Crystal Polymorphism as a Probe for Molecular Self-Assembly during Nucleation from Solutions: The Case of 2,6-Dihydroxybenzoic Acid R. J. Davey,* N. Blagden, S. Righini, H. Alison, M. J. Quayle, and S. Fuller
CRYSTAL GROWTH & DESIGN 2001 VOL. 1, NO. 1 59-65
Colloids, Crystals and Interfaces Group, Department of Chemical Engineering, UMIST, P.O. Box 88, Manchester M60 1QD, U.K. Received September 5, 2000
ABSTRACT: The relationship between molecular self-assembly processes and nucleation during crystallization from solution is an important issue, both in terms of fundamental physical chemistry and for the control and application of crystallization processes in crystal engineering and materials chemistry. This contribution examines the extent to which the occurrence of crystal polymorphism can be used as an indicator of the nature of molecular aggregation processes in supersaturated solutions. For the specific case of 2,6-dihydroxybenzoic acid a combination of solubility, spectroscopic, crystallization, and molecular modeling techniques are used to demonstrate that there is a direct link between the solvent-induced self-assembly of this molecule and the relative occurrence of its two polymorphic forms from toluene and chloroform solutions. Introduction The classic kinetic model of a first-order phase transition involving crystal nucleation from a supersaturated phase, developed originally by Volmer,1 has been continually refined by a variety of subsequent workers.2 In this model the spontaneous formation of molecular clusters (embryos) having a range of sizes is the central tenet. The viability of these clusters is size-dependent, and the concept of a critical size at which the gain in bulk free energy is balanced by the penalty of the surface free energy is well-known.3 Such a model has been successful in describing the major macroscopic kinetic features of the nucleation process, such as the existence of a metastable zone within which, despite supersaturation, nucleation is negligible and beyond which the system is labile. In the context of current concepts of crystallization as a supramolecular assembly process,4 such a visualization of the nucleation event is clearly limited and totally void of structural considerations. Thus, the nature and importance of intermolecular interactions in supersaturated solutions as well as the existence and precise structural nature of precrystalline transition states do not form part of the conventional considerations of nucleation theory. In the broad context of materials chemistry and especially in the field of crystal engineering, where the ability to control the molecular assembly processes is crucial, the role of molecular aggregation in determining the structural outcome of a nucleation event is clearly an important issue. Hints of a link between solute clustering and nucleation have appeared sporadically in the literature since Mullin and Leci’s classic experiment in columns of concentrated citric acid solution.5 Hussmann et al.6 and McMahon et al.7 demonstrated the existence of solidlike species in aqueous alkali-metal nitrate solutions using Raman spectroscopy. Garside and Larson8 extended Mullin and Leci’s experiments to urea, sodium nitrate, and potassium sulfate and estimated cluster diameters to be between 3 and 10 nm. Myerson and Yo9 confirmed
cluster formation by measurement of the concentration dependence of diffusion coefficients. More recently,10 mass spectral analysis has led to the direct observation of pyridine-pyrrole complexes in nucleating aqueous solutions. From grazing incidence X-ray diffraction experiments it is now clear that, in the case of R-glycine growing from aqueous solution, centrosymmetric dimers form the essential building block,11 while twinning studies of the growth of saccharin crystals suggest that the nature of the growth synthon can be solventdependent.12 In the world of molecular modeling similar issues are being addressed. For example, Anwar and Boateng13 used molecular dynamics to examine the nucleation of a “Lennard-Jones” crystal from solution and found a liquidlike state to precede crystal formation. Gavezzotti14 reported an identical result for simulations of the nucleation of acetic acid in carbon tetrachloride and found evidence for two structural motifs of tetrolic acid corresponding to its two polymorphs in simulations of its solutions in carbon tetrachloride.15 Studies in which there is direct structural evidence for the molecular assembly processes and of their link to subsequent nucleation behavior would clearly be desirable but, as yet, have not been reported. In this context polymorphic systems appear to offer a potential probe, since they provide macroscopic evidence that in many systems there is not a unique nucleus structure and that often the initial crystal structure that forms is not the most stable.16 Previous studies17,18 in this area have assumed a priori that clusters are present whose packings resemble the known structures of the polymorphs. In this way additives have been successfully designed to direct the polymorphic outcome by selective inhibition of unwanted structures using the concept of tailor-made additives.4,17-19 Such results, however, do not have a unique interpretation, since the additives may be active during the growth or nucleation phases of crystallization or both; hence, these studies do not provide evidence for the structure of self-assembled clusters in solution. In the work reported here we have attempted to
10.1021/cg000009c CCC: $20.00 © 2001 American Chemical Society Published on Web 11/15/2000
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Davey et al.
Figure 1. Projections of the known structures of form 1 (a) and form 2 (b) of DHB.
overcome this problem by combining an investigation of the solvent dependence of polymorph appearance of 2,6-dihydroxybenzoic acid (DHB) in chloroform and toluene solutions with a study of the related solution chemistry in order to probe the relationship between molecular aggregation and nucleation. 2,6-Dihydroxybenzoic Acid. The crystal structure of this compound was first determined in 1994 by Gnaniec et al.,20 who obtained crystals from chloroform solution. This structure is orthorhombic, belonging to the noncentric space group Pna21 with a ) 14.174 Å, b ) 12.132 Å, and c ) 3.8280 Å and is referred to here as form 2. Later in the same year MacGillivray and Zaworotko21 reported a second, monoclinic structure, P21/c, with a ) 5.408 Å, b ) 5.224 Å, c ) 22.986 Å, and β ) 94.69°. Crystals of this form (form 1) were grown from hot toluene. In the context of the current work the significance of these two structures lies in the fact that they are built from two distinct H-bonding motifs; in the form 1 structure centrosymmetric carboxylic acid dimers, in which there is proton disorder, are packed into a classic herringbone motif with hydroxyl groups in the 2,6-positions involved in intramolecular H-bonds to the carbonyl oxygens (Figure 1a). In the form 2 structure the molecular conformation is switched, with one of the hydroxyl groups now involved in an intermolecular H-bond to the carbonyl oxygen of a neighboring molecule so that infinite hydrogen-bonded chains are created (Figure 1b), propagating along [011]. Overall Strategy. The experiments reported here were designed to meet two objectives. First, solubility, spectroscopic, modeling, and database studies were carried out in order to explore the existence and likely nature of molecular aggregation of DHB in both toluene and chloroform solutions. Second, the relative nucleation rates of the DHB polymorphs from both solvents and over a range of supersaturations was studied in order to examine any link between solution chemistry and the solvent dependence of nucleation kinetics. Experimental Section Preparation of Polymorphic Forms. Form 1 was crystallized by rapid cooling of a stirred, boiling toluene solution (5.0 mg of DHB/mL) to 50 °C followed by cooling at 0.7 °C/ min to 5 °C. The solution was left unstirred at 5 °C overnight, and crystals were harvested and vacuum-dried at 30 °C for 5 h. Form 2 was isolated from hot chloroform solution (50 °C, 4.6 mg of DHB/mL) by cooling with agitation at 0.1 °C/min to
Figure 2. Molecular structure of DHB showing the torsions, τ1 and τ2, used in the conformational search. 30 °C and left at that temperature for 3 h. The polymorphic purity of samples prepared using these methods was assessed using powder X-ray diffraction (Scintag XDS 2000 powder X-ray diffractometer, λ ) 1.541 78 Å, 2θ ) 15.5° (form 1) and 10° (form 2)). In this way the samples of pure forms were judged to contain less than 2 wt % of the other polymorph. Powder XRD was additionally used to check for the occurrence of the known hydrate,20 which was detected in some initial samples but subsequently eliminated by use of dry solvents (water content
