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Rolf Huisgen’s Legacy

2019; Elsevier BV; Volume: 5; Issue: 10 Linguagem: Inglês

10.1016/j.chempr.2019.09.009

2451-9308

K. N. Houk, Hans‐Ulrich Reißig,

Fluorine in Organic Chemistry

Rolf Huisgen was born in Gerolstein, a small town in western Germany near the Benelux states, on June 13, 1920. He started to study chemistry and mathematics at the University of Bonn in spring 1939, but the beginning Second World War caused him to move after one semester to the Ludwig-Maximilian-University in Munich. He joined the group of Heinrich Wieland (Nobel Prize in chemistry in 1927) as one of his last doctoral students and did research on strychnos alkaloids. He achieved Dr. rer. nat. in 1943 at the age of 23 years, worked as a research assistant in Munich at the end of war, and a few years after, in part in a wooden shack outside of Munich, and received his habilitation in 1947. As the rising star of the German chemistry community, he soon was appointed associate professor at the University in Tübingen (with Georg Wittig as senior colleague, Nobel Prize in chemistry in 1979). Already in 1952, he returned to Munich as successor of his academic teacher Wieland and as head of the Organic Chemistry Institute where he's taught and performed research ever since, even after his retirement in 1988. He received major awards and honors worldwide, among those the Liebig Memorial Medal, the Roger Adams Award, and the Otto Hahn Prize. Just recently, he was awarded the Citation Laureate of "Nobel Class" 2019 in chemistry together with Morten P. Meldal. Huisgen published more than 600 scientific papers in various areas of mechanistic, physical-organic, and heterocyclic chemistry and established a school of distinguished academic scholars in Germany and around the world. His legacy looms much larger than these impressive achievements. Early kinetic studies on reactions of diazoalkanes, performed in Huisgen's lab in 1957 to 1958, initiated the breakthrough concept of 1,3-dipolar cycloadditions. While isolated examples of some cycloadditions were scattered in the literature, Rolf Huisgen systematically classified these species, named the reaction, and predicted yet-unknown 1,3-dipoles. In our work on 1,3-dipolar cycloadditions, in the first year one coworker was engaged in exploration. At the beginning of the second year two more people joined the effort. Now, in the third year, seventeen coworkers reap the harvest and contribute to further expansion of this reactionIn the Centenary Lecture in London in 1960, published in 1961, Rolf Huisgen described how the laboratory's attention mushroomed: "In our work on 1,3-dipolar cycloadditions, in the first year one coworker was engaged in exploration. At the beginning of the second year two more people joined the effort. Now, in the third year, seventeen coworkers reap the harvest and contribute to further expansion of this reaction."1Huisgen R. 1,3-Dipolar Cycloadditions.Proc. Chem. Soc. 1961; : 357-369Google Scholar That initial announcement was followed by Huisgen's famous two articles in Angewandte Chemie in 1963.2Huisgen R. 1,3-Dipolar Cycloadditions Past and Future.Angew. Chem. Int. Ed. Engl. 1963; 2: 565-598Crossref Google Scholar, 3Huisgen R. Kinetics and Mechanisms of 1,3-Dipolar Cycloadditions.Angew. Chem. Int. Ed. Engl. 1963; 2: 633-645Crossref Google Scholar By 2019, the first of these articles had accumulated 1,871 citations, about the same as the famous Woodward-Hoffmann article on orbital symmetry that was published not long later in 1969 (1,885 citations).4Woodward R.B. Hoffmann R. The Conservation of Orbital Symmetry. Elsevier, 1971Crossref Google Scholar Huisgen represented the reaction as a concerted cycloaddition.2Huisgen R. 1,3-Dipolar Cycloadditions Past and Future.Angew. Chem. Int. Ed. Engl. 1963; 2: 565-598Crossref Google Scholar, 3Huisgen R. Kinetics and Mechanisms of 1,3-Dipolar Cycloadditions.Angew. Chem. Int. Ed. Engl. 1963; 2: 633-645Crossref Google Scholar This mechanistic formulation gained strong theoretical support from Woodward and Hoffmann's rules of conservation of orbital symmetry.4Woodward R.B. Hoffmann R. The Conservation of Orbital Symmetry. Elsevier, 1971Crossref Google Scholar Immediately, Rolf Huisgen grasped the importance of these results, and the complete correspondence of the Diels-Alder reaction and the 1,3-dipolar cycloadditions as [4π + 2π] processes was established. Huisgen rationalized reactivity and regioselectivity in concerted cycloadditions without requiring the immediacy of diradicals or zwitterions. On the basis of frontier molecular orbital (FMO) theory, three different reactivity types were derived by Reiner Sustmann (a former doctoral student of Huisgen) for 1,3-dipolar cycloadditions and Diels-Alder reactions.5Sustmann R. A simple model for substituent effects in cycloaddition reactions. I. 1,3-dipolar cycloadditions.Tetrahedron Lett. 1971; 12: 2717-2720Crossref Scopus (400) Google Scholar About the same time, a simple procedure to predict regioselectivities within the FMO formalism was devised by Houk.6Houk K.N. Sims J. Watts C.R. Luskus L.J. Origin of reactivity, regioiselectivity, and periselectivity in 1,3-dipolar cycloadditions.J. Am. Chem. Soc. 1973; 95: 7301-7315Crossref Scopus (889) Google Scholar However, in the late 1960s, Firestone presented mechanistic arguments that propose diradicals as intermediates in Diels-Alder reactions and 1,3-dipolar cycloadditions.7Firestone R.A. Mechanism of 1,3-dipolar cycloadditions.J. Org. Chem. 1968; 33: 2285-2290Crossref Scopus (336) Google Scholar A long-lasting controversy initiated new key experiments to prove the concertedness of the cycloadditions.8Huisgen R. Mechanism of 1,3-dipolar cycloadditions.Reply. J. Org. Chem. 1968; 33: 2291-2297Crossref Scopus (444) Google Scholar Two crucial studies involved the authors of this article: Reissig et al. showed that 1,3-dipolar cycloadditions of diazomethane with two E/Z-isomeric alkenes occurred with extremely high stereospecificity9Bihlmaier W. Geittner J. Huisgen R. Reissig H.-U. The Stereospecificity of Diazomethane Cycloadditions.Heterocycles. 1978; 10: 147-152Crossref Google Scholar and later, Houk and Firestone published similar experiments with a nitrile oxide and dideuteroethylene.10Houk K.N. Firestone R.A. Munchhausen L.L. Mueller P.H. Arison B.H. Garcia L.A. Stereospecificity of 1,3-dipolar cycloadditions of p-nitrobenzonitrile oxide to cis- and trans-dideuterioethylene.J. Am. Chem. Soc. 1985; 107: 7227-7228Crossref Scopus (71) Google Scholar Ironically, the first doubtless stepwise 1,3-dipolar cycloaddition was also established in the Munich laboratories: Huisgen, Langhals, and Mlostoń demonstrated that sterically crowded thiocarbonyl ylides add to very electron-deficient alkenes via 1,5-zwitterions.11Huisgen R. Mloston G. Langhals E. The first two-step 1,3-dipolar cycloadditions: non-stereospecificity.J. Am. Chem. Soc. 1986; 108: 6401-6402Crossref Scopus (116) Google Scholar Huisgen predicted new 1,3-dipoles, and his group developed new methods for their generation.1Huisgen R. 1,3-Dipolar Cycloadditions.Proc. Chem. Soc. 1961; : 357-369Google Scholar, 2Huisgen R. 1,3-Dipolar Cycloadditions Past and Future.Angew. Chem. Int. Ed. Engl. 1963; 2: 565-598Crossref Google Scholar, 3Huisgen R. Kinetics and Mechanisms of 1,3-Dipolar Cycloadditions.Angew. Chem. Int. Ed. Engl. 1963; 2: 633-645Crossref Google Scholar Unknown 1,3-dipoles, such as nitrile ylides and imines, and azomethine ylides and imines were proposed and subsequently studied. Their (3+2) cycloadditions with alkenes or alkynes allowed novel and highly flexible accesses to nitrogen-containing five-membered heterocycles, demonstrating the high synthetic value of 1,3-dipolar cycloadditions.121,3-Dipolar Cycloaddition Chemistry. Volume 1 and 2. John Wiley & Sons, 1984Google Scholar, 13Padwa A. Pearson W.H. Synthetic Applications of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles and Natural Products. John Wiley & Sons, 2002Crossref Google Scholar The generation and the reactivity of a new class of mesoionic compounds named münchnones (in analogy to the long-known sydnones) that incorporates an azomethine ylide moiety as 1,3-dipole were also carefully studied in the Munich laboratories (see Figure 4A).14Reissig H.-U. Zimmer R. Münchnones--new facets after 50 years.Angew. Chem. Int. Ed. Engl. 2014; 53: 9708-9710Crossref Scopus (45) Google Scholar Huisgen's 1968 general review of cycloadditions presented a general classification and definition that is now used universally.Huisgen's 1968 general review of cycloadditions presented a general classification and definition that is now used universally.15Huisgen R. Cycloadditions – Definition, Classification, and Characterization.Angew. Chem. Int. Ed. Engl. 1968; 7: 321-328Crossref Scopus (294) Google Scholar Rolf Huisgen's approach is based on the number of atoms incorporated in the new ring. The Huisgen group made countless contributions—discoveries, kinetics, detailed mechanisms—to many types of cycloadditions, such as (2+2) cycloadditions of highly electrophilic alkenes—such as tetracyanoethylene and ketenes to alkenes—and 1,4-dipolar cycloadditions. Huisgen also provided careful kinetic analyses of many other types of pericyclic reactions, such as electrocyclic ring-opening and ring-closing reactions; the work on aziridine-azomethine ylide ring opening or octatetraene-cyclooctatriene-bicyclo[6.2.0]octadiene isomerization are notable textbook classics. The kinetic studies and exquisite stereochemical analyses are landmarks in the field. Early studies on the generation and reactions of benzynes were carried out in the 1950s—parallel to seminal contributions of Roberts, Wittig, Bunnett, and others. The investigations of the properties of medium ring lactones were performed from 1955 to 1963, and organosulfur chemistry was another major Huisgen interest.16Huisgen R. The Adventure Playground of Mechanisms and Novel Reactions. American Chemical Society, 1994Google Scholar, 17Houk K.N. Rolf Huisgen's Profound Adventures in Chemistry.Helv. Chim. Acta. 2010; 93: 1241-1260Crossref Google Scholar The cycloadditions of organic azides to alkenes and alkynes were long known in literature (back to Arthur Michael in 1893). As a 1,3-dipolar cycloaddition, the reaction of azides with alkenes and alkynes were carefully studied in the Huisgen laboratories. The thermal reactions with alkynes usually require heating, and the regioselectivity is low, affording mostly mixtures of 1,4- and 1,5-substituted triazoles of interest to theory, but not so much in synthesis. Based on first examples of Meldal, Sharpless developed the Cu-catalyzed reaction of azides with terminal alkynes in 2002, and he coined the handy name "click chemistry" for this and related reactions, thus causing a renaissance in Huisgen chemistry.18Rostovtsev V.V. Green L.G. Fokin V.V. Sharpless K.B. A stepwise huisgen cycloaddition process: copper(I)-catalyzed regioselective "ligation" of azides and terminal alkynes.Angew. Chem. Int. Ed. Engl. 2002; 41: 2596-2599Crossref PubMed Scopus (9938) Google Scholar The complementary bio-orthogonal "copper-free click reaction" developed by Bertozzi uses strained cyclic alkynes as dipolarophile.19Agard N.J. Prescher J.A. Bertozzi C.R. A strain-promoted [3 + 2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems.J. Am. Chem. Soc. 2004; 126: 15046-15047Crossref PubMed Scopus (1844) Google Scholar The impact of these Huisgen reactions involved not only azides but also nitrile imines and oxides, sydnones, and münchnones among others is having strong influence on the development of many fields of chemistry, material science and biochemistry, including the search for lead candidates in medicinal chemistry. We have emphasized Huisgen's legacy in chemistry and its still-growing impact in chemistry. Chemists of future generations will learn to expand the scope of the "Huisgen reaction," a large family of enormously powerful transformations. Rolf Huisgen gave the world a chemical reaction that is a staple of synthesis of heterocycles, natural products, and materials. The Huisgen reaction is now an important tool for cellular imaging and metabolic exploration and a novel method of drug discovery.Rolf Huisgen gave the world a chemical reaction that is a staple of synthesis of heterocycles, natural products, and materials. Beyond the chemistry Huisgen created, there is Huisgen as teacher, mentor, and symbol of scientific excellence and elegance, a legacy that lives on in those who were trained by him or had the inspiration from his lectures or even only heard the insightful and penetrating questions he invariably asks at seminars. Rolf Huisgen is a gentleman and model professor in the old-fashioned sense of German scientific tradition. To his students and fellows, this meant challenge and high demand. His extraordinatry memory and analytical mind are legend among his colleagues and friends. Huisgen's love of art, especially German expressionism and African art, is a passion beyond chemistry that he shared with his friends. Visiting a picture gallery under his guidance or being guest in his home is an unforgettable experience. His interest in ancient civilization and art resulted in travel he could report on in textbook style.