They were destined to become a major player in our understanding of numerous aspects of life, ranging from diseases and their treatment to the production of plastics.
You wouldn’t think that a paper published in 1900 in the Journal of the American Chemical Society with a rather unimposing title, An Instance of Trivalent Carbon: Triphenylmethyl, would have a huge impact on life. But did it ever!
The paper described the first-ever production of a free radical, a highly reactive species destined to become a major player in our understanding of numerous aspects of life, ranging from diseases and their treatment to the production of plastics. Free radicals would even offer a glimpse into the process of aging and possible dietary modifications to slow it down.
The story, however, starts with a different kind of radical, one that ended a life. The life was that of Russia’s Tsar Alexander II. The radical was Ignacy Hryniewiecki, who hoped that assassinating Alexander would lead to an overthrow of the tsarist autocracy. The bomb he hurled at Alexander killed the Tsar, but not the tsarist regime. The 1881 assassination triggered unrest in Russia and a series of pogroms against Jews even though the assassin was a Catholic.
Alexander’s successor, Tsar Alexander III, in 1882 passed the “May laws” that imposed residency and business restrictions on Jews. As a result, Hirsh Gomberg’s farm was confiscated and in 1884 the family, including 18-year-old son Moses, fled to the United States as did some 2 million other Russian Jews.
In Chicago while attending high school, young Gomberg worked under brutal conditions in the stockyards that would be described in Upton Sinclair’s epic 1905 book, The Jungle. Gomberg learned English and in 1886 was accepted into the University of Michigan where he went on to obtain a doctorate in chemistry based on his research into the chemistry of caffeine.
At the time, Germany was the hotbed of chemical research, so Gomberg decided that his career could be best furthered by working with one of the German luminaries. Adolf von Baeyer was one such luminary, already having achieved fame for his synthesis of indigo. Working under von Baeyer, Gomberg became interested in making molecules that were notoriously difficult to synthesize. One of these was hexaphenylethane in which two carbon atoms are bonded together with each one attached to three bulky benzene rings. The thinking was that the large benzene rings could not be made to fit happily around the two carbons.
Gomberg’s idea was to start with triphenylchloromethane, a compound that had three benzene rings and a chlorine atom attached to a central carbon. He hoped that removing the chlorine atom would allow the denuded carbon atoms to join together. There was precedence for this because French chemist Charles Wurtz had shown that such coupling reactions were possible when molecules containing chlorine attached to carbon were treated with sodium.
When Gomberg tried this reaction, he did get a product, but its elemental composition, that is the per cent of carbon and hydrogen, did not match that of the desired hexamethylethane. It did match a structure in which three benzene rings are attached to a single carbon. But this seemed impossible! German chemist August Kekule, who had been von Baeyer’s mentor, and Scottish chemist Archibald Scott Couper had in 1858 simultaneously established that the carbon atom always forms four bonds. Now Gomberg was proposing that he had actually isolated a substance in which carbon was “trivalent” that is, it formed only three bonds.
Upon his return to the U.S. in 1899, he was appointed assistant professor at the University of Michigan where he would spend the rest of his career, eventually serving as chair of the chemistry department. Just a year after his appointment, Gomberg published his classic paper in which he proposed that he had managed to produce a molecule in which carbon formed only three bonds and he suggested that such a species would be highly reactive since carbon was not happy to be in this deprived state.
He described different reactions that proved that this “free radical,” as the novel species was termed, was indeed extremely reactive and formed products that were predictable based upon its trivalent structure. Gomberg recognized that this discovery could have far-reaching consequences and ended his paper with the rather curious statement: “This work will be continued and I wish to reserve the field to myself.”
That was not to happen. Thousands and thousands of papers have been published since then dealing with free radicals, although at first the chemical community was very skeptical of Gomberg’ s claim. It took 30 years before the existence of free radicals was accepted with a critical step being taken by University of Chicago chemist Morris Kharasch, another Russian Jewish immigrant, who demonstrated that some reactions that seemed to be inexplicable could in fact be explained if free radicals were involved. He then went on to show that highly reactive free radicals could initiate a chain reaction leading to the formation of polymers. This would prove to be of critical importance during the Second World War with the production of synthetic rubber using free radical polymerization.
However, these days we are more likely to connect free radicals to biological effects and to diets that feature antioxidants, substances that neutralize them. That takes us back to 1954 when University of Rochester biologist Rebeca Gerschman proposed that during the process of cellular respiration, as glucose reacts with oxygen to produce energy, reactive oxygen species (ROS), including free radicals, are created and cause cells to age and die. This, too, was received with skepticism and was not proven to be correct until 1969 when Irwin Fridovich at Duke University discovered an enzyme that was christened “superoxide dismutase” because it was found to catalyze the destruction of a free radical, termed “superoxide” that was a product of respiration as Gerschman had suggested.
Denham Harman had become intrigued by Gerschman’s 1954 paper because he had been interested in the aging process since 1945 when his wife had shown him a magazine article about Russian scientist Alexander Bogomolets’s efforts to prolong life. At that time, Harman was working as a research chemist for Shell Oil, but after being captivated by the article decided to go to medical school because he believed that would provide a background for the anti-aging research in which he was interested.
On learning of Gerschman’s oxygen free radical theory, he recalled his days at Shell when he had been working on free-radical polymerization and was familiar with antioxidants that interfered with the process. In 1956, Dr. Harman published a landmark paper in the Journal of Gerontology in which he proposed his “free radical theory of aging.” He then went on to show that dietary antioxidants administered to mice countered the effects of free radicals and prolonged their lives. Despite this never having been demonstrated in humans, a giant industry of antioxidant supplements has mushroomed based on unsubstantiated claims. I think Moses Gomberg would not be amused.