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Crystal Structures, Dehydration Mechanism, and Chiral Discrimination in the Solid State of a Hydantoin Derivative Published as part of a virtual special issue of selected papers presented at the 9th International Workshop on the Crystal Growth of Organic Materials (CGOM9) Youness Amharar, Samuel Petit,* Morgane Sanselme, Yohann Cartigny, Marie-No€elle Petit, and Gerard Coquerel Laboratoire Sciences et Methodes Separatives (SMS), Equipe de cristallogenese, EA 3233, Universite de Rouen, IRCOF, rue Tesniere, F-76821 Mont Saint Aignan cedex, France
bS Supporting Information ABSTRACT: (() 5-Methyl-5-(40 -ethylphenyl) hydantoin (18H) crystallizes in usual organic solvents as a conglomerate in the P212121 space group. A new monohydrated racemic compound of 18H could however be obtained by antisolvent induced crystallization. The structure of this first hydrate of a hydantoin was successfully resolved by single crystal X-ray diffraction. It crystallizes in space group P21/c, and the crystal packing shows an association of homochiral molecular ribbons resulting from strong hydrogen bonds involving the water molecule and the hydantoin rings. At 30 °C and under low relative humidity (in the range 030%), the monohydrate exhibits an efflorescent behavior, with a reversible evolution toward a metastable anhydrous racemic phase through a cooperative zip-like mechanism. But under specific conditions (4060% R.H., 30 °C), dehydration also leads to the nucleation and growth of the stable conglomerate, as confirmed by dynamic vapor sorption and X-ray powder diffraction analyses. The detailed analyses of solidsolid transformations between a hydrated racemic phase, an anhydrous racemic phase, and/or two anhydrous enantiomerically pure phases provide an opportunity to investigate examples of chiral recognition mechanisms in the solid state. The way the water molecules are released from the racemic monohydrate at 30 °C plays a decisive role in the nucleation and growth of the conglomerate.
1. INTRODUCTION Beside the asymmetric synthesis, chiral resolution remains of great importance in the pharmaceutical industry.1,2 Among the different preparative resolution routes, preferential crystallization (PC) is a cheap and efficient method for the separation of enantiomers at an industrial scale but requires that the racemic mixture crystallizes as a conglomerate, that is, a physical mixture of enantiomerically pure crystals.3 This constitutes a major limitation to the applicability of PC since only 510% of the racemic mixtures crystallize as conglomerates,4 whereas a vast majority of racemic mixtures gives 1-1 stoichiometric compounds containing the two enantiomers, named racemic compounds. This prevalence for racemic compounds is not yet fully understood, inducing the absence of rational methodology or prediction tools for the preparation of stable conglomerates, consequently often detected by means of a trial-and-error approach. The implementation of PC can therefore only be envisaged after a screening step consisting of chemical derivatization5 or formation of salts,69 solvates, cocrystals, r 2011 American Chemical Society
etc.10,11 In this context, the rationalization of relationships between homo- and heterochiral solid phases by comparing their physical and structural features constitutes a major issue for scientists involved in the production of pure enantiomers and in the development of new chiral pharmaceutical compounds. In 1895, it was deduced from the comparisons between crystal densities of eight racemic compounds and their chiral counterparts that racemic compounds tend to be denser, from which it was inferred that the presence of both enantiomers in a crystal lattice allows a more efficient packing than for a single enantiomer (so-called Wallach’s rule).12 Almost one century later, Brock et al. have reconsidered the systematic comparison of homo- and heterochiral packings.13 Using a larger set of data, they have proposed a detailed discussion covering three complementary aspects: (i) In terms of thermodynamics, they have shown that racemic and enantiopure solids have the same entropy, Received: February 22, 2011 Revised: April 14, 2011 Published: April 18, 2011 2453
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Crystal Growth & Design demonstrating that the conglomerate is not disadvantaged by a lower entropy associated to the separation of the enantiomers, as previously stated by Jacques et al.14 (ii) From a structural point of view, they have also shown that the Wallach’s rule derived from density comparisons between racemic compounds and conglomerates is statistically biased since most of the molecules studied crystallized as stable racemic compounds and metastable conglomerates. Moreover, they have highlighted that the prevalence for racemic crystals is actually a consequence of the number of available space groups and possibly of their symmetry elements.15 Indeed, conglomerates can crystallize only in the 65 chiral space groups, whereas any of the 230 space groups is permitted for racemic compounds. (iii) A third approach consisted of considering the incidence of kinetics during crystallization from a racemic solution, postulating that the rate of formation of nuclei is likely to be lower for the conglomerate than for the racemic compound, due to the presence of the counter enantiomer acting as an inhibitor or at least as an impurity. This kinetic aspect as well as the diffusion in solution may therefore favor the crystallization of heterochiral phases from racemic solutions and melts.16 Other comparisons of structural features for racemic compounds and conglomerates have been performed, from which the lower stability of single enantiomer crystal structures was accounted by considering various factors such as the number of crystallographically independent molecules in the asymmetric unit,17 significant differences in atomic displacement ellipsoids and intermolecular bondings,18 or supplementary repulsive interactions in the structure of single enantiomers.19 The incidence of partial or complete solid solutions between enantiomers was also considered in relation to the relative stability of conglomerates.20,21 More recently, various solid state transitions between racemic compounds and conglomerates have been investigated and different situations have been envisaged: (i) thermodynamic equilibrium between a low-temperature conglomerate and a hightemperature racemic compound through a eutectoid invariant;22 (ii) reverse situation through a peritectoid invariant;23,24 (iii) irreversible transition from a metastable conglomerate toward a stable racemic compound;16,25 (iv) reverse situation, of particular interest since it corresponds actually to a spontaneous resolution, either from a racemic compound toward a conglomerate2629 or by transition from an anomalous conglomerate toward a usual one.30 When possible, another interesting approach consists of considering the evolution of the relative stability of homo- and heterochiral solid phases within a series of chemical derivatives as a function of the molecular structure.19,25,30,31 For instance, Nemak et al. have shown that increasing the length of the alkyl chain in the series of (N-alkyl)-20 ,60 -pipecoloxylidides decreases the relative stability of the racemic compound, thus inducing the formation of a conglomerate for the longest butyl chain.31 Another chemical family of interest is that of 5-alkyl-5-arylhydantoins,3234 since an unusual high propensity to crystallize as conglomerates has been reported among these derivatives. Several of them could therefore be resolved by means of PC,3436 with the interesting perspective to reach synthetic optically pure R,R-disubstituted aminoacids,36,37 for which the proportion of conglomerates is “normal”. The present paper reports the preparation and the structural characterization of several crystalline phases of 5-methyl-5-(40 -
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Figure 1. Molecular formula of 5-methyl-5-(40 -ethylphenyl) hydantoin (18H).
ethylphenyl) hydantoin, labeled 18H hereafter (Figure 1) as well as the study of solid state transitions between these phases. Owing to its crystallization behavior and to the specific features of the system formed between its two enantiomers, this hydantoin derivative provides an interesting opportunity to investigate molecular recognition phenomena in the solid state during transitions between homo- and heterochiral solid phases on the basis of physical characterization, thermodynamics, and structural data.
2. EXPERIMENTAL SECTION 2.1. Materials. Racemic 18H was synthesized by using the one-pot B€ucherer’s reaction from the corresponding ketone, 40 -ethylacetophenone38 (yield > 90%), and was recrystallized in ethanol and acetone (purity > 99%). HPLC-grade acetone, methanol, and ethanol were purchased from Sigma Aldrich (Lyon, France). These high-purity solvents as well as Milli-Q water were used for crystallization experiments. 2.2. Crystallization of Solid Phases. A routine crystallization protocol consisting of cooling a solution of methanol saturated with (()18H from 35 to 22 °C in 5 h under magnetic stirring gives access to the stable conglomerate denoted C-18H. Single crystals of this phase could be prepared by slowly cooling a saturated solution of (()18H in a water/methanol mixture (45/55 v/v) from 28 to 22 °C in five days. A less stable crystalline form labeled HR-18H was obtained by injecting quickly 1 mL of a methanolic solution saturated with (()18H at 35 °C in 3 mL of pure water (acting as an antisolvent) at 25 °C. After filtration, the saturated solution was placed in a pierced vial at room temperature so as to promote the formation of single crystals by slow evaporation of the solvent. 2.3. X-ray Powder Diffraction (XRPD). XRPD analyses were performed with a D8 diffractometer (Bruker Analytical X-ray Systems, Karlsruhe, Germany) with a BraggBrentano geometry, in thetatheta reflection mode. The instrument is equipped with a X-ray source (CuKR1 = 1.5406 Å, Cu-KR2 = 1.5444 Å, 40 kV, 40 mA), a nickel filter and a lynx-eye detector with angular aperture of 1.5°. The diffraction patterns were collected by steps of 0.04° (2-theta) over the angular range 330°, with a counting time of 0.5 s per step. PowderCell software was used for data processing (v. 2.4, 2000). Temperature-resolved XRPD analyses were carried out with a Siemens D5005 diffractometer (Bruker Analytical X-ray Systems, Karlsruhe, Germany) in similar conditions as that given above, except a counting time of 4 s per step in isothermal conditions. The heating rate between two temperature steps (5 °C) was 1.8 K 3 min1. 2.4. Thermal Analysis. Thermogravimetric-differential scanning calorimetry (TG-DSC) measurements were carried out by using a Netzsch STA 449C Jupiter apparatus (Selb, Germany). The purge gas was helium (flow = 40 mL 3 min1) and the reference material was an empty covered aluminum pan. The samples were weighed in covered pierced aluminum pans and then placed in the analyzer. Analyses were performed in the temperature range 20180 °C using a 5 K 3 min1 2454
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Figure 2. Experimental XRPD patterns of C-18H, HR-18H, and AR18H.
heating rate. After acquisition, the PROTEUS software was used for data processing (v. 4.8.4, 2007).
2.5. Dynamic Vapor Sorption (DVS) and Control of the Relative Humidity (R.H.). Moisture sorption isotherms at 30 °C of the anhydrous crystalline phases were obtained by using a DVS-1 automated water sorption analyzer (Surface Measurement Systems, Alperton, U.K.). About 3 mg of solid was placed in the analyzer for each experiment. Mass variations were recorded while relative humidity (R.H.) was successively decreased or increased from 90% to 0% R.H. by steps of 10% R.H. The automated analyzer was allowed to proceed with the following step as soon as the mass variation of the sample was less than 103 % 3 min1. For experiments carried out at a constant relative humidity, the solid samples were stored out in a HFS91 hot-stage (Linkam Scientific Instrument, Tadworth, Surrey, U.K.) fitted with a WETSYS gas humidity generator (Setaram Instrumentation, Caluire, France). Between 10 to 100 mg of solid sample were placed on the sample stage at 30 °C and under different relative humidities (5%, 40%, or 90% R.H.) with a constant gas flow rate of 50 mL 3 min1. The solidsolid transformations were monitored by gravimetric measurements and XRPD analyses. 2.6. Crystal Structure Determination. Structural analyses were carried out at room temperature by means of single crystal X-ray diffraction on a full three-circle goniometer Bruker SMART APEX diffractometer equipped with a CCD area detector, using a monochromator for MoKR (0.7107 Å). The cell parameters and the orientation matrix of the crystal were determined in a preliminary step by using SMART Software.39 Data integration and global cell refinement were performed with SAINT Software.40 Intensities were corrected for Lorentz, polarization, decay and absorption effects (SAINT and SADABS Softwares) and reduced to FO2. SHELX in WinGX program package41 was used for space group determination, structure solution and refinement. 2.7. Second Harmonic Generation (SHG). Measurements were carried out using the SHG setup developed in our lab, equipped with a Nd:YAG Q-switched laser (Quantel) operating at 1.06 μm, delivering 360 mJ pulses of 5 ns duration with a repetition rate of 10 Hz. Further information about this apparatus has been published by Galland et al.8 2.8. Scanning Electron Microscopy. Scanning electron microscopy (SEM) pictures were obtained with a Netscope benchtop JCM5000 instrument (JEOL Europe, Croissy-sur-Seine, France). Crystals were stuck on SEM stub with gloss carbon and coated with gold to reduce charging during analysis.
3. RESULTS AND DISCUSSION 3.1. Crystallization and Identification of Phases. Routine recrystallizations carried out by cooling a saturated solution in
Figure 3. TG-DSC curves of C-18H and HR-18H at 5 K 3 min1 heating rate (no weight loss for C-18H: data not shown).
acetone, methanol, or ethanol produced a highly crystalline powder that could be identified from comparisons of XRPD patterns as a conglomerate-forming orthorhombic form (C18H), isomorphous to previously described 5-alkyl-5-aryl hydantoin derivatives.3234 However, when a solution of methanol saturated with (()18H at 35 °C was quickly injected in water, a new phase precipitated and was subsequently identified as a racemic monohydrate metastable under ambient R.H. and temperature (HR-18H). Nevertheless, complementary crossseeding experiments performed by slurrying C-18H and HR18H in H2O at various temperatures revealed that HR-18H is the most stable phase in aqueous medium below 20 °C, whereas the conglomerate becomes predominant from 30 °C upward. Despite its fast crystallization, one can see in Figure 2 that the crystallinity of HR-18H is only slightly lower than that of C-18H. To our knowledge, the preparation of HR-18H is the first reported case of a hydrated phase among 5-5 chiral hydantoin derivatives. Upon static dehydration under 0% R.H. (P2O5) at 30 °C, this monohydrate leads within 4 h to a crystalline anhydrous phase (AR-18H) of lower crystallinity identified from its XRPD pattern (Figure 2). 3.2. Thermal Behavior of Solid Phases. Characterization of HR-18H and C-18H by TG-DSC is presented in Figure 3. For HR-18H, this analysis shows a first endothermic phenomenon (onset 48.6 °C) associated with a mass loss of 6.69% (calculated value for one water molecule: 7.61%). Therefore, this thermal event corresponds to dehydration and reveals that the departure of water molecules begins at room temperature, indicating an efflorescent character of HR-18H under a ventilated atmosphere (purge gas). The absence of thermal event in the range 80140 °C suggests that the complex endothermic phenomena observed at 149 °C (interpreted below) starts with the melting of the anhydrous phase AR-18H, occurring about 3 °C below the melting point of the conglomerate C-18H, detected at 151.8 °C. Temperature-resolved XRPD analyses have been carried out on HR-18H in order to identify the solid phases produced during and after dehydration. Figure 4 shows that the dehydration starts, under these specific experimental conditions, at 30 °C and is almost completed at 35 °C since only the diffraction peaks of AR18H are observed at this temperature. Between 80 and 130 °C, the specific diffraction peaks of AR-18H are progressively replaced by those of C-18H, revealing that the experimental constraints of these analyses (low heating rate and long duration for every XRPD data collection) allow not only the detection of 2455
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Figure 4. Temperature-resolved XRPD analysis of HR-18H between 15 and 130 °C showing the successive transformations into AR-18H and C-18H (only selected patterns are shown).
the dehydration of HR-18H into AR-18H (in consistency with TG-DSC results) but also the complete conversion of AR-18H into C-18H (not observed in the DSC curve). Moreover, a more detailed analysis of the AR-18H melting peak (Figure 3) confirmed the existence of two overlapping phenomena with two onset temperatures, which may correspond to close melting point for AR-18H and C-18H. It can therefore be postulated that a transformation occurred during the DSC measurement (in covered pierced pans) but only partially because of a higher heating rate during the DSC analysis (5 K 3 min1) compared to temperature-resolved XRPD experiment (0.03 K 3 s1 and isothermal steps - ca. 45 min. - required for XRPD data collection). This provides evidence that the solidsolid conversion between AR-18H and C-18H occurs at a low pace even at high temperature. 3.3. Second Harmonic Generation Measurement (SHG). The SHG method allows the detection of non-centrosymmetric space groups and is therefore used for prescreening of conglomerates.8 In order to assess the chiral nature of the solid phase AR-18H, its SHG activity has been measured and compared to that of C-18H and HR-18H. C-18H is a conglomerate and consequently generates a positive SHG signal - here of high intensity. This signal is about 800% that of the reference (quartz at 100 μm) which is consistent with the structure of C-18H crystallizing in a non-centrosymmetric - even chiral - space group (P212121, see below). Conversely, no signal was obtained for HR18H, in agreement with its centrosymmetric space group P21/c. The detection test has also been applied to AR-18H and no SHG effect was detected. This reveals that AR-18H is very likely to crystallize in a centrosymmetric space group, indicating that AR18H is also a racemic compound. Thus, the binary system formed between the two enantiomers of 18H can be described as a stable conglomerate (C-18H) with a eutectic melting at 152 °C, on which a metastable racemic compound (AR-18H, TF = 149 °C) is superimposed. 3.4. Structural Investigations. The preparation of single crystals allowed the crystal structure determination for C-18H and HR-18H. Both structures could be resolved and refined up to a satisfactory level of accuracy, as shown from data collected in
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Table 1. Various attempts to prepare single crystals of the AR18H phase remained unsuccessful. C-18H crystallizes in the orthorhombic system with the P2 1 2 1 2 1 space group. Consistent with previous structural descriptions of hydantoins,3234 the b axis was selected as the short crystallographic parameter. C-18H shares extensive similarities with the orthorhombic polymorph of 5-methyl5-(4 0 -methylphenyl) hydantoin, labeled 17H, since both structures crystallize in the same space group with closely related crystallographic parameters and packing features.34 Owing to the presence of both H-bond donor and acceptor groups in the hydantoin ring, the main intermolecular interactions consist of hydrogen bonds. It can be seen from Figure 5 and Table 2 that all heteroatoms of the hydantoin molecule are involved in hydrogen bonding, resulting in the existence of strong molecular ribbons running along the b axis (Figure 5) that constitute a common feature among the family of 5-alkyl-5-aryl hydantoin derivatives. 3133 The translation of these molecular ribbons along the c axis gives rise to molecular slices (200) of high density, and the stacking of these slices involves the binary screw axis 21 parallel to the a direction, thus inducing a reverse orientation of successive slices (Figure 6). The crystal cohesion along the a and c directions is ensured by van der Waals interactions and by contacts between neighboring molecular ribbons consisting of CH-π and T-shaped ππ interactions between aromatic moieties. The monohydrated racemic compound of 18H crystallizes in the monoclinic system with the P2 1 /c space group. It can be seen from Figure 5 that, as in C-18H, the main structural feature consists of infinite ribbons made of H-bonded molecules (Table 2). However, in HR-18H, the water molecule is strongly involved in these ribbons, participating to three hydrogen bonds with three different hydantoin rings. As a consequence of the presence of the water molecule in this new type of 1D ribbon, the hydantoin molecules are more distant from each other than in the crystal structure of C-18H, which may account for the large difference in density and in the volume of the asymmetric unit. Since the two subribbons made of parallel 18H molecules are related through the 2 1 axis, each molecular ribbon is homochiral. However, it can be seen from Figure 6 that successive ribbons along the c direction are generated by the c glide plane, thus leading to series of alternate (R) and (S) ribbons. The cohesion between molecular ribbons along a and c directions is ensured by T-shaped ππ interactions between aromatic rings of same chirality, giving rise to homochiral (101) slices. The main interactions between successive (101) layers consist of CH- π contacts in the range 3.0 ( 0.2 Å. 3.5. Transitions between Solid Phases As a Function of Relative Humidity. At 30 °C under static dry atmosphere (0% R. H.), the dehydration of HR-18H is completed within 4 h and leads to AR-18H. This anhydrous solid phase has been analyzed by DVS at 30 °C in order to characterize its behavior as a function of R.H. (Figure 7). The sorptiondesorption isotherm shows that under high relative humidity (90% R.H.), AR-18H undergoes a mass uptake of 6.3%, not far from the 7.6% value expected for a 1-1 stoichiometric hydrate. The relative humidity was then decreased by steps of 10%, and two different phenomena could then be identified: • From 90% to 40% R.H., the sample mass decreases slowly, at an approximate rate of 1.3 105 mg 3 min1. 2456
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Table 1. Crystallographic Data and Refinement Parameters for C-18H and HR-18H Crystal Structures conglomerate (C-18H) formula
C12H14N2O2
molecular weight (g 3 mol1)
218.25
236.27
CCDC 812250
CCDC 812249
CCDC deposition numbera
a
racemic monohydrate (HR-18H) C12H14N2O2.H2O
T (K)
295
295
wavelength (Å)
0.71073
0.71073
crystal dimension (mm)
1 0.1 0.1
0.4 0.3 0.1
crystal morphology
colorless needle
colorless prism
system space group
orthorhombic P212121
monoclinic P21/c
a (Å)
24.5078(15)
15.774(10)
b (Å)
6.2205(4)
6.181(4)
c (Å)
7.2839(5)
16.277(8)
β (°)
90
126.02(4)
Z, Z0
4, 1
4, 1
V (Å3)
1110.44(12)
1283.5(13)
dcalc (g 3 cm3) μ (mm1)
1.305 0.09
1.223 0.089
F000
464
504
θ range (°)
1.66 to 26.48
1.60 to 26.50
h, k, l ranges
30/30, 7/7, 9/9
19/16, 7/7, 20/18
no. of collected/unique reflections
11897/2280
6150/2565
no. of reflections (I > 2σI)/parameters
2242/148
1779/164
residual electronic density (e 3 Å3)
0.216/0.187
0.205/0.176
absolute structure parameter R1, wR2 (I > 2σI)b
0.5(11) 0.0320, 0.0885
none 0.0556, 0.1534
R1, wR2 (all data)
0.0324, 0.0889
0.0878, 0.1827
goodness of fit
1.065
1.051
See Supporting Information for the CIF files. b R = Σ(||FO| |FC||)/Σ|FO|, wR2 = [Σ[w(FO2 FC2)2]/Σ[w(FO2)2]]1/2.
• From 30% R.H. downward, the mass decreases dramatically (6.8 104 mg 3 min1) until complete dehydration. The sorption behavior consists of a mass uptake starting in the range 5060% R.H. Nevertheless, the final sample mass, after the second sorption, is slightly lower than its initial value, revealing an incomplete rehydration. Owing to the reproducibility of this unexpected phenomenon cycle after cycle, the total mass of the sample at 90% R.H. decreases continuously and represents only ca. 60% of the initial mass of hydrate after four cycles. It should be noticed that the physical state of the solid sample (particle size distribution), its mass, and the operating conditions (dm/dt) have an impact on the kinetics of the transformations (weight loss per cycle and cycle durations). In order to identify the nature of the solid phases involved during these transitions, complementary experiments have been carried out in various conditions. When C-18H was stored under moist atmosphere (90% R.H.) at 30 °C, no mass change was detected after one week. By contrast, the same treatment applied to AR-18H induced an increase of the sample mass by 7.6% after 5 h, and XRPD analysis confirmed that the solid phase obtained was HR-18H. On the other hand, the storage of HR-18H in the dehydration conditions identified during DVS measurements (30 °C and 40% R.H.) produced a slow mass loss (about 1% per day) and the identification of the resulting sample revealed that under these specific conditions, pure C-18H was produced after 8 days (within the limits of detection of conventional XRPD). This kind of slow solidsolid transition from a heterochiral to a
homochiral phase has also been observed by Larsen et al. in the case of meta-chloro-3-hydroxy-3-phenylpropionic acid with a complete spontaneous resolution of the racemic compound after 2 years.19 Hence, these results indicate that two distinct dehydration behaviors of HR-18H can take place, depending on temperature and R.H. conditions. At 30 °C a residual humidity in the range 4060% promotes a slow and irreversible transition toward the stable conglomerate C-18H, whereas a R.H. close to or lower than 30% induces a faster reversible dehydration toward the metastable anhydrous racemic compound AR-18H. These results could account for the incomplete rehydration during the first sorption cycle, since the mass uptake (6.3%) is lower that the theoretical expected value (7.6%), indicating that the irreversible transition may have already started during the storage of the sample before DVS analysis. 3.6. Dehydration Mechanisms of Racemic 18H Monohydrate. The preparation routes of the two anhydrous phases of 18H from the racemic monohydrate are summarized in Figure 8. To get more insights about the molecular mechanisms involved in these transformations, single crystals of HR-18H have been stored under different conditions (Figure 8, pathways 1, 2, and 3) and then analyzed by scanning electron microscopy (Figure 9). Dehydration of HR-18H toward AR-18H can be easily achieved at 30 °C and 0% R.H (pathways 1 and 4). The macroscopic consequences of this fast and reversible phenomenon are shown in Figure 9a, revealing its high anisotropic 2457
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Figure 6. Projection along the b axis of the crystal packing of C-18H (upper) and HR-18H (lower). In HR-18H structure, the (S) enantiomer is represented in light gray, the (R) enantiomer in dark gray and water molecules in spacefill for clarity. Figure 5. Hydrogen bond networks and resulting molecular ribbons in the crystal structures of C-18H (upper) and HR-18H (lower).
Table 2. Hydrogen-Bond Lengths and Angles in C-18H and HR-18H Crystal Structures (see Figure 5 for Atom Numbering) C-18H d(A 3 3 3 H) (Å)
bond
d(A 3 3 3 D) (Å)
O1 3 3 3 H2N2 O2 3 3 3 H1N1
2.77
1.95
157.5
2.87
2.01
176.2
bond
angle (AHD) (deg)
HR-18H d(A 3 3 3 D) (Å) d(A 3 3 3 H) (Å) angle (AHD) (deg)
O1 3 3 3 HW1OW O1 3 3 3 HW2OW O2 3 3 3 H1N1
2.75 2.81
1.90 1.96
173.4 176.1
2.87
2.01
170.9
OW 3 3 3 H2N2
2.75
1.89
174.3
Figure 7. Sorptiondesorption cycles performed at 30 °C starting from the metastable anhydrous racemic compound of 18H (AR-18H).
character. Thanks to the assignment of crystallographic directions by single crystal X-ray diffraction, it could be established that macroscopic cracks produced by dehydration are parallel to the b axis, thus indicating that water molecules are probably 2458
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Figure 8. Summary of experimental conditions required for solidsolid transformations between HR-18H, AR-18H, and C-18H.
evacuated out of the crystal along this direction. This assumption is actually consistent with structural data since it cannot reasonably be postulated, for a flawless structure, that the departure of water molecules could occur along crystallographic directions a or c (see Figure 6). Owing to the reversible character of this dehydration at low temperature, the transformation probably proceeds according to a nondestructive and cooperative mechanism inducing a persistence of the main structural features in the crystal lattice. The necessary disruption of the strong onedimensional (1D) molecular ribbons can be described as a zipmechanism proceeding by continuous molecular glides (Figure 10). Although attempts to get structural information about AR-18H were unsuccessful, it can be supposed that the crystal packing of the latter is probably closely related to that of HR-18H, composed of alternate R and S layers made of H-bonded 1D molecular ribbons. A similar behavior has been reported by Giovannini and co-workers, showing that the reversible dehydration at room temperature of the racemic dihydrate of zopiclone leads to a metastable anhydrous racemic compound.26 In this latter study, the structures of both phases were determined and were shown to be isomorphous. This dehydration behavior has been extensively described by various authors, corresponding for instance to type WET 3C in Galwey’s classification42 and described as a topotactic reaction with the advance of an interface in which the crystal spacings change sufficiently to cause cracking (Figure 10). In the unified model proposed by Petit and Coquerel,43 this dehydration process is depicted as a release of water molecules through specific directions of the mother phase (HR-18H) or its deformation, associated with a cooperative rearrangement with persistence of contacts, thus inducing structural filiations between parent and daughter phases. It should also be highlighted that the rehydration process may occur through a distinct mechanism, since the reversibility of a solidsolid transformation is not necessarily associated with a mechanistic reversibility.43 By contrast with this cooperative mechanism, the transformation of HR-18H into C-18H occurs under specific conditions, either by a slow and concomitant dehydration-conversion at low temperature and humid atmosphere (pathway 3) or by two successive steps: dehydration into AR-18H (pathway 1) and fast conversion of the latter at high temperature or slow conversion at 30 °C and R.H. e 50% (pathway 2). Owing to the intrinsic nature of HR-18H (heterochiral particles) and C-18H (homochiral particles), a cooperative mechanism is unlikely
Figure 9. SEM photographs of HR-18H crystals after pathway 1 (a), HR-18H during pathway 3 (b), HR-18H after pathways 1 and 2 (c) (see Figure 8 for description of pathways).
during this spontaneous resolution process since the occurrence of alternate homochiral planes in HR-18H prevents the possibility of filiations between the two structures (Figure 6). It must therefore be assumed that the transformation of HR-18H into C-18H as well as the solid to solid decomposition from AR-18H to C-18H proceed through nucleations and growth mechanisms. This assumption is confirmed by Figure 9b depicting a crystal of HR-18H during its transformation into C-18H and showing crystalline needles that have nucleated and grown from the inner part of initial particles, mainly visible on defective 2459
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Figure 10. Schematic representation of the probable dehydration mechanism from HR-18H to AR-18H through a zip-mechanism.
Figure 12. Schematic representation of the dehydration mechanism of KAl(SO4)2 3 12H2O according to Galwey et al. (adapted from ref 45). Figure 11. Schematic representation of the hypothetical mechanism for the transformation between HR-18H and C-18H. The bold arrow indicates the direction of propagation of the interface.
surfaces at the extremities of elongated crystals, that is, along the b axis. Since DVS investigations have revealed that C-18H is produced during the dehydration of HR-18H at 30 °C exclusively if the relative humidity is high enough (in the range 50 ( 10% R. H.), the existence of an intermediate reactant phase containing a significant amount of water between the hydrated crystal and the recrystallized product can be postulated. One could envisage the formation of tiny drops of aqueous solution of (()18H from which the conglomerate could nucleate and grow. However, the very poor solubility of 18H in water (less than 0.05% w/w) makes this hypothesis unreliable. It is more likely that the progressive departure of water molecules produces a highly defective crystal packing of 18H that can be assimilated to an
amorphous phase, and the presence of residual water in this intermediate zone could facilitate the crystallization of the conglomerate. The nucleation and growth of homochiral crystals from a racemic phase at such a low temperature require a sufficient molecular mobility that could be provided by the released water molecules acting as plasticizer, thus improving the “fluidity” of the amorphous material and ensuring the crystallization of C-18H. This mechanism is illustrated in Figure 11 and corresponds to situation WET 3E in Galwey’s classification,42 in which an amorphous material is produced and subsequently recrystallizes. In this interpretation, the most striking feature of the transformation of HR-18H into C-18H is therefore the important role played by water. To our knowledge, this phenomenon has only been observed and studied in detail by Galwey et al. during the dehydration study of aluminum alum KAl(SO4)2 3 12H2O.44 It could be demonstrated that the water “product”, temporarily retained in the propagating interface, enhances the nucleation, which constitutes a key step during 2460
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Crystal Growth & Design the difficult recrystallization process (Figure 12). It is noteworthy that the glass transition temperature of amorphous (()18H produced by melt-quench process - has been estimated at ca. 40 °C by DSC analysis (see Supporting Information). Moreover, the behavior of amorphous 18H was shown to be highly sensitive to relative humidity: under 40% R.H. at 30 °C, a recrystallization is observed after two days, whereas no evolution was detected for a sample stored under very dry atmosphere at the same temperature during several weeks (product standing in a close container over P2O5). These observations confirm the important role played by water molecules during the solid state transformations of (()18H. The temperature-induced transition between AR-18H and C-18H also involves a nucleation and growth mechanism. Figure 9c shows that crystalline needles have grown from the cracked crystal of AR-18H, and the nature of these tiny crystals of C-18H resulting from a spontaneous resolution was confirmed by XRPD. A similar situation has been reported by van Eupen et al. during the spontaneous resolution of the free base of Venlafaxine:24 this racemic compound is made of homochiral molecular slices and the transition toward the stable conglomerate is unlikely to proceed through a transfer of complete layers of R and/or S molecules. However, since this transition occurs only 4 °C below the melting point of the heterochiral phase, the authors have suggested that the migration of the molecules involves a local molten phase. In our case, the transformation of the racemic compound into the conglomerate occurs about 30 °C below the melting point of AR-18H so the existence of an intermediate amorphous zone instead of a local melting is more probable. Moreover, this transition occurs in the absence of water, through the destruction of the heterochiral network and the nucleation and growth of homochiral crystals. It can be supposed that this transformation occurring at high temperature (120 °C) between anhydrous phases is made possible by large thermal motions providing a sufficient molecular mobility.
4. CONCLUSION At 30 °C, the racemic mixture of 18H can exist either as a stable anhydrous conglomerate or as a metastable anhydrous racemic compound resulting from the dehydration of an effluorescent racemic monohydrate. The different transformations involving these three solid phases have been investigated and have shown that variations in molecular mobility have decisive consequences during dehydration of the racemic hydrate, leading either to the stable conglomerate or to a metastable racemic compound at 0% R.H. Indeed, the spontaneous chiral discrimination is prevented if the molecular mobility is not sufficient and the heterochiral anhydrous phase is then obtained. This observation is consistent with Brock’s statement that the conglomerate is disadvantaged during crystallization from a racemic mixture because of insufficient diffusion. The latter can be improved either by increasing the temperature or by working under a sufficient relative humidity. This particular role played by water, highlighted in this work, gives new insights on dehydration mechanisms in which water should not be only considered as a byproduct but also as a potential reagent, provided that its residence time in the material is sufficient to promote difficult recrystallizations occurring during these transformations. This contribution of surrounding water may actually be relevant in any type of solidsolid transformation under humid environment.
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’ ASSOCIATED CONTENT
bS
Supporting Information. CIF file produced after the crystal structure determinations of C-18H and HR-18H. Superimposition of experimental and calculated XRPD patterns for C-18H and HR-18H. Determination of glass transition temperature of (()18H by DSC analysis. This material is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION Corresponding Author
*E-mail:
[email protected]. Phone: þ33 2 35 52 24 28. Fax: þ33 2 35 52 29 59.
’ ACKNOWLEDGMENT Crihan (Region Haute-Normandie, France) is acknowledged for providing access to molecular modeling tools (Cerius2 software v.4.9, 2003, Accelrys Inc.). Thanks are also due to Thomas Morelli and Damien Martins (SMS, Universite de Rouen, France) for their contribution to the experimental work. ’ REFERENCES (1) Collins, A. N.; Sheldrake, G. N.; Crosby, J. In Chirality in Industry II; John Wiley: New York, 1997. (2) Francotte, E.; Lindner, W. Chirality in Drug Research, WileyInterscience: Weinheim, 2006. (3) Coquerel, G. In Topics in Current Chemistry (Novel Optical Resolution Technologies); Sakai, K., Hirayama, N., Tamura, R., Eds.; Springer: Berlin-Heidelberg, 2007; Vol. 269, Chapter 1, pp 150. (4) (a) Eliel, E. L.; Wilen, S. H.; Mander, L. N. Stereochemistry of Organic Compounds; John Wiley: New York, 1994; pp 297464. (b) Coquerel, G.; Amabilino, D. B.; In Chirality at the Nanoscale; Amabilino, D. B., Ed.; Wiley-VCH Verlag: Weinheim, 2009; pp 305341. (5) Polonski, T.; Milewska, M. J.; Konitz, A.; Gdaniec, M. Tetrahedron: Asymmetry 1999, 10, 2591–2604. (6) Kinbara, K; Hashimoto, Y; Sukegawa, M.; Nohira, H.; Saigo, K. J. Am. Chem. Soc. 1996, 118, 3441–3449. (7) Saha, M. K.; Ramanujam, R.; Bernal, I.; Fronczek, F. R. Cryst. Growth Des. 2002, 2, 205–212. (8) Galland, A.; Dupray, V.; Berthon, B.; Morin-Grognet, S.; Sanselme, M.; Atmani, H.; Coquerel, G. Cryst. Growth Des. 2009, 9, 2713–2718. (9) Tauvel, G.; Sanselme, M.; Coste-Leconte, S.; Petit, S.; Coquerel, G. J. Mol. Struct. 2009, 936, 60–66. (10) Toda, F.; Tanaka, K. Tetrahedron: Asymmetry 1990, 1, 359–362. (11) Yoshizawa, K.; Toyota, S.; Toda, F. Tetrahedron 2004, 60, 7767–7774. (12) Wallach, O. Liebisch Ann. Chem. 1895, 286, 90–143. (13) Brock, C. P.; Schweizer, W. B.; Dunitz, J. D. J. Am. Chem. Soc. 1991, 113, 9811–9820. (14) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates and Resolutions; Krieger Publishing Company: Malabar, FL, 1994. (15) Kitaigorodsky, A. I. Molecular Crystals and Molecules; Academic Press: New-York, 1973. (16) (a) Dufour, F.; Gervais, C.; Petit, M.-N.; Perez, G.; Coquerel, G. J. Chem. Soc., Perkin Trans. II 2001, 10, 2022–2036. (b) Dufour, F.; Perez, G.; Coquerel, G. Bull. Chem. Soc. Jpn. 2004, 77, 79–86. (17) Blazis, V. J.; Koeller, K. J.; Rath, N. P.; Spilling, C. D. Acta Crystallogr. 1997, B53, 838–842. (18) Forni, A.; Moretti, I.; Torre, G.; Br€uckner, S.; Malpezzi, L.; Di Silvestro, G. J. Chem. Soc. Perkin Trans. II 1984, 4, 791–797. (19) Larsen, S.; Marthi, K. Acta Crystallogr. 1997, B53, 803–811. 2461
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