Investigating the Stability of Double Head to Tail Dimers and Ribbons

Article pubs.acs.org/crystal

Investigating the Stability of Double Head to Tail Dimers and Ribbons in Multicomponent Crystals of cis-4-Aminocyclohexanecarboxilic Acid with Water and Oxalic Acid Asiloé J. Mora,*,† Lusbely M. Belandria,† Edward E. Á vila,†,¶ Luis E. Seijas,‡ Gerzon E. Delgado,† Aira Miró,‡ Rafael Almeida,‡ Michela Brunelli,§ and Andrew N. Fitch§ †

Laboratorio de Cristalografı ́a and ‡Laboratorio de Procesos Dinámicos en Química, Departamento de Química, Facultad de Ciencias, Universidad de Los Andes, La Hechicera, Mérida 5101 Venezuela § ESRF, BP 220, F-38043 Grenoble Cedex, France ¶ Laboratorio de Síntesis y Caracterización de Nuevos Materiales, Centro de Química, Instituto Venezolano de Investigaciones Científicas (IVIC), Caracas 1020-A, Venezuela S Supporting Information *

ABSTRACT: The current contribution aims to investigate the stability of commonly occurring motifs present in certain amino acid structures after introducing additional molecules to form multicomponent crystals. The crystal structures of the amino acid cis-4-aminocyclohexanecarboxylic acid hemihydrate I and dehydrate II forms and that of its oxalate salt cocrystallized with oxalic acid III, were investigated employing a combination of techniques. Both single-crystal and powder X-ray diffraction were used to solve the structures, while temperature-control powder X-ray diffraction was used to follow the dehydration of I. Regardless of the added molecules that induce modifications of the intermolecular interactions within the crystals, some recurring supramolecular structures were identified: double head to tail dimers, graph symbol R22(16), and ribbons, graph symbol R22(16)R43(10). Stabilities of these supramolecular motifs were investigated using theoretical modeling with DFT/B3LYP/6-31++G (d,p) and PM6-D2H calculations. The theoretical calculations reproduced the experimental findings, confirming the extraordinary stability of these motifs. The molecular recognition of amino acid pairs to form double head to tail-dimers is undoubtedly the initial driving force for the crystal formation in all the three crystals investigated.

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different sizes,8−11 which has proved particularly useful when this information is not available from a crystallographic study alone. In 2005, Laszlo et al. investigated the crystal structures of four homologous cis-alicyclic β-amino acids,6 which displayed recurrent layered patterns of Hydrogen bonds formed by double head to tail N−H···O heterosyntons. The robustness of this motif was demonstrated by the isostructurality of the four crystals. Moreover, variations on the component molecule were introduced to change the electronic properties, rigidity and stereochemistry of the formed motifs, always rendering hydrogen bond ring patterns with a R22(12) graph set. Ring hydrogen bond patterns has also been observed in α, β, γ, and δ amino acids, with graph sets R22(10),12 R22(14),13 R24(18),14 and R22(16),15 respectively. It is also recurrent to observe in these crystal structures ribbon motifs formed by joining two adjacent rings. To gain further information on the stability and recurrence of these double head to tail dimers and ribbon motifs observed in some amino acid crystals, we have combined crystallography and theoretical calculations to study cis-4-aminocyclohexanecarboxylic

INTRODUCTION Crystal engineering design aims to predict the crystal structure of new materials from previously selected molecular components. By using information, such as molecular shape, topology, and electronic properties, crystal engineers expect to foretell the spontaneous assemble leading to a crystal structure.1 Although, in general, this is not yet possible,2 it remains as a topic of great interest within the scientific community. In particular, that of assessing the likelihood of polymorphism has captured great attention.3 Thanks to this, advances in crystal structure prediction have undergone steady progress; however, it has been limited to small organic molecules or to molecules with a limited flexibility. Thus, it is not surprising that in recent years, the goal of several works4−7 has been understanding the physical and chemical properties of supramolecular structures, and based on this, being able to predict the manifestation of commonly occurring structural motifs observed in the crystal and cocrystal structures of similar molecules. X-ray diffraction is frequently used to carry out the analysis needed to describe the structural and geometrical motifs characteristics. In recent literature, computational approaches have been used to obtain information on geometry, stability, and interaction strengths of supramolecular Hydrogen bond motifs of © XXXX American Chemical Society

Received: October 1, 2012 Revised: March 11, 2013

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dx.doi.org/10.1021/cg3014392 | Cryst. Growth Des. XXXX, XXX, XXX−XXX

Crystal Growth & Design

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acid in its hemihydrate form I,15 dehydrate form II, and its oxalate salt cocrystallized with oxalic acid III.

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Table 1. Crystallographic Data for III systematic name

EXPERIMENTAL TECHNIQUES AND THEORETICAL METHODS

chemical formula Mr cell setting, space group temperature (K) a, b, c, (Å) α,β, γ (deg) V (Å3) Z Dx (Mg·m−3) μ (mm−1) radiation type crystal form, color refinement on R[F2 > 2σ(F2)], wR(F2), S no. of parameters

Temperature-Controlled Powder Diffraction Experiment. A small amount of commercial dehydrated cis-4-aminocyclohexanecarboxylic acid II (Aldrich, 98%) was dissolved with a 1:8 ethanol/water solvent mixture and let to rest for several weeks. The slow evaporation of the solvent mixture yielded colorless lamellar microcrystals of cis-4aminocyclohexanecarboxylic acid hemihydrate I (see Scheme 1).

Scheme 1. Dehydration of cis-4-Aminocyclohexanecarboxylic Acid Hemihydrate I to the Dehydrate Form II

cis-4-carboxycyclohexanaminium oxalate: oxalic acid C9H15O6N1 233.22 triclinic, P1̅ (No. 2) 293 6.286(3), 8.879(4), 9.839(4) 93.625(4), 98.813(4), 95.604(4) 538.4(4) 2 1.439 0.122 Mo Kα single crystal, rectangular, colorless 0.0572, 0.1743, 1.13 145

publication material were prepared using PLATON24,25 and DIAMOND.26 Thermogravimetric Analysis and Differential Scanning Calorimetric Measurements. Thermogravimetric Analysis (TGA) of I and III were performed in a Perkin-Elmer TGA7 thermobalance. A sample of 5.9 mg of the amino acid was placed in an aluminum pan and heated from 298 to 573 K at a rate of 10 K min−1, under a nitrogen flux of 50 mL min−1. For the differential scanning calorimetry (DSC) experiment, a sample of 4.0 mg contained in an aluminum vessel was placed inside a Perkin-Elmer DSC7 oven and heated at a rate of 10 K min−1 using the same temperature range and nitrogen flux as above. Semiempirical and DFT Calculations. The geometrical features and packing of molecular clusters are determined in good measure by noncovalent interactions, that is, van der Waals and hydrogen bonds, between the molecules making up the clusters. As a consequence of this fact, detailed and exact theoretical characterization of molecular clusters, as those studied here, involves intensive and demanding calculations and requires expensive computational tasks. It is for this reason that approximated methods, such as semiempirical calculations, have been widely used in molecular clusters. However, it is important to know the extent of the applicability of these methods to describe the many-body interactions that accounts for the molecular polarization and charge delocalization among the cluster components, which play a major role in describing cooperative effects.27 In recent years, corrections have been introduced into a wide range of semiempirical and DFT methods.27 In particular, for this version of the PM6 method,28 a second-generation correction for the description of hydrogen bonds (DH2)29 has been implemented and used in this work. This correction describes the dispersion effect as a pairwise interatomic force field,30 while the energy corrections, because of the presence of hydrogen bonds, are dependent on the steric donor−acceptor arrangement, defined by six internal coordinates: the H···A distance, the A···HD and RA···H angles, and the three torsional angles defining the relative position of the hydrogen bond. DFT calculations were performed employing the Becke’s three parameter hybrid exchange functional (B3)31 and the Lee−Yang−Parr correlation functional (LYP),32 using the 6-31++G(d,p) basis set that includes diffusion and polarization effects. These calculations were carried out using the Gaussian 0333 suite of programs. The B3LYP/ 6-31++G(d,p) method was selected because it leads to sufficiently realistic equilibrium geometries and reasonable stabilization energies of hydrogen-bonded clusters.34 The initial structure for the monomer was built up using the bond distances and angles reported for I.15 The double head-to-tail dimers were built up from the arrangement reported in the crystal structure. All the geometry optimizations were performed using the Berni algorithm; analytical Hessian calculations were used along all the optimizations. The thresholds for convergence were 0.000450 (a.u.) and 0.000300 (a.u.) for maximum force and root-mean-square (rms) force, respectively. The B3LYP/31++G(d,p) calculations where performed only for monomers and dimers to compare with the PM6-DH2 results.

For the temperature controlled powder diffraction experiment, a sample of I was grounded with an agatha pestle and mortar and loaded at room temperature into a 1.5 mm diameter thin-walled borosilicate capillary. The experiment was run on the high resolution X-ray Powder diffractometer of beamline ID31 at ESRF16,17 with a wavelength of 0.33497(6) Å . The glass capillary was spun at approximately 1 Hz, and heated by means of a hot air blower,18 mounted vertically and perpendicular to the capillary. High-quality powder diffraction data were collected at 373 K and used for the structural solution and Rietveld refinement of II (see Scheme 1). Synthesis of Cocrystal III and Single-Crystal X-ray Diffraction Experiment. The cis-4-carboxycyclohexanaminium oxalate: oxalic acid cocrystal III (see Scheme 2) was prepared as follows: 0.0214 g

Scheme 2. Preparation of cis-4-Carboxycyclohexanaminium Oxalate: Oxalic Acid Cocrystal III

(0.1496 mmol) of II was pulverized in an Agatha mortar with a pestle and dissolved in 2 mL of water; 0.0345 g (0.3833 mmol) of thinly grounded oxalic acid (Aldrich 99%) was also separately dissolved in 2 mL of water. The solutions were mixed and stirred with a magnetic stirrer for over an hour at room temperature. Colorless parallelepiped crystals (mp 516.6−517.8 K) of ∼0.5 mm precipitated from the liqueur solution by slow evaporation over a period of 1 month. Single crystal data were collected at room temperature in a Rigaku AFC7S diffractometer coupled with a CCD area detector using graphitemonocromated Mo Kα radiation (0.71073 Å). The trail unit cell parameters were found by indexing of reflections from the first 20 frames and refined along with diffractometer constants to give the final cell parameters using the program Crystal Clear.19 Integration, scaling correction, and data reduction were accomplished using Crystal Structure.20 Absorption corrections were performed using the multiscan method.21 The structure was solved using the program SIR0822 and refined by the full-matrix least-squares methods in SHELXL02.23 The non-hydrogen atoms were modeled anisotropically. All H-atoms were placed in calculated positions and were assigned an isotropic displacement parameter 1.2Ueq of that of their parent atoms and refined using a riding model. Each hydroxyl H-atom was placed in the position that was coplanar with the other carboxylic acid atoms and had the nearest potential hydrogen bond acceptor N or O atom. Experimental details of the X-ray analysis are provided in Table 1. Diagrams and B



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RESULTS Thermogravimetric Analysis (TGA) and Differential Scanning Calorimetry (DSC). The TGA of I showed two transitions. The first one is associated with the exit of water molecules from the crystal lattice at 374.2 K with a mass loss of 5.83%, giving a ratio amino acid: water of 2:1. The DSC showed that this transition is endothermic with ΔH = 4.32 kcal mol−1. The second transition at 546.5 K with a mass loss of 92.6%, results from melting and decomposition of I. DSC calculations show this to be an endothermic process with ΔH = 32.9 kcal mol−1. The TGA of III displayed a complex melting and decomposition scheme; however, it is important to highlight that none of the transitions observed for III matches those observed in pure oxalic acid or pure amino acid, with the cocrystal starting to melt at 503 K. Dehydration Study. Figure 1 shows the three-dimensional plot of the diffraction profiles versus temperature of I.

determined manually and then modeled using the Chebyshev polynomial functions. Restraints were applied to bond distances (deviations ±0.01 Å) and bond angles (deviations ±1°) using average values derived with the program MOGUL 1.143 run on the CSD44 (CSD version 5.33, Feb 2012 update). Restraints involving hydrogen atoms were kept tight with deviations for bond distances and bond angles set at ±0.005 Å and ±1°, respectively. The isotropic atomic displacement parameters were refined as one overall Uiso for the non-hydrogen atoms starting from a value of 0.03 Ǻ 2.The isotropic displacement coefficients of each of the hydrogen atoms were calculated as 1.3 times the value of the temperature factor of their riding non-hydrogen atom. The refinement was stable and convergence was readily achieved. Finally, to inquire if the diffraction data contained systematic errors or if modeling of the peak shapes and background was incorrect, a refinement without a model45 was conducted. These problems were ruled out by the excellent agreement observed between the Le Bail refinement (with background/without background Rp/Rp′ = 0.031/0.036, Rwp/Rwp ′ = 0.040/0.047, and χ2 = 1.569 for 43 variables) and the Rietveld refinement (Rp/Rp′ = ′ = 0.064/0.116, Rexp = 0.032, χ2 = 4.241, 0.045/0.069, Rwp/Rwp 2 and RF = 0.1926, 1463 reflections). The observed, calculated, and difference profiles of the final fit are shown in Figure 2.

Figure 1. Three-dimensional temperature-dependent X-ray diffraction plot showing the dehydration process.

Figure 2. Final observed (dots), calculated (lines) and difference profiles of the Rietveld plot for II at 373 K. The vertical scale of the 4.8° and 9.8° portions of the profiles has been multiplied by a factor of 50 and 200, respectively.

The hemihydrate I exists up to approximately 368−375 K, where it loses its water molecules to form the dehydrate II. This transition matches the one observed in the TGA/DSC experiment. We observed that powder X-ray patterns of I displayed strong texture effects that disappeared after the conversion into II. Therefore, it is likely that dehydration breaks up the crystallites to produce better powders. Rietveld Refinement. The autoindexing program DICVOL35 indexed the powder diffraction pattern of II in a monoclinic P21/n (no. 14) cell, with cell parameters of a = 13.5626 (3) Å, b = 6.2486 (2), c = 9.8068 (2) Å, and β = 112.201(1)° (refined). The indexing figures of merit were M20 = 49.4 and F20 = 467.9 (0.002, 34).36 The structure was solved using the simulated annealing algorithm of the program DASH 3.0.37 The structure was refined by the Rietveld method38 with the program GSAS.39 The hydrogen atoms were placed in calculated positions with restricted geometries. The peak shapes were modeled using the pseudo-Voigt peak shape function 4,40 which included the axial divergence correction at low angle41 and the anisotropic line-shape broadening model.42 Background was initially

Table 2 shows experimental details for the data collection, structural solution, and the Rietveld refinement.

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DISCUSSION Supramolecular Structures. Figure 3 shows the asymmetric unit of I,15 II, and III. Forms I/II are zwitterions confirmed by the presence of carboxylate groups, as depicted by the similar distances C1−O1 (1.261(2)/1.251(1) Å) and C1−O2 (1.245(2)/1.255(1) Å), and by the presence of three hydrogen atoms attached to N1. On the other hand, for III there is an unambiguous assignment of a carboxylic acid group attached to the cyclohexane ring, with clearly different distances C1− O1 (1.327(3) Å) and C1−O2 (1.215(3) Å), while N1 is attached to three hydrogen atoms and, therefore, charged positively. An oxalate group, C2O4=, acting as the counterion sits in a 1h Wycoff special position and an oxalic acid, H2C2O4, sits in a 1c Wycoff special position. The displayed arrangement of molecules within C



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Table 2. Crystallographic Data for II systematic name chemical formula Mr cell setting, space group temperature (K) a, b, c, (Å), β (deg) V (Å3) Z Dx (Mg·m−3) μ (mm−1) radiation type and wavelength of incident radiation (Å) specimen form, color refinement R factors with background (without background) and goodness of fit

cis-4-aminocyclohexanecarboxylic acid C7H13NO2 143.19 monoclinic, P21/n (No. 14) 373(1) 13.5626(3), 6.2486(2), 9.8068(3), 112.201(1) 769.49(6) 4 1.236 0.03 synchrotron radiation 0.33497(6), Beamline ID31, ESRF, Grenoble, France cylinder (particle morphology = powder), white Rietveld method Rp = 0.045 (R′p = 0.069), Rwp = 0.064 (R′wp = 0.116), Rexp = 0.032, R2F = 0.1926 (1463), S = 2.06

Figure 4. Catameric coiled chains of oxalic acid-oxalate molecules link by hydrogen bonds of the type O3−H3···O5 [(i) 2 − x, 3 − y, 1 − z] seen in III.

Table 3. Hydrogen-Bond Geometries for II and IIIa D---H···A

D−H

H···A

D···A

∠DHA

1.88 1.82 2.00

2.77(1) 2.69(1) 2.87(1)

168 169 166

1.77 2.11 2.11 2.54 1.77 2.04 2.27 2.53 2.44

2.51(3) 2.99(3) 2.96(3) 3.18(3) 2.58(3) 2.89(3) 2.86(3) 3.41(3) 2.82(3)

149 173 160 129 172 159 124 149 103

II N1−H1N···O1i N1−H2N···O2ii N1−H3N···O2iii

0.91 0.89 0.89

O3−H3···O5i N1−H1C···O2ii N1−H1A···O3ii N1−H1A···O4iii O1−H1···O6iv N1−H1B···O5iii N1−H1B···O6iv C2−H2···O4i C7−H7B···O1

0.82 0.89 0.89 0.89 0.82 0.89 0.89 0.98 0.9700

III

the asymmetric unit ensures the electroneutrality and mass balance of the crystal, with amino acid/oxalic acid/oxalate ratio of 1:0.5:0.5. The structure is a multicomponent crystal,4 in which a salt, cis-4-carboxycyclohexanaminium oxalate, is cocrystallized with a neutral molecule, oxalic acid. Let us point out that oxalic acids cohabitating with oxalate ions have been observed in other cocrystals.46−51 The oxalic acid moiety is planar, the distances C8O3 and C8O4 are 1.314(3) and 1.206(3) Å, respectively, while for the oxalate ion, the distances C9−O5 and C9−O6 are 1.262(2) and 1.239(3) Å, respectively. A search in the CSD44 showed conformations, ranging from planar to 90°-bent ones are allowed for the oxalate ion; however, for oxalic acid the planar conformation is clearly the most common one, with the exception of a recently reported47 bent conformation. The oxalic acid moieties are in a trans conformation. A search in the CSD44 in crystals containing oxalic acid molecules showed that 28 structures are “trans”, 3 structures display the “cis” conformation, with the above-mentioned torsion angle close to 0°, and 1 structure displays a torsion angle of 97.87°.47 Figure 4 shows how the oxalic acid and the oxalate moieties interact with each other through a O3−H3···O5 [(i) 2 − x, 3 − y, 1 − z] hydrogen bond (see Table 3), forming intercalated oxalic

a

The distances are in ångstrom (Å), and the angles are in degrees (deg). Symmetry codes: II (i) −1/2 + x, 5/2 − y, −1/2 + z; (ii) 1 − x, 2 − y, 1 − z; (iii) −1/2 + x, 3/2 − y, −1/2 + z; III (i) 2 − x, 3 − y, 1 − z; (ii) 1 − x, 2 − y, −z; (iii) x, −1 + y, z; (iv) 1 − x, +y, z; (v) 2 − x, 2 − y, −z.

acid-oxalate chains described by graph set C22(10). On the other hand, the mean plane passing through atoms O3, C8, and O4, of the oxalic acid and the mean plane passing through atoms O5, C9, and O6, of the oxalate ion form an angle of 72.67(8)°, indicating that it correspond to a coiled chain. In the CSD, six cocrystals display linear catameric chains of oxalic acid−oxalate ions; the angle described above for these chains vary from 0° (planar) to 77° (coiled).48−53 Evaluation of the asymmetry parameters of the cyclohexane rings54 shows that for the three forms, the ring have a chair

Figure 3. Asymmetric units of cis-4-aminocyclohexanecarboxylic acid forms, (a) I, (b) II, and (c) III, showing atom labeling. Ellipsoids are represented with a 50% probability for I and III. Newman projections along the C1−C2 bond for (d) I, (e) II, and (f) III. D



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Figure 5. Double head-to-tail dimer structures observed in (a) the cis-4-aminocyclohexanecarboxylic acid dehydrate II form (geometrically equivalent to the one observed in the hemihydrates I,15 and both acting as zwitterions) and (b) the ion cis-4-carboxycyclohexanaminium of III.

Figure 6. Double head-to-tail dimers, graph symbol R22(16), observed in III link to (a) an oxalic acid of the catameric oxalic acid-oxalate chain through hydrogen bonds N1−H1A···O3 [(ii) 1 − x, 2 − y, −z] and N1−H1A···O4 [(iii) x, −1 + y, z] forming a ring, graph symbol R21(5); (b) an oxalate ion of the oxalic acid−oxalate chain through hydrogen bonds N1−H1B···O6[(iv) 1 − x, +y, z] and N1−H1B···O5 [(iii) x, −1 + y, z], and O1−H1···O6 [(iv) 1 − x, +y, z] forming rings, graph symbol R21(5) and R23(8).

Figure 5b. This supramolecular structure is also observed, almost to the slightest structural detail, in I15 and II, which makes this motif the basic building block of their crystal packing. This result demonstrates the great stability of the dimer motifs, owing it to two structural characteristics: the privileged 1, 4 position of the NH3+ and COOH/COO substituents, and the flexibility displayed by the cyclohexane chair conformation that enables the molecule to adopt a bow-shape as shown in Figure 5, which allows the formation of the double head-to-tail hydrogen bonds in the dimer. I, II, and III, differ in the way the R22(16) ring of Figure 5 interact with the catameric oxalic acid−oxalate chain of Figure 4. In III, the second hydrogen, H1A, of the NH3+ group interacts with an oxalic acid molecule through a bifurcated hydrogen bond, N1−H1A···O3 [(ii) 1 − x, 2 − y, −z] and N1−H1A···O4 [(iii) x, −1 + y, z], constructing a graph set of the type R21(5). In this way, as illustrated in Figure 6a, the R22(16) dimer bonds to the coiled chain of oxalic acid-oxalate molecules. The third Hydrogen, H1B, of the NH3+ group interacts with an oxalate moiety of the linear chain through a bifurcated hydrogen bond N1−H1B···O6 [(iv) 1 − x, +y, z] and N1−H1B···O5 [(iii) x, −1 + y, z], forming a ring with graph set R21(5) (shown in Figure 6b). Finally, H1 of the hydroxyl group of the amino acid interacts with O6 of the oxalate ion of the linear chain through a hydrogen bond O1H1···O6 [(iv) 1 − x, +y, z]. O6 acts as a bifurcated acceptor

conformation, with the carboxylate (forms I/II) and carboxylic acid (form III) substituent axial to the ring and the amino group equatorial to the ring.55 Figure 3d, e, and f shows the Newman projections of the amino acid along the C1−C2 bond. The views show that for (I/II) that the orientation of the carboxylate and amino groups are qualitatively similar, while the cocrystal III displays a rotation of the carboxylic acid group of approximately 30° clockwise. This information can be used to assess the crystalline environment around the amino acid; thus, it can be inferred that the crystalline environment in II should be similar to that in I, while in III the environment changes, with the carboxylic acid forced to rotate to allow the formation of hydrogen bonds with the nearest oxygen of the oxalate moiety [see Figure 3c and f]. Hence, it is expected that III displays a crystal packing somehow different from those displayed by I and II.8 In the three structures, the NH3+ group of the amino acid have three nonplanar Hydrogen atoms, enabling this group to form Hydrogen bonds with neighboring molecules to produce 3-D crystal packings. In cocrystal III, H1C forms a hydrogen bond of the type N1−H1C···O2 [(ii)1 − x, 2 − y, −z] with a carbonyl group of another amino acid molecule related by an inversion center. This head to tail interaction is repeated in the other extreme of the molecule, forming through this doubled interaction, 16-member ring dimers, with graph set R22(16), depicted in E



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Figure 7. Adjacent double head to tail dimers in (a) I, (b) II, and (c) III. In panels a and b, the dimers join by means of hydrogen bonds N1−H3N···O2 [(iii) x, −1 + y, z] and N1−H1N···O1 [(iv) 1 − x, +y, z] forming the ring with graph symbol R34(10). In panel c, the dimers join by cross-linking of an oxalate ion of the oxalic acid−oxalate catameric chain in between two double head to tail dimers to form four rings, two of the type R21(5) and two of the type R23(8).

molecules related by 2-fold screw axes and c glide planes perpendicular to the b axis. In the case of III, the adjacent R22(16) motifs are linked through an oxalate ion, which appears intercalated as a different motif in the above-mentioned ribbons [see Figure 7c]. Figure 8 shows the 3D crystal packing down the b axes in I/II and down the c axes in III. The views clearly show the way in which adjacent ribbons are hydrogen-bonded through water molecules, in I, and oxalic acid molecules, in III. The water or oxalic acid molecules are occluded in the pseudorectangular channels parallel to b, and anchored to the polar ends of the double head to tail dimer structures that makeup the ribbons. It is important to highlight that even though form I losses the water molecules by dehydration, the ribbon structures in the dehydrated form II remain intact, only held by van der Waals interactions up to the melting point at 546.5 K (see section 3.1). Energetic and Geometric Characterization of cis-4Aminocyclohexanecarboxylic Acid Zwitterions Clusters Interacting with Water Molecules. Both, B3LYP/6-31+ +G(d,p) and PM6-DH2 calculations show that the most stable structure of the cis-4-aminocyclohexanecarboxylic acid exists as a neutral species with cyclohexane rings adopting the boat

because this oxygen also interacts with H1B, in a similar fashion as described above. This additional interaction constructs a ring with graph set R23(8) (see Figure 6b). As a whole, the oxalate ion acts as acceptor of 4 hydrogen bonds: two from the amino group of the amino acid, one from the carboxylic acid of the amino acid, and one from the oxalic acid. Taking into account the inversion center where the oxalate molecule is sitting, a total of 8 hydrogen bonds are in fact formed so the acceptor capacity of this group is saturated. Likewise, the oxalic acid molecule acts as acceptor and donor of two hydrogen bonds, respectively. Because of the special symmetry position where the molecule is located, it is able to act as an acceptor in 4 hydrogen bonds and as a donor in two hydrogen bonds, leaving some electron pairs of the carbonyl and hydroxyl groups able to form nonconventional Hydrogen bonds with C−H groups from the cyclohexane ring of nearby aminoacids: C2−H2···O4 [(i) 2 − x,3 − y, 1 − z ] and C7− H7B···O1 (see Table 3 for geometrical details). Figure 7a and b shows the manner by which the two adjacent R22(16) rings in I/II join, by means of two hydrogen bonds of the type N1−H3N···O2 [(iii) x, −1 + y, z] and N1H1N···O1[(iv) 1 − x, +y, z] (see ref 15 and Table 3) to form a new graph symbol R34(10). In this way, ribbons are formed, extending along c for I and along [010] for II. These ribbons are built from amino acid F



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Figure 8. Views of the crystal packing of (a) I, (b) II, and (c) III.

Figure 9. Geometries of cis-4-animocyclohexanecarboxylic acid in (a) neutral form and interacting with (b) one, (c) two, (d) three, (e) four, (f) five, (g) six, and (h) seven water molecules.

molecules increasingly stabilizes the clusters, interaction with 5 water molecules induce the cyclohexane ring to adopt a twisted-chair conformation, Figure 9f, while interaction with 6 water molecules produces a transition to a chair conformation, Figure.9g, which is the most stable one in the solid state.15 Interactions with additional water molecules do not induce any

conformation, which allows the formation of an intramolecular Hydrogen bond of the type N−H···O, Figure 9a. Once one water molecule is explicitly introduced in the surroundings of the amino group, the zwitterionic form becomes the most stable one, with the cyclohexane ring remaining in its boat conformation, Figure 9b. The successive inclusion of water G



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Figure 10. Variation of the stabilization energy at PM6-D2H level, ΔE (kcal/mol), and of the stabilization energy per water molecule, ΔE/n, as a function of the number of water molecules for clusters of cis-4-aminocyclohexane and water molecules.

cis-4-aminocyclohexanecarboxylic acids as the most stable cluster, with stabilization energies per molecule of −25.01 and 13.05 kcal/mol, respectively, due to a proton transfer from the NH3+ to the COO−. The explicit inclusion of water molecules reverts this condition and stabilizes the zwitterionic form of the amino acid. Moreover, as shown in Figure 11, successive inclusion of water molecules at the polar ends of the amino acids causes a progressive stabilization of the zwitterionic dimer system. However, the ΔE/n curve (Figure 11b) reveals that, contrary to what was previously obtained, the interaction with one water molecule translates into an energy gain of −24.64 kcal/mol and inclusion of any extra water molecule produces a smaller stabilization than that caused by including only the first one. This observation seems to imply that the 2: 1 amino acid: water stoichiometric ratio, observed in the crystal structure of I,15 is the most favorable one. In the water-zwitterion-zwitterion system the amino acid molecules interact through four Hydrogen bonds [see Figure 11 (a)] of the type N−H···O, with average N···O distance of 2.743 Å, H···O distance of 1.908 Å and an average N−H···O angle of 134.5°. The water molecule forms three additional hydrogen bonds with the dimer, acting simultaneously as hydrogen donor to one of the amino acid molecules, with average O···O, H···O distances, and O−H···O angle of 2.983 and 2.17 Å and 100.5°, respectively, and as a hydrogen acceptor to the other amino acid molecule, with N···O, H···O, and N−H···O distances and angle of 2.718 and 2.360 Å and 99.34°, respectively. It is interesting to point out that these geometrical values are similar to those found in the crystal structure of I.15 Energetic and Geometric Characterization of Zwitterionic cis-4-Aminocyclohexanecarboxylic Acid Ribbons. The complex interactions among double head-to-tail dimers were investigated at a PM6-DH2 level of calculations. It was found that they lead to the formation of ribbons, similar to those found in the crystal structures of I and II. Figure 12c shows the conglomerate comprised of six amino acid molecules (m = 6). There, the central dimer displays a conformation very close to that observed in the crystal structures of I and II, and hence, as in these structures, the hydrogen bond network is also described by the graph set R22(16). Nevertheless, the geometrical results show that, within these clusters, dimers interacting with each other form rings of the type R22(6) and R24(8), contrasting with the graph set R34(10) observed in the crystal structures of I and II. This difference is attributed to the fact that the considered finite size clusters are not able to reproduce the exact 3-D crystal Hydrogen bond network, in which the donor and acceptor

additional conformational change in the amino acid molecule; instead, it is found that addition of extra water molecules induces the formation of a second hydration sphere. We think that this result and the condensed phase stability of the chair conformation is due to the saturation of the hydrogen donor capacity of the amino (with 3 hydrogens) and carboxylate groups (with 4 acceptor electron pairs) of the amino acid, which is reached with 6 water molecules, Figure 9g. The system stabilization energy, ΔE, was defined as ΔE = E T − (mEaa + nE H2O)

where ET is the total energy of the considered system, Eaa is the energy of the optimized monomer of the cis-4-aminocyclohexanecarboxylic acid, m is the number of amino acid molecules considered, and n is the number of water molecules, explicitly surrounding the amino acid. The variation of ΔE as a function of the number of water molecules is displayed in Figure 10a. By inspection of this figure, one can observe that stabilization grows with the number of water molecules interacting with the amino acid molecule. This trend changes after the hydrogen-donor capacity of the amino acid is reached for 6 water molecules after which there is a global interaction regime change (formation of the second hydration sphere) reflected in the slope change. A measure of the cooperative enhancement in the stabilization energy of the clusters is given by ΔE/n, whose variation is depicted in Figure 10b. From there, one can notice that the interaction of two water molecules with the amino acid molecule causes a significant stabilization of the system (from −4.62 to −9.16 kcal/mol), which afterward slowly augment until stabilizing at about −10 kcal/mol, decreasing for more than 6 water molecules. To understand this, one can look at Figure 9b−f, which reflect the formation of supramolecular bridged structures that connect both polar extremes of the amino acid. The bridge water molecules act simultaneously as acceptor and donor of proton, which allows the formation of a network of Hydrogen bonds connecting amino-water, water−water, and water-carboxylate moieties, and, hence, the development of cooperative effects responsible for the supramolecular structure stabilization. In the crystal, the connecting role is played by another cis-4-cyclohexanecarboxylic acid molecule to form the dimer. The interaction of two zwitterionic amino acids, as those seen in the crystal structures of I and II, has been explored at both B3LYP/6-31++G(d,p) and PM6-D2H levels of calculations. The results always render a double head to tail dimer of neutral H



Article

Figure 11. (a) Geometry of the dimer of cis-4-aminocyclohexanecarboxylic interacting with one water molecule; (b) Variation of the stabilization energy, ΔE (kcal/mol), and of the stabilization energy per water molecule and (c) ΔE/n(kcal/mol), as a function of the number of water molecules for double head to tail cis-4-aminocyclohexanecarboxylic acid dimers.

Figure 12. (a) Variation of the stabilization energy per amino acid molecule, (b) ΔE/n (kcal/mol) as a function of the inverse of the number of amino acid molecules, n. (c) Geometry of the ribbons constructed from the interaction of three double head to tail dimers.

ribbon (n → ∞). It is interesting to point out that this stabilization energy is similar to that resulting from the interaction of a dimer with a single water molecule. Energetic and Geometric Characterization of cis-4Carboxycyclohexanaminium: Oxalate Ribbons. For the cis4-carboxycyclohexanaminium ion, the B3LYP/6-31++G(d,p) and PM6-D2H level calculations, with initial geometrical parameters taken from the crystal structure of III, show that the chair as its most stable conformation, result consistent with that of the X-rays. The dimer also displays a similar structure to that found in III, forming two hydrogen bonds of the type N−H···O, with

capacity of the amino and carboxylate groups of the amino acid tend to be satisfied.8 The cooperative effects responsible for the formation of ribbons made up of arrays of dimers were explored by calculating the stabilization energies per amino acid molecule, ΔE/n, whose results are exhibited in Figure 12a. This figure exhibits the gradual stabilization of ΔE/n, with the molecular conglomerates size, showing the appearance of an asymptotic plateau after 10 amino acid molecules interact with each other. The value of this asymptotic stabilization can be estimated from a graph of ΔE/n vs 1/n, or which the value at 1/n = 0, −24.31 kcal/ mol, gives an approximation of the stabilization of an infinite I



Article

Figure 13. (a) Variation of the stabilization energyΔE/m (kcal/mol) versus n + m; been n = oxalate; m = cis-4-carboxycyclohexanaminium and (b) ΔE/m (kcal/mol) as a function of 1/(n + m).

proved successful for investigating the stability of commonly recurrent motifs observed in certain amino acids, such as the double head to tail dimers and ribbons seen in cis-4-aminocyclohexanecarboxylic acid. Moreover, the results conduct us to think that molecular recognition of amino acid pairs, which leads to formation of double head to tail dimers, followed by linking of adjacent dimers, should be the initial driving forces that induces the crystal formation in the three crystals here investigated.

H···O and N···O distances of 1.91 and 2.60 Å, respectively, and angle N−H···O of 120.9°. Nevertheless, its calculated ΔE/n is 12.3 kcal/mol, indicating that these intermolecular interactions are not enough to stabilize the two positive charges of the system. Optimization of neutral clusters composed of two cis-4carboxycyclohexanaminium ions and one oxalate acting as a counterion, leads to minimum energy structures where a proton is transferred from the NH3+ of the amino acid ion to the oxalate. This type of migration was observed in all clusters build with up to 8 cis-4-carboxycyclohexanaminium ions and 4 oxalate ions. These results suggests that the interactions of the third hydrogen atom of the NH3+ of the cis-4-carboxycyclohexanaminium ions with the oxalic acid molecule (seen in the crystal structure of III and displayed in Figure 6a) are of great relevance to the stabilization of the 3-D supramolecular structures observed in III. Finally, cooperative effects present in the neutral clusters composed of 4-carboxycyclohexanaminium and oxalate ions, with the ribbon shape displayed in Figure 7c were explored through fixed geometries calculations using the parameters of the crystal structure of III. Figure 13a shows the stabilization energy per neutral cluster versus the number of molecules (n + m; n = oxalate; m = 4-carboxycyclohexanaminium). The curve displays the typical behavior previously observed for systems stabilized by cooperative effects. Figure 13b shows a graph of ΔE/(n + m) versus 1/(n + m), which allows to approximate the stabilization of an infinite ribbon (n + m → ∞); ΔE/(n + m) at 1/(n + m) = 0, is −51.58 kcal/mol, value that doubles that found in the previous case, results that emphasized the importance of the oxalate in the stabilization of the system.

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ASSOCIATED CONTENT

* Supporting Information S

Selected geometrical parameters for the cluster cis-4-aminocyclohexanecarboxylic acid/water in a ratio 2:1 optimized at PM6-DH2 level of calculations and crystallographic information files. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*Address: Laboratorio de Cristalografı ́a, Departamento de ́ Quimica, Facultad de Ciencias, Universidad de Los Andes, La Hechicera, Mérida, 5101, Venezuela, Tel. 58-274-2401409. Email: [email protected]. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Notes

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The authors declare no competing financial interest.

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CONCLUSIONS After the preparation of two multicomponent crystals: an hemihydrate of cis-4-aminocyclohexanecarboxylic acid and a cis-4-aminocyclohexanaminium oxalate: oxalic acid cocrystal, inclusion of extra molecules in the crystals has allowed to alter the crystal environment of the Hydrogen bonds, and explore if recurrent motifs were still present in the modified crystals. Single-crystal and powder X-ray diffraction showed that the double head to tail dimers and ribbons formed by connecting adjacent dimers were recurrent in all the structures investigated. DFT/B3LYP and PM6-D2H calculations were able to reproduce in vacuum the geometries of the motifs in a reliable way, and provided us the means to assign stabilization energies to these molecular clusters. Thus, the approach employed here has

ACKNOWLEDGMENTS The authors thank the finatial support of FONACIT-Venezuela (grant LAB-97000821), and the CDCHT-ULA (grants 1618-0808-AA and 1784-12-08-B), Also, we thank A. Briceño and T. Gonzáles (IVIC-Venezuela) for their valuable time and the use of beamline ID31, ESRF, France.

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REFERENCES

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Investigating the Stability of Double Head to Tail Dimers and Ribbons

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