Olah G.A. - A Life of Magic Chemistry (2001)(en)

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Under the oars held up by members of my rowing club after our wedding July 9, 1949

of any scientist is very demanding. If marriage is to be a real partnership, having a common understanding and interests in our professional life could help to make, or so I hoped, a marriage even more successful. I believe it worked out this way, but only through Judy’s efforts and understanding. I can only hope that she indeed has forgiven me after all these years.

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laboratories which I have seen in the early 1950s at the Humboldt University in Berlin—to provide better air circulation because Fischer suffered from chronic hydrazine poisoning from his research). The fume hoods were vented by a gas burner providing draft through the heated air, certainly a not very efficient system by today’s standards.

Zemplen, like Fischer, also ran his Institute in an autocratic way. Because the University was able to provide only an extremely meager budget, he purchased laboratory equipment, chemicals, books, etc. with his own earnings and consulting income. Like Fischer, Zemplen too expected his doctoral students to pay their own way. Fischer even charged them a substantial fee for the privilege of working in his laboratory. Becoming a research assistant to the professor was a great privilege, and, although it meant no remuneration, it also exempted one from any fees.

Zemplen was also a formidable character, and working for him was quite an experience, not only in chemistry. He liked, for example, ‘‘pubbing,’’ and these events in neighborhood establishments could last for days. Certainly one’s stamina and alcohol tolerance developed through these experiences. Recalling on occasion his Berlin days, Zemplen talked with great fondness of his lab mate, the Finnish chemist Komppa (of later camphene synthesis fame), who he credited not only with being a fine chemist but also with being the only one able to outlast him during such parties. In any case, none of this ever affected his university duties or his research.

Zemplen helped his students in many ways. I remember an occasion in the difficult postwar period. The production of the famous Hungarian salami, interrupted by the war, was just in the process of being restarted for export. The manufacturer wanted a supportive ‘‘analysis’’ from the well-known professor. Zemplen asked for a ‘‘suitable’’ sample of some hundreds of kilograms, on which the whole institute lived for weeks. When it was gone he rightly could offer an opinion that the product was ‘‘quite satisfactory.’’ After the war, grain alcohol was for a long time the only available and widely used laboratory solvent, and, not unexpectedly, it also found other uses. Later, when it was ‘‘denatured’’ to prevent human consumption, we devised clever ways for its ‘‘purification.’’ The lab also ‘‘manufactured’’ saccharine, which was

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then bartered for essential food staples in the countryside. One of my colleagues suffered serious burns one day when a flask containing chlorosulfuric acid broke in a water-ice bath, spraying acid into his face. Such was the price of moonlighting for survival.

Zemplen was a strong-minded individualist who opposed any totalitarian system, from Nazism to Communism. He was briefly jailed toward the end of World War II by the Hungarian Fascists for refusing to join in the evacuation of the Technical University to Germany when the Russian armies advanced on Budapest. He was also strongly opposed to the Communists.

As Zemplen was a student of Emil Fischer, therefore, I can consider myself Fischer’s ‘‘scientific grandson.’’ My initial research with Zemplen was along the lines of his interest in natural products and specifically centered on glycosides. Besides synthetic and some structural work, there also emerged practical aspects. Many glycosides present in nature have substantial pharmaceutical use. For example, some of the most effective heart medications were isolated from the pretty foxglove plant (Digitalis purpurea). Three cardiac agents had been prepared by the Swiss chemist Stoll, working for the Sandoz Company (digitoxin, gitoxin, and gitalin). Another member of the Digitalis family, Digitalis lanata, contains lanataglucoside C, whose aglucone is also digitoxin (still one of the most effective heart medications). As it turned out, the mild climate of the Tihany peninsula, jutting into famed Lake Balaton, favored the cultivation of this plant, and each year boxcar loads of its leaves were shipped to Sandoz in Switzerland. While working with Zemplen, I developed an improved process for the efficient isolation of lanataglycoside C, using treatment and solvent extraction of fresh leaves suppressing enzymatic degradation. This greatly increased yields, and a gram of pure lanataglycoside C could be obtained from a kilogram of leaves. Our process with Zemplen was patented in 1952 and, together with a process for partial hydrolysis to digitoxin, was successfully commercialized and used for years by the Richter Pharmaceutical Company. A booklet commemorating the 100th anniversary of the Hungarian Patent Office mentioned our patent as well as other Hungarian patents, such as those issued in the 1920s to Albert Einstein and Leo Szilard for an thermoelectric refrigerator (which, I

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understand, regrettably never brought any income to the inventors). In the 1930s in England, Szilard, the remarkable Hungarian-born physicist, applied for a patent on another invention, the principle of a thermonuclear device, the basis of the atomic bomb! In 1952, he and Enrico Fermi were issued an American patent for it, which by law the US Government acquired. What wide scope some inventors’ creative minds cover!

I have fond memories of my brief period as a natural product chemist, particularly because it de facto still involved collecting and isolating products from nature’s diverse plant life and doing chemistry directly on them. Most natural product chemists these days do not have this experience.

Around 1950, after having read about organic fluorine compounds, I became interested in them. I suggested to Zemplen that fluorinecontaining carbohydrates might be of interest in glycoside-forming coupling reactions. I believed that selective synthesis of - or - glycosides could be achieved by treating either acetofluoroglucose (or other fluorinated carbohydrates) or their relatively stable, deacetylated free fluorohydrins with the appropriate aglucons. His reaction to my suggestion was, not unexpectedly, negative. To try to pursue organofluorine chemistry in postwar Hungary was indeed far fetched. Zemplen thought that the study of fluorine compounds, which necessitated ‘‘outrageous’’ reagents such as hydrogen fluoride, was foolish. It became increasingly clear that my ideas and interests did not match his. Eventually, however, I prevailed and, with some of my early dedicated associates, Attila Pavlath (who, after a career in industry and governmental laboratory research, at the time of this writing, had been elected the President of the American Chemical Society) and Steve Kuhn, started to study organic fluorides. Laboratory space and particularly fume hoods were scarce in the Zemplen laboratories, and even when I became an assistant professor I was not welcome to ‘‘pollute’’ space intended for ‘‘real chemistry.’’ However, at the top floor of the chemistry building, overlooking the Danube and badly damaged during the war, was an open balcony used to store chemicals. In an unexpected gesture, Zemplen allowed me the use of this balcony. With some effort we enclosed it, installed two old fume hoods, and were soon in business

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in what was referred to as the ‘‘balcon laboratory.’’ I am not sure that Zemplen ever set foot in it. We, however, enjoyed our modest new quarters and the implicit understanding that our fluorine chemistry and subsequent study of Friedel-Crafts reactions and their intermediates was now approved.

Carrying out fluorine research in postwar Hungary was clearly not easy. There was no access even to such basic chemicals as anhydrous HF, FSO3H, or BF3, and we had to prepare them ourselves. HF was prepared from fluorspar (CaF2) and sulfuric acid, and its reaction with SO3 (generated from oleum) gave FSO3H. By treating boric acid with fluorosulfuric acid we made BF3. The handling of these chemicals and their use in a laboratory equipped with the barest of necessities was indeed a challenge. Zemplen’s consent to our work was even more remarkable, because he truly belonged to the ‘‘old school’’ of professors who did not easily change their mind. For example, he never believed in the electronic theory of organic chemistry. In 1952, he was persuaded to publish a Hungarian textbook of ‘‘Organic Chemistry,’’ which contained a wealth of information and discussion of natural products but otherwise still treated organic chemistry only in the descriptive ways of the nineteenth and early twentieth centuries. An interesting side aspect of this book was that it contained a substantial index, for which, with a faculty colleague (Lajos Kisfaludy), we were commissioned by the state publishing house on a per page basis. Our rather precarious financial existence (our meager university salary amounted to the equivalent of less than $50/month, which was gone by the middle of the month) inspired us to a remarkable effort. Our index eventually contained 250 pages (a fifth of the book) and even displayed the preparers’ names. I believe it is the longest index of any textbook of chemistry. It had, however, seen us through some difficult times.

No mechanistic aspects of organic chemistry (or, for this reason, any reaction intermediates) were ever mentioned by Zemplen in his lectures or writings, nor did he consider or accept their existence. I never heard him mention the names of Meerwein, Ingold, Robinson, or any other pioneers of the mechanistic electronic theory of organic chemistry. The possible role of organic ions was similarly never mentioned. He was,

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however, not alone at that time in this attitude. Continental, particularly German chemistry generally was slow to accept Robinson and Ingold’s electronic-mechanistic trends. Roger Adams, one of the leading American organic chemists of the time (and a descendent of the family that gave two presidents to America), for example, never believed in organic ions, and for a long time his influence prevented anybody (including Whitmore, who pioneered the concept of the role of cationic intermediates in organic chemistry in America) from publishing any article in the Journal of the American Chemical Society mentioning such ions. Clearly, working on such problems in the Zemplen Institute came close to sacrilege, but I somehow got away with it. Perhaps this was in part due to the fact that Zemplen’s health was declining at the time in his long battle with cancer; he came less frequently to the Institute, working mostly at his nearby apartment.

Did the Technical University in Budapest at this time provide a reasonable education and research atmosphere in chemistry? In retrospect, it is difficult to answer this question because of the prevailing isolation and primitive working conditions. The scope and topics of major courses taught, with some exceptions, mainly demanded memorization of facts and not understanding and discussion of concepts. Laboratory experimental work and research were much emphasized, despite the very limited facilities and opportunities. The overall system, however, prepared students well for self-study. I myself discovered at an early age the joy of broadening my scope and knowledge during long hours spent in the library in extensive reading and self-study (a habit I have kept all my life). Professors always lectured themselves, which was considered a major prerequisite of the professorship. Attendance by all students was strictly obligatory (the system was tailored on the German example). Lectures by popular professors were considered worthy and were well-attended events. I remember also attending many lectures outside my field in the Budapest universities such as by philosophers historians, which were always packed to the rafters with interested students.

In chemistry, there was clearly a great need to move ahead and bridge the gap between the earlier, entirely empirical approach of teaching and research and that incorporating the new trends of chem-

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istry. The emerging understanding of mechanistic-structural aspects, application of physical methods and considerations, and the basic principles of bonding, reactivity, etc. were rarely mentioned at the time. When as a young assistant professor I had a chance starting in 1953 to teach my own course, it was entitled ‘‘Theoretical Organic Chemistry’’ (although really it was mechanistic and structural, i.e., physical organic chemistry). It filled a gap for which I tried to introduce the evolving new frontiers of organic chemistry. I published a two-volume text based on my notes from the two-semester course given in 1953– 1954. An extended and reworked first volume in German was submitted to the publisher in 1956 but was published only in 1960 (G. Olah, Theoretische Organische Chemie, Akademie Verlag, Berlin, 1960) because of events that led to my move to America. The second volume of the German edition was never published. At that time in Germany, physical organic chemistry was also slow to develop. There was an early prewar text by Eugen Mu¨ ller, but it was Heinz Staab’s book in the 1950s that opened up the field. Looking up my own book occasionally, I realize that despite my isolation beyond the Iron Curtain, I still somehow managed to get myself oriented in the right direction. My book at the time was reasonably up to date and in some aspects maybe even novel and original.

During my time on the faculty of the Technical University I was also involved in helping to start a technical high school associated with the university. This school also filled a gap, because it was set up to allow evening study for those who did not have the opportunity for a high school education and were working at the university and in the surrounding community. It provided solid secondary education with an emphasis on the sciences and technology, qualifying its students for meaningful employment as technicians and in other technically oriented jobs. I remember that I even taught physics for a year, when we had difficulty finding a teacher for physics. To my surprise, I managed it quite well.

My teaching experience was, however, only secondary to my research interest. Through my initial research work involving reactions of fluorinated carbohydrates I became interested in Friedel-Crafts acylation and subsequently alkylation reactions with acyl or alkyl fluo-

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rides, with boron trifluoride used to catalyze the reactions. This also was the beginning of my long-standing interest in electrophilic aromatic and later aliphatic substitution reactions.

These studies at the same time aroused my interest in the mechanistic aspects of the reactions, including the complexes of RCOF and RF with BF3 (and eventually with other Lewis acid fluorides) as well as the complexes they formed with aromatics. I isolated for the first time at low temperatures arenium tetrafluoroborates (the elusive -complexes of aromatic substitutions), although I had no means to pursue their structural study. Thus my long fascination with the chemistry of carbocationic complexes began.

My early work with acyl fluorides also involved formyl fluoride, HCOF, the only stable acyl halide of formic acid, which was first made in 1933 by Nyesmeyanov, who did not, however, pursue its chemistry. I developed its use as a formylating agent and also explored formylation reactions with CO and HF, catalyzed by BF3.

Another aspect of my early research in Budapest was in nitration chemistry, specifically the preparation of nitronium tetrafluoroborate, a stable nitronium salt. I was able to prepare the salt in a simple and efficient way from nitric acid, hydrogen fluoride, and boron trifluoride.

This salt turned out to be remarkably stable and a powerful, convenient nitrating agent for a wide variety of aromatics (and later also aliphatics). Over the years, this chemistry was further developed, and nitronium tetrafluoroborate is still a widely used commercially available nitrating agent.

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In the course of my studies I also introduced silver tetrafluoroborate, AgBF4, as a metathetic cation forming agent suitable for forming varied ionic (electrophilic) reagents.

My publications from Hungary in the early 1950s somehow caught the eye of Hans Meerwein, a towering and pioneering German chemist. It is still a mystery to me how he came to read them. In any case I received an encouraging letter from him, and we started corresponding (even this was not easy at the time in a completely isolated Hungary). He must have sympathized with my difficulties, because one day through his efforts I received as a gift a cylinder of boron trifluoride. What a precious gift it was indeed, because it freed us from laboriously making BF3 ourselves.

My early research on organofluorine compounds starting in 1950 centered on new methods of their preparation and use in varied reactions. At the time I also started a collaboration with Camillo Sellei, a wonderful physician associated with the Medical University of Budapest, on the study of the pharmacological effect of organofluorine compounds and particularly on the use of some organic fluorine compounds in cancer research. Sellei and his researcher wife Gabi became close friends and the godparents of our older son, George. Our joint publications from 1952 to 1953 must be among the earliest ones in this intriguing field. In subsequent years, the work of Charles Heidelberger (who became a colleague of mine when I moved to the University of Southern California in Los Angeles) and other researchers introduced such widely used fluorinated anticancer drugs as 5-fluoro- uracil. The pursuit of the biological activity of fluorinated organic compounds clearly was a worthwhile early effort, as progress in this still rapidly expanding field was and still is remarkable.

At the time, I was so fascinated by the potential of our organofluorine compound-based pharmaceutical research that, to learn more about