30WWW.CEN-ONLINE.ORG OCTOBER 29, 2007

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 chemi-cally 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 anal-ogy (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 flip-ping a coin once results in a single outcome, either a head or a tail. Zheng and Long rea-soned that they could apply these statistical principles to chemically control homochiral crystallization without the aid of a chiral cata-lyst, 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 heli-cal coordination polymer is significantly skewed, and in an ideal case, only one enan-tiomeric form is produced,” Zheng says.

The researchers demonstrated the phenomenon by synthesizing a three-dimensional network polymer consist-ing of helical chains of copper succinate bridged by 4,4′-bipyridine groups. They ran dozens of experiments under varying con-ditions, such as differing pH and rates of solution evaporation. The team evaluated the crystals by circular dichroism spectros-copy, a method that measures differences

in the way molecules absorb right- and left-handed circularly polarized light.

An initial set of syntheses and crystal-lizations 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 forma-tion 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)4

2+ and reducing the rate of poly-mer formation.

The researchers showed that manipulat-ing the pH and ammonia evaporation rate permitted careful control of the ammonia concentration. When the concentration of reactants was just right, crystallization initi-ated 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 re-tained 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 crystalliza-tion began, the concentration of ammonia remained low enough for polymer growth to continue but high enough to prevent forma-tion of additional primary nuclei that could disrupt the homochirality.

THE CONCEPT of “chiral symmetry break-ing” is not new. Homochiral crystallization has manifested itself in several ways in dif-ferent scientific disciplines for more than a century, says Yale University’s J. Michael McBride, who studies the growth and disso-lution of molecular crystals. But the concept is not widely known, and it wasn’t well-un-derstood 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 chemi-cal reactions in which the outcome depends

on the rate of stirring or the rate of evapora-tion of the solvent,” Kondepudi adds. He has shown that a high rate of stirring and slow solvent evapora-tion can lead to chiral symmetry breaking during crystal forma-tion. “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 re-discovering this phe-nomenon and finding

unique ways of expressing it,” McBride ob-serves. 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 impor-tance for developing single-enantiomer drugs and advanced materials for optical de-vices, says Zheng, who splits his time at Xia-men 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. ■

SCIENCE & TECHNOLOGY

BREAKING THE CHIRAL BARRIER

Chemically manipulating CRYSTALLIZATION KINETICS

yields enantiopure productsSTEPHEN K. RITTER, C&EN WASHINGTON

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.

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