Viedma Ripening of Conglomerate Crystals of ... - ACS Publications

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Viedma Ripening of Conglomerate Crystals of Achiral Molecules Monitored Using Solid-State Circular Dichroism Dylan T. McLaughlin, Thi Phuong Thao Nguyen, Leinjo Mengnjo, Cheng Bian, Yat Hei Leung, Elliot Goodfellow, Parsram Ramrup, Simon Woo, and Louis A. Cuccia* Department of Chemistry & Biochemistry, Concordia University, 7141 Sherbrooke Street West, Montréal, Québec, H4B 1R6 Canada S Supporting Information *

ABSTRACT: Viedma ripening is the attrition-induced spontaneous chiral amplification of a conglomerate crystal mixture. To demonstrate the general nature of this deracemization process, we have extended attrition-enhanced chiral amplification to 10 achiral organic molecules that form conglomerate chiral crystals: benzil (1), diphenyl disulfide (2), benzophenone (3), tetraphenylethylene (4), guanidine carbonate (5), butylated hydroxytoluene (6), hippuric acid (7), ninhydrin (8), cytosine (9), and adeninium dinitrate (10). In these experiments the time required to reach homochirality was as low as 3 h and typically ranged from 25 to 50 h. In most cases amplification to homochirality of both enantiomers was observed in repeat experiments, although often in a nonstochastic fashion, reflecting the scalemic nature of the starting material. We have also demonstrated the utility of quantitative circular dichroism (CD) to determine enantiomeric excess in systems where chirality exists only in the solid-state.

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INTRODUCTION

The process of conglomerate crystallization is referred to as spontaneous resolution since all individual crystals are homochiral. However, to take advantage of conglomerate crystallization to obtain bulk homochiral material is a challenge. Simultaneous crystallization of the two enantiomers and the method of entrainment provide two approaches to resolve chiral molecules that crystallize as conglomerates.10,11 In the case of achiral or rapidly racemizing molecules, spontaneous mirror symmetry breaking and asymmetric amplification can sometimes occur due to slow undisturbed crystallization,12 and more often by cloning of secondary nuclei from a single mother crystal as a result of vigorous stirring.13,14 Both scenarios depend on minimizing stochastic primary nucleation while relying on secondary nucleation to amplify chirality. More recently, and remarkably, Viedma obtained homochirality in conglomerate systems via crystal grinding in saturated solution.15 This attrition-enhanced deracemization, sometimes referred to as “Viedma ripening”, relies on Ostwald ripening coupled with homochiral cluster recognition (i.e., enantiomerspecific oriented attachment).16−19 A cartoon representation of the Viedma ripening mechanism is given in Scheme 1.20 In brief, a racemic mixture of conglomerate crystals in saturated solution is stirred under attrition conditions. The mirror symmetry can be broken due to a biased weight ratio and/or an unequal crystal size

Although it has been 165 years since Pasteur’s discovery of molecular chirality and spontaneous resolution, understanding and controlling crystal nucleation, growth, and dissolution remain critical to the investigation of solid-state dissymmetry.1 The elegant yet painstaking Pasteur process of manual sorting crystals of sodium ammonium tartrate based on their macroscopic hemihedrism has led researchers to seek more practical and generalizable chiral resolution methods for over a century.2 In addition to the fundamentals of the problem, the ability to generate enantiopure crystals under reasonably simple conditions is of profound importance in the pharmaceutical and agrochemical industries, where the global market for chiral technology is forecast to reach $7.2B by 2016.3 On the basis of recent surveys of crystal structures reported in the Cambridge Structural Database (CSD) and the Inorganic Crystal Structure Database (ICSD), the probability for achiral molecules to crystallize in noncentrosymmetric space groups is estimated to be between 8% and 13%.4−6 This ability for achiral molecules to form chiral crystals vastly increases the richness of the chiral crystal library, whose potential is often overlooked. For example, as many as 20 different chiral silicate zeolites were reported showing potential enantioselective applications in chromatography.7 In addition, chiral crystals from achiral molecules have been reported to effectively trigger asymmetric autocatalysis reactions and to act as solid-state reagents for absolute asymmetric synthesis.8,9 Clearly, such applications present a need for homochiral material. © 2014 American Chemical Society

Received: October 22, 2013 Revised: January 25, 2014 Published: February 5, 2014 1067

dx.doi.org/10.1021/cg401577m | Cryst. Growth Des. 2014, 14, 1067−1076

Crystal Growth & Design

Article

mirror symmetry breaking could be directed on the basis of the chirality of the additive (i.e., following the “rule of reversal” implemented under attrition conditions).27,28 To date, there are 13 crystalline systems that undergo Viedma ripening that can be classified as having the following: (i) achirality in solution, (ii) a racemizing state in solution, or (iii) a reversible racemizing reaction in solution (Table 1). To our knowledge,

Scheme 1. Key Steps in the Mechanism of Viedma Ripening:a (a) Chiral Crystals Dissolve and Achiral Molecules in Solution (Grey Background) Can Transfer to Either Enantiomorph via Secondary Nucleation; (b) Crystal Attrition Increases the Amount of Small Crystals (Increases Total Surface Free Energy) Thereby Increasing the Solubility According to the Gibbs−Thomson Rule; (c) Enantiomer-Specific Oriented Attachment Shifts Crystal Growth towards the Major Population until Homochirality Is Achieved

Table 1. Conglomerate Crystals (Molecules That Undergo Viedma Ripening)

a

Black and white rhomboids represent enantiomorphous conglomerate crystals (levorotatory (l) and dextrorotatory (d), respectively).

distribution, including random fluctuations during the attrition process.21 In this case, the system is beginning at 33% enantiomeric excess (Scheme 1a). Large crystals are continuously ground into smaller crystals that dissolve into achiral molecules in solution (i.e., Gibbs−Thomson rule), a necessity for complete deracemization, while crystallization via secondary nucleation is also occurring (Scheme 1b).22 Note that there is no driving force for stochastic primary nucleation, which would clearly hamper the deracemization process. It is generally believed that a key component for Viedma ripening is the requirement for enantiomer-specific oriented attachment of crystallites and/or chiral clusters (i.e., nonclassical crystal growth).17,23−25 This is evident in this cartoon where the small crystallites in the dominant population have twice the chance for enantiomer-specific oriented attachment and therefore are less likely to dissolve. This is not the case for the crystallites of the minor population, which will therefore have an increased probability to dissolve to eventually feed into the growth stream of the major population (Scheme 1c). Viedma’s first example was the deracemization of racemic sodium chlorate crystals under grinding conditions in saturated aqueous solution.15 Experiments in our laboratory have shown that conglomerate crystals of ethylenediammonium sulfate can also be driven to homochirality under similar attrition conditions.26 Furthermore, by merging an enantioselective interaction with this autocatalytic amplification process, the

a

(i) achiral in solution, (ii) racemization in solution, (iii) racemizing reaction in solution.

there are only two reported examples where deracemization of conglomerate crystals was not achieved under Viedma ripening conditions: 3-hydroxy-3-phenylisoindolin-1-ones (type ii)29 and a diindenylzinc organometallic complex (type ii).30 Surprisingly, given the relative abundance of achiral molecular conglomerates, sodium chlorate, sodium bromate, and ethylenediammonium sulfate are the only three examples of this family shown to undergo Viedma ripening (Table 1, type i). These systems can be considered as the simplest, given that the molecules are inherently achiral in solution. Herein, we have expanded our investigation of Viedma ripening to 10 conglomerate crystals of achiral organic molecules in an effort 1068



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Table 2. Conglomerate Crystals (Organic Molecules Optically Active in Crystalline State Only)

a Enantiomeric excess of as-received commercial material (N.B. adeninium dinitrate was prepared from adenine and HNO3). bOptical rotatory power (589 nm) of [CD(+)400] and [CD(−)400] enantiomorphs of benzil crystals is −22.3°/mm and +22.3°/mm, respectively (literature value: 24.9°/ mm57). cOptical rotatory power (589 nm) of [CD(−)252] and [CD(+)252] enantiomorphs of guanidine carbonate crystals is −13.6°/mm and +13.6°/mm, respectively (literature value: 14.6°/mm58). dGuanidine carbonate does not show a λmax between 250 and 400 nm; the signal at 252 nm was arbitrarily chosen to determine enantiomeric excess. eSigma-Aldrich (racemic), Acros Organics (14% ee), and Anachemia (>90% ee).

macroscopic anisotropies such as circular birefringence (CB) and linear dichroism (LD), solid-state circular dichroism (v) is, in most cases, the best method to investigate the chirality of microcrystalline materials.62 In fact, there are numerous examples where solid-state circular dichroism was used as a qualitative measure to identify chiral conglomerate crystal formation from achiral molecules.4,62,65−68 However, an extensive search of the literature has identified only one research group who has reported the quantitative use of solidstate circular dichroism of chiral crystals from achiral compounds. Lennartson, Håkansson, and co-workers have shown a linear relationship for the CD signal versus the mass of enantiopure single crystals of metal coordination complexes.69−71 In their case, standards with variable amounts of homochiral material were used to prepare calibration curves, whereas here, calibration curves to determine enantiomeric excess were prepared using standards with a constant mass of various percentages of both enantiomorphous crystals, in an effort to minimize variability in the transparency of the KBr pellet or Nujol mull. All 10 molecules investigated here, except for adeninium dinitrate (10), were commercially available (Table 2). To our surprise, most of the crystalline molecules as obtained were scalemic with enantiomeric excess values ranging from 0% (racemic) to >90% (Table 2). The origin of this solid-state

to validate the generality of the Viedma ripening process (benzil (1), diphenyl disulfide (2), benzophenone (3), tetraphenylethylene (4), guanidine carbonate (5), butylated hydroxytoluene (BHT, 6), hippuric acid (7), ninhydrin (8), cytosine (9), and adeninium dinitrate (10); Table 2). Furthermore, through this investigation we have developed the use of quantitative solid-state circular dichroism (CD) for studying the enantiomeric excess of conglomerate crystals in the solid-state.

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RESULTS AND DISCUSSION Since all molecules in this investigation are achiral in solution and form enantiomorphous crystals, only solid-state methods can be applied to investigate their chirality. At the single crystal level, the chirality of these materials can be investigated by the following: (i) single crystal X-ray diffraction,59 (ii) hand-sorting of crystals displaying hemihedrism,60 (iii) polarimetry (i.e., optical rotatory power),4 (iv) polarized light microscopy (i.e., optical rotatory dispersion (ORD)),61 or (v) circular dichroism (CD).62−64 The absolute chirality of a single crystal can only be determined through anomalous scattering of X-rays in molecules containing second row or heavier atoms (i.e., by determining the Flack parameter; method i). Methods ii−v require well-formed macroscopic crystals that either display hemihedrism or a prominent optic axis. Although prone to 1069



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Figure 1. Left: Solid-state CD spectra of the chiral crystals of benzil (1) in Nujol: (a) [CD(+)400], (b) [CD(−)400], and (c) an equal mixture of a and b. Right: Viedma ripening to the [CD(+)400] form starting from 0.25 g of c suspended in 1 mL of saturated solution in acetone stirred at 2400 rpm. Inset: Calibration curve of CD absorption at 400 nm in Nujol.

Figure 2. Left: Solid-state CD spectra of the chiral crystals of diphenyl disulfide (2) in KBr: (a) [CD(+)313], (b) [CD(−)313], and (c) an equal mixture of a and b. Right: Viedma ripening to the [CD(−)313] form starting from 0.25 g of c suspended in 1 mL of saturated solution in acetone stirred at 2400 rpm. Inset: Calibration curve of CD absorption at 313 nm in KBr.

Figure 3. Left: Solid-state CD spectra of the chiral crystals of benzophenone (3) in KBr: (a) [CD(+)359], (b) [CD(−)359], and (c) an equal mixture of a and b. Right: Viedma ripening to the [CD(−)359] form starting from 0.25 g of c suspended in 1 mL of saturated solution in acetone stirred at 3600 rpm. Inset: Calibration curve of CD absorption at 359 nm in KBr.

synthesis/purification. As a result of the scalemic nature of our starting material, various methods were used to prepare crystalline material with known chirality required to prepare the CD calibration curves and as starting material for Viedma ripening experiments (i.e., racemic starting material). In most cases, recrystallization yielded a racemic mixture of crystals that could be analyzed by solid-state CD and resolved. However, for benzophenone (3), butylated hydroxytoluene (6), hippuric acid (7), and cytosine (9), stirred crystallization was used to obtain

chirality remains a mystery and is somewhat analogous to the phenomenon of “disappearing polymorphs” (in this case, “disappearing conglomerates”).72,73 It is believed that either (i) stirring during the synthesis/purification of the commercial molecules might have caused mirror symmetry breaking and partial chiral amplification during crystallization, akin to Kondepudi’s stirred crystallization,13 or more fittingly to the topic of this research, (ii) some degree of Viedma ripening may have taken place if some form of attrition was involved during 1070



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Figure 4. Left: Solid-state CD spectra of the chiral crystals of tetraphenylethylene (4) in KBr: (a) [CD(+)355], (b) [CD(−)355, and (c) an equal mixture of a and b. Right: Viedma ripening to the [CD(−)355] form starting from 0.25 g of c suspended in 1 mL of saturated solution in toluene stirred at 2400 rpm. Inset: Calibration curve of CD absorption at 355 nm in KBr.

Figure 5. Left: Solid-state CD spectra of the chiral crystals of guanidine carbonate (5) in Nujol: (a) [CD(+)252], (b) [CD(−)252], and (c) an equal mixture of a and b. Right: Viedma ripening to the [CD(+)252] form starting from 0.25 g in c suspended in 1 mL of saturated solution in distilled water stirred at 2400 rpm. Inset: Calibration curve of CD absorption at 252 nm in Nujol.

Figure 6. Left: Solid-state CD spectra of the chiral crystals of butylated hydroxytoluene (6) in KBr: (a) [CD(+)285], (b) [CD(−)285], and (c) an equal mixture of a and b. Right: Viedma ripening to the [CD(−)285] form starting from 0.25 g of c suspended in 1 mL of saturated solution in acetone stirred at 2400 rpm. Inset: Calibration curve of CD absorption at 285 nm in KBr.

(4), guanidine carbonate (5), butylated hydroxytoluene (6), hippuric acid (7), ninhydrin (8), cytosine (9), and adeninium dinitrate (10) are given in Figures 1−10, respectively. All the calibration curves show a satisfactory linear relationship between the CD signal and the crystalline enantiomeric excess from homochiral [CD(−)] crystals to homochiral [CD(+)] crystals and were subsequently used to determine the enantiomeric excess of samples of our Viedma ripening experiments at various times (Figures 1−10).

predominantly homochiral crystalline material. In the case of adeninium dinitrate (10), Viedma ripening was used to prepare sufficient amounts of homochiral crystalline material. The solid-state circular dichroism spectra (i.e., of separate enantiomorphs and an equal mixture of both chiral forms), the corresponding calibration curve (i.e., CD signal versus enantiomeric excess), and the Viedma ripening amplification profile (i.e., enantiomeric excess versus time) for benzil (1), diphenyl disulfide (2), benzophenone (3), tetraphenylethylene 1071



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Figure 7. Left: Solid-state CD spectra of the chiral crystals of hippuric acid (7) in KBr: (a) [CD(+)260], (b) [CD(−)260], and (c) an equal mixture of a and b. Right: Viedma ripening to the [CD(+)260] form starting from 0.25 g of c suspended in 1 mL of saturated solution in ethanol stirred at 2400 rpm. Inset: Calibration curve of CD absorption at 260 nm in KBr.

Figure 8. Left: Solid-state CD spectra of the chiral crystals of ninhydrin (8) in KBr: (a) [CD(+)345], (b) [CD(−)345], and (c) an equal mixture of a and b. Right: Viedma ripening to the [CD(+)345] form starting from 0.25 g of c suspended in 1 mL of saturated solution in distilled water stirred at 2400 rpm. Inset: Calibration curve of CD absorption at 345 nm in KBr.

Figure 9. Left: Solid-state CD spectra of the chiral crystals of cytosine (9) in KBr: (a) [CD(+)290], (b) [CD(−)290], and (c) an equal mixture of a and b. Right: Viedma ripening to the [CD(−)290] form starting from 0.25 g of c suspended in 1 mL of saturated solution in anhydrous ethanol stirred at 2400 rpm. Inset: Calibration curve of CD absorption at 290 nm in KBr.

This is not unexpected since there is inevitable variability in the preparation of the desired “racemic” starting material used for these experiments. In other words, the already broken mirror symmetry of the slightly scalemic starting material gets amplified to homochirality via the Viedma ripening process.21,26,37 All 10 compounds (1−10) successfully underwent Viedma ripening, and this research brings the total number of conglomerate crystals of achiral molecules capable of Viedma ripening to 13. Furthermore, we did not come across any

In most cases, the deracemization process of the studied conglomerate crystals shows the signature sigmoidal autocatalytic profile as previously reported.34 The experiments began with a nearly racemic mixture (zero CD signal) and progressed, within error, to homochirality. The time required to reach homochirality was as low as ca. 3 h for benzil (1) or ca. 10 h for diphenyl disulfide (2) and typically ranged from 25 to 50 h for molecules 3−10. In most cases amplification to homochirality of both enantiomers was observed in repeat experiments, although often in a nonstochastic fashion (Table 3). 1072



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Figure 10. Left: Solid-state CD spectra of the chiral crystals of adeninium dinitrate (10) in Nujol: (a) [CD(+)250], (b) [CD(−)250], and (c) an equal mixture of a and b. Right: Viedma ripening to the [CD(−)250] form starting from 0.25 g of c suspended in 1 mL of saturated solution in 4.6 M nitric acid, stirred at 2400 rpm. Inset: Calibration curve of CD absorption at 250 nm in Nujol.

phenomena, including a deeper understanding of the underlying mechanism behind Viedma ripening.

Table 3. Direction of Viedma Ripening name benzil (1) diphenyl disulfide (2) benzophenone (3) tetraphenylethylene (4) guanidine carbonate (5) butylated hydroxytoluene (6) hippuric acid (7) ninhydrin (8) cytosine (9) adeninium dinitrate (10)

CD λmax 400 313 359 355 252 285 260 345 290 250

nm nm nm nm nm nm nm nm nm nm

CD(−) amplified

CD(+) amplified

8 6 3 5 2 1 0 2 5 3

1 3 2 0 6 4 5 3 2 2

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MATERIALS AND METHODS

Benzil (1; [CAS 134-81-6], 37% ee [CD(+)400]), diphenyl disulfide (2; [CAS 882-33], 34% ee [CD(−)313]), tetraphenylethylene (4; [CAS 632-51-9], 3% ee [CD(+)355]), guanidine carbonate (5; [CAS 593-85-1], racemic), 2,6-di-tert-butyl-4-methylphenol (butylated hydroxytoluene (BHT), 6; [CAS 128-37-0], 50% ee [CD(+)285]), benzoylaminoethanoic acid (hippuric acid, 7; [CAS 495-69-2], 30% ee [CD(+)260]), and cytosine (9; [CAS 71-30-7], 28% ee [CD(−)290]) were purchased from Sigma-Aldrich. A second stock of guanidine carbonate (5; >90% ee [CD(−)252]) and benzophenone (3; [CAS 119-61-9], 28% ee [CD(+)359]) were purchased from Anachemia Science, and a third stock of guanidine carbonate (5; 14% ee [CD(−)252]) was obtained from Acros Organics. 2,2-Dihydroxyindane-1,3-dione (ninhydrin, 8; [CAS [485-47-2], 29% ee [CD(−)345]) was obtained from Matheson Coleman & Bell. Adeninium dinitrate (10; racemic) was prepared by dissolving adenine ([CAS 73-24-5], Sigma-Aldrich) in 4.6 M nitric acid ([CAS 7697-37-2], Sigma-Aldrich) at 45 °C as previously reported.76 Most of the molecules investigated were found to be scalemic as commercially obtained. The enantiomeric excess of the commercial materials was determined with solid-state circular dichroism as described below. All the crystallization solvents were purchased from Fisher and used as obtained. Potassium bromide ([CAS 7758-02-3]; 99% pure; from Sigma-Aldrich) was heated to 440 °C and was stored in an oven at 130 °C. Nujol mineral oil [CAS 8012-95-1] was from Plough Inc. The scalemic nature of most of the starting materials necessitated manually mixing equal amounts of enantiomorphic crystals from slow crystallization or the appropriate amounts of scalemic material obtained by stirred crystallization. The near racemic nature of the mixtures was confirmed by the absence of CD signals. In the cases of guanidine carbonate and tetraphenylethylene, the commercial materials were racemic based on CD analysis, and were used as obtained. Circular Dichroism. The circular dichroism spectra were recorded from 250 to 450 nm using a Jasco J-710 spectropolarimeter. The resolution was 5 points/nm, and each curve represents 3 or 5 accumulations collected at a scan rate of 50 nm/min. In cases where high noise was observed, a Savitzky−Golay filter was used for smoothing with a convolution width of 25 points. All efforts were made to maximize signal while minimizing the HT voltage (Supporting Information Figures S1−S10). The solid-state samples were prepared as either Nujol mulls or KBr pellets (13-mm diameter). Nujol mulls were prepared by grinding the crystals in a mortar and pestle in Nujol mineral oil to a homogeneous mixture (9−10% wt/wt). A portion of this mixture, weighing ca. 10 mg, was sandwiched between two quartz plates (quartz windows: 1.05 cm diameter; 0.3 cm thick), and the sample assembly was mounted using a standard circular

examples of conglomerate crystals formed from achiral molecules that did not amplify to homochirality. Under the conditions described for these experiments, the systems under investigation did not display polymorphism or form solvates that would hinder the deracemization process.74 For example, note that cytosine (9) crystallizes as a conglomerate from anhydrous ethanol, but cytosine monohydrate (9·H2O) belongs to the achiral P21/c space group.75 As such, both crystallization and Viedma ripening of cytosine were carefully carried out in anhydrous ethanol, and CD measurements were recorded as soon as possible to avoid moisture uptake. In conclusion, this work highlights the wide-ranging applicability of the Viedma ripening process for conglomerate crystals formed from achiral molecules, and we have demonstrated the use of circular dichroism to determine enantiomeric excess in systems where chirality exists only in the solid-state. We also observed that the commercially available achiral molecules that crystallize in noncentrosymmetric space groups investigated in this work were, more often than not, scalemic. Conglomerates of achiral molecules can be considered as polymorphic, and as such, this work provides new insight into polymorphism. Our ongoing efforts aim to understand, control, and design stereoselective interactions at surfaces of chiral conglomerate crystals. In particular, we are pursuing the use of tailor-made chiral additives to direct the Viedma ripening process toward the desired enantiomorph. On the basis of Viedma and co-workers’ recent report of the enantiomerselective oriented attachment of sodium bromate and sodium chlorate,17 we will explore this very interesting phenomenon in other conglomerate systems. This research direction is expected to have an important impact on chiral crystallization 1073



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cell holder. KBr pellets were prepared by grinding the crystals in a mortar and pestle with 50 mg of potassium bromide (concentrations noted below), and this mixture was then vacuum-pressed at ca. 8 tons for ca. 20 s to form a translucent and homogeneous pellet. The pellet, supported by a homemade slip, was mounted using the same cell holder. The sample was placed as close to the detector as possible. Correspondence of the HT voltage curves provided an indication that the multiple pellets prepared were representative of each sample at the same concentration. The specific mixtures for each molecule were the following: benzil (1), 9% wt/wt in Nujol; diphenyl disulfide (2), 1.2% wt/wt in KBr; benzophenone (3), 0.8% wt/wt in KBr; tetraphenylethylene (4), 0.6% wt/wt in KBr; guanidine carbonate (5), 9% wt/wt in Nujol; butylated hydroxytoluene (6), 2.0% wt/wt in KBr; hippuric acid (7), 2.0% wt/wt in KBr; ninhydrin (8), 3.0% wt/wt in KBr; cytosine (9), 1.2% wt/wt in KBr; adeninium dinitrate (10), 10% wt/wt in Nujol. It should be noted that compounds 2−4 and 6−9, prepared with KBr, did not give reproducible CD profiles in Nujol. However, compounds 1, 5, and 10 gave reproducible results with Nujol, and therefore, Nujol was used to provide quick sample preparation and analysis. The relatively large standard error in CD absorption measurements (Figures 1−10) is likely due to subtle differences in the sample mass in each measurement and/or nonhomogeneous KBr pellets or Nujol mulls. Calibration Curves. The enantiomeric excess (% ee) of the crystalline sample was calculated using eq 1, where x(+) and x(‑) are weights of CD-positive and CD-negative crystals, respectively.

enantiomeric excess (%) =

x(+) − x(−) x(+) + x(−)

materials with predominantly the same chirality, which was otherwise difficult to obtain via slow solvent evaporation. (i) One method is stirred crystallization from the melt (benzophenone (3) and butylated hydroxytoluene (6)): In a 20 mL vial, ca. 3 g of the molecule was melted completely and stirred with a magnetic stir bar (3 mm × 13 mm; straight) at ca. 1300 rpm. The melt was slowly cooled to room temperature, and the resulting crystalline mass was crushed into a powder using a mortar and pestle. If a particular chirality was desired, the melt was seeded with ca. 10−30 mg of crystallites (obtained from slow evaporation) with the appropriate handedness during the initial cooling process. CD analysis revealed ±100% ee for benzophenone (3), and −100% ee and ca. +80% ee for butylated hydroxytoluene (6) stirred melt crystallites (in comparison to CD spectra of single homochiral crystals). (ii) A second method is stirred crystallization from saturated solution (hippuric acid (7): ca. 9.5 g of hippuric acid (7) was dissolved in 200 mL of 95% ethanol to achieve saturation. The solution was stirred with a magnetic stir bar (1 cm × 2.5 cm) at ca. 1300 rpm overnight at room temperature while the solvent gradually evaporated. CD analysis revealed ca. ±75% enantiomeric excess for hippuric acid (7) with respect to CD spectra of single homochiral crystals. For cytosine (9) the following method applies: ca. 1 g of cytosine (9) was dissolved in 150 mL of anhydrous methanol under reflux in a 250 mL beaker. The solution was then stirred with a magnetic stir bar (1 cm × 2.5 cm) at ca. 1300 rpm and allowed to cool to room temperature at which point the precipitate was collected and dried under vacuum for 24 h. CD analysis revealed ca. ±100% enantiomeric excess for cytosine (9) with respect to CD spectra of single homochiral crystals. Stirred crystallization of adeninium dinitrate (10) was attempted to obtain homochiral material according to Mineki et al.; however, in our hands only a racemic mixture was obtained after numerous trials. In this case, homochiral material was obtained by Viedma ripening as described below.76 Viedma Ripening. A sample of racemic powder (0.25 g) and grinding media (3.0 g of 0.8 mm YTZ Zirconia ceramic beads) were suspended in a saturated solution of the same molecule (1 mL, specified solvent; see figures) in a sealed round bottomed flask (5 mL). The sample was then stirred with a stir bar (10 mm × 4 mm, oval shape) at 2400 rpm (for benzil (1), diphenyl disulfide (2), tetraphenylethylene (4), guanidine carbonate (5), butylated hydroxytoluene (6), hippuric acid (7), ninhydrin (8), cytosine (9), and adeninium dinitrate (10)) or 3600 rpm (for benzophenone (3)). Slurry samples (ca. 100 μL) were collected at regular intervals using an automatic pipet and deposited on filter paper to dry prior to CD analysis as described above. The round-bottom flask was replenished with the same volume of saturated solution after each sampling.

× 100% (1)

Samples varying in enantiomeric excess were prepared by mixing appropriate ratios of left-handed and right-handed crystalline powder while maintaining a constant total weight. A calibration curve was generated by plotting the CD signal at a specified wavelength versus the enantiomeric excess of the standards. For each standard, multiple pellets were prepared and measured to determine the average CD signal and standard deviation. The calibration curves were subsequently used to determine the enantiomeric excess of the samples from Viedma ripening experiments. Chiral crystallites used as standards for the construction of calibration curves were obtained either by crushing single crystals obtained from slow evaporation (for benzil (1), diphenyl disulfide (2), tetraphenylethylene (4), guanidine carbonate (5), ninhydrin (8), and adeninium dinitrate (10)-[CD(+)250]) or from the crystalline powders generated by stirred crystallization (for benzophenone (3), butylated hydroxytoluene (6), hippuric acid (7), and cytosine (9)). In the case of adeninium dinitrate (10), single crystals of the [CD(−)250] form were not obtained from slow evaporation. Instead, the homochiral (10)-[CD(−)250] required for the calibration curve was provided by Viedma ripening of the racemic mixture of adeninium dinitrate. Crystallization by Slow Evaporation. Crystallization by solvent evaporation was carried out by dissolving the compound in its respective solvent to form an almost saturated solution, which was placed in a crystallizing dish covered with a large filter paper and left to stand at room temperature. After approximately one week, crystals were harvested. Upon visual inspection, only single crystals were selected for subsequent CD measurements. The crystallization solutions were made using the following concentrations: benzil (1), ca. 10.1 g in 100 mL of xylene; diphenyl disulfide (2), ca. 16.7 g in 100 mL of acetone; benzophenone (3), ca. 57.1 g in 100 mL of acetone; tetraphenylethylene (4), ca. 2.7 g in 100 mL of toluene; guanidine carbonate (5), ca. 21.0 g in 100 mL of distilled water; butylated hydroxytoluene (6), ca. 14.0 g in 100 mL of ethanol (95%); hippuric acid (7), ca. 4.8 g in 100 mL of ethanol (95%); ninhydrin (8), ca. 5 g in 100 mL of water; cytosine (9), ca. 1 g in 160 mL of anhydrous methanol; and adeninium dinitrate (10), ca. 0.7 g of adenine in 140 mL of 4.6 M aqueous nitric acid (initially at 45 °C). Stirred Crystallization. Stirred crystallization was applied in the cases of benzophenone (3), butylated hydroxytoluene (6), hippuric acid (7), and cytosine (9) to obtain a substantial amount of crystalline

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ASSOCIATED CONTENT

S Supporting Information *

HT signals from representative CD curves of 1−10. 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 Cristóbal Viedma is thanked for inspiration and insightful discussions. We thank the anonymous reviewers for useful suggestions to improve this manuscript. NSERC, FQRNT, CFI, and Concordia University are thanked for financial support, and we also acknowledge our membership in the FQRNTsupported, multiuniversity Centre for Self-Assembled Chemical Structures (CSACS). 1074



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