen atoms and oxygen acceptors, resulting in a periodicity of 5.01 Å,34 a periodicity that is smaller than that of GLYDKP in the tape superstructure. Consequently, the mismatch between the packing periodicity of GLYDKP in tapes (> 6.2 Å) and fumaric acids (5.01 Å) results in the disruption of tapes and a packing arrangement that is a compromise of this mismatch (Figure 9d).

Amide-Amide vs Amide-Acid Bond Lengths. Shown in Figure 10a is a comparison of the lengths of the hydrogen bonds (i.e., N(H)‚‚‚OdC between molecules of GLYDKP and O(H)‚‚‚OdC hydrogen bonds between guest molecules and GLYDKP) in cocrystals that have the tape superstructure. Bond lengths are measured between non-hydrogen atoms and data are plotted as a function of the packing periodicity of the corresponding guest molecule. The packing periodicity is defined as Wcos(θ), where W is the width of the guest molecule and θ is the twist angle of the guest molecule relative to the long axis of the tapes (cf. Figure 6). Inspection of Figure 10a reveals that the lengths of the O(H)‚‚‚OdC bonds are between 2.6 and 2.7 Å and thus are independent of the size or packing periodicity of the guest molecule. In contrast, the lengths of the N(H)‚‚‚OdC bonds are between 2.8 and 3.5 Å, increasing linearly with increase in the periodicity of packing of the guest when the value of Wcos(θ) is greater than 6.6 Å. The length of the N(H)‚ ‚‚OdC bonds in a pure crystal of GLYDKP is 2.8 Å.13 The longest N(H)‚‚‚OdC bond occurs in the cocrystal of GLYDKP and 2,5-dichloroterephthalic acid (cf. Figure 4, C-4b). These data show that the sterics of the guest molecule has a greater impact on the amide-amide interactions than the acid-amide interactions and thus provides a mechanism for predicting which guest mol-

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Figure 8. Four patterns of hydrogen bonds (P-a, P-b, P-c, P-d) that can occur between GLYDKP and carboxylic acid guests. A fifth pattern (P-e) is derived from P-d when the guest molecule lacks a carbonyl acceptor, which requires the hydroxyl group to function as both hydrogen-bond donor and hydrogen-bond acceptor.

ecules will prevent the formation of tapes when cocrystallized with GLYDKP. In addition, these data augment our previous results showing that the spacing between tapes can be controlled systematically by changing the length (L) of the guest molecule.17 Three of the seven cocrystals of GLYDKP that exhibit tapes have their tapes packed in parallel to form decks of tapes. The periodicity of adjacent decks of tapes varies according to the length of the guests. For example, crystallographic data of GLYDKP cocrystallized with 2b, 5a, and 5b show that the periodicity of decks of tapes is 20.3, 12.1, and 9.8 Å, respectively. Both studies show that formation of a cocrystal is not influenced by the length (L) of the guest molecule. Linear Relationship between the Width of the Guest Molecule and its Twist Angle. The linear relationship between the width (W) of the guest molecule and its twist angle (θ) relative to the long axis of the tapes is illustrated in Figure 10b. Inspection of the solid line fit of the data reveals that the twist angle approaches a value of zero when the width of the guest molecule approaches 6.5 Å. When a guest molecule is wider than 6.5 Å, the guest molecule will twist to reduce its steric impact on the assembly of GLYDKP into supramolecular tapes. The largest values observed for θ are 34.9° and 35.6° in C-2b and C-5b, respectively.

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Predicting the Packing Arrangement of Guest Molecules when Cocrystallized with GLYDKP. As stated earlier, Figure 10a provides a means by which to predict which guest molecules will impede the formation of tapes when cocrystallized with GLYDKP. Provided the guest molecules are planar and rigid, Figure 10a in combination with Figure 10b should enable prediction of the packing arrangement of guest molecules using a single parameter (e.g., width of aromatic acids). To illustrate, the width of a guest molecule is determined from a model of the guest molecule with a computer-generated surface. On the basis of the assumption that the tape superstructure will be present in the cocrystal, the twist angle (θ) then can be extrapolated from the corresponding width of the guest molecule using the solid line fit of the data (O) in Figure 10b. Once the twist angle is known, the bond length of the amide-amide interaction (N(H)‚‚‚OdC) can be extrapolated from the data in Figure 10a. On the basis of the data shown in Figure 10a,b, planar guest molecules up to 8.5 Å in width are not likely to disrupt the formation of the tape superstructure. Weak CdO‚‚‚H-C Hydrogen Bonds. The distance between guest molecules and GLYDKP along a weak hydrogen-bonding interaction (i.e., CdO‚‚‚CH2 and Cd O‚‚‚H-C-H) is plotted as a function of twist angle in Figure 11a. Distances were measured between the oxygen acceptor on the guest molecule and either (i) the carbon atom on GLYDKP (i.e., DOC for upper curve with b data) or (ii) a methylene hydrogen atom on GLYDKP (i.e., DOH for lower curve with 9 data) (Figure 11b). The inverse relationship of these distances indicates that the methylene group of GLYDKP encloses the oxygen acceptor of the guest molecules. Shifting the oxygen acceptor of the guest molecule away from the center of the methylene group of GLYDKP strengthens a CdO‚ ‚‚H-C interaction. Although the energy of this interaction is small, it suggests that the formation of the tape superstructure is dependent not only on amide-amide interactions between adjacent molecules of GLYDKP, but also is facilitated by this weak interaction.35,36 The same phenomenon was observed in cocrystals of ASPDKP and derivatives of pyridine.17 Figure 11c shows the O-C-H angle plotted as a function of twist angle (i.e., curve with b data). The O-C-H angle, defined by the oxygen acceptor of the guest, the carbon atom, and one of the hydrogen atoms of the methylene group of GLYDKP, is illustrated in Figure 11d. This angle reveals the relative position of the carbonyl acceptor on the guest (represented as open circles) to the methylene group of GLYDKP. The largest O-C-H angle observed in a cocrystal of GLYDKP is 63°, the angle at which the carbonyl acceptor of the guest is positioned at the exact center of the methylene group. In theory, the minimum value of the O-C-H angle could be zero,37 indicating that the carbonyl acceptor interacts directly with a hydrogen atom on the methylene group. Such low angles, however, were not observed in all seven cocrystals exhibiting the tape superstructure. A pure crystal of GLYDKP has both the smallest O-C-H angle at 31.5° and the largest value for DOC compared to the cocrystals of GLYDKP that possess the tape superstructure. Since no other acceptor is present in a pure crystal of GLYDKP, the CdO‚‚‚H-C



Figure 9. Hypothetical arrangements of propiolic acid (a) or fumaric acid (b) cocrystallized with GLYDKP when the tape superstructure is present (only one of the two methylene-hydrogen atoms is shown for clarity). Corresponding experimentally determined arrangements (c and d). (e) Parallel packing of two fumaric acids in its pure crystalline form exhibit a packing periodicity of 5.01 Å.

interaction occurs between adjacent tapes within the same layer. The smallest value for the O-C-H angle in a cocrystal of GLYDKP is 43.4° (i.e., C-5a). The smaller O-C-H angles occur when the width of the guest molecule is either 6.5 or 8.5 Å. Other guest molecules with widths between these values have larger O-C-H angles (∼60°), resulting in the carbonyl oxygen atom of the guest molecule centered between the hydrogen atoms of the methylene group on GLYDKP. The result

of these larger angles is that the carbonyl acceptor is in a position to interact with the amide donor on GLYDKP (cf. Figure 4, C-4b). The affect of this interaction is revealed in a plot of the calculated energies of host-guest interactions as a function of twist angle, also shown in Figure 11c. Calculations were limited to only those interactions between host and guest when arranged in patterns P-a and P-b (cf. Figure 8). The results indicate that the most stable interaction (i.e., most negative energy) occurs when the oxygen acceptor

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Figure 10. (a) The N(H)‚‚‚OdC bond length increases linearly with Wcos(θ) when the value of Wcos(θ) is > 6.6 Å. In contrast, the O(H)‚‚‚OdC bond length remains constant (2.6-2.7 Å) regardless of the width or packing periodicity of the guest molecule. (b) The solid line illustrates the linear relationship between the width (W) of the guest molecule and its twist angle (θ) relative to the long axis of the tapes.

of the guest molecule is centered between the two hydrogen atoms of the methylene group on GLYDKP. This position favors a weak interaction between guest acceptor and amide donor (e.g., C-2a and C-4b). With the exception of C-5b, the energies of host-guest interactions for the other cocrystals of GLYDKP are above -10 kcal mol-1 and therefore of lower stability than those found in C-2a and C-4b. The absence of the interaction between the carbonyl acceptor of the guest molecule and the amide donor of GLYDKP is the source of this reduced stability. In these cocrystals, the carbonyl oxygen atom simply interacts with one of the hydrogen atoms of the methylene group on GLYDKP resulting in small O-C-H angle (Figure 11d). Cocrystal C-5b is unique relative to the other cocrystals because its chlorine substituent also interacts with the methylene group of GLYDKP, an interaction that gives C-5b added stability. Changing the methylene group on GLYDKP or removing the carbonyl group on the guest molecule removes the O‚‚‚H-C interaction. The result is either the cocrystal does not form, or, if it does, tapes are absent. This point is illustrated with compounds 6a and 6b. Despite the absence of carbonyl groups in both 6a and 6b, these molecules cocrystallize with GLYDKP by using their hydroxyl groups as both hydrogen-bond donor and acceptor (Figure 12). The absence of a carbonyl group in these guest molecules, however, results in the formation of the P-e pattern of hydrogen bonds (cf. Figure 8) and thus prevents GLYDKP from assembling into tapes. It is significant, therefore, that all cocrystals of GLYDKP exhibiting the tape superstructure have guest molecules with a hydroxyl donor and a carbonyl acceptor in their molecular structure. The hydroxyl group functions as hydrogen-bond donor to the carbonyl acceptor on GLYDKP, while the carbonyl group of the carboxylic acid functions as a hydrogenbond acceptor to the methylene group or amide donor of GLYDKP. We conclude, therefore, that the tape superstructure will not assemble in a cocrystal of

GLYDKP in the absence of a carbonyl group on the guest molecule. Interconversion between the R22(8) and R22(8) Motif of Hydrogen Bonds. Molecules of GLYDKP are disordered in its cocrystal with 2,5-dichlorobenzoic acid (C-2b), a guest molecule with a molecular width of 8.0 Å. This disorder manifests as either an R22(8) motif of hydrogen bonds between adjacent molecules of GLYDKP, resulting in the formation of tapes, or an R44(16) motif of hydrogen bonds between GLYDKP and two neighboring guest molecules (Figure 13). The R44(16) motif is similar to that found in C-4b (cf. Figure 4), which has the widest guest molecule (W ) 8.2 Å) of all the guest molecules in the cocrystals that exhibit the tape superstructure. Note that for C-2b, switching between the two hydrogen-bonding motifs is accomplished by rotating GLYDKP in the ab-plane by 40.1°. A comparison of C-4b and C-2b reveals that, although both structures have the tape superstructure, the Cd O‚‚‚H-N bond lengths in C-4b are the longest of all the cocrystals examined in this study, and thus the amideamide interactions are the weakest. Moreover, both C-4b and C-2b have chlorine-hydrogen interactions between adjacent guest molecules that are strong enough to maintain parallel packing of guests and GLYDKP.38 Energy of Guest-Guest Interactions. The energies for different intermolecular interactions between adjacent guest molecules are listed in Table 2. The results show that interaction I (-5.82 kcal mol-1) is the strongest interaction of the four interactions listed in Table 2. GLYDKP cocrystallized with 2b or 4b exhibit interaction I between adjacent guest molecules. The importance of this interaction is reflected by its ability to hold guest molecules together despite the weak amide-amide interactions (i.e., long N-H‚‚‚OdC bond length) between molecules of GLYDKP in both of these cocrystals. On the basis of our calculations, the Cl‚‚‚H-C39 interactions are stronger than the O‚‚‚H-C interactions.



Figure 11. (a) The effect of θ on the length of weak hydrogen-bonding interactions (i.e., DOC and DOH) between guest and GLYDKP. (b) Side view (left) and top view (right) of a tape (two molecules of GLYDKP) with the carboxylic acid group of a guest molecule. The blue and red double arrows define DOC and DOH, respectively, in (a). (c) The relationship between θ and (i) the angle (OC-H) defined by the oxygen acceptor of the guest and the carbon and a hydrogen atom of the methylene group of GLYDKP, (ii) and the total energy of the host-guest interactions. (d) Illustration of the O-C-H angle viewed down the long axis of a tape. The approximate position of the carbonyl acceptor of different guest molecules relative to the methylene group of GLYDKP is shown as open circles.

Thus, two adjacent molecules of 2c favor an arrangement that has interaction I between them instead of interaction II. In addition, because asymmetric molecules tend to pack with opposing dipoles, the two molecules of 2c are biased further to form interaction I, which ultimately prevents the formation of the tape superstructure (Figure 14). Interaction III was observed in C-2a, C-4a, and C-5a, in which all guest molecules are in the same plane. Although interaction III (O‚‚‚ H-C interaction) is weak, it is essential for linking two adjacent guest molecules. Compared to compound 11 (cf. Figure 7), the presence of a hydroxyl substituent on 2a, 4a, and 5a not only facilitates the parallel packing of guest molecules, but it also maintains the planar conformation of the guest molecules via intramolecular hydrogen bonds. The energy of interaction IV between two adjacent molecules of 5b is -3.88 kcal mol-1 and, therefore, is the weakest of the four interactions listed in Table 2. When two molecules of 5b are simulated to interact with each other via IV, the most stable struc-

ture is not coplanar, indicating that interaction IV is not likely to occur in the presence of tapes. The calculated configuration is similar to the pattern observed in the cocrystal C-5b, in which each guest molecule is rotated 35.6° out of the plane of the tapes to increase the chlorine-chlorine interaction between adjacent guest molecules.40 Conclusions Our earlier studies on the crystalline solids of cyclic dipeptides reveal that the tape superstructure dominates the pattern of packing adopted by cyclic dipeptides in the presence of steric bulk14 as well as other hydrogenbond donors or acceptors (e.g., carboxylic acid substituent of ASPDKP).16 In addition, the donor-acceptor properties of carboxylic acids were shown to facilitate the positioning of guest molecules between tapes comprised of ASPDKP.17 In this study, we examined the noncovalent interactions that can occur between GLY-

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tapes if the guest molecule meets the following criteria. First, the width (W) of the guest molecule should be between 4.5 and 8.5 Å. The length (L) of the guest molecule is not a factor in the formation of tapes. Second, interactions between adjacent guest molecules should be stronger than a van der Waals contact. Ideally, the guest molecule should possess a functional group that can establish an interaction with an adjacent guest molecule worth at least -3.88 kcal mol-1 (e.g., O‚ ‚‚H-C or Cl‚‚‚H-C interactions). Third, a hydrogenbond donor (e.g., hydroxyl group) and a hydrogen-bond acceptor (e.g., carbonyl group) should be present in the structure of the guest with their separation no greater than two bond lengths between the carbon atom of the carbonyl group and the oxygen atom of the hydroxyl group. (i.e., (H)O-C(O) in 2a, 2b, 4a, 4b, or (H)O-CC(O) in 5a, 5b). Otherwise, the absence of the carbonyl acceptor forces the hydroxyl group to function as both hydrogen-bond donor and acceptor, resulting in the disruption of tapes. The amide group, however, should be avoided since it can prevent the formation of tapes. Fourth, the strength of interactions between molecules in the cocrystal should be of the following order: hosthost > host-guest > guest-guest, so that tapes dominate the overall pattern of packing of molecules in the cocrystal. Experimental Section Figure 12. Guest molecules such as 1,4-dichloro-2,5-dihydroxybenzene (6a) and 2,5-hydroquinone (6b) have only one hydrogen-bond acceptor and, therefore, interfere with the formation of the tape superstructure.

DKP and a carboxylic acid guest. This study complements our earlier studies on ASPDKP by exploring further the possibility of using hydrogen-bonded tapes to control the assembly of guest molecules in a crystalline lattice. The differences between these two studies are the location of the carboxylic-acid group (i.e., host vs guest) and the type of host-guest interactions (i.e., O-H‚‚‚N and C-H‚‚‚O vs C-H‚‚‚O and O-H‚‚‚O). On the basis of the 11 cocrystals of GLYDKP reported herein, we conclude that GLYDKP will assemble into

All regents were purchased from Aldrich and used without further purification. Unless described otherwise, all cocrystals were obtained by cooling an aqueous solution of methanol (50% v/v) containing 0.2 M of GLYDKP and guest molecule. In general, equivalent amounts of both compounds were dissolved in hot solvent and allowed to cool to room temperature. Cocrystals usually appeared in one or 2 days. GLYDKP + Propiolic Acid (1). GLYDKP was dissolved in pure propiolic acid at 40 °C. The saturated solution was sealed in a vial and cooled to room temperature. White crystals (mp ) 104-108 °C) appeared after 1 day. GLYDKP + 2,5-Dihydroxy Benzoic Acid (2a). A solution of GLYDKP (0.2 M) was added to an equal volume of methanol containing 0.2 M of 2,5-dihydroxy benzoic acid. Thin colorless plates (mp ) 222 °C) crystallized after several hours. GLYDKP + 2,5-Dichloro Benzoic Acid (2b). A solution of GLYDKP (0.2 M) was added to an equal volume of methanol

Figure 13. Molecules of GLYDKP are disordered in the crystal structure of GLYDKP cocrystallized with 2,5-dichlorobenzoic acid (C-2b). Each molecule of GLYDKP either interacts with adjacent molecules of GLYDKP via an R22(8) motif of hydrogen bonds to form tapes (left) or interacts with neighboring guest molecules by rotating 40.1° in the ab-plane to generate an R44(8) motif of hydrogen bonds (right).



Table 2. Calculated Energies of Intermolecular Interactions between Adjacent Guest Molecules

a Only interacting fragments of adjacent guest molecules are shown for clarity. b Guest molecules in cocrystals where tapes are present. Guest molecules in cocrystals where tapes are absent. d Observed experimentally. e Hypothetical interaction between adjacent guest molecules.

c

Figure 14. Asymmetric molecules such as 2c pack with a center of inversion, thus positioning functional groups to form interaction I instead of interaction II, the interaction that facilitates the formation of the tape superstructure. containing 0.2 M of 2,5-dichloro benzoic acid. The mixture was stirred well and allowed to sit for several hours. Blocks of yellow crystals (mp ) 174 °C) appeared after 1 day. GLYDKP + 5-Chloro-2-hydroxy Benzoic Acid (2c). A solution of GLYDKP (0.2 M) was added to an equal volume of methanol containing 0.2 M of 5-chloro-2-hydroxy benzoic acid. The mixture was stirred well and allowed to sit for several hours. Blocks of colorless crystal appeared after 1 day (mp ) > 300 °C). GLYDKP + Fumaric Acid (3). Fumaric acid (98.6 mg) was dissolved in 2.4 mL of hot solution (H2O/ethyl acetate/MeOH ) 1:1:1). An aqueous solution of GLYDKP (5 mL, 0.17 M) subsequently was added. The mixture was stirred well and allowed to cool to room temperature. Blocks of colorless crystals (mp ) 230-232 °C) appeared after 1 day. GLYDKP + 2,5-Dihydroxy Terephthalic Acid (4a). GLYDKP (34 mg) and 2,5-dihydroxybenzoic acid (59 mg) were added to 4 mL of hot DMSO solution (DMSO/H2O ) 9:1). The suspension was heated and stirred for 2 h. The remaining solids were removed by filtration and the solution was moved to an open container. Long, stick-shaped crystals that were yellow in color (mp ) 220 °C) appeared after several days. GLYDKP + 2,5-Dichloro Terephthalic Acid (4b). Onehalf equivalent of 2,5-dichloro terephthalic acid was suspended

in a methanol solution (methanol/H2O ) 1:1) containing 0.1 M of GLYDKP. This solution was heated in a water bath for 2 h. The upper layer of the solution subsequently was transferred to a sealed container and allowed to cool slowly to room temperature. Colorless, rod-shaped crystals (mp > 300 °C) appeared after 1 day. GLYDKP + 2,5-Dihydroxy Benzoquinone (5a). Five milliliters of a 0.1 M solution of 2,5-dihydroxy benzoquinone was added to 10 mL of a 0.2 M GLYDKP solution. The suspension was heated and methanol was added until all solids dissolved. The hot solution was allowed to cool slowly to room temperature. Thin yellow plates (mp ) 200 °C) appeared after several days. GLYDKP + Chloranillic Acid (5b). Chloranillic acid (80 mg) was dissolved in 8 mL of hot ethanol solution (EtOH/H2O ) 1:1). The deep purple solution subsequently was mixed with 2 mL of a 0.2 M solution of GLYDKP. Hexagonal shaped crystals that were orange in color (mp ) 172-174 °C) appeared overnight. GLYDKP + 1,4-Hydroquinone (6a). 1,4-hydroquinone (22 mg) was dissolved in 2 mL of a 0.1 M aqueous solution of GLYDKP. The solution was allowed to evaporate in an open container. Block-shaped crystals (mp ) 218-220 °C) appeared after several days. GLYDKP + 2,5-dichloro 1,4-Hydroquinone (6b). A solution of 2,5-dichloro 1,4-hydroquinone (0.2 M) in methanol was mixed with an equal volume of an aqueous solution of 0.2 M GLYDKP. The mixture was stirred and allowed to sit for several hours. Long stick-shaped crystals (mp > 300 °C) appeared after several hours. All X-ray data were collected at 90 K on a Siemens Smart diffractometer equipped with a CCD area detector. Lattice parameters were determined from least-squares analysis of 36 reflections, and the reflection data were integrated using the program SAINT. Structures were solved by direct methods and refined by full matrix least-squares on F2 using SHELXTL97.41 All atoms except hydrogen atoms were refined anisotropically. Hydrogen atoms involved in hydrogen bonding were refined after location on a difference map with isotropic temperature factors. The remaining hydrogen atoms were placed in idealized positions with assigned isotropic thermal parameters. Method for Screening Guest Molecules via Computer Modeling. The following procedure was used to select molecules for cocrystallization studies from the list of guest molecules identified through the four procedures outlined in the introduction. GLYDKP and guest molecules with the desired shape and functional groups were modeled using Cerius2 from MSI (Accelrys Inc., version 4.2). The energy of each molecule was minimized separately using the DREIDING force field in the Minimizer module.42,43 The resulting energyminimized conformations of GLYDKP and guest molecule

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subsequently were brought into close contact and defined as a single unit. The single unit, comprised of GLYDKP and a guest molecule, was optimized using the steepest descent algorithm in the absence of any molecular constraints. The energy of a single unit with the best geometry was minimized until the RMS of the energy was less than 0.1 kcal mol-1 Å-1. This unit subsequently was expanded into a periodic array of four units possessing identical symmetry as that in the cocrystal of GLYDKP and formic acid using the crystal builder module. The periodic structure, with each unit of GLYDKP and guest molecule treated as a rigid body, was minimized using crystal minimizer. If the tape superstructure remained intact, the guest molecule was selected for cocrystallization studies. Method for Calculating the Energy of Intermolecular Interactions between GLYDKP and Guest. Using crystallographic data for each cocrystal, the molecular structures within a unit cell were optimized by minimizing the total energy of structure without any constraints. The symmetry of the unit cell subsequently was converted to the P1 space group prior to any calculations. The cell parameters and the conformation of all molecules were allowed to change during the minimization. Two molecules of GLYDKP and one guest molecule were extracted from these minimized structures and the energy of all intermolecular interactions between GLYDKP and a guest molecule was calculated without further minimization. Method for Calculating the Energy of Intermolecular Interactions between Adjacent Guest Molecules. Each molecule with the desired functional group on one side of the aromatic ring (cf. Table 2) was built using Cerius2 and its energy minimized using the DREIDING force field. The resultant structure was treated as a rigid body. Two of these structures were brought together and the energy between the two rigid bodies was optimized using the same conditions described for calculating the energy of host-guest interactions. This last step was repeated after one of the two molecules was moved 1.0 Å in a randomly chosen direction. This procedure was repeated until the configuration of the two molecules converged with the lowest energy.

Acknowledgment. The authors are grateful to the National Science Foundation and the ACS Petroleum Research Fund for generous support. Supporting Information Available: Crystallographic information files (CIF) for all cocrystals reported herein are available free of charge via the Internet at http://pubs.acs.org.

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CG025535D

Engineering Crystalline Architecture with Supramolecular Tapes

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