CRYSTAL GROWTH & DESIGN
Ordered Aggregation of Benzamide Crystals Induced Using a “Motif Capper” Additive Blagden,†
Nicholas Colin C. Seaton†
Mike
Song,‡
Roger J.
Davey,*,‡
Linda
Seton,§
2005 VOL. 5, NO. 2 467-471
and
Colloids, Crystals and Interfaces Group, Molecular, Materials Centre, Department of Chemical Engineering, UMIST, P.O. Box 88, Manchester M60 1QD, United Kingdom, School of Pharmacy, University of Bradford, Bradford BD7 1DP, United Kingdom, and School of Pharmacy and Chemistry, Liverpool John Moores University, James Parsons Building, Byrom Street, Liverpool L3 3AF, United Kingdom Received June 4, 2004;
Revised Manuscript Received October 25, 2004
ABSTRACT: This paper reports on the growth of benzamide crystals in the presence of 2′-aminoacetophenone. The resulting self-replicating intergrowth of benzamide crystals gives rise to ordered crystal aggregates in which individuals share a common c*. This behavior is interpreted using the concept of a “motif capper” additive which is able to halt the extension of structural motifs at the surface of a growing crystal. In this case the additive was selected to terminate the hydrogen-bonding ribbons, which extend along the b axis of the benzamide structure. Introduction In the overall context of materials science, the microscopic phenomena that contribute to the process of crystallization are of wide ranging importance in areas as diverse as polymer processing, pharmaceutics, and biomineralization. A high level of molecular control over crystallization has numerous ramifications for the processing of fine chemicals and pharmaceuticals, where crystal morphology and polymorphic form are critical to the successful isolation and formulation of the material. It is well documented in the literature that additives are capable of inhibiting crystal growth and nucleation, stabilizing crystal polymorphs, and modifying crystal habits.1-4 Controlled crystal agglomeration using surfactants or growth conditions can also be used to manipulate the process behavior of crystalline solids. This has been reported in the form of solvent- and additive-induced twinning of molecular crystals5,6 as well as morphologically induced flocculation in inorganic systems.7 In the current contribution, we demonstrate the use of a “motif capper” additive and show how it leads to the creation of ordered crystalline aggregates. The general concept is shown in Chart 1 where we differentiate between an additive that adopts a crystallographic surface site (tailor-made2) from an additive which binds to and “caps” a developing intermolecular motif. Nature appears to utilize this mode of action in both malaria8 and ice.9,10 In the former, quinine and water act together to block surface sites on crystals of β-hematin, and in the latter, antifreeze proteins found in fish and other organisms act by multiple binding to prism and pyramidal planes of ice. In a previous study11 undertaken on the polymorphism of 2,6-dihydroxybenzoic acid, we successfully used a related approach to aid the selection of benzaldehyde as an additive. This additive was chosen as a traditional tailor-made additive, but it did successfully demonstrate that it was † ‡ §
University of Bradford. UMIST. Liverpool John Moores University.
Chart 1. (a) Tailor-Made Inhibitor (Additive in Grey); (b) Motif Stopper Inhibitor (Additive in Grey); (c) Benzamide; (d) AAP
possible to terminate the polar H-bonded chain which characterizes the stable noncentric polymorph.11 In this way the metastable form could be kinetically stabilized. In our current work in this area, we have used benzamide as a test system since its crystal structure is based on a simple H-bonded ribbon motif and it has been the subject of significant previous studies on tailormade additives.12 Benzamide Benzamide (Chart 1c) crystallizes in the monoclinic space group P21/c with four molecules (Z ) 4) in a unit cell of dimensions a ) 5.607(2) Å, b ) 5.046(2) Å, and c ) 22.053(8) Å with β ) 90.66(3)°.13 The crystal packing
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Figure 1. (a) AAP as a tailor-made additive; (b) AAP as a motif capper. Benzamide chains lie in the (104) plane.
is characterized by a dimeric ribbon comprising hydrogenbonded cyclic amide dimers interlinked along the b axis by means of NH‚‚‚O hydrogen bonds. These ribbons are stacked along the a axis to yield {001} bilayers. From the indexed experimental morphology,12,14 it is clear that the primary directions of growth are along the a and b axes, while growth along c is the slowest. The dominant faces are (001), (011), and (101). Previous studies12 of the effect of tailor-made additives on the morphology of benzamide have been undertaken: growth along the a, b, and c axes is retarded by o-toluamide, benzoic acid, and p-toluamide, respectively. It has also been shown that growth of benzamide from amide/ ethanol solvent mixtures yields [001] twins because of the stereospecific adsorption of the amide cosolvent at the {001} faces of the crystal.15 Additive Selection In the work reported here, the dimension of the H-bonded ribbon (Figure 1) has been used to guide additive selection. On this basis, 2′-aminoacetophenone (AAP, Chart 1d) was chosen as a molecule capable of binding across the carbonyl and amine groups exposed at the end of the ribbon (“capping”) and terminating its further extension. Figure 1a,b shows two possible ways in which this molecule might bind across the exposed surface of the motif. In the former of these, it is acting as a conventional tailor-made additive, while in the latter, Figure 1b, it is acting as a motif capper. The efficacy of this capping strategy and the mode of additive action were tested in a series of simple experiments described below. Experimental Section Crystals were grown from a 50:50 vol % ethanol/water mixture. Twenty-five milliliters of a solution of composition 0.27 g benzamide/cm-3 solvent was prepared at 40 °C and cooled at a controlled rate (1 °C/min) to 25 °C. This created a supersaturation ratio of 1.14. The effect of AAP was explored using the same solution conditions with the appropriate level of AAP added (0.1-20 mol % based on the total moles of benzamide). Crystals were characterized by polarizing light microscopy (Zeiss Axiophot), scanning electron microscopy (SEM) (Hitachi), and both powder (Rigaku 2000 XDS) and single-crystal (Stoe Weissenberg Camera) X-ray diffraction (XRD). The extent of uptake of APP in the crystals was explored by measuring the UV/vis spectra (APP absorption at 365.24 nm) of both solution and crystalline (redissolved) phases.
Figure 2. State of aggregation and morphology of benzamide crystals as a function of APP concentration: (a) 0, (b) 0.1, (c) 1.0, and (d) 10 mol % (scale: 1 cm ) 200 µm).
General Observations In all experiments, crystals appeared after the solutions had cooled to 25 °C. Figure 2a shows typical crystals grown from pure solution. As expected, (001) plates were obtained, which typically grew up to 5 mm in the b direction and 1 mm in thickness along c. Upon addition of AAP to the crystallizing solution, the crystals grew as aggregated clusters of much (60-100 µm) thinner (001) plates. Examples of these are shown in Figure 2b-d where the influence of increasing AAP concentration on crystal morphology and extent of aggregation is seen. At 0.1 and 1.0 mol %, the number of single crystals is significantly lessened (90% reduced to 20%, respectively), while by 10% there are no clearly identifiable single crystals. In addition, the thinning of the crystals implies a reduction in the [001] growth rate with inhibition of b-axis growth not observed. It was often difficult to align these aggregated crystals horizontally; thus their projected geometry often appeared distorted from rectangular. From the optical micrographs, however, it would appear (see especially Figure 2d) that crystals within an aggregate are stacked with their {001} faces in contact. The precise nature of this aggregation is discussed further below. The measured distribution coefficient of AAP between the solution and crystal phases for APP concentrations in the range 1-0.001 mol % showed random scatter in the range 0.01-0.1, indicating preferential segregation of AAP into the solution phase. Agglomerate Geometry The conclusion that the aggregates are ordered was confirmed by SEM examination. Thus Figure 3a shows three crystals grown from pure solution while Figure 3b shows an example of a two-crystal aggregate grown in the presence of 0.1%AAP. The morphologies have been indexed by visual inspection. The implication from these images and the optical micrographs (see for example Figure 2c) is that not only do the aggregate crystals share a common c* but also that the crystal-
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Figure 5. Optical microscope image of an aggregate of benzamide crystals used for single-crystal XRD of each member.
Figure 3. SEM images of benzamide crystals and indexed morphologies: (a) pure solution; (b) 0.1 mol % APP.
crystal was found to be a single crystal with the orientation of crystals within an aggregate related by rotation. Thus c* is conserved and the a and b axes interchange every 90° rotation between adjacent members of the group. This is shown schematically in Figure 7 and clearly agrees with the SEM, optical microscopy, and powder XRD. Modeling of Growth Processes
Figure 4. Powder XRD patterns of unmilled benzamide crystals showing preferred orientation within aggregates: green ) 0.02 mol % AAP; red ) 0.12 mol % AAP.
lographic a and b axes interchange every 90° between adjacent members of a group. This latter notion is also consistent with the additional observation that upon rotation of an aggregate between crossed polars, in the optical microscope, each component crystal reached extinction simultaneously. X-ray powder diffractograms of unmilled aggregated samples are shown in Figure 4. These patterns show extreme preferred orientation with only the {00l} peaks evident. This is sufficient to demonstrate unequivocally that the c* direction is indeed conserved within the aggregates as suggested from the morphological examination. The peak splitting observed presumably results from slight misalignment of the aggregates in the sample holder. To elucidate the precise crystallographic relationship between individual crystals in the a/b plane, the threecrystal aggregate shown in Figure 5 was examined. Each single crystal was sequentially extracted and mounted on its contact face, and the unit cell and orientation were determined using oscillation, zero and first layer Weissenberg photographic analyses. Each
The final stage of the work was an attempt to rationalize the experimental observations with a molecular visualization of the mechanism of action of AAP. Action as a tailor-made additive (Figure 1a) might have been expected to inhibit growth along the b axis in a manner akin to the known effect of benzoic acid.12 From our data, there is no evidence for such a marked effect on the morphology (i.e., a transition to a-axis needles) nor indeed is there any evidence, from previous work, of the contrary effect in which tailor-made additives yield aggregates. Taken together these factors confirm that binding of AAP as a tailor-made additive does not rationalize the experimental observations. Consideration of the alternative mode of action as a motif capper (Figure 1b) seems to offer a more plausible rationalization of the data. Consider Figure 6, which shows two fragments of crystal lattice. These are oriented such that their +c* axes are coincident and parallel. Imagine the lower half to be growing and an AAP molecule to adopt a motif capper site along the +b axis as shown. By virtue of the orientation of the phenyl ring of the AAP molecule, it is possible that binding of additive molecules in this way, to the (010) face, essentially “converts” it to a (100) face. Such a mode of additive interaction may induce growth of a new crystal along the +a axis but with its c* axis conserved, allowing the creation of the upper crystal shown in Figure 6. The size of such a 2D array of adsorbed AAP molecules is 22.053 Å (c axis) by 5.607 Å (a axis) so that the implied epitaxy only requires the new (100) interface to adjust to the b-axis dimension of 5.046 Å since the c axis is shared by the two surfaces. To confirm that this is a favorable match, we utilized the geometrical fitting function for epitaxy as described by Hillier and Ward.16 Calculation was performed over a 15 × 15 surface unit cell overlayer of (100) on (010) with the azimuthal angle search from 0 to 360° in 0.1° steps. Well-defined minima were found
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Figure 6. Visualization of the interface between two benzamide crystals showing the inferred location of APP and the conserved c*.
Figure 7. Schematic visualization showing how repeated nucleation of (100) faces on existing (010) facets leads to the observed crystal aggregates.
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at 90 and 270° with a value of 0.28. This is consistent with the +a to +b epitaxy and indicates an acceptable match; a value of zero, for example, would indicate completely commensurate alignment, while a value above 1 would indicate complete mismatch. Any resulting steric clashes may be accommodated through strain at the interface. This mechanism creates, of course, a fresh set of “virgin” (010) faces to which the additive can again bind resulting in a repetition of the process. In this way alternate interchange of the +a and +b axes can occur so that the aggregation process becomes selfreplicating as is indeed observed. The sequential way in which this epitaxial process leads to ordered aggregation is visualized in Figure 7. We note that this model as summarized in Figure 6 does place some restriction on the possible hydrogenbonding mode of the AAP molecule. In Figure 1b we have selected a possible binding site in which the AAP molecule itself is held essentially planar by the intramolecular hydrogen bond (as found, for example, in the crystal structure of para-bromoAAP17) and its carbonyl oxygen is involved in a bifurcated hydrogenbond attachment to the benzamide amine hydrogen. The result of this choice is that the AAP molecule adopts an appropriate orientation for its phenyl ring to mimic the first (100) layer of the new crystal. An alternative H-bonded location for AAP is possible in which the bifurcated H-bond is removed. However this leads to AAP having an orientation incompatible with the new crystal and hence is unlikely to trigger the new growth. It is also noted that in the chosen orientation the methyl group is directed along [102], a feature which may account for the decreased [001] growth rate and the associated thinness of the crystals. Overall this interaction model allows for the main experimental observations and offers strong support to the conclusion that AAP does act in motif capper mode. The work confirms that this can be a successful strategy for additive design which is likely to offer a new, flexible, and effective route for controlling crystallization processes. Conclusions The work reported here has explored the impact of an additive designed as a motif capper on the process of crystal growth. This class of additives may be differentiated from “tailor-made” additives since they only need to exercise recognition in one dimension and have no requirement to fully fit into a surface. In the case of
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AAP, chosen to terminate the hydrogen-bonded molecular ribbon of the benzamide structure, it has been shown that this molecule is able to induce ordered intergrowth of crystals. This yields self-replicating crystalline aggregates in which c* is conserved, while epitaxial nucleation and growth enable the a and b axes to interchange, features which have enabled us to confirm the motif capper action. Acknowledgment. We acknowledge helpful support and advice through discussions with Professor L. Leiserowitz of the Weizmann Institute of Science, Rehovot, Israel, and Professor J. M. McBride, Department of Chemistry, Yale University, USA. References (1) Mullin, J. W. Crystallisation, 3rd ed.; Butterworth Heinemann: London, 1993. (2) Weissbuch, I.; Popovitz-Biro, R.; Leiserowitz, L.; Lahav, M. In The Lock and Key Principle; Behr, J. P., Ed.; John Wiley: Chichester, 1994; Chapter 6. (3) Davey, R. J.; Polywka, L. A.; Maginn, S. J. In Advances in Industrial Crystallisation; Garside, J., Davey, R. J., Jones, A. G., Eds.; Butterworth Heinemann: London, 1991. (4) Davey, R. J.; Garside, J. From Molecules to Crystallisers; Oxford Chemistry Primer, No. 86; Oxford University Press: Oxford, U.K, 2000. (5) Lieberman, H. F.; Williams, L.; Davey, R. J.; Pritchard, R. G. J. Am. Chem. Soc. 1998, 120, 686-691. (6) Davey, R. J.; Williams-Seton, L.; Lieberman, H. F.; Blagden, N. Nature 1999, 402, 797-799. (7) Blagden, N.; Heywood, B. R. Cryst. Growth Des. 2003, 3, 167-173. (8) Buller, R.; Peterson, M. L.; Almarsson, O.; Leiserowitz, L. Cryst. Growth Des. 2002, 3, 553-562. (9) Antson, A. A.; Smith, D. J.; Roper, D. I.; Lewis, S.; Caves, L. S. D.; Verma, C. S.; Buckley, S. L.; Lillford, P. J.; Hubbard, R. E. L. Mol. Biol. 2001, 305, 875-889. (10) Jia, Z.; Davies, P. L. Trends Biochem. Sci. 2002, 27, 101106. (11) Davey, R. J.; Blagden, N.; Righini, S.; Alison, H.; Ferrari, E. J. Phys. Chem. B 2002, 106, 1954-1959. (12) Berkovitch-Yellin, Z.; van Mil, J.; Addadi, L.; Idelson, M.; Lahav, M.; Lieserowitz, L. J. Am. Chem Soc. 1985, 107, 3111-3122. (13) Blake, C. C. F.; Small, R. W. H. Acta Crystallogr. B 1972, 28, 2201. (14) Lifson, S.; Hagler, A. T.; Dauber, P. J. Am. Chem. Soc. 1979, 101, 5111-5121. (15) Edgar, R.; Schultz, T. M.; Rasmussen, F. B.; Feidenhans’l, R.; Leiserowitz, L. J. Am. Chem. Soc. 1999, 121, 632-637. (16) Hillier, A. C.; Ward, M. D. Phys. Rev. B 1996, 54, 1403714051. (17) Baker, L. J.; Copp, B. R.; Rickard, C. E. F. Acta Crystallogr. E 2001, 57, o540.
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