Photo by Peter Cutts

Ronald Breslow, a chemistry professor and University Professor at Columbia University, received the $300,000 Welch Award on Oct. 27, at a banquet in Houston, for lifetime achievements in basic chemical research that affect humankind.

In a career spanning nearly 50 years, Breslow has tackled an astonishing range of chemical topics and pioneered many of them; for example, biomimetic chemistry. But long before that, he figured out how to make and measure the simplest aromatic and antiaromatic systems and how to use the hydrophobic effect to determine the geometries of transition states in chemical reactions. His other insights led to the invention of potent enzyme mimics and compounds that modulate gene transcription in cancer cells, resulting in useful anticancer properties for compounds that are now undergoing advanced trials in humans.

In such a sweeping career, it is not surprising that Breslow has had more than his share of "Aha! Moments." He shares several of them here.

"The first came when I was puzzling over how thiamine pyrophosphate could act as a catalyst for many key biochemical reactions. Nothing in the structure of thiamine offered a clue, in terms of known chemistry. I finally realized that a particular C-H bond must be quite acidic, although this was not precedented, and that if it was broken, the resulting anion on a thiazolium ring would be able to do the biochemical reactions. As soon as I realized this, I looked at that hydrogen by infrared and NMR techniques, using heavy water, and saw that, sure enough, the insight was correct. The resulting concept is in every biochemistry book and indeed was also the stimulus for the development of a new class of compounds--stabilized carbenes--in organic chemistry. It also stimulated the invention of other methods of achieving polarity reversal in organic chemistry.

"Another moment came as I was puzzling over how to make the cyclopropenyl cation, the simplest aromatic system, for the first time. A relevant precursor was known with too many chlorines. I had to remove three of the chlorines and leave one, and I suddenly realized that a tin hydride reaction would carry out the three needed steps but that each would be slower than the preceding one, so we could stop the process with the one remaining chlorine. This could ionize to the desired cation, the first example of an aromatic ring with other than six electrons.

"The cyclopropenyl anion is terribly unstable--it is the simplest antiaromatic compound (we coined the term antiaromatic to describe these special instabilities), so there was no known way to generate it and determine its energy. In an 'Aha! Moment,' I realized that we could use electrochemistry to generate it and use the energy involved in the electrochemistry to determine the energy of the anion itself by relating it to other thermodynamic quantities. The technique gave us a way to determine the energies of such other species as the methyl anion and various free radicals. The resulting pKa of methane is now in every textbook--it is very different from previous estimates--and the technique has been widely applied to determine bond dissociation energies, which are also fundamental quantities in every text."

But wait, there's more!

"We had been interested in studying the hydrophobic effect of water solvent in organic chemistry and had been using various antihydrophobic agents to show its presence. I realized that we could use the effects of antihydrophobic agents such as ethanol--in water--to determine the geometries of the transition states of such organic reactions as displacements and additions. The geometric information that this method supplies was confirmed with those few cases where one knows what it must be, such as Diels-Alder reactions. The technique lets us see the structure of that most elusive but very important species, the transition state. The results can be used to design novel reactions and catalysts and also to check the ability of modern computational methods to predict such transition-state geometries.

"Some other areas of our research had important insights, though perhaps not quite up to the standard of an 'Aha! Moment,' but I will share one area anyhow. We set out to imitate the ability of enzymes to perform reactions whose selectivity is dominated by the geometry of the enzyme/substrate complex, not by the intrinsic reactivity of the substrate. In this field, which we named biomimetic chemistry, we developed a novel general method of using templates to direct free-radical reactions to particular spots of the substrate, the so-called radical relay method. This had not been done before."

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