WITTIG, GEORG

(b. Berlin, Germany, 16 June 1897;

d. Heidelberg, Germany, 26 August 1987), organic chemistry.

Wittig’s work was guided by the general idea of establishing the field of carbanion chemistry as equal in importance to the fields of free radical and carbonium ion chemistry. His studies led him to a great variety of new structures. Best known is his work on phosphorus ylides, which condense with carbonyl compounds to form alkenes. This concept, the Wittig reaction, opened the door to important classes of substances, such as vitamins and hormones, which are nowadays synthesized on an industrial scale. In 1979 he was awarded the Nobel Prize in Chemistry.

Early Life and Career. Wittig was born in Berlin, Germany, and grew up in Kassel, where his father was a professor of applied arts. Strongly encouraged by his mother, he learned to play the piano with enthusiasm. Nevertheless, he decided to study chemistry in Tübingen after having finished school in 1916. His academic career was interrupted by World War I, when Wittig was drafted into the army. He became a prisoner of war in 1918. After his return to Germany in 1919, Wittig found it difficult to get into a German university because the universities were overcrowded at that time. Following several rejections, he finally was accepted by the director of the Chemical Institute in Marburg, Karl von Auwers. Because of this experience, he later supported students who came back after World War II as former prisoners of war.

After Wittig completed his doctoral thesis in 1923, von Auwers encouraged him to pursue an academic career. In 1926 Wittig was appointed lecturer at the University of Marburg after the completion of his Habilitation (permission to lecture in a university). In his early days in Marburg, he and Karl Ziegler (a 1963 Nobel laureate in chemistry) became lifelong friends. Both chemists were not only extraordinary scientists but enthusiastic rock climbers in the Alps. Another friend and colleague of Wittig’s who accompanied him on his hikes and climbing tours was Walter Hückel, a professor of chemistry in Breslau and later in Tübingen.

When Hans Meerwein succeeded von Auwers as director of the Chemical Institute, he renewed Wittig’s contract and employed him as a senior research assistant, having been deeply impressed by his textbook, Stereochemie(1930). In Marburg, Wittig married Waltraud Ernst, who also worked in von Auwers’s group. They had three daughters. Waltraud Wittig, who also had a doctoral degree, took great interest in the scientific work of her husband until her early death in 1978. She also regularly invited the members of Wittig’s research group to social events.

In 1932 Wittig received his first permanent position with an appointment as Auæerplanmäæiger Professor (a title awarded to lecturers who are neither full nor associate professors) at the Technische Hochschule in Braunschweig. However, his time in Braunschweig proved to be a problematic period in Wittig’s academic career. The director of the institute, Karl Fries, who was well-known for the discovery of the Fries rearrangement, strongly opposed the Nazi regime. Eventually, the Nazi government forced him to retire. Wittig, who had always supported Fries, feared that he, too, would lose his academic position.

Fortunately, he was invited by Hermann Staudinger, the director of the Chemical Institute at the University of Freiburg in Breisgau, to become an associate professor at that institution in 1937. (In Braunschweig there was a strong Nazi among the lecturers at that time. Staudinger also refused the Nazi regime and had to suffer under political pressure. Fortunately he could hold his position in this difficult period because of his very high scientific reputation.) Wittig presumably was chosen for this position because he had supported Staudinger’s concept of high polymers in his Stereochemie in the face of much scientific opposition to the latter’s fundamental work. (Staudinger eventually was awarded the Nobel Prize in Chemistry in 1953.)

Many of Wittig’s important contributions were planned and begun at the University of Freiburg. Examples are the formulation of dehydrobenzene; the Wittig rearrangement of ethers; and the discovery of the new class of ammonium ylides. However, because this work was started during World War II, these concepts were not examined thoroughly until later, in the postwar period.

At Tübingen and Heidelberg. In 1943 Wilhelm Schlenk, a very capable organometallic chemist, died in Tübingen. The faculty of the University of Tübingen nominated Wittig as his successor there, and he was appointed full professor and director of the university’s Chemical Institute. Finally, at the age of forty-seven years, Wittig reached a position where he would have the facilities and equipment that he needed.

After the end of the war, the number of students increased and Wittig was able to establish a very active research group. It was characteristic of him that he took care of each graduate student personally, even later in Heidelberg, when he had a large group. Often, he made sure to be present when an important experiment was started, maintaining that “four eyes see more than two.” Wittig particularly wanted to see whether color changes occurred during a reaction, being one of those chemists who were interested in the relationship between the constitution and color of a substance. The purity of the reagents and solvents that were used was an important consideration for Wittig. The practical abilities of a graduate student were to be supervised through his personal control of all elemental analyses of new compounds isolated in his group. This procedure prevented him from drawing false conclusions.

Wittig set high standards regarding his students’ qualifications and enthusiasm and demanded careful experiments performed at a clean laboratory space. On the other hand, he acknowledged the contributions and merits of each graduate student in his lectures.

Wittig gave strong attention to his academic duties. In Tübingen he chose promising younger colleagues— Walter Theilacker, Karl Dimroth, Rolf Huisgen, Friedrich Weygand—as associate professors; all got appointments as full professors from other universities in short order.

In 1956 Wittig moved once more. The director of the Chemical Institute at the University of Heidelberg, Karl Freudenberg, famous for his work in the field of natural products, retired, and the faculty nominated Wittig as his successor. Wittig accepted this prestigious appointment at the age of fifty-nine, although he had had great success during his time in Tübingen.

Heidelberg offered several advantages to Wittig. He could move into a large new building and establish a group of from thirty to forty members. The BASF company, where the Wittig reaction was being run on an industrial scale, was nearby in Ludwigshafen am Rhine. Two institutes, one for organic chemistry and a second one for inorganic chemistry, had recently been founded in Heidelberg. This made it possible to appoint three additional full professors for organic chemistry: Heinz A. Staab, Hermann Schildknecht, and Hans Plieninger. As a result, up to fourteen different research groups were active in the organic chemistry institute. The appeal of this institute is documented by the list of its distinguished visiting professors, including Donald J. Cram, Herbert C. Brown, Gerhard M. J. Schmidt, and Arthur G. Anderson Jr.

Wittig also had a great success as mentor. In Heidelberg, he encouraged many young scientists to start an academic career. The first one was Ulrich Schöllkopf, who demonstrated the value of the Wittig reaction as a graduate student. Other former students of Wittig had the same opportunity at other universities. Nearly all of them were appointed professors in Germany, the Netherlands, Switzerland, and the United States.

In 1979 Georg Wittig, together with Herbert C. Brown, was awarded the Nobel Prize in Chemistry. The Royal Swedish Academy of Science honored Brown and Wittig “for their development of the use of boron- and phosphorus-containing compounds, respectively, into important reagents in organic synthesis.”

Between 1953 and 1979, Wittig received many awards, honorary doctorates, and other forms of recognition. He was the first German after World War II to receive an honorary doctorate from the Sorbonne, in Paris, in 1957. This was an acknowledgment of his meritoriousness for reestablishing the reputation of German science after the war.

Wittig’s last years in Heidelberg were dominated by the sudden death of his wife and his own physical weakness. Wittig died a few weeks after his ninetieth birthday.

During his long career, more than three hundred graduate students and postdoctoral colleagues were associated with Wittig. The more than three hundred scientific papers that were published between 1924 and 1980 demonstrate the fruitfulness of his career. With his demise, the international community of organic chemists lost one of its greatest representatives in the twentieth century.

From Arenes to Organometallics. The first independent work of Wittig in Marburg followed from the chemistry of his academic teacher, von Auwers. He synthesized aromatic compounds with oxygen functionality and related hetero-cycles. However, Wittig soon entered new fields. His aim was to find highly strained three- and four-membered ring systems with a tendency to form diradicals. Physical methods to detect radicals were not available to Wittig at that time, so his efforts could not be brought to completion.

Nevertheless, Wittig’s interest in radicals had a great impact on his further scientific work because it led him to organometallic chemistry. He needed sterically hindered compounds with phenyl groups as starting material. These substances were usually synthesized by the addition of organomagnesium derivatives, the Grignard compounds, to ketones. This classical reaction failed in the case of the ketone 1 in Figure 1. Therefore, Wittig used phenyllithium (2 ), the preparation of which had just been reported by his friend Ziegler. Indeed, phenyllithium proved to be superior to phenylmagnesium bromide and formed the desired product 3 in high yield.

This success led Wittig to a new orientation of his research interests. He now wanted to study the chemistry of the new reagent 2 in detail. In this way he entered the field of “carbanion chemistry,” as he called it. Later, organometallic chemistry or carbanionoid chemistry became the preferred terms.

Discoveries with Phenyllithium. The most important discoveries of Wittig fall into the period between 1937 and 1956. In 1942 his review, “Phenyl-lithium, der Schlüssel zu einer neuen Chemie metallorganischer Verbindungen” (Phenyllithium, the key to a new chemistry of organometallic compounds), was published. In the course of his investigations, he observed the exchange of hydrogen for lithium and the exchange of bromine against lithium, the metalation and the halogen-metal exchange reactions. Simultaneously and independently, Henry Gilman, at Iowa State University in Ames, Iowa, observed the same behavior upon treating aryl halides with n-butyl-lithium. At that time, both exchanges were considered very unusual, but since then, they have become among the most widely used reactions in organometallic chemistry.

The treatment of fluorobenzene with phenyllithium gave surprising products again, which led Wittig in 1942 to propose dehydrobenzene C₆ H₄ (benzyne 4 ) as a reactive intermediate (see Figure 2). At first he hesitated to publish this adventurous hypothesis because he feared for his scientific reputation. Fortunately, John D. Roberts, at the California Institute of Technology (Caltech) at Pasadena, and Rolf Huisgen at the University of Munich found evidence to support the concept of dehydroaromatic compounds (arynes) in independent studies. Wittig himself succeeded in trapping the reactive intermediate 4 with furan (5 ) by means of a Diels-Alder reaction that proceeded to give 6 proceeded in high yield (see Figure 2).

The arynes and strained cycloalkynes that were generated in Heidelberg were later developed as valuable building blocks in organic synthesis because they undergo

manifold additions and cycloadditions. Reinhard W. Hoffmann, later professor at Marburg, published a comprehensive monograph, Dehydrobenzene and Cycloalkynes, in 1967. The diversity of reactions of organolithium derivatives was also demonstrated by the metalation of benzyl ethers. As in Figure 3, the lithiated ethers like 7 rearrange to carbinolates 8. The Wittig rearrangement of the type 7→8 has an interesting mechanism and a broad scope of application that is discussed in modern textbooks of organic chemistry.

Encouraged by the success with phenyllithium, Wittig began another bold research project in Freiburg. A dogma was often a challenge for him. Therefore, he sought to overthrow the octet rule for nitrogen compounds. To that end, he tried to prepare the pentacovalent compounds, tetramethylphenyl- and pentamethylnitrogen. As a result of his efforts, he discovered the new class of ammonium ylides.

Other authors later showed that derivatives containing a lithium salt should be considered as lithiated ammonium salts rather than as ylides. The ammonium ylides undergo various rearrangements and elimination reactions. In the course of this work Wittig always used benzophenone to determine the position of lithiation. This principle of obtaining crystalline derivatives for characterization sounds trivial, but it was just this procedure, using benzophenone, that led him in 1953 to the discovery of the Wittig reaction.

New Topics at Tübingen Wittig’s time in Tübingen was characterized by further successful research topics. The first organic ate-complexes with the structure 10 in Figure 4 were synthesized. The role of these complexes as reaction-determining intermediates was outlined and later found broad acceptance in the field of organometallic chemistry. In this context Wittig repeatedly pointed to the work of Hans Meerwein on onium-complexes 9 in cation chemistry. He was able to demonstrate that the basic concept of anionic activation of ligands in ate-complexes 10 as a counterpart to cationic activation in onium-complexes 9 is a useful one. A well-known representative is sodium tetraphenylborate (11. ), which was introduced in analytical chemistry as an excellent reagent for the quantitative determination of potassium and ammonium ions in aqueous solution.

Continuing the work on hypervalent compounds of the elements in the main groups 5–7 of the periodic table, Wittig was able to synthesize pentaphenyl phosphorane. Its higher homologues, tetraphenyltellurium and triphenyliodine, followed later.

In the course of these investigations, methyltriphenylphosphonium iodide (12 ) in Figure 5 was treated with phenylllithium (2 ). By analogy to the behavior of related ammonium salts, 2 did not add to the central atom but yielded triphenylphosphonium methylide (13 ) by proton abstraction. The use of the above-mentioned benzophenone (14 ) for the determination of the deprotonated position gave surprising products. Triphenylposphine oxide (16 ) and 1.1-diphenylethylene (17 ) were formed in high yield via the intermediate (15 ).

Wittig immediately recognized the need to examine the significance of this experiment. This was done by Ulrich Schöllkopf, later professor at Göttingen, in his doctoral thesis. Only one year later, Wittig and Schöllkopf published a pioneering paper, “Über Triphenyl-phosphinmethylene als olefinbildende Reagenzien (I. Mitteil)” (1954; Triphenyl phosphine methylene derivatives as reagents for the formation of olefins), in Chemische Berichte in which they demonstrated the broad scope of the reaction of 13 and higher homologues with ketones and aldehydes. In all cases, the new carbon-carbon double bond was formed in the original position of the former carbon-oxygen double bond. Such a regioselective carbonyl olefination under mild conditions without use of acids was not known at that time. Now, many unsolved problems could be overcome. For some fields, such as the synthesis of polyenes, this method was a revolution. Well-known examples are vitamin A and æ-carotene, for which syntheses on a large scale were developed by the chemical industry. Horst Pommer at BASF converted the Wittig reaction to industrial practice.

The Wittig reaction is one of the very important reactions in organic chemistry for industrial applications as well as academic research. This principle, modified and improved by many groups throughout the world, turned out to be highly reliable in numerous cases.The formation of the carbon-carbon double bond in the original position of the former carbon-oxygen bond was a prerequisite for the total synthesis of natural products performed with the aim of proving a proposed structure. In Germany, Leopold Horner at the University of Mainz developed related valuable olefination reactions.

The Wittig reaction was not designed—real novelties are seldom planned. It was, rather, the result of a theoretical quest, the search for pentacovalent compounds. In this context, Wittig possessed the ability to interpret an unexpected observation and to perceive at once its potential for the future.

Accomplishments at Heidelberg. The efforts of his many co-workers and the excellent equipment in Heidelberg made it possible for Wittig to fulfill his lifework. About 150 of his papers appeared in print between 1958 and 1980. The last one was Wittig’s Nobel lecture. It is noteworthy that only eleven publications deal with the carbonyl olefination, the Wittig reaction. A new aldehyde synthesis was presented in one of these contributions. It was typical for Wittig not to accumulate analogous examples of a known method but, rather, to enter new territory. However he promoted the work of Manfred Schlosser, later a professor at the University of Lausanne in Switzerland, who found methods for performing the Wittig reaction in a stereoselective manner.

In Heidelberg, much effort was made to examine the generation of the highly strained lower cycloalkynes (cycloheptyne, cyclohexyne, and cyclopentyne) with a bent carbon-carbon triple bond as reactive intermediates. The alkyne synthesis from 1,2-diketones via 1,2-bishydrazones, developed by Theodor Curtius in 1891, proved to be especially suitable for this project. New approaches to the related arynes were also elaborated. A nonorganometallic route started with a heterocycle (1,2,3-benzothiadiazole-1,1-dioxide) that could be cleaved to give dehydrobenzene, nitrogen, and sulfur dioxide. Using different precursors for dehydrobenzene, Huisgen proved the existence of the intermediate C₆ H₄ in cycloadditions.

The development of the directed aldol condensation was one of the new topics at that time. This method leads to βunsaturated carbonyl compounds such as β-phenyl cinnamic aldehyde. The reaction sequence is a complement of the carbonyl olefination because unsaturated aldehydes and ketones are not available via phosphonium ylides.

The discovery of the directed aldol condensation is an impressive example of Wittig’s persistence in his research. In 1942 a graduate student made an observation that could not be understood without the use of spectroscopic methods not available at that time. Later two other graduates were engaged to solve this problem in their doctoral theses. Only twenty years afterward did things become clear when it could be shown that lithium diethylamide, used in the earlier experiment, serves as lithium hydride donor to benzophenone.

This unusual redox reaction, which probably proceeds via an ate-complex, was the key to the solution of the problem and confirmed once more the importance of ate-complexes in organometallic chemistry. Wittig himself used this redox system for the enantioselective reduction of prochiral ketones with chiral amides. Later, other authors could obtain enantioselectivities up to 95 percent by the use of improved chiral lithium amides.

The syntheses of hypervalent phosphorus and arsenic compounds were continued in Heidelberg with the aim of exploring their interesting stereochemistry. Aside from Wittig, his former student, Dieter Hellwinkel, later a professor at Heidelberg, worked successfully in this field. Also, the interest of the Wittig group in strained compounds was shown by the elaboration of new cyclopropane syntheses via ylides and organozinc derivatives.

After his formal retirement Wittig came back to aromatic compounds and diradicals in which he had been interested more than fifty years earlier as a young lecturer. These late studies as professor emeritus opened an elegant way for other authors after his death to a dendrimer, a member of a modern class of macrocycles.

Finally, it should be noted that female graduate students participated in important developments. Utta Pockels found the hydrogen- and bromine-lithium exchange at Braunschweig, Maria-Helene Wetterling obtained trimethylammonium methylide at Freiburg, Lisa Löh-mann observed the Wittig rearrangement at the same university, Liselotte Pohmer succeeded in trapping dehydrobenzene with furan at Tübingen, and Hannelore Renner worked out the fundamentals for the directed aldol condensation in Heidelberg.

Outlook. How can great contributions such as Wittig’s be summarized briefly? The progress of organic syntheses in the twentieth century may be attributed to the use of derivatives of nearly all elements of the periodic table. Using simple compounds such as triphenylborane, phenyllithium, and triphenylphosphine, Wittig opened new possibilities of fundamental importance.

On the occasion of the one hundredth anniversary of his birth in 1997, the Chemische Gesellschaft zu Heidelberg organized a special symposium, “The Research of Georg Wittig—Relevance to Chemistry Today.” In his published lecture, “The Wittig and Related Reactions in Natural Product Synthesis” (1997), K. C. Nicolaou of the Skaggs Institute for Chemical Biology at La Jolla, California, concluded on pages 1297–1300:

Having experienced the Wittig and related reactions in total synthesis, one can only attempt to imagine the state of art without them. Very few reactions can claim similar status to the Wittig reaction in revolutionizing organic synthesis. It is to say that, collectively, these discoveries have changed not only the way we do chemistry today, but, most significantly the way we live, through developments in chemistry that have found application in nutrition, cosmetics, agriculture, clothing, dyestuffs, plastics, high-tech materials, and medicine.

In 1999 the Georg Wittig Lectureship was inaugurated at the University of Heidelberg. Reinhard W. Hoffmann of the University of Marburg gave a lecture titled, “Wittig and His Accomplishments—Still Relevant beyond His 100th Birthday.” Therein he not only summarized the most significant results but presented also examples of other authors who benefited from Wittig’s work after his death. Hoffmann closed his review on page 1416 (2001) with these words: “The many examples provided in this essay show that Wittig’s accomplishments become and remain important to chemists in changing contexts far beyond his hundredth birthday. The next generation of chemists has only to realize that Wittig’s oeuvre is still a gold mine of facts and concepts to be exploited.”

BIBLIOGRAPHY

A comprehensive list of the publications and awards of Georg Wittig can be found in the obituary by Werner Tochtermann in Liebigs Annalen/Recueil (1997): i–xxi. Additional unpublished documents relating to Wittig can be found in the University Library and in the Library of the Chemical Institute in Heidelberg.

WORKS BY WITTIG

Stereochemie. Leipzig, Germany: Akademische Verlagsgesellschaft, 1930.

“Phenyl-lithium, der Schlüssel zu einer neuen Chemie metallorganischer Verbindungen.” Naturwissenschaften 30 (1942): 696–703.

With Ulrich Schöllkopf. “Über Triphenyl-phosphin-methylene als olefinbildende Reagenzien (I. Mitteil).” Chemische Berichte 87 (1954): 1318–1330.

“Small Rings with Carbon-Carbon Triple Bonds.” Angewandte Chemie(International Edition in English) 1 (1962): 415–419.

“1,2-Dehydrobenzene.” Angewandte Chemie(International Edition in English) 4 (1965): 731–737.

“The Role of Ate Complexes as Reaction-Determining Intermediates.” Quarterly Reviews(Chemical Society, London) 20 (1966): 191–210.

With Helmut Reiff. “The Directed Aldol Condensations.” Angewandte Chemie(International Edition in English) 7 (1968): 7–14.

“From Diyls over Ylides to My Idyll.” Accounts of Chemical Research 7 (1974): 6–14.

OTHER SOURCES

Hoffmann, Reinhard W. Dehydrobenzene and Cycloalkynes. New York: Academic Press, 1967.

———. “Wittig and His Accomplishments—Still Relevant beyond His 100th Birthday.” Angewandte Chemie(International Edition in English) 40 (2001): 1411–1416.

Maercker, Adalbert. “The Wittig Reaction.” In Organic Reactions, edited by Arthur C. Cope. Vol. 14. New York: Wiley, 1965.

Nicolaou, K. C., Michael W. Härter, Janet L. Gunzner, et al. “The Wittig and Related Reactions in Natural Product Synthesis.” Liebigs Annalen/Recueil (1997): 1283–1301.

Pommer, Horst. “The Wittig Reaction in Industrial Practice.” Angewandte Chemie (International Edition in English) 16 (1977): 423–429.

Tochtermann, Werner. “Structures and Reactions of Organic Ate-Complexes.” Angewandte Chemie (International Edition in English) 5 (1966): 351–371.

Werner Tochtermann