Asymmetric Synthesis of Optically Active Sodium Chlorate and

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Perspective Asymmetric Synthesis of Optically Active Sodium Chlorate and Bromate Crystals Richard M. Pagni*,† and Robert N. Compton*,†,‡ Departments of Chemistry and Physics, University of Tennessee, Knoxville, Tennessee 37996 Received May 23, 2002

ABSTRACT: The readily available sodium chlorate is an interesting ionic compound because, although achiral, it forms optically active crystals. When unperturbed, an aqueous solution of sodium chlorate yields a random distribution of + and - crystals on evaporation. Some chiral perturbations profoundly alter this distribution, however. These include seeding, the addition of the optically active cosolutes D-mannitol and D-sorbitol, and the energetic and chiral beta particles and positrons. The chiral weak interaction inherent in all atomic nuclei and thus atoms and molecules does not alter the distribution of + and - crystals. Stirring during evaporation, an achiral perturbation, affects the distribution of crystals in a given crystallization; when crystals from a large number of experiments are considered, however, the distribution of + and - crystals is random. There is much current interest in optically active crystals. These solid and liquid crystals can be used to create interesting optical phenomena, with potential utility in optical devices.1-10 In addition, they have been used successfully as media in which to carry out asymmetric photochemistry,11-12 a task that has proven very difficult to do in fluid solution.13 Optically active crystals have also provided very useful environments for asymmetric synthesis, often yielding products with very high enantiomeric excesses (ee).14,15 There has also been much speculation that optically active crystals, namely, quartz, may have provided the chiral influence through which optically active molecules, essential for life, came to be in the prebiotic world.16 To favor a specific chiral selection, it is necessary that one enantiomer of quartz was more common in the prebiotic world than the other enantiomer. In general, if one is to use optically active crystals for synthetic, prebiotic, optical, and other applications, one must be able to control the chirality of crystals during synthesis. This issue will be addressed in our brief perspective. Before doing so, a little background is useful. It is well-known that molecules crystallize in one of 230 possible space groups.17 Of these 230 groups, only 65 are chiral.18 Crystals residing in one of the 65 chiral * To whom correspondence should [email protected]; [email protected]. † Department of Chemistry. ‡ Department of Physics.

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space groups are innately chiral. Their chirality does not depend on whether the molecules in the crystal are themselves chiral. Chiral crystals, which are fairly common, thus exist in enantiomeric forms, just as chiral molecules do. Optically active molecules can only crystallize in a chiral space group. Racemic molecules, on the other hand, most often form racemic heterochiral crystals.19 About 10% of the time, however, racemates yield a conglomerate of equal numbers of d and l homochiral crystals,19 where d or dextrorotary refers to a + or clockwise rotation of plane-polarized light passing through the crystal, and l or levorotatary to a - or counterclockwise rotation. This spontaneous resolution is the method Louis Pasteur used to convert racemic sodium ammonium tartrate into its enantiomers. 1,1′Binaphthyl, a chiral molecule, which forms chiral crystals, is an interesting case because it spontaneously resolves into homochiral crystals when crystallized from acetone and forms racemic heterochiral crystals when crystallized from other solvents.20,21 Sodium chlorate (NaClO3) represents another interesting case. It is an achiral ionic compound consisting of spherical sodium ions and ClO3- anions of C3v symmetry. Sodium chlorate crystallizes in the chiral space group P213.22,23 Figure 1 is a stereographic picture of one of the enantiomers of NaClO3. When crystallized from water, sodium chlorate yields large, well-formed colorless d and l crystals. The crystals yield normal optical rotatory dispersion curves and, when viewed through cross polarizers,

10.1021/cg0200154 CCC: $22.00 © 2002 American Chemical Society Published on Web 06/11/2002

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Figure 1. Stereographic picture of sodium chlorate/bromate in the P213 space group.

afford beautiful colors as seen in Figure 2 for NaClO3 and the related NaBrO3. Note that although NaClO3 and NaBrO3 share the same space group, their crystal morphologies are different.

What is desired is a methodology to convert an achiral molecule such as NaClO3 into all d or all l crystals. If one defines the enantiomeric excess ee as (#d - #l)/ (#d + #l), where #d and #l are, respectively, the number of d and l crystals formed in a given experiment, all d crystals will yield ee ) +1 and all l crystals will yield ee ) -1. Leaving aside the possible effect of the weak interaction in nuclei to be discussed later, asymmetric synthesis in the absence of external (chiral) perturbations is not possible. As shown by Kipping and Pope more than 100 years ago24 and more recently by Kondepudi,25-27 Wu and co-workers,28 and Pagni, Compton, and co-workers,29 one obtains a 50:50 mixture of d and l NaClO3 crystals from water if a sufficient number of crystallization experiments are performed. However, on an individual basis, there may be small statistical deviations from equal numbers of d and l crystals. A plot of frequency with which a specific ee is observed in an experiment versus ee yields a Gaussian curve centered at ee ) 0, the result expected for the creation of a random distribution of d and l crystals. It is also worth noting that the number of crystals formed in a given experiment depends on how rapidly the water is evaporated. Fast evaporation yields numerous small crystals, while very slow evaporation will yield 1 or a few very large crystals. Seeding with optically active crystals is perhaps the most obvious method used to perturb the distribution of crystals. Seeding aqueous NaClO3 with either d or l NaClO3 yields d or l NaClO3 crystals, respectively.30 Interestingly, seeding aqueous NaClO3 with d or l NaBrO3, which also crystallizes in the P213 space group,

Figure 2. Plane-polarized light passing through sodium chlorate (rectangular) and bromate (triangular) crystals. Different colors appear by rotating the second polarizer.

yields l and d NaClO3 crystals, respectively.30 This is a consequence of the fact that, although NaClO3 and NaBrO3 have the same absolute configuration, they rotate light in the opposite direction.22,23 Not surprisingly, seeding aqueous NaBrO3 with d or l NaClO3 crystals yields l or d NaBrO3 crystals, respectively. It is important to note that the above seeding experiments were carried out on stirred solutions in which secondary nucleation is encouraged. When a static aqueous solution of NaClO3 is seeded with a NaBrO3

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seed crystal, approximately equal numbers of d and l NaClO3 crystals are generated.31 What then occurs upon stirring when no seed crystals are added? In 1990, Kondepudi showed that stirring a sodium chlorate solution during crystallization yields either mostly d or l crystals, i.e., ee ≈ +1 or -1, in a given experiment, but ee ≈ 0 if the crystals from a large number of experiments are considered.25 Since stirring is not a chiral perturbation, the direction of stirring is not correlated with the sign of the ee. Temperature is found to greatly affect the resulting ee. Vogl et al. showed that crystallization above 40 °C yields ee’s of ( 1.30 Below 40 °C, the ee’s drop off. Thus, in a given experiment one will obtain predominantly d or l crystals, but one cannot predict in advance which of the homochiral crystals will dominate. This is a consequence of the fact that the primary nucleating event randomly gives a d or l crystallite. Secondary nucleation from the primary crystallite will ensure that the chirality of the initial crystal is maintained during the remainder of the crystallization. Kondepudi contends that secondary nuclei grow in the environment around the chiral surface which may itself be chiral.27 These new crystallites are then swept away by convection and seed the growth of still new crystals. Martin and Wu, on the other hand, have presented evidence that stirring breaks off crystallites from the growing primary crystal.28 Stirring during crystallization is an effective method to induce spontaneous resolution of NaClO3 crystals, but the outcome, i.e., d or l, cannot be predicted a priori. Chiral perturbations, however, may yield homochiral crystals in a controlled, predictable manner. D-Mannitol and D-sorbitol are polyhydroxy sugars derived from D-mannose and D-glucose, respectively. Crystallization of NaClO3 from water containing the cosolute D-mannitol yields d NaClO3 exclusively (ee ) 1), while aqueous NaBrO3 with the same cosolute yields mainly l NaBrO3 (ee ) -0.97).32 Recall that d NaClO3 and l NaBrO3 have the same absolute configuration. D-Sorbitol has the opposite effect, yielding mostly l NaClO3 (ee ) -0.9) and d NaBrO3 (ee ) 1). Interestingly, the sugars, D- and Larabinose and D-sucrose, and the crystals, + and quartz, have no effect on the distribution of d and l NaClO3 crystals.33

Mannitol and sorbitol profoundly affect the distribution of d and l NaClO3 and NaBrO3 crystals, albeit in opposite senses. This unexpected effect could be due to competitive inhibition in which a sugar preferentially binds to the surface of one enantiomer of the crystal over the other, thus inhibiting growth of bound crystals. This has been seen in other cases.34 Sugars are known to bind metal cations.35 If the optically active sugar is complexed to a sodium cation involved in primary nucleation, the resulting crystallite may preferentially be

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either d or l. This would present a genuine example of asymmetric induction. One can also perturb the ee distribution of crystal growth using chiral particles. Spin-polarized electrons are generated in the beta decay of radioactive atoms as a consequence of the fact that nuclei are chiral due to presence of the weak nuclear force.36,37 Beta particles are very energetic and mostly left-handed (an observer will see the oncoming electrons spinning clockwise). The combination of translation and spin renders the electrons chiral. Positrons, i.e., positively charged electrons, also resulting from radioactive decay, are also spin polarized. Unlike beta particles, they are mostly righthanded. When a room-temperature aqueous solution of NaClO3 was exposed to beta particles (38Sr90 source yielding 0.554 MeV electrons, and from its decay produce 39Y90, 2.28 MeV electrons; 7.4 × 107 Bq), NaClO3 crystals were produced which were predominantly d with an overall ee ) 0.32.29 In a second set of experiments using a more energetic source of beta rays (1.6 × 109 Bq; 1 × 109 beta particles/s), an overall ee ) 0.47 was obtained. These and the positron experiments described below were performed over a period of two years. Half of all of the experiments gave ee’s at or very close to 1. About 10% of the experiments gave ee’s at or close to -1, with the remainder giving ee’s scattered about 0. Since approximately 80% of the electrons are left-handed, there appears to be a correlation between the electron helicity and crystal helicity. The data indicate that left-handed electrons favor d crystals while right-handed electrons favor l crystals. Independent nucleating events not influenced by the beta particles yield the ee’s scattered about 0. Positron exposure (11Na22 source yielding 0.54 MeV positrons and 1.38 and 2.75 MeV gamma rays; 108 Bq) afforded mostly l crystals (ee ) -0.55). About half the experiments gave ee ) -1. Again, there is a correlation between positron helicity (mostly right-handed) and crystal helicity. Why do left-handed electrons and positrons apparently favor d crystals and right-handed particles favor l crystals? It is unclear at present. Energy from the beta particles is deposited into the first few millimeters of the solution where evaporation and presumably primary nucleation is taking place. It is known that, when energetic electrons collide with the surface of water, a complex chemistry is initiated which produces showers of polarized secondary electrons and circularly polarized gamma rays.38 Primary nucleation seems to involve two events: an initial bringing together of solute molecules to form an amorphous-like droplet, which in a second step organizes itself into the crystallite.39 The polarized secondary electrons and gamma rays may influence the way in which the droplet organizes itself. Also, any role that the hydrated electron might play in the process is unknown. A summary of the sodium chlorate experiments described in this paper is shown in Table 1. Seedingand-stirring seems to be the best current method for making optically active NaClO3 (and NaBrO3) of known absolute configuration. In time, the use of chiral cosolutes and spin-polarized electrons and positions may be equally useful, but their modes of action are too

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Table 1. Asymmetric Synthesis of NaClO3 Crystals perturbation

is perturbation chiral?

result

none stirring NaClO3 seeding with stirring NaBrO3 seeding with stirring NaClO3, seeding, no stirring D-mannitol cosolute D-sorbitol cosolute D- and L-arabinose cosolutes + and - quartz D-sucrose β-particles positrons weak interaction in nuclei

no no yes yes yes yes yes yes yes yes yes yes yes

50:50 distribution of d and l crystals spontaneous resolution; 50:50 distribution of d and l overall d seed f d crystals, l seed f l crystal d seed f l crystal, l seed f d crystal no effect d crystals exclusively l crystals greatly favored no effect no effect no effect d crystals favored l crystals favored none

poorly understood for this to be the case now. They may be more useful, however, as probes into the mechanism of the still poorly understood primary nucleation. There is yet another chiral perturbation that could affect the asymmetric synthesis of optically active crystals. This is due to the weak interaction which is present in all nuclei. Of the four fundamental forces in nature, only the weak force, which is responsible for beta decay, is fundamentally chiral. Because electrons in atoms penetrate their nuclei, atoms and thus all molecules are innately chiral. This results in an energy difference between pairs of enantiomers. The parity violating energy difference is called PVED. For molecules such as amino acids which only contain atoms with small atomic numbers (Z), PVED is calculated to be exceedingly small (∼10-15 eV). Larger PVEDs are expected for molecules containing atoms with large Z because PVED scales approximately with Z6.2. See ref 40 and references therein for more details. What is exciting is the possiblity that this very small effect in individual molecules may be amplified in polymers and crystals where many molecules exist.41 We have summarized these studies in an earlier review.16 The implications of parity violating interactions in asymmetric transformations have also been discussed by Avalos et al.42 Salam recently speculated that the Z interactions might explain why L-amino acids are dominant in living systems.43 He postulated that quantum mechanical cooperative and condensation effects similar to those in Cooper-pairing and Bose Einstein condensation could give rise to a second-order phase transitions below a critical temperature Tc. Such secondorder phase transitions in amino acids could give rise to a preponderance of the L-enantiomers. Very recently, Wang et al. described three tests of the Salam proposal on single crystals of D- and L-alanine (and valine).44 Differential scanning calorimetry, mass susceptibility, and Raman spectroscopy revealed different temperature-dependent differences for the enantiomeric crystals. The differences usually occurred near 270 K, which is very close to the freezing point of water. Verification of these results is crucial and is ongoing in our laboratories. PVED may have an effect on the behavior of D- and L-alanine crystals. However, it clearly has no effect on the asymmetric crystallization of NaClO3 in the absence of other perturbations because one obtains a random distribution of d and l crystals. Its effect on the crystal growth of molecules containing atoms with much larger Z’s has yet to be examined, including NaBrO3 and NaIO3.45

The myriad experiments described above are important because they may ultimately afford a better understanding of the still poorly understood primary nucleation. They are also important from a practical point of view as well because they show how to make + and - crystals of all sorts, useful in creating new optical phenomena and devices in a controlled manner. Acknowledgment. The authors thank the National Science Foundation for support of their work on chirality. We also thank graduate student Rodney Sullivan for assistance in preparing Figures 1 and 2. References (1) Ivchenko, E. L.; Pikus, G. E. Ferroelectrics 1982, 43, 131136. (2) Pellat-Finet, P.; Lebreton, G. Proc. SPIE-Int. Soc. Opt. Eng. 1983, 400, 151-158. (3) Kukhtarev, N. V.; Dovgalenko, G. E.; Starkov, V. N. Appl. Phys. A. 1984, A33, 227-230. (4) Nestrizhenko, Y. A. Opt. Spektrosk. 1988, 65, 210-212. (5) Berezhnoi, A. A.; Plakhotnik, E. N. Opt.-Mekhi Prom-St. 1990, 5, 19-23. (6) Brodin, M. S.; Volkov, V. I.; Kukhtarev, N. V.; Privalko, A. V. Opt. Commun. 1990, 76, 21-24. (7) Tomiyasu, H.; Fukushima, Y.; Uesu, Y.; Toyoda, S. Ferroelectrics 1992, 134, 335-340. (8) Murray, J. T.; Peyghambarian, N.; Powell, R. C.; Stolzenberger, R. A.; Jie, S.; Jassemnejad, B. Phys. Rev. A.: At., Mol., Opt. Phys. 1994, 49, 4066-4076. (9) Konstantinova, A. F.; Tronin, A. Y.; Nabatov, B. V. NATO ASI Ser., Ser. 3 1997, 28, 19-32. (10) Muthuraman, M.; Le Fur, Y.; Bagieu-Beucher, M.; Masse, R.; Nicound, J.-F.; Desiraju, G. R. J. Mater. Chem. 1999, 9, 2233-2239. (11) Sakamoto, M. Chem. Eur. J. 1997, 3, 684-689. (12) Leibovitch, M.; Olovsson, G.; Scheffer, J. R.; Trotter, J. Pure Appl. Chem. 1997, 69, 815-823. (13) Kagan, H. B.; Balavoine, G.; Moradpour, A. J. Mol. Evol. 1974, 4, 41-48. (14) Soai, K.; Osanai, S.; Kadowaki, K.; Yonekubo, S.; Shibata, T.; Sato, I. J. Am. Chem. Soc. 1999, 121, 11235-11236. (15) Sato, I.; Kadowaki, K.; Soai, K. Angew. Chem., Int. Ed. 2000, 39, 1510-1512. (16) Compton, R. N.; Pagni, R. M. Adv. At. Mol. Opt. Phys., in press. (17) Brand, J. C. D.; Speakman, J. C. Molecular Structure-The Physical Approach; Edward Arnold: London, 1960; pp 3136. (18) Sakamoto, M. Chem. Eur. J. 1997, 3, 684-689. (19) Collet, A. In Problems and Wonders of Chiral Molecules; Simonyi, M., Ed.; Akade´mai Kidao´: Budapest, 1990; pp 91108. (20) Bader, Y.; Cheung, K. L. C.; Cooke, A. S.; Harris, M. M. J. Chem. Soc. 1965, 1543-1544. (21) Di Bari, L.; Pescitelli, G.; Salvadori, P. J. Am. Chem. Soc. 1999, 121, 7998-8004. (22) Abrahams, S. C.; Bernstein, J. L. Acta Crystallogr. 1977, B33, 3601-3604.

Perspective (23) Abrahams, S. C.; Glass, A. M.; Nassau, K. Solid State Commun. 1977, 24, 515-516. (24) Kipping, F. S.; Pope, W. J. J. Chem. Soc. (London) Trans. 1898, 73, 606-617. (25) Kondepudi, D. K.; Kaufman, R.; Singh, N. Science 1990, 250, 975-976. (26) Kondepudi, D. K.; Bullock, K. L.; Digits, J. A.; Hall, J. K.; Miller, J. M. J. Am. Chem. Soc. 1993, 115, 10211-10216. (27) Kondepudi, D. K.; Asakura, K. Acc. Chem. Res. 2001, 34, 946-954. (28) Martin, B.; Tharrington, A.; Wu, X.-I. Phys. Rev. Lett. 1996, 77, 2826-2829. (29) Mahurin, S.; McGinnis, M.; Bogard, J. S.; Hulett, L. D.; Pagni, R. M.; Compton, R. N. Chirality 2001, 13, 636-640. (30) Vogl, O.; Qin, M.; Bartus, J.; Jaycox, G. D. Monatsh. Chem. 1995, 126, 67-73. (31) Buhre, T.; Durand, D.; Kondepudi, D. K.; Laudadio, J.; Spilker, S. Phys. Rev. Lett. 2000, 84, 4405-4408. (32) Niedermaier, T.; Schlenk, W., Jr. Chem. Ber. 1972, 105, 3470-3478. (33) Pagni, R. M.; Compton, R. N., unpublished results. (34) Addadi, L.; Weinstein, S.; Gati, E.; Weissbach, I.; Lahav, M. J. Am. Chem. Soc. 1982, 104, 4610-4617.

Crystal Growth & Design, Vol. 2, No. 4, 2002 253 (35) Angyal, S. J. Adv. Carbohydr. Chem. Biochem. 1989, 47, 1-43. (36) Lee, T. D.; Yang, C. N. Phys. Rev. 1956, 104, 254-258. (37) Wu, C. S.; Ambler, E.; Hayward, R. W.; Hoppes, D. D.; Hudson, R. P. Phys. Rev. 1957, 105, 1413-1415. (38) Mozander, A. Fundamentals of Radiation Chemistry; Academic Press: San Diego, 1999. (39) Anwar, J.; Boateng, P. K. J. Am. Chem. Soc. 1998, 120, 9600-9604. (40) Lahamer, A. S.; Mahurin, S. M.; Compton, R. N.; House, D.; Laerdahl, J. K.; Lein, M.; Schwerdtfeger, P. Phys. Rev. Lett. 2000, 85, 4470-4473. (41) Yamagata, Y. J. Theor. Biol. 1966, 11, 495-498. (42) Avalos, M.; Babiano, R., Cintas, P.; Jimenez, J. L.; Palacios, J. C. Tetrahedron: Asymmetry 2000, 11, 2845-2874. (43) Salam, A. J. Mol. Evol. 1991, 33, 105-113. (44) Wang, W.; Yi, F.; Ni, Y.; Zhao, Z.; Jin, X.; Tang, Y. J. Biol. Phys. 2000, 26, 51-65. (45) See Keszthelyi, L. J. Biol. Phys. 1994, 20, 241-245 for the possible effect of PVED on the enatiomers of l- and dtris(1,2-ethanediamine)iridium complexes. Z is large (77) for iridium.

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