Fischer, Emil Hermann

(b. Euskirchen, near Bonn, Germany, 9 October 1852; d. Berlin, Germany, 15 July 1919)

chemistry

Fischer was the son of Laurenz Fischer, a successful merchant, and Julie Poensgen Fischer. His father hoped that he would become a businessman; but after a trial period in business ended in failure, the elder Fischer consented to his son’s desire for a university education. Fischer entered the University of Bonn in 1871 and attended the lectures of Kekulé. He transferred to Strasbourg the following year, where he studied chemistry under Adolf von Baeyer and obtained the doctorate in 1874. He accompanied Baeyer to Munich in 1875, and qualified as Privatdozent in 1878 and as assistant professor in 1879. He became professor of chemistry at Erlangen in 1882, at Würzburg in 1885, and at Berlin in 1892.

Fischer married Agnes Gerlach in 1888; she died seven years later. Two of their three sons were killed in World War I, but the eldest, Hermann Fischer, became an outstanding organic chemist.

Emil Fischer received the Nobel Prize for chemistry in 1902 in recognition of his syntheses in the sugar and purine groups. During World War I he was active in organizing the German chemical resources and headed the commissions for chemical production and food supplies. After the war, he helped to reorganize the teaching of chemistry and to establish research facilities. His work in organic chemistry was primarily on the constitution and synthesis of substances present in organisms. He laid the chemical foundations for biochemistry by his study of sugars, enzymes, purines, and proteins.

Hydrazine Chemistry. Fischer’s first publications (1875) dealt with the organic derivatives of hydrazine. He discovered this new group of compounds, considering them to be derivatives of the as yet unknown compound N₂ H₄, which he named hydrazine to indicate its relation to nitrogen (azote). In 1866 Kekulé had formulated diazonium compounds as R–N=N–X, similar to the azo formula (R–N=N–R). Since azo compounds were very stable and diazonium compounds were not, chemists disputed Kekulé’s formula. In 1871 Adolf Strecker obtained a salt from benzenediazonium nitrate and potassium hydrogen sulfite. Fischer repeated this work and proved that Strecker’s salt was a reduction product—potassium phenylhydrazine sulfonate (C₆ H₅ NHNH₂—SO₃ K)—of the diazonium compound. This work confirmed the Kekulé formula, and Strecker’s compound was a salt of phenylhydrazine. Fischer then prepared phenylhydrazine itself and established its formula by 1878. He prepared many organic derivatives of hydrazine and explored their reactions. The reaction of hydrazines with carbon disulfide led to dyestuffs. Oxidation produced tetrazenes, compounds with chains containing four nitrogen atoms. Aryl hydrazines with ketones and keto acids condensed to form derivatives of indole (the Fischer indole synthesis, 1886).

In 1884 Fischer discovered that phenylhydrazine was a valuable reagent for aldehydes and ketones. It formed solid, crystalline compounds (phenylhydrazones) which had a definite melting point. He then found that it formed not only the hydrazone with carbohydrates but also attacked the hydroxyl group

adjacent to the carbonyl group. He called these compounds osazones. The osazones were also crystalline solids and thus were useful in the identification of sugars. By 1888 he had established the structures of hydrazones and osazones. He was to utilize these reactions of phenylhydrazine in elucidating the chemistry and structure of the carbohydrates.

Aniline Dyestuffs. Fischer’s doctoral thesis had been on the chemistry of colors and dyes. He extended this interest to the new synthetic dyestuffs. He and his cousin Otto Fischer examined the constitution of rosaniline, the basic dyestuff prepared by August von Hofmann in 1862 by the oxidation of toluidine and aniline. There were several conjectures on the constitution of this base but no satisfactory solution until the Fischers succeeded in showing that it was a triphenylmethane derivative. They reduced rosaniline to a colorless derivative, which they called leucaniline and converted, by removal of its nitrogen atoms, into a hydrocarbon of composition C₂₀ H₁₈. They carried out similar reactions with pararosaniline (from p-toluidine and aniline), obtaining a hydrocarbon with the formula C₁₉ H₁₆, which proved to be identical to triphenylmethane. In 1878 they proved that the rosaniline dyes were homologues and were triamine derivatives of triphenylmethane and its homologues, rosaniline being a derivative of metatolyldiphenylmethane and p-rosaniline of triphenylmethane

Purines . Fischer began a study of uric acid and related substances in 1881 and continued his investigations until 1914, when he achieved the first synthesis of a nucleotide. These were biologically important substances. Xanthine, hypoxanthine, adenine, and guanine were present in the cell nucleus of animals. Theobromine, caffeine, and theophylline were stimulants in plants. Baeyer had studied these compounds in the 1860’s and partially clarified their relations. The Würzburg chemist Ludwig Medicus proposed structural formulas for several of them in 1875. Fischer became the prime investigator in the field, and it is to him that almost all knowledge of the purines is due. He explored the whole series, established their structures, and synthesized about 130 derivatives by 1900.

Fischer studied the reactions and degradation products of the purines. In 1882 he ventured structural formulas for uric acid, caffeine, theobromine, xanthine, and guanine. He synthesized theophylline and caffeine (1895) and uric acid (1897); but further research convinced him that his structures were incorrect, since his reaction products were not reconcilable to his formulas. In 1897 he provided a new set of formulas. He had come to realize that uric acid and related compounds were oxides of a hypothetical base C₅ N₄ H₄, which he named purine:

He proposed that purine was a heterocyclic compound and also proposed the notation system now used in purine chemistry:

Subsequently, he synthesized hypoxanthine, xanthine, theobromine, adenine, and guanine. Finally, in 1898 he succeeded in reducing trichloropurine to purine, the parent substance of the class. These researches involved an immense series of preparations and very difficult reactions. He continued this work, combining it with his research on carbohydrates, and in 1914 prepared glucosides of theophylline, theobromine, adenine, hypoxanthine, and guanine. From theophylline-D-glucoside he prepared the first synthetic nucleotide, theophylline-D-glucoside phosphoric acid.

Fischer’s purine research was of interest to the German drug industry. His laboratory methods became the basis for the industrial production of caffeine, theophylline, and theobromine. In 1903 he synthesized 5, 5-diethyl-barbituric acid. Under various trade names—Barbital, Veronal, and Dorminal—this compound proved to be a valuable hypnotic. Another commercially valuable purine was phenyl, ethylbarbituric acid, prepared by Fischer in 1912 and known as Luminal or phenobarbital.

Carbohydrates. Fischer carried on his purine research simultaneously with his carbohydrate studies and became the prime investigator in both fields. When he began his carbohydrate studies in 1884, there were four known monosaccharides: two aldohexoses (glucose, galactose) and two ketohexoses (fructose, sorbose), all with the formula C₆ H₁₂ O₆. There were three known disaccharides (sucrose, maltose, lactose). The general structure of the simple sugars had been established. Glucose and galactose were straight-chain pentahydroxy aldehydes, and the ketohexoses were straight-chain pentahydroxy ketones. Fischer in an enormous effort elaborated the complex structures and chemistry of the carbohydrates, synthesized many of them, and established the configurations of the sixteen possible stereoisomers of glucose.

In 1885 Heinrich Kiliani developed the method of lengthening the carbon chain in sugars by means of the addition of hydrocyanic acid to the carbonyl group, followed by hydrolysis and reduction. Fischer utilized this method to convert pentoses into hexoses, the latter into heptoses, etc., synthesizing sugars with as many as nine carbon atoms:

Starting with glycerylaldehyde

he built up the molecule step-by-step and synthesized several pentoses and hexoses, including glucose, fructose, and mannose, by the Kiliani method.

Fischer achieved his first synthesis of a sugar in 1887. He wanted to synthesize glyceraldehyde and use it as a starting point for building up the carbon chain in sugars. To prepare glyceraldehyde he combined acrolein dibromide and barium hydroxide:

Instead of glyceraldehyde he obtained a syrup which he named acrose:

With phenylhydrazine he obtained two different osazones and isolated from them two sugars. He proved that these were fructose and sorbose, the first naturally occurring sugars to be synthesized.

The reaction of sugars with phenylhydrazine yielded first the hydrazone and then the osazone. Fischer found that glucose, fructose, and mannose formed the same osazone. Therefore, the three sugars had the same configuration below the second carbon atom. Osazones on hydrolysis with hydrochloric acid eliminate phenylhydrazine and form osones, a new type of glucose derivative, possessing adjacent carbonyl groups. By reducing these, he obtained sugars, although an aldose is converted into a ketose:

At the other end of the carbon chain the primary alcohol could be reduced or oxidized. Oxidation of this group in glucose gave glucuronic acid; oxidation of the carbonyl group at the other end of the chain, a gluconic acid; and oxidation at both sites, a dicarboxylic acid. By differential reductions and oxidations Fischer could transfer the carbonyl group from one end of the chain to the other, and by testing the products for their properties and their optical rotation of the plane of polarized light, he could elucidate the structures of his compounds.

Using the van’t Hoff theory of stereoisomers, Fischer realized that there were sixteen possible configurations for the aldohexoses. By his methods of oxidation, reduction, degradation, addition, etc., he identified the structures of these by 1891. He established the configurations for all members of the Dseries of aldohexoses, i.e., those derived from D-glyceraldehyde, where D, according to Fischer’s practice, refers to the hydroxyl group’s being positioned to the right of the carbon atom next to the primary alcohol group:

Fischer prepared several artificial sugars. He had established the structures of the natural pentoses arabinose and xylose. He found that by extending the carbon chain of each of these pentoses he obtained two products. The Kiliani method introduced a new asymmetric atom and therefore two reaction products:

This phenomenon enabled him to prepare the artificial sugars l-gulose, d-talose, and d-idose from l-mannonic, d-galactonic, and d-gulonic acids, respectively; and the pentoses l-ribose and d-lyxose from l-arabonic and l-xylonic acids, respectively.

By reaction of the carbonyl group with alcohols, Fischer prepared α-and β-methyl glucoside, the first synthetic glucosides (1893). Since there were two methyl glucosides, he suggested that they must have a cyclic structure:

He never extended the ring structure to the sugars themselves, although in 1883 Tollens had suggested ring structures for glucose and fructose. Fischer thought that the disaccharides might have such rings and represented them as two hexoses united through an oxygen linkage: lactose was a glucose-β-galactoside, maltose a glucose-α-glucoside. He regarded the synthesis of glucosides as important because the polysaccharides were glucosides of the sugars themselves, and there was now the possibility of synthesizing polysaccharides.

Fischer examined the properties of enzymes, the substances responsible for the fermentation of sugars. He laid the foundations for enzyme chemistry and provided a new perspective concerning the action of enzymes. In 1894 he tested the action of yeasts on various sugars and noted the specificity of enzymes: maltase, for example, hydrolyzed α-methyl glucoside but not β-methyl glucoside, while emulsin hydrolyzed β-methyl glucoside but not α-methyl glucoside. For sugars of identical composition but different stereometric configuration, an enzyme was active only with a particular configuration. He concluded that enzymes were asymmetric agents capable of attacking molecules of only specific geometric configurations. The action of enzymes in hydrolyzing glucosides led him to use the analogy of a lock-and-key structural relationship between the enzyme and the sugar (1894). Molecular asymmetry gained new significance: the chemical transformations in the organism depended on asymmetry.

As an extension of his work in carbohydrates, Fischer from 1908 studied tannins, the gallic acid derivatives of sugars. In 1912 he showed that tannins were not glucosides but esters and synthesized a pentadigalloy) glucose that had the properties of a tannin. In 1918 he established the composition of Chinese tannin as a penta(meta-digalloy)glucose. He also synthesized hepta(tribenzoylgalloyl)-p-iodophenylmaltosazone. This derivative of maltose had a molecular weight of 4021, far exceeding that of any synthetic product.

Amino Acids and Proteins. In 1899 Fischer turned to the proteins in the hope of revealing their chemical nature. He knew of thirteen amino acids that had been obtained as hydrolysis products of proteins. He discovered additional amino acids, synthesized several of them, and resolved the d-l forms by fractional crystallization of the salts prepared from the benzoyl or formyl derivatives, which he combined with the optically active bases strychnine or brucine.

In 1901 he modified a method for the separation of amino acids developed by Theodor Curtius in 1883. A mixture of amino acids could be separated by esterifying the acids and distilling them at reduced pressure. Furthermore, Curtius showed that the ethyl ester of glycine eliminates alcohol to form a cyclic diketopiperazine, which on ring opening formed glycylglycine:

Fischer used Curtius’ method to separate mixtures of amino acids from protein hydrolysates by fractionally distilling their esters. He discovered valine, proline, and hydroxyproline in this manner. He prepared the esters of several amino acids and condensed two molecules of them into dipeptides. By 1907 he was preparing polypeptides, the largest one consisting of fifteen glycyl and three leucyl residues and having a molecular weight of 1213: leucyl-triglycyl-leucy-l-triglycyl-leucyl-octaglycylglycine. He suggested that the peptide linkage—CONH—was repeated in long chains in the polypeptide molecule. His synthetic methods involved either attacking the amino or the carbonyl group in the amino acid (e.g., using a halogen-containing acid to combine with the amino group and exchanging the halogen by another amino group):

In this way he could introduce glycyl, leucyl, and other groups into a peptide.

Fischer recognized the complexity of proteins. Even his simple peptides would have numerous isomers, and it would be extremely difficult to establish the constitution and structure of any protein. By 1905 he had differentiated twenty-nine polypeptides and tested their behavior with various enzymes. He characterized proteins by the number, kind, and arrangement of amino acids. In 1916 he summarized his work on the synthesis of about 100 polypeptides and cautioned that these represented only a tiny fraction of the possible combinations that might be found in natural proteins.

Fischer used the Walden inversion in synthesizing amino acids. In 1895 Paul Walden had found that in some substitution reactions the optical antipode of the expected compound was obtained. Fischer examined such reversals of optical rotatory power with regard to amino acids. In 1906 he described the following reaction:

Comparison with other inversion reactions failed to show at which step the inversion of optical rotation corresponded to a change in the atomic sequence on the asymmetric carbon atom. In 1911 Fischer developed a model to explain such rearrangements, his only excursion into theories of reaction mechanisms. He proposed that substitution is preceded by an addition step in which the entrant group need not take the place of the dislodged one, but that a relative distribution of substituents may take place. Thus, the configuration of the substituted compound may differ from the original.

Fischer’s last work was on the esterification of glycerol by fatty acids. The aim of all his investigations was to apply the methods of organic chemistry to the synthesis and processes of substances in living matter.

BIBLIOGRAPHY

I. Original Works. Fischer’s publications were collected in eight large volumes: Untersuchungen über Aminosäuren, Polypeptide und Proteine, 1899–1906 (Berlin, 1906); Untersuchungen in der Puringruppe, 1882–1906 (Berlin, 1907); Untersuchungen über Kohlenhydrate und Fermente, 1884–1908 (Berlin, 1909); Untersuchungen über Depside und Gerbstoffe, 1908–1919 (Berlin, 1920); Untersuchungen über Kohlenhydrate und Fermente, II, 1908–1918 (Berlin, 1922); Untersuchungen über Aminosäuren, Polypeptide und Proteine. II, 1907–1919 (Berlin, 1923); Untersuchungen über Triphenylmethanfarbstoffe, Hydrazine und Indole (Berlin, 1924); and Untersuchungen aus verschiedenen Gebieten, Vorträge und Abhandlungen allgemeinen Inhalts (Berlin, 1924).

His autobiography is Aus meinem Leben (Berlin, 1922), and his Nobel lecture is in Nobel Lectures. Chemistry 1901–1921 (Amsterdam–New York, 1966), pp. 21–35.

II. Secondary Literature. Informative studies of Emil Fischer include Max Bergmann, in G. Bugge, ed., Das Buch der grossen Chemiker, II (Berlin, 1930), 408–420; Martin Onslow Forster, “Emil Fischer Memorial Lecture,” in Journal of the Chemical Society, 117 (1920), 1157–1201; Burckhardt Helferich, in Eduard Farber, ed., Great Chemists (New York, 1961), pp. 981–995; and Kurt Hoesch, Emil Fischer, sein Leben und sein werk (Berlin, 1921). “Gedächtnis—Feier für Emil Fischer,” in Berichte der Deutschen chemischen Gesellschaft, 52A (1919), 125–164, contains addresses by H. Wichelhaus, Ludwig Knorr, and Carl Duisberg.

Eduard Farber

Fischer, Emil Hermann

GERMAN CHEMIST
1852–1919

Emil Hermann Fischer, born October 9, 1852, in Euskirchen, Germany, received the Nobel Prize in chemistry in 1902 for his elucidations of the structure of sugars and the synthesis of purines. His father, a very successful lumber merchant, intended Emil to join the family business upon completion of his secondary school education. Young Fischer showed exceptional abilities as a student in the natural sciences, particularly in physics. In 1859 he dutifully entered his father's business, but showed little aptitude for commerce. In frustration his father enrolled him at the University of Bonn in 1871 to study chemistry, which at least had practical applications.

The following year he transferred to the University of Strasbourg, where he attended the lectures of Adolf von Baeyer. He gave up any remaining interest in physics for a career in organic chemistry. Fischer pursued graduate studies in chemistry under von Baeyer's mentorship, and was awarded a doctorate degree in 1874. In the course of his doctoral research he synthesized the compound phenylhydrazine, which would prove to be invaluable in his studies of carbohydrates (but would also, because of his prolonged exposure to it, leave him with cancer).

In 1875 Fischer followed von Baeyer to the University of Munich, and in 1881 he obtained his first academic post as professor of organic chemistry at the University of Erlangen. This was followed by his being called to the University of Würzburg in 1888, and finally, in 1892, to the University of Berlin, where he remained until his death in 1919. His son Hermann Otto (1888–1960) went on to have a distinguished career in biochemistry.

Fischer's most important scientific work was carried out between 1882 and 1906. Little was known about the naturally occurring sugars when Fischer began his investigations of them in 1884. Four sugars were known at that time: glucose , galactose , fructose, and sorbose, each having the formula C₆H₁₂O₆. It was known that each had a six-carbon chain, and five alcohol groups as well as a carbonyl (aldehyde or ketone ) functional group attached to the chain.

Fischer saw in the sugars what no one else had seen. In 1874 Dutch chemist Jacobus van't Hoff had proposed that molecules in which a central carbon atom is bonded to four constituent atoms had a tetrahedral geometry in space, and that if a carbon atom were bonded to four different constituents, the molecule could exist in two forms (as stereoisomers) that were mirror images of one another. These two forms would possess distinct right- and left-handedness. Fischer realized that in glucose there were four carbon atoms that met the criteria for exhibiting stereoisomerism. A glucose molecule would exist as one of sixteen possible stereoisomers, each differing only by its orientation in space. Using the methods of chemical synthesis and degradation that were available to him, he was able by 1891 to identify the structures of all isomers of the naturally occurring d-glucose.

To enable representation of these isomers on the flat surface of a page, Fischer developed a notation system (Fischer projections). Fischer projections denoted right- and left-handed isomers. These were called D (dextrorotatory) and L (levorotatory), respectively, and the compound glyceraldehyde (which exists in two forms) was used as a reference.

With the Fischer projections, the constituents on the horizontal lines may be envisioned as coming out of the page, and the vertical constituents, as pointing backward, away from the onlooker. Fischer assumed the d isomer corresponded to the projection in which the OH group was to the right of the CH₂OH group. This assignment (which was a guess) was proven correct in 1954 when the orientations in space of the glyceraldehyde stereoisomers were established by x-ray analysis.

Fischer's identification of the stereoisomers of d-glucose (naturally occurring d-glucose was the sugar that Fischer worked with) was important validation of the ideas of van't Hoff.

In 1899 Fischer turned his attention to the study of proteins, wishing to understand their chemical structures. It was known at that time that proteins were composed of amino acids, and thirteen naturally occurring ones were identified. Fischer was able to isolate via the hydrolysis of proteins three additional naturally occurring amino acids: valine, proline, and hydroxyproline. Amino acids exhibit stereoisomerism, and Fischer was able to separate individual forms from mixtures of stereoisomers for several of these compounds.

Another Fischer achievement was the synthesis of small peptides via the condensation of amino acids. Fischer suggested that there was a common linkage that held pairs of amino acids together in all proteins—the peptide bond. He understood that proteins were tremendously complex, owing to the large number of constituents and the fact of stereoisomerism. By 1916 Fischer had synthesized and characterized 100 peptides, but knew they represented a tiny fraction of what was possible.

see also Amino Acid; Carbohydrates; Isomerism; van't Hoff, Jacobus.

Martin D. Saltzman

Bibliography

Farber, Eduard (1972). "Emil Fischer." In Dictionary of Scientific Biography, Vol. 5. New York: Scribner.

Fruton, Joseph S. (1990). Contrasts in Scientific Style: Research Groups in the Chemical and Biochemical Sciences. Philadelphia: American Philosophical Society.

Lucier, J. J. (1993). "Emil Fischer." Nobel Laureates in Chemistry, 1901–1992, ed. Laylin K. James. Washington, DC: American Chemical Society; Chemical Heritage Foundation, pp. 8–14.