Mechanochemical Conversions Between Crystalline Polymorphs of a

Jun 12, 2013 - ... and a Henry Dreyfus Teacher-Scholar grant (MAM) from the Camille and Henry Dreyfus Foundation. The single crystal X-ray diffractome...
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Mechanochemical Conversions Between Crystalline Polymorphs of a Complex Organic Solid Benjamin D. Altheimer,† Silvina Pagola,‡ Matthias Zeller,§ and Manish A. Mehta*,† †

Department of Chemistry and Biochemistry, Oberlin College, 119 Woodland Street, Oberlin, Ohio 44074, United States Department of Applied Science, College of William and Mary, Williamsburg, Virginia 23187, United States § Department of Chemistry, Youngstown State University, 1 University Plaza, Youngstown, Ohio 44555, United States ‡

S Supporting Information *

ABSTRACT: We report the conversion between three crystalline polymorphs of a capped amino acid, N-acetyl-L-phenylalanyl-NH2, using mechanochemistry, with conversion between the α and γ polymorphs being reversible, depending on the milling conditions used. Solvent drop grinding of the α and β polymorphs with water yields the γ polymorph, whereas dry grinding of the β or γ polymorph yields the α polymorph. The α and β polymorphs are also accessible from solution (from methanol and water, respectively), and their structures were solved from single crystal diffraction data. The γ polymorph, so far only accessible mechanochemically, was solved and refined from powder X-ray diffraction data. The polymorphs show various degrees of crystallographic disorder, and the numbers of crystallographically independent molecules vary. These observations are supported by 13C and 15N magic angle spinning solid-state NMR data. Possible reasons for the formation of multiple polymorphs and their respective stability as a function of Z′, degree of disorder, and molecular shape and conformation are discussed. The results have implications for understanding the accessibility of new polymorphs of complex, low-symmetry organic solids with multiple dihedral degrees of freedom.

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INTRODUCTION There has been intense activity in the pharmaceutical industry and materials chemistry community in the past few years in the search for new polymorphs and new ways to control conversions between polymorphs.1 Crystalline polymorphs, salts, and co-crystals of active pharmaceutical ingredients (APIs) are known to exhibit different physical properties, such as solubility and bioavailability.1−6 Sonochemistry7 and mechanochemistry4,6 offer promising, alternative methods of access to new polymorphs, though the mechanisms by which they effect conversions are poorly understood. For the most part, their use remains phenomenological, although an eventual mechanistic understanding may pave the way toward their rational use. Mechanochemistry, in particular, has been shown to be useful in controlling the phase of APIs.5,8−10 It has also grown in importance in the production of industrial scale commercial pharmaceuticals, often providing a green alternative to more traditional techniques. Mechanochemical transformations can be performed under neat (dry) conditions or with the addition of a small amount of solvent in a procedure known as solvent-drop grinding (SDG). The latter often increases the conversion rate11 and sometimes results in different polymorphs.4−6,9,12,13 Most known examples of polymorph control using mechanochemistry involve salts or co-crystals, but in several cases control over polymorph formation for single molecular species has been observed.1,4,6,12 Here, we report the interconversion between three polymorphs of the capped amino acid N-acetyl-L-phenyl© 2013 American Chemical Society

alanyl-NH2 (Ac-Phe-NH2) using either dry milling or SDG. In particular, we report the reversible phase transition between two of these polymorphs made possible by the use of both dry grinding and SDG with water, with one of the phases thus far accessible only by milling. These transformations show the potential for mechanochemical discovery of new polymorphs and the utility of mechanochemistry in preparing desired polymorphs. In addition, the reversible phase transformation may give some insight into the mechanism of mechanochemical transformations. We speculate on the reasons for the formation of multiple polymorphs and their respective stability as a function of the number of crystallographically independent molecules (Z′), and we discuss the degree of disorder observed in the structures. The results may have implications for understanding the accessibility of new polymorphs of complex, low-symmetry organic solids with multiple dihedral degrees of freedom.

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EXPERIMENTAL SECTION

Ac-Phe-NH2 was obtained from Bachem (Switzerland) and used without further purification. All milling experiments were conducted at room temperature in a Retsch MM400 ball mill using 5 mL stainless steel milling cups and two 7 mm stainless steel ball bearings. The ball mill was operated at 30 Hz with 50−70 mg of Ac-Phe-NH2 for 60 min Received: March 6, 2013 Revised: June 6, 2013 Published: June 12, 2013 3447

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18.024(6) Å, b = 4.9974(17) Å, c = 19.569(7) Å, β = 104.622(5)°, V = 1705.6(10) Å3, 296 K, Z = 6, Z′ = 3, R = 0.0436 (I > 2σ(I)), GOF = 1.021; β-polymorph (100 K): C11H14N2O2, 206.24, monoclinic, P21, colorless, a = 17.440(5) Å, b = 5.0094(13) Å, c = 19.515(5) Å, β = 105.986(5)°, V = 1639.0(8) Å3, 100 K, Z = 6, Z′ = 3, R = 0.0478 (I > 2σ(I)), GOF = 1.025. γ-polymorph (RT): C11H14N2O2, 206.24, monoclinic, C2, colorless, a = 38.5979(4) Å, b = 4.97425(5) Å, c = 23.1869(3) Å, β = 99.7718(9)°, V = 4387.20(8) Å3, 298 K, Z = 16, Z′ = 4, χ2 = 1.81, Rwp = 5.43%, RI = 5.83%.

for each milling. For solvent-drop grinding experiments, 20 μL of water were added. CP-MAS NMR spectra were collected on a custom assembled NMR spectrometer with a Discovery console (Tecmag; Houston, TX), 14.1 T magnet (600.381 MHz for 1H; 150.987 MHz for 13C; 60.84 MHz for 15N; Magnex Scientific; Oxford, England), a 39channel matrix shim system (Resonance Research, Inc.; Billerica, MA), and a triple-resonance 4 mm magic angle spinning probe (Doty Scientific Inc.; Columbia, SC). See Supporting Information for experimental details. The crystalline phases of the samples were identified using powder X-ray diffraction (PXRD) with a Rigaku Ultima IV instrument (Cu Kα, 1.5418 Å). The PXRD patterns were compared to those calculated from the single-crystal structures of the α and β polymorphs using the software CrystalMaker 8.3 and CrystalDif f ract 5.2 and by Rietveld refinement using the program Topas (see Supporting Information). Single crystal diffraction data for the α and β polymorphs were collected on a Bruker AXS SMART APEX CCD diffractometer using monochromatic Mo Kα radiation with the omega scan technique at both room temperature and 100 K. Data for all structures were collected, their unit cells were determined, and the data were integrated and corrected for absorption and other systematic errors using the Apex2 suite of programs. The structures were solved by direct methods and refined by full matrix least-squares against F2 with all reflections using SHELXTL. Hydrogen atoms were placed in calculated positions with N−H distances of 0.86 Å, and C−H distances of 0.93, 0.97, and 0.96 Å for aromatic, methylene, and methyl H atoms, respectively. The isotropic thermal parameters of methyl H atoms were set to values 1.5 times that of their respective carrier atom. Other H atoms were assigned a value of 1.2 times the isotropic thermal parameter of their carrier atom. All structures show disorder of at least some of the phenyl rings (see Supporting Information and cif files for details). For the γ polymorph, which we have only been able to obtain by SDG, no single crystal structure determination was possible. However, single-phase powders could be obtained with relative ease, which opened up the possibility to solve and refine the structure from PXRD data. PXRD data of the γ polymorph were collected at the beamline X16C of the National Synchrotron Light Source, Brookhaven National Laboratory, using a 1.5 mm diameter glass capillary in transmission geometry, with a wavelength of 0.699680 Å. The pattern was indexed using the CRYSFIRE suite of indexing programs14 yielding a monoclinic C-centered cell with Z = 16. On the basis of the number of resonances in the CP-MAS solid-state NMR spectra, the chiral nature of the compound and observed systematic absences in the PXRD pattern, the space group was tentatively assigned as C2, with Z′ = 4. The structure was solved from the synchrotron PXRD data using direct-space methods and the simulated annealing algorithm15 as implemented in the program PSSP,16 and it was refined by the Rietveld method using the program GSAS.17 The atom positions of 12 non-hydrogen and hydrogen atoms of each crystallographically independent molecule were refined subjected to a rigid body geometry, whereas the remaining atom positions of flexible fragments of the molecule were refined subject to soft bond length and angle restraints, in both cases using target values obtained from single crystal diffraction results of the α and β polymorphs. The isotropic thermal displacement parameters of all non-hydrogen atoms in each crystallographically independent molecule were refined using a group constraint. Hydrogen atoms were initially placed in calculated positions using the program WinGX.18 The isotropic thermal displacement parameters of all hydrogen atoms were constrained to a value 1.2 times larger than the one of their respective bonded nonhydrogen atom. α-Polymorph (RT): C11H14N2O2, 206.24, orthorhombic, P212121, colorless, a = 5.073(4) Å, b = 8.309(7) Å, c = 26.37(2) Å, V = 1111.6(15) Å3, 293 K, Z = 4, R = 0.0406 (I > 2σ(I)), GOF = 1.021; αpolymorph (100 K): C11H14N2O2, 206.24, orthorhombic, P212121, colorless, a = 5.0837(7) Å, b = 8.2864(12) Å, c = 25.802(4) Å, V = 1086.9(3) Å3, 100 K, Z = 4, R = 0.0349 (I > 2σ(I)), GOF = 1.096; βpolymorph (RT): C11H14N2O2, 206.24, monoclinic, P21, colorless, a =

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RESULTS Three distinct crystalline polymorphs of Ac-Phe-NH2 were identified in this study. The α polymorph was prepared by evaporation from methanol. Evaporation from water gave the β polymorph, and sometimes a mixture of both α and β forms. All attempts to obtain the γ polymorph using evaporative methods from a variety of solvents were unsuccessful, though the γ polymorph can be consistently prepared mechanochemically. A sample of the α polymorph obtained from evaporation from methanol was solvent-drop ground with 20 μL of water to give the γ polymorph. On subsequent dry milling, the γ phase was seen to convert back to the α polymorph. The PXRD patterns, collected after each conversion, are shown in Figure 1.

Figure 1. Reversible transformation of the α and γ polymorphs can be seen in the PXRD patterns collected: (a) after evaporation from methanol and grinding by hand with mortar and pestle to give a powder of the α polymorph, (b) after SDG with water, giving the γ polymorph, and (c) after dry grinding, regenerating the α polymorph. Slight differences between (a) and (c) are due to changes in crystallite size upon milling and preferred orientation effects.

To our knowledge, such a reversible conversion has been reported in only two other systems, for anthranilic acid and for (±)-2-(benzhydrylsulfinyl)acetamide, or modafinil, the active ingredient of a range of analeptic drugs.4,6,19 In contrast to the relatively rigid anthranilic acid, Ac-Phe-NH2 and modafinil exhibit many more conformational degrees of freedom, so any phase change can include both packing changes as well as conformational changes. For modafinil, polymorphs I and III, the two that can be reversibly interconverted, feature only one type of conformation. In addition, all reported reversibly convertible polymorphs of anthranilic acid and modafinil have been obtained from solution, allowing single-crystal structure determination, whereas we have been able to obtain the γ polymorph of Ac-Phe-NH2 only by mechanochemical means. The β polymorph was grown by evaporation from water. Note that although we have seen evaporation from water give a mixture of the α and β polymorphs, samples with >90% β polymorph were obtained (based on Rietveld refinement, Figure S4). One such sample was ground dry and another with 20 μL of water, giving polymorphs α and γ, respectively. These 3448

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resonances and their relative amplitudes in the respective 13C and 15N CP-MAS NMR spectra, we infer three distinct molecules in the β phase and four in the γ phase. (The NMR spectra are shown in the Supporting Information.) Broadening of some 13C resonances in the phenyl regions in all three phases indicates structural disorder, which is consistent with the crystallographic refinements.

transformations can be seen in the PXRD patterns shown in Figure 2, which were collected before and after milling.

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DISCUSSION Ignoring different packing interactions, the most striking difference between individual molecules in the three polymorphs is their conformation. Two distinct conformations are observed, shown in Figure 3. In conformations I and II, the χ1

Figure 2. (a) PXRD pattern of the β polymorph. (b) Mechanochemical transformation to the α polymorph upon dry grinding, and (c) to the γ polymorph upon solvent drop grinding with water.

To test the stability of the three polymorphs at ambient conditions, the PXRD-checked samples of the α, β, and γ polymorphs were left under ambient lab conditions for at least 10 days. PXRD patterns collected after this time showed no phase changes. In addition, the α and γ polymorphs underwent no further changes upon additional dry grinding or SDG, respectively (see Supporting Information). The various room temperature phase transformations are summarized in Scheme 1.

Figure 3. Conformations II (left) and I (right) present in the four polymorphs. The difference lies in the χ1 torsion angle about the Cα and Cβ that orients the side chain phenyl ring relative to the peptide backbone. C = gray, O = red, N = blue, H = light gray.

Scheme 1. Observed Phase Transformationsa

torsion angles around the bond connecting the phenylalanine Cα and Cβ are approximately −65° and −175°, respectively. For both conformations, the Ramachandran peptide backbone torsion angles (φ, ψ) are around (100°, −100°). The α polymorph contains one molecule in conformation II, whereas the β polymorph has two molecules in conformation I and one in conformation II. The γ polymorph features three molecules in conformation I and one in conformation II. In a previous structure determination of a cyclodextrine clathrate of Ac-PheNH2, both conformations I and II had been observed.21 The presence of the different conformers directly affects the packing of the molecules in the three polymorphs, which will be discussed in some detail below. None of the polymorphs form the commonly observed homomeric dimers that are often observed for simple amide compounds.4−6,9,12,13,22,23 Instead, the carbonyl oxygen and −NH groups of adjacent identical type molecules are hydrogen bonded forming R22(12) units which are linked into one-dimensional (1-D) chains as shown in Scheme 2. This hydrogen bonding motif and primary building block has been previously observed for the acetyl capped chiral dipeptides N-acetyl-L-valinamide and N-acetyl-L-isoleucinamide.24,25 All other structurally described acetyl capped dipeptides with no additional functionalities capable of hydrogen bonding (four chiral26−28 and three racemic29,30 structures have been reported) feature structures with variable primary packing motifs that all involve tightly hydrogen bonded two-dimensional (2-D) layers of molecules. In the α polymorph of Ac-Phe-NH2 (Figure 4), two of these 1-D chains are in turn connected through additional hydrogen bonds between an -NH2 proton and a carbonyl oxygen to form double strands with 2-fold screw axis symmetry between the two parallel chains. Phenyl rings within the double strands are

a

The dashed line indicates that evaporation from water gives predominately the β polymorph. Here, SDG was always conducted with water.

The structures of the α and β polymorphs were determined at room temperature and 100 K from laboratory single crystal X-ray diffraction data. The structure of the γ polymorph was solved from synchrotron powder diffraction data and was refined using the Rietveld method (see above and the Supporting Information for details). The α, β, and γ structures crystallized in orthorhombic and monoclinic settings in the chiral space groups P212121, P21, and C2, respectively, with the number of crystallographically independent molecules per unit cell (Z′) equal to 1, 3, and 4 for the three polymorphs. The numbers of distinct molecules in the unit cell for the α, β, and γ forms were independently verified using 13C and 15N cross-polarization-magic angle spinning (MAS) solid-state NMR spectroscopy.5,8−10,20 The 13 C and 15N CP-MAS NMR spectra of the α phase show one set of resonances, with the number of resonances equal to the number of carbon and nitrogen sites. From the number of 3449

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for the α polymorph shows substantial broadening for several of the phenyl carbons. The room-temperature β polymorph (Figure 5) contains three crystallographically distinct molecules in the asymmetric

Scheme 2. 1-D Hydrogen Bonded Chains, the Primary Building Unit Realized in All Polymorphs of Ac-Phe-NH2

Figure 5. Crystal structure of the β polymorph viewed along the b-axis. Disorder of the phenyl groups is only shown within unit cell boundaries. Hydrogen bonds are shown with dashed light blue lines. C = gray, O = red, N = blue, H = light gray.

unit. All three of these molecules form 1-D chains as in the α polymorph. Two of these chains are hydrogen bonded with each other in a manner analogous to the α polymorph, again forming double strands. However, in the β polymorph, the molecules involved are not related by crystallographic symmetry, and both conformations are of type I rather than type II. The third 1-D chain does not form a double strand but instead donates a hydrogen bond to the double strand of the other two chains, leading to the three 1-D chains being tied together to one triple strand with phenylalanine carbonyl oxygen atoms involved in three, two, or only one hydrogen bonds. This third more solitary strand has type II conformation. The triple strands interdigitate via their acetate groups that reach into voids of a neighboring triple strand, leading to the formation of a layered structure with areas dominated by polar functional groups alternating with regions with only phenyl groups. The phenyl rings of two of the distinct molecules show signs of substantial dynamic disorder with pronounced thermal libration and larger anisotropic thermal ellipsoids for two of the three crystallographically independent molecules. One of the phenyl rings of one of the three molecules was modeled as being 2:1 disordered over two distinct positions, which is supported by the NMR findings for this polymorph, similar to what was observed for the α form. At 100 K, the β polymorph has the same general packing and hydrogen bonding motifs as the RT β form but differs in the type of disorder of the phenyl rings. Upon cooling, there is additional ordering of the phenyl groups within the phenyl sublayers. Two of the three crystallographically distinct molecules now show 3-fold disorder of the phenyl rings with an equal probability of one-third each. At both temperatures, the disorder extends somewhat into the peptide backbone. Within one sublayer of phenyl groups, the three distinct orientations are correlated  similar to what was observed in the α polymorph  but information about this additional ordering is again not transferred through the polar

Figure 4. Crystal structure of the α polymorph viewed along the baxis. Disorder of phenyl groups is only shown within unit cell boundaries. Hydrogen bonds are indicated as light blue lines. C = gray, O = red, N = blue, H = light gray.

offset π-stacked, and close contacts of phenyl H atoms in neighboring strands force the rings to adopt slightly different orientations that alternate between neighboring double strands. The alternating disorder of the phenyl rings extends within layers perpendicular to the c-axis, and it can be assumed that 2D domains of substantial size are formed within the crystal. Information about the orientation of the phenyl rings is, however, not conveyed to the next parallel layer. The relative orientation of phenyl rings in neighboring layers is thus random, and for the crystals at large no superstructure with additional ordering of phenyl rings is observed. This presence of disorder is supported by the solid-state NMR spectra, which 3450

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presence of line broadening in the aromatic region of the carbon NMR spectrum indicate solid state disorder for at least one of the four crystallographically distinct molecules. One crystallographically distinct molecule does indeed feature a higher average thermal libration (all atoms of each crystallographically independent molecule were assigned common isotropic thermal displacement parameters). Refined values are 0.056(2) Å2 for the molecule in question, one of the two involved in the tetrameric chains, color coded in red in Figure 6 and Figures S20−S25, versus 0.036(2) Å2 to 0.043(2) Å2 for the other three molecules, indicating the possibility of unresolved dynamic or static disorder for this one molecule. The complexity of the crystal structure did not allow, however, quantitative modeling of any disorder of the phenyl groups. The suggested lesser degree of disorder  only one out of four molecules  could be seen as an indication for the γ polymorph to be intrinsically more stable than the other two polymorphs. However, the very presence of disorder makes a calculation and quantification of relative stabilities of the three solid-state phases difficult and unreliable at best. A commonly employed measure of relative stability of polymorphs independent from complications such as disorder is the density of the structure,31 with phases with higher density commonly regarded as thermodynamically more stable than those with lower density. For the three room-temperature phases described here, the β polymorph has the lowest density, as derived from the crystal structure, with a room temperature value of only 1.205 g/cm3. Upon cooling to 100 K, this value increases substantially to 1.254 g/cm3. The α polymorph, with RT and 100 K values of 1.232 and 1.260 g/cm3, respectively, appears somewhat more densely packed. The increase in density upon cooling is less pronounced, in agreement with the only small changes in structure upon cooling for the α polymorph. The densities of the α and β polymorph at 100 K are virtually the same. The γ polymorph, for which only room temperature data have been obtained, is under ambient conditions the most densely packed, with a value of 1.249 g/ cm3. (The increase in room temperature density from β to α is 2.2%, from β to γ 3.6%, and from α to γ 1.4%, which is above the threshold given by Burger and Bamberger32 at which a difference in density can be meaningfully employed for the estimation of the relative polymorph stability.) Melting points of the three phases taken from differential scanning calorimetry data are very similar (the same within 2−3 °C, 179 °C for the γ phase and 182 °C for the α and β polymorphs; see Supporting Information) and thus are not helpful in distinguishing relative stabilities. Taking the densities as a reasonable proxy for relative thermodynamic stability would suggest the room temperature stabilities increase from β to α to γ, in agreement with the observed mechanochemically induced transformations. The least stable β polymorph can only be obtained by direct crystallization from solution, but not from the other two polymorphs by grinding. The α polymorph, with its apparent intermediate stability, can be obtained from solution and by dry milling from either the β polymorph or the γ polymorph. The latter can be obtained by SDG from both the α and the β polymorphs (Scheme 1). With no information on the crystallization or mechanochemical mechanism at hand, an unambiguous explanation as to why each polymorph does form under the conditions described is not possible at this time. However, the fact that three different polymorphs can be obtained with relative ease is by itself in need of a more detailed analysis. The three structures are

layers to the next layer of phenyl rings. The additional 2-D superstructure within the layers thus does not translate into a three-dimensional (3-D) superstructure, and a 1:1:1 disorder of phenyl ring orientations is observed instead. Crystal structure solution and refinement yielded a packing even more complex for the γ polymorph than those of the α and β forms, with four crystallographically distinct molecules in the crystal structure (Figure 6). As for the other two structures,

Figure 6. Crystal structure of the γ polymorph, viewed down the baxis. Crystallographically equivalent molecules are shown in the same color. Hydrogen bonds are indicated as light blue lines.

all four molecules again form the 1-D chains described above, which extend along the direction of the monoclinic b-axis. Each of these two chains form hydrogen bonded double chains, with the second strand of each double chain being created by a 2fold screw axis operation from the first, but with different hydrogen bonding motifs and chain geometries (Figures S22− S25 in the Supporting Information). One of the double chains (yellow in Figure 6) mimics the geometry found in the α polymorph with hydrogen bonds between an -NH2 proton and the carbonyl oxygen of the amide groups, but the conformation of the molecules is of type I rather than type II (i.e., the torsion angle of the phenyl group is different; see Figure S24). In the other double chain, the hydrogen bonds are between -NH2 protons and carbonyl oxygen atoms of the acetyl rather than the amide groups, and the chains are connected via two parallel sets of N−H···O hydrogen bonds. Molecules wrap themselves in a “tubular” fashion around the 2-fold screw axis (Figure S23). Molecules are again of type II. The 1-D chains made up from the two remaining crystallographically distinct molecules do not form double strands, but have four parallel chains connected through N−H···O hydrogen bonds arranged around a 2-fold rotation axis. Hydrogen bonds are again between amide -NH2 groups and amide carbonyl oxygen atoms. Acetyl oxygen atoms are not involved in the interchain hydrogen bonding. These tetrameric chains feature both types of conformations; half of the molecules involved are of type I and half of type II (Figure S25). No disorder of phenyl groups could be resolved in the structure of the γ polymorph, which would set it apart from its α and β counterparts. With the structure being based on PXRD data, disorder cannot be unambiguously ruled out. Indeed, the 3451

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polymorph transformations remain poorly understood, and at present atomistic mechanisms of reliable predictive value remain elusive. Results such as those reported here may help in the formulation of accurate mechanisms, and they provide a challenge to emerging de novo crystal design approaches.

distinguished not only by the way molecules are arranged in the solid state, but especially by their respective number of crystallographically independent molecules, i.e., by their Z′ number and by the degree of disorder observed in the structures. Both large Z′ values and pronounced solid state disorder are often seen as indicators of packing frustration  namely, molecules cannot be easily arranged in a lattice that maximizes intermolecular interactions while minimizing residual void space in the packing arrangement.33,34 Competing strong directional interactions, or directional interactions in combination with chirality of the molecule, have been pointed out as particularly common in crystal structures with Z′ > 1,33−36 and earlier, stress has been placed on molecular shape as a driving factor.37 For chiral enantiopure N-acetyl-L-phenylalanyl-NH2, all of these factors do apply and might contribute to both the formation of structures with high Z′ values and of multiple polymorphs with similar energetics that readily form upon slight variation of crystallization conditions. Intermolecular interactions in all three polymorphs are dominated by strong hydrogen bonds, and, as described above, the primary building blocks in all structures are indeed the same: strongly hydrogen bonded 1-D chains with acetyl, N−H···Oacetyl, and NH2···Ophenylalanine interactions (Scheme 2). The fact that the primary building blocks do not need to be destroyed when transforming one polymorph into another might be one of the reasons for the ease with which the three phases can be transformed into one another via grinding. These primary building blocks are further connected via additional weaker NH2···O hydrogen bonds into secondary building units. Further arrangement of the secondary building units into the final structures leads to substantial packing frustration as evidenced by the degree of disorder, and  for the β and γ polymorphs  by the large Z′ numbers and combination of molecules with different conformations in one crystal structure. This frustration can be partially attributed to the odd shape of the molecules. Their chirality and enantiopurity prohibit the use of any inversion, glide, or mirror operations in structure formation, so crystal symmetry is limited to rotation, screw axes, and translation. Crystallization with more than one crystallographically independent molecule can help optimize the ways molecules can be arranged in the solid without breaking the energetically favorable hydrogen bonds that form the primary and secondary building units while at the same time retaining efficient packing.

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ASSOCIATED CONTENT

S Supporting Information *

Experimental and calculated powder diffraction patterns, Rietveld refinements for mixtures of polymorphs α and β, results of polymorph stability controls, polymorph stability to additional milling, solid-state 13C and 15N magic angle spinning NMR spectra of the α, β, and γ phases, ORTEP style plots, detailed single crystal structure descriptions and tables, and crystallographic information files (cif) files of the α, β, and γ polymorphs. Details of solution and Rietveld refinement for the γ polymorph, including a GSAS plot of the PXRD pattern and Rietveld fit, and additional figures. Differential scanning calorimetric (DSC) traces for the α, β, and γ phases. This material is available free of charge via the Internet at http:// pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by NSF-CAREER Grant CHE0449629, NSF RUI Grant CHE-1012813, NSF-MRI Grant DMR-0922588 for the acquisition of a powder X-ray diffractometer, and a Henry Dreyfus Teacher-Scholar grant (MAM) from the Camille and Henry Dreyfus Foundation. The single crystal X-ray diffractometer was funded by NSF Grant 0087210, Ohio Board of Regents Grant CAP-491, and by Youngstown State University. We gratefully acknowledge high resolution X-ray powder diffraction data from the National Synchrotron Light Source, Brookhaven National Laboratory, which is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences (Contract No. DEAC02-98CH10886).

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ABBREVIATIONS RT, room temperature; Ac-Phe-NH2, N-acetyl-L-phenylalanylNH2

CONCLUSION The transformations reported here are of interest for several reasons. First, we have been able to reach the γ polymorph by only mechanochemical means. Given the interest in controlling polymorphic phases, especially in the pharmaceutical sector, this result adds to a growing literature that shows the utility of mechanochemistry in searching for new phases. Mechanochemical preparations consume fewer reagents per mole of product and are often solvent-free, and as such, constitute an alternative, economically advantageous and environmentally friendly green chemistry method. Second, Ac-Phe-NH2 is a complex, chiral, low-symmetry compound, with four significant dihedral degrees of freedom. Most of the compounds reported in the literature to date that exhibit mechanochemical conversions have tended to be relatively rigid with high local symmetry. Finally, the reversible nature of the transformations in Ac-Phe-NH2 emphasizes the importance of controlling and exploring the milling conditions. The mechanisms by which grinding causes

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dx.doi.org/10.1021/cg400344z | Cryst. Growth Des. 2013, 13, 3447−3453