Volume 85 Issue 44 | p. 30
Issue Date: October 29, 2007

Breaking The Chiral Barrier

Chemically manipulating crystallization kinetics yields enantiopure products
Department: Science & Technology
News Channels: Materials SCENE
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Right From Left
Random crystal formation leads to crystal clusters containing right- or left-handed forms of a helical polymer (left), as shown by circular dichroism spectra. But when crystallization is chemically controlled (right), one primary crystal nucleus forms and a cluster of homochiral single crystals—all right-handed in this case—is achieved.
Credit: Zhiping Zheng
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Right From Left
Random crystal formation leads to crystal clusters containing right- or left-handed forms of a helical polymer (left), as shown by circular dichroism spectra. But when crystallization is chemically controlled (right), one primary crystal nucleus forms and a cluster of homochiral single crystals—all right-handed in this case—is achieved.
Credit: Zhiping Zheng

WOULDN'T IT BE NICE if isolating a single-enantiomer form of a compound were as simple as flipping a coin? For Zhiping Zheng, La-Sheng Long, and coworkers at Xiamen University, in China, the ability to chemically control the probability of a helical polymer crystallizing with only a right- or left-hand twist, rather than a mix of the two forms, is based on that easy coin-flip analogy (Angew. Chem. Int. Ed., DOI: 10.1002/anie.200703443). Their work could aid the development of enantiomeric drugs and advanced materials.

Flipping a coin many times naturally tends toward a 50–50 ratio of heads and tails. But flipping a coin once results in a single outcome, either a head or a tail. Zheng and Long reasoned that they could apply these statistical principles to chemically control homochiral crystallization without the aid of a chiral catalyst, template, or chiral starting materials.

"By chemically manipulating the statistical fluctuation in crystallization, the otherwise equal probability of attaining the left- or right-handed isomers of a helical coordination polymer is significantly skewed, and in an ideal case, only one enantiomeric form is produced," Zheng says.

The researchers demonstrated the phenomenon by synthesizing a three dimensional network polymer consisting of helical chains of copper succinate bridged by 4,4′-bipyridine groups. They ran dozens of experiments under varying conditions, such as differing pH and rates of solution evaporation. The team evaluated the crystals by circular dichroism spectroscopy, a method that measures differences in the way molecules absorb right- and left-handed circularly polarized light.

An initial set of syntheses and crystallizations yielded optically inactive racemic mixtures of polymer or samples with low enantiomeric excesses of either helical form. The researchers say the fast rate of polymerization and formation of a large number of primary seed crystals means that there was equal probability for formation of both forms, as expected.

The team then modified the polymer synthesis by adding ammonia. Ammonia competed with succinate and bipyridine for copper ions, resulting in formation of Cu(NH3)42+ and reducing the rate of polymer formation.

The researchers showed that manipulating the pH and ammonia evaporation rate permitted careful control of the ammonia concentration. When the concentration of reactants was just right, crystallization initiated with the formation of a single primary crystal nucleus that contained polymer with either a right-hand or a left-hand twist. As secondary crystals grew, the polymer retained the single-handedness of the primary crystal, leading to a homochiral product. The specific handedness of the seed crystal couldn't be controlled, however. Important in this process was that, once crystallization began, the concentration of ammonia remained low enough for polymer growth to continue but high enough to prevent formation of additional primary nuclei that could disrupt the homochirality.

THE CONCEPT of "chiral symmetry breaking" is not new. Homochiral crystallization has manifested itself in several ways in different scientific disciplines for more than a century, says Yale University's J. Michael McBride, who studies the growth and dissolution of molecular crystals. But the concept is not widely known, and it wasn't well-understood until work by Dilip K. Kondepudi at Wake Forest University and by his own group about 10 years ago, McBride notes.

"This phenomenon is very interesting, because usually we do not encounter chemical reactions in which the outcome depends on the rate of stirring or the rate of evaporation of the solvent," Kondepudi adds. He has shown that a high rate of stirring and slow solvent evaporation can lead to chiral symmetry breaking during crystal formation. "The effect of these rates can be quite dramatic in that the asymmetry can change from an even 50% to greater than 95% of one isomer," he says.

"Chemists are destined to keep rediscovering this phenomenon and finding unique ways of expressing it," McBride observes. The Xiamen researchers' approach in using ammonia as a kind of buffer to control homochirality "is quite a clever way of doing it," he says.

The ability to control homochirality in chemical synthesis is of practical importance for developing single-enantiomer drugs and advanced materials for optical devices, says Zheng, who splits his time at Xiamen and at the University of Arizona. The study may also provide "new insight into the much debated origin of the homochirality of the sugar and amino acid building blocks of the biological world," he adds.

 
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