Chapter 14 Wittig Reaction

Georg Wittig was born in Berlin, Germany on June 16, 1897. Shortly after he was born, he moved with his family to Kassel. His father was a professor there at the applied arts high school. He was educated in Kassel. Early in his life he became keenly interested in science, music and mountain climbing, and he pursued these passions for his entire life. He began his studies in chemistry at the University of Tubingen in 1916. But his education was interrupted by his military service during World War I. He was captured as an English prisoner of war in 1918. After he was released in 1919, he restarted his chemistry studies, which was complicated because the universities were overcrowded. By a direct plea to Karl von Auwers, a professor of organic chemistry at the University of Marburg at that time, Wittig was able to rejoin a university. After three years he received his Ph.D. in organic chemistry at the University of Marburg. Karl von Auwers convinced him to start an academic career. He did his habilitation in 1926 and then became a close friend to Karl Ziegler, who was also doing his habilitation with Auwers during that time. He was assumed as lecturer by Hans Meerwein, who was the successor of Karl von Auwers, partly because Meerwein was impressed by Wittig’s new 400-page book on stereochemistry. In 1931 he married Waltraud Ernst, a colleague from the Auwers research group. Karl Fries invited him as a professor at the University of Braunschweig in 1932. Then he went to the University of Freiburg. In 1944, and later he moved to Tubingen as Professor and head of the Institute of Chemistry. Finally he moved in 1956 to the University of Heidelberg as head of the department where he became Professor Emeritus in 1967.

In the early 1950s, the synthesis of alkenes with complete control of the position of carbon-carbon double bond was impossible. Mixtures of alkenes, sometimes having rearranged carbon frameworks, were often formed upon base-induced dehydrohalogenation of alkenes and acid-catalyzed dehydration of alcohols. This situation was about to change, however, its initial discovery was not easy or straightforward at all. Wittig was seeking to synthesize compounds having five carbon atoms bonded to a nitrogen atom. He assumed that phenyl lithium’s strong nucleophilic nature would allow its negatively charged phenyl group to attach to the positive nitrogen in quaternary ammonium salt NR4+. Unexpectedly, what he found was that phenyl lithium’s strong basic property led to the removal of a positive proton from one of the four carbon atoms that were bonded to the nitrogen. This produced a novel type of compound that Wittig called ylide, which had a double bond character between nitrogen and carbon. The partial positive charge on the nitrogen and negative change on the carbon in the product was similar to the type of bonding force found in salts or ionic compounds, which prompted Wittig to adopt a suffix “-ide” for naming the product.

Nevertheless, ylides of the nitrogen were really hard to form and very unstable. Wittig had to turn to analogues made through phosphorus reactants. Phosphorus ylides should be more stable and easier to form because the weaker electronegativity of phosphorus reduces the destabilizing ionic character in the P = C bond. Indeed in 1953 Georg Wittig and one of his students, George Geissler, replaced quaternary ammonium salt with quaternary phosphonium salt, succeeded in extracting its proton from the carbon atom directly bonded to the P atom by alkyllithium, and observed the stable formation of dialkylphosphorane compound. Upon noticing the facile reaction of 1,1-diphenylphosphorane with a ketone, benzophenone, they studied the chemistry of the new pentavalent organophosphorus compounds, a new type of ylides, and published the unexpected result as a small part of a paper summarizing other aspects of the chemistry of these organophosphorus compounds.

Because Wittig and Geissler were unaware of a related reaction that had been reported 30 years earlier by Herman Staudinger, they were astonished by their result. However, Wittig recognized the importance of the discovery. He and another student, Ullrich Schollkopf, almost immediately published a second paper on the reactions of methylenetriphenylphosphorane with a variety of aldehydes and ketones to give alkenes under very mild conditions and with no isomerization. For the first time, it was possible to prepare alkenes with predicable structure, because the carbon-carbon double bond that was produced by the reaction always replaces the carbon-oxygen bone of the carbonyl-containing reagent.

Soon the reaction was being widely used in research laboratories throughout the world. Today the Wittig reaction and variants thereof stand as some of the most important reaction in organic chemistry for the efficient synthesis of a diverse array of substituted alkenes. In research laboratories, the Wittig synthesis of alkenes is commonly applied to the preparation of small quantities of alkenes, but it may also be carried out on a large scale in industry where it has been used to prepare tonnage quantities of Vitamin A.

Wittig was involved in many areas of research including the concept of ring strain, valence tautomerism, diradicals, the formation and reactions of dehydrobenzenes, carbanions, and organophosphorus chemistry. His interest in the latter two subjects gave rise to his work with the ylides that were formed upon deprotonation of alkyltriphenylphosphonium salts. In due course, this research resulted in his discovery of the Wittig synthesis of alkenes, work for which he shared the Nobel Prize in Chemistry in 1979 with Herbert Brown of Purdue University. His studies of carbanions also led to important discoveries with metalated derivatives of Schiff bases or imines, which are termed metalloenamines; these reactive intermediates have been proven to be very useful in directed aldol reactions and for effecting the monoalkylations and for effecting the monoalkylations of aldehydes and ketones. But it is for his serendipitous discovery of the reaction that bears his name that Wittig is best remembered.

Preparation of Simple Ylide

In the Wittig reaction, an aldehyde or ketone reacts with a triphenyl phosphonium ylide (often called a Wittig reagent) to generate an alkene and triphenylphosphine oxide. Ordinarily, the Wittig reagent is made from a phosphonium salt, which is in turn given by the reaction of triphenylphosphine with an alkyl halide. The Wittig reagent is formed by the suspension of the phosphonium salt in a solvent such as diethyl ether or THF with the addition of a strong base such as phenyllithium or w-butyllithium, which is used to remove the proton from the carbon attached to P.

Methylenetriphenylphosphorane (Ph3P = CH2) is the simplest ylide used. This also serves as the basis of an alternative synthesis of Wittig reagents. Substituted ylides can be prepared by alkylation of Ph3P=CH2with a primary alkyl halide R-CH2-X, resulting in a substituted phosphonium salt, which can be deprotonated with C4H9Li to give Ph3P = CH - CH2-R.

The Structure of Ylide

The Wittig reagent may be written in two forms, the phosphorane form, which is the more familiar representation, or the ylide form:

However, expansion of the octet on phosphorus is required for the phosphorane resonance. Standard bonding theory cannot yet well explain this hypervalency. In addition, this resonance is rather less favored than the more familiar p-p overlap that has been seen in π-bonded compounds such as alkenes or imines. This indicates that the ylide form makes a significant contribution, and the carbon is quite nucleophilic. Obviously, the phosphorane form can accommodate the extra electron pair with its vacant d-orbitals.

Reactivity

Simple phosphoranes are very reactive, and they are unstable with air of moisture present. Therefore, they are made in a scrupulously dry solvent (typically THF) under nitrogen or argon atmosphere. Additionally, once the phosphorane has been formed, the carbonyl compound is immediately added. More stable phosphoranes can be obtained when the ylide contains a group that stabilizes the negative charge from the carbanion, for example, Ph3P=CH -COOR or Ph3P=CH-Ph. These phosphoranes are formed more readily, and they require treatment of the phosphonium salt only with Na OH. These are usually isolable, crystalline compounds, less reactive compared with simple ylides, and so they usually cannot react with ketones, making it necessary to use the Homer-Wadsworth-Emmons reaction as an alternative.

Examples of Applications

The Wittig reaction has been a standard synthetic technique for organic chemists because of its reliability and wide applicability. The most popular use of the Wittig reaction is to introduce a methylene group using methylenetriphenyiphosphorane (Ph3P=CH2). even camphor, a sterically hindered ketone, can be converted with success to its methylene derivative by heating with methyltriphenylphosphonium bromide and potassium fert-butoxide, which forms the Wittig reagent in situ.

In a second example, the phosphorane is prepared using sodium amide as a base, The reaction is conducted in cold THF, and the sensitive functional groups such as nitro, azo, and phenoxide all survive intact. Incorporating the resultant compound with a photostabilizer into a polymer can protect the polymer from damage by UV radiation.

Today many important alkenes are made using the Wittig process. These include squalene (which is the precursor of cholesterol), vitamin D3, and various steroids.

Although Wittig retired in 1967, he continued publishing with his former students and colleagues until the age of 90. He compared in 1979 his paths of research work to mountaineering-nothing straightforward from the starting point to the desired goal, “although intention predisposes the route, chance or occurrences along the way often enforce a change of course.”