Ultrasound-Enhanced Deracemization: Toward the Existence of

Article pubs.acs.org/crystal

Ultrasound-Enhanced Deracemization: Toward the Existence of Agonist Effects in the Interpretation of Spontaneous Symmetry Breaking Céline Rougeot,†,‡ Frédéric Guillen,‡ Jean-Christophe Plaquevent,‡ and Gérard Coquerel*,† †

Normandie Univ, France−SMS Unité de Cristallogenèse EA3233−Université de Rouen, 76821, Mont-Saint-Aignan Cedex, France SPCMIB, UMR 5068−Université Paul Sabatier, 118 route de Narbonne, 31062 Toulouse Cedex 09, France

‡

S Supporting Information *

ABSTRACT: Both isothermal attrition-enhanced and ultrasoundenhanced deracemizations of an organic compound were compared in productivities and in the evolution of the crystal size distributions. These shed new light on the underlying mechanisms, drawing attention to the existence of several agonist effects and particularly the role of entrainment in the deracemization process.

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owadays, the access to pure enantiomers is a considerable scientific and economical issue.1 Unfortunately, asymmetric synthesis or resolution of racemic mixtures are generally expensive and may turn out to be tedious. In 2005, Viedma completed for the first time the transformation of a racemic suspension of NaClO3 into an enantiopure solid phase under stirring in the presence of glass beads (Viedma ripening or attrition-enhanced deracemization).2 Three years after, Noorduin et al. expanded this process to intrinsically chiral organic compounds crystallizing as conglomerates and undergoing fast racemization in solution.3 Without initial enantiomeric excess (ee) nor any chiral impurity, the final handedness of the solid phase was stochastic. Many studies have tried to elucidate the conundrum of deracemization: how can a racemic conglomerate be spontaneously and autocatalytically converted into one pure enantiomer while racemization occurs in solution? The currently accepted mechanism includes the recycling of crystals (Ostwald ripening), the reincorporation of chiral clusters, and agglomeration as key steps.4−6 Attrition ensured by glass beads allows the production of small crystals and of a high number of clusters; the smaller the crystals, the faster the evolution of the ee. Recent studies shed new light on the deracemization process. Hein et al. observed “a transient growth in crystal size” by monitoring the evolution of the crystal size during deracemization of an amino-acid derivative by means of glass beads7 and Gherase and co-workers described the importance of balance between size and number of crystals of the two antipodes.8 Suwannasang et al. achieved the deracemization of 1-(4chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)pentan-3one 1 (Figure 1), a precursor of the plant growth inhibitor © 2015 American Chemical Society

Figure 1. Chemical structure of 1.

Paclobutrazol, by using temperature cycles at near ambient conditions without any glass bead and highlighted the role of the entrainment effect to explain the increase of the ee of the solid phase.9 In the present study, the results obtained by using attritionenhanced deracemization and a new alternative method, called ultrasound-enhanced deracemization, are presented. The comparison between these two methods on the model compound 1, which crystallizes as a conglomerate, and particularly the monitoring of the evolution of the particle size distribution provides new clues to help to answer the question of how symmetry breaking occurs in heterogeneous systems. Three deracemizations of 1, by using glass beads, were carried out under the same operating conditions: 2 g of 1 were suspended into 10 g of a methanol/water mixture (80/20 wt %) with 0.1 g of NaOH (as racemizing agent) at 25 °C, and 10 g of glass beads (ø2 mm) were added. The heterogeneous mixture was then stirred at 750 rpm by a cross magnetic stirrer. In these conditions, the solubility of 1 is 5.5%wt. Small samples were Received: December 4, 2014 Revised: March 10, 2015 Published: March 12, 2015 2151

DOI: 10.1021/cg501765g Cryst. Growth Des. 2015, 15, 2151−2155

Article

Crystal Growth & Design

Figure 2. (a) Evolution of the ee of three different experiments by using glass beads and conducted under the same experimental conditions. (b) Evolution of ln(ee) vs time.

regularly taken, filtered then washed with water to remove all traces of the sodium hydroxide. The solid was then analyzed by chiral HPLC to follow the evolution of the crystal enantiomeric excess. In each case, the racemic solid phase spontaneously evolved toward pure enantiomer with a sigmoidal kinetic profile (Figure 2). As the chirality of the final solid phases is stochastic, only the absolute value of the enantiomeric excess is presented. Experiments A, B and C were achieved after ca. 4, 5, and 7 days, respectively. Representations of ln(ee) versus time are linear, as expected for a nonlinear catalysis, but they are also parallel. Deracemization rates are therefore identical for the three experiments, only the induction period varies. It is likely that below a certain threshold, the ee can fluctuate near the racemic composition; however, beyond this threshold, deracemization is irreversible and occurs at the same rate in all experiments. This observation emphasizes the stochastic feature of the onset of the deracemization process. Because of the sampling method, the yield cannot be exactly calculated. However, no degradation was observed by NMR or HPLC, and the recovered mass of final enantiopure product (above 50% yield) was consistent with the number of samples and the solubility data of 1. Because of attrition by the glass beads, the size of crystals progressively decreased until it reached a steady state (Figures 3 and 4 and Supporting Information).10 Then, the mean size of particles did not evolve anymore, even at 100% ee; the transient growth described by Hein et al. was not observed. It should be noticed that grinding was efficient throughout the experiment, including when the ee remained at 0% for many hours. Furthermore, once the steady state has been established, the crystal size distributions were scattered with particles ranging from about 1 to 10 μm; it is easy to imagine that the dissolution of the smallest particles promotes the growth of the large ones, i.e., Ostwald ripening. In 2008, Song and co-workers provoked the crystallization of NaClO3 from supersaturated solutions by applying ultrasound, both with and without seeding.11 In both cases the final ee was close to 100%. Up to now, ultrasound has never been used without concomitant glass bead-induced grinding to complete the total symmetry breaking of chiral organic compounds.12 In order to study the effect of sonication without any glass bead on deracemization of 1, an ultrasonic probe was used. The experimental conditions were kept as close as possible to those using glass beads; the substrate/base/solvent proportions were identical, and the temperature of the system was also maintained at 25 °C. Only the scale of the experiment was

Figure 3. SEM pictures of particles of 1 during deracemization using glass beads: Experiment A.

modified to take in consideration the size of the ultrasonic probe; 20 g of 1 was used instead of 2 g when using glass beads. A cross magnetic stirrer (750 rpm) was added to ensure a good homogeneity of the suspension inside the reactor. Four different powers were tested: 50, 130, 170, and 325 kJ·h−1.13 In every case, the ee evolves toward 100% with a sigmoidal kinetic profile (Figure 5a); ultrasound only is therefore also able to achieve the total symmetry breaking of organic compounds. It should be noted that almost two months were necessary to complete deracemization in the same experimental conditions (mass of components, reactor, magnetic stirrer, temperature, etc.) but without ultrasound: the effect of continuous stirring only can therefore be safely neglected. Moreover, latent periods without ee takeoff also exist when isothermal sonications are applied: the duration required to reach 100% ee for the experiments carried out at 130 and 170 kJ·h−1 were significantly different, even if the powers were rather close. The corresponding 2152


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Figure 6. SEM pictures of the final particles of 1 after deracemization using ultrasound.

It should be noted that the evolution of the ee can easily be stopped, e.g., during a full night, by switching off the generator and stirring. It is essential to keep the system at 25 °C to prevent any phenomenon of dissolution or crystallization due to temperature fluctuations of the overall system. Figure 8 shows the whole experiment of deracemization of 1 by using the lowest power of ultrasound, i.e., the evolution of the ee by taking in account periods without sonication and stirring. Values of the ee delimiting these periods correspond to samples taken just before switching off the devices and 15 min after switching them on; that explains why the values of ee are not exactly the same. Besides the practical aspect, the nonevolution of the ee in stagnant conditions shows the relative inertia of the system; it is worth noting that, despite the racemizing conditions, no return to a lower ee was noticed. In the experimental conditions used in this study, we can notice that the ee evolved faster with ultrasound than with glass beads. Efficient energies involved in the different operating conditions are difficult to evaluate, even for the sonication experiments (for instance, our experimental rig does not permit an accurate assessment of the amount of energy dissipated by thermal exchange). Therefore, we cannot compare the mechanical energy (under attrition) and the acoustical energy (under ultrasound) involved in the deracemization. We can easily imagine that by using a stronger grinding, by use of an

Figure 4. SEM pictures of particles of 1 during deracemization using glass beads: Experiment C.

ln(ee) = f(t) curves are almost parallel (Figure 5b), meaning that the exponential parts of the evolution of the ee are similar. As for glass beads, periods without visible evolution of the ee are not due to a poor efficiency of ultrasound, and no transient growth was observed (see Supporting Information). Initial periods without ee takeoff are therefore not only a feature due to attrition by means of glass beads, but a general feature of the deracemization phenomenon. The time required to achieve a full chiral purity of the solid phase depends on the power of ultrasound: the stronger the power, the faster the evolution of the ee and the smaller the particles (Figure 6). Figure 7 shows that there is proportionality between deracemization rate and ln(power of ultrasound). The similar behavior was observed by Viedma when he studied the effect of the stirring rate and of the number of glass beads.2

Figure 5. (a) Evolution of the ee during deracemizations by using ultrasound at constant temperature. (b) Evolution of ln(ee) vs time. 2153


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Figure 7. Evolution of the time required to achieve chiral purity of the solid phase depending on the power of ultrasound at 25 °C. To remove the uncertainties due to the initial and final stages of the experiments, only the time between 10% and 90% were taken in account.

showed that temperature cycles at near ambient conditions were able to deracemize 1, without the help of grinding.9 Viedma and Cintas also described the deracemization of a racemic mixture of NaClO3 into a single-chirality solid phase due to the temperature gradient existing in a boiling solution.18 Iggland et al. performed the conversion of a racemic conglomerate (N-(2-methylbenzyli-dene)-phenylglycineamide) by using a high-pressure homogenization setup where the release of the pressure was responsible of an increase of the temperature.19 In those cases, the entrainment effect due to supersaturation combined with the racemization in solution plays an indisputable role in the final enantiopurity of the solid phase. Besides the mechanical effect, sonication is also responsible for an increase of temperature due to cavitation.15 Indeed, it was necessary to regulate the temperature of the reactor to keep the suspension at 25 °C. Because of many local variations in temperature there are numerous confined cycles of dissolution/ recrystallization, which provoke the evolution of the ee, similarly as described by Suwannasang and co-workers, but at a different scale, resulting in the enlargement of the particles. The results presented here do not contradict the previous studies but give a broader view on the spontaneous symmetry breaking when a flux of energy passes through the heterogeneous system. In every mode of deracemization (glass beads, ultrasound, temperature cycles, pressure, etc., and we can surmise the same global effect with microwaves), the exchanges of matter necessary to transform the racemic mixture into pure enantiomer are due to concomitant and agonist phenomena with different intensities, such as Ostwald ripening, reincorporation of chiral clusters, agglomeration, and entrainment. For instance, entrainment effect20 due to local fluctuations in temperature is rather modest when glass beads are used, but its contribution is difficult to ignore in the case of ultrasound. When temperature cycles are applied to the heterogeneous system, it is most probably the predominant phenomenon responsible for the evolution of the ee. In terms of application, ultrasound-enhanced deracemization is a valuable variant of Viedma ripening; the required time to totally convert the racemic mixture into pure enantiomer is significantly shortened, and both the implementation at large scale and the workup are made easier. For instance, deracemization could occur in a fluidized bed crystallizer coupled with ultrasound, as described by Midler.21 A combination of ultrasound and damped macroscopic temperature cycles could have cumulative effects and may be promising for industrial applications of deracemization.

Figure 8. Evolution of the ee during deracemization by using ultrasound at 325 kJ·h−1. (△) The whole experiment; periods without sonication and stirring are represented by dotted lines.

industrial bead mill, for example,12 the particle size will be significantly reduced, and so the evolution of the system sped up. However, the workup is easier when sonication is used, as a simple filtration yields the desired product without the need to separate the solid phase from the beads. The collapse of cavitational bubbles produced by ultrasonic waves is known to induce a strong mechanical effect.14,15 If this mechanical effect is stronger than that due to glass beads, particles should be smaller, therefore causing faster exchange of matter: that could explain the enhanced efficiency of ultrasonic radiations. Surprisingly, final particles of deracemizations by using glass beads (Figures 3 and 4) are smaller than those obtained by using ultrasound, whatever the power (Figure 6). Therefore, mechanical effects due to ultrasound are not sufficient to explain their impact on deracemization of 1. Sonication is also known to produce a high number of clusters.16 As the reincorporation of clusters is considered to be a key step of the deracemization process, it is not surprising that the high number of clusters speeds up the rate of the evolution of the ee by increasing the exchanges of matter. However, another phenomenon can also explain this difference: the local temperature variations. The importance of temperature variations to complete total symmetry breaking was demonstrated by Levilain et al. by performing the complete deracemization of 1 by combining Viedma ripening and a cooling rate of 15 K·h−1.17 As for Suwannasang et al., they 2154


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(14) Cintas, P. On Cavitation and Chirality: A Further Assessment. Cryst. Growth Des. 2008, 8, 2626−2627. (15) Zeiger, B. W.; Suslick, K. S. Sonofragmentation of Molecular Crystals. J. Am. Chem. Soc. 2011, 133, 14530−14533. (16) Medina, D. D.; Gedanken, A.; Mastai, Y. Chiral Amplification in Crystallization under Ultrasound Radiation. Chem.Eur. J. 2011, 17, 11139−11142. (17) Levilain, G.; Rougeot, C.; Guillen, F.; Plaquevent, J.-C.; Coquerel, G. Attrition-Enhanced Preferential Crystallization Combined with Racemization Leading to Redissolution of the Antipode Nuclei. Tetrahedron: Asymmetry 2009, 20, 2769−2771. (18) Viedma, C.; Cintas, P. Homochirality beyond Grinding: Deracemizing Chiral Crystals by Temperature Gradient under Boiling. Chem. Commun. 2011, 47, 12786−12788. (19) Iggland, M.; Fernández-Ronco, M. P.; Senn, R.; Kluge, J.; Mazzotti, M. Complete Solid State Deracemization by High Pressure Homogenization. Chem. Eng. Sci. 2014, 111, 106−111. (20) Coquerel, G. Preferential Crystallization. In Topics in Current Chemistry (Novel Optical Resolution Technologies); Springer GmbH: Berlin, Germany, 2007; pp 1−50. (21) Midler, M. Production of crystals in a fluidized bed with ultrasonic vibrations. US3510266, 1970.

ASSOCIATED CONTENT

S Supporting Information *

Additional explicit information over all conducted experiments and SEM pictures of the particles. 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]. Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript. Funding

This work has been partially funded by the European Commission within the seventh Framework Program (INTENANT Research Project No. 214 129). Notes

The authors declare no competing financial interest.

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REFERENCES

(1) Lorenz, H.; Seidel-Morgenstern, A. Processes To Separate Enantiomers. Angew. Chem., Int. Ed 2014, 53, 1218−1250. (2) Viedma, C. Chiral Symmetry Breaking During Crystallization: Complete Chiral Purity Induced by Nonlinear Autocatalysis and Recycling. Phys. Rev. Lett. 2005, 94, 065504. (3) Noorduin, W. L.; Izumi, T.; Millemaggi, A.; Leeman, M.; Meekes, H.; Van Enckevort, V. J. P.; Kellogg, R. M.; Kaptein, B.; Vlieg, E.; Blackmond, D. G. Emergence of a Single Solid Chiral State from a Nearly Racemic Amino Acid Derivative. J. Am. Chem. Soc. 2008, 130, 1158−1159. (4) McBride, J. M.; Tully, J. C. Physical Chemistry: Did Life Grind to a Start? Nature 2008, 452, 161−162. (5) Noorduin, W. L.; Vlieg, E.; Kellogg, R. M.; Kaptein, B. From Ostwald Ripening to Single Chirality. Angew. Chem., Int. Ed. 2009, 48, 9600−9606. (6) Igglang, M.; Mazzotti, M. Population Balance Modeling with Size-Dependent Solubility: Ostwald Ripening. Cryst. Growth Des. 2012, 12, 1489−1500. (7) Hein, J. E.; Cao, B. H.; Viedma, C.; Kellogg, R. M.; Blackmond, D. G. Population Balance Modeling with Size-Dependent Solubility: Ostwald Ripening. J. Am. Chem. Soc. 2012, 134, 12629−12636. (8) Gherase, D.; Conroy, D.; Matar, O. K.; Blackmond, D. G. Experimental and Theoretical Study of the Emergence of Single Chirality in Attrition-Enhanced Deracemization. Cryst. Growth Des. 2014, 14 (3), 928−936. (9) Suwannasang, K.; Flood, A. E.; Rougeot, C.; Coquerel, G. Using Programmed Heating−Cooling Cycles with Racemization in Solution for Complete Symmetry Breaking of a Conglomerate Forming System. Cryst. Growth Des. 2013, 13, 3498−3504. (10) Crystal size distribution measurement by LASER diffraction could not be applied because 1 is soluble in n-heptane, the solvent usually used for this analysis. Only water was found as a nonsolvent for 1. Unfortunately the dispersion of particles was not sufficient to perform accurate analyses. (11) Song, Y.; Chen, W.; Chen, X. Ultrasonic Field Induced Chiral Symmetry Breaking of NaClO3 Crystallization. Cryst. Growth Des. 2008, 8, 1448−1450. (12) Noorduin, W. L.; van der Asdonk, P.; Bode, A. A. C.; Meekes, H.; van Enckevort, W. J. P.; Vlieg, E.; Kaptein, B.; van der Meijden, M. W.; Kellogg, R. M.; Deroover, G. Scaling Up Attrition-Enhanced Deracemization by Use of an Industrial Bead Mill in a Route to Clopidogrel (Plavix). Org. Process Res. Dev. 2010, 14, 908−911. (13) These powers were directly given by the sonicator (Vibra Cell 75043; 750 W, 20 kHz) and were obtained by using a percentage (between 20 and 60%) of the maximal power of the generator. 2155


Ultrasound-Enhanced Deracemization: Toward the Existence of

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