Hans Fischer

The German organic chemist Hans Fischer (1881-1945) was awarded the Nobel Prize in Chemistry in 1930 for his researches into the constitution of hemin and chlorophyll and especially for his synthesis of hemin.

Hans Fischer, the son of Dr. Eugen Fischer, a manufacturer of chemicals, was born at Höchst am Main, on July 27, 1881. He entered the University of Lausanne in 1899, read chemistry and medicine, and subsequently transferred to the University of Marburg, where he graduated in chemistry in 1904. Two years later he qualified in medicine at Munich. In 1908 he graduated as a doctor of medicine at Munich. He was assistant to the chemist Emil Fischer at Berlin (1908-1910) and did some early work on bile pigments at Munich (1910-1912).

After a year as a teacher of internal medicine and three as lecturer in physiology at Munich, Fischer held the chair of medical chemistry at Innsbruck (1916-1918) and then at Vienna (1918-1921). From 1921 until his death he was professor of organic chemistry at the Technische Hochschule in Munich.

From 1911 Fischer studied the pyrrole group of the heterocyclic compounds. In 1915 he showed that the urine and feces of a case of congenital porphyria, a disease then recently discovered, contained uroporphyrin and coproporphyrin.


Structure of Hemoglobin

Fischer then began to study hemoglobin, a very important member of the pyrrole group. Its molecule consists of the pigment heme combined with the protein globlin. Heme contains iron, and its chloride, which is easier to work with, is hemin. Hemoglobin possesses the unique property of forming a loose reversible combination with oxygen, so that oxygen taken up by it in the lungs can be given off in the tissues. In this loose combination the active part is heme, and heme combined with any other protein except globin does not possess the property of giving up combined oxygen. It was already known, partly through the work of Fischer himself, that hemin has the formula C34H32O4N4FeCl, and his problem now was to determine the steric arrangement of the 76 atoms in this molecule of hemin.

When Fischer started his work it was known that, when the iron atom is removed from hemin, porphyrins are formed. These substances occur widely in nature, and, though their exact chemical composition was unknown, it >was realized that they all contained the pyrrole ring, consisting of four carbon atoms with a nitrogen atom closing the ring. His first problem was therefore to clarify the structure of the porphyrins. At a later stage of this investigation he synthesized the substance "porphin," which is not known to occur naturally. Porphin consists of four pyrrole rings, arranged as at the four points of the compass. These four rings are linked together by four methene bridges (=CH—) so that the whole forms a closed square. Fischer then showed that all porphyrins contain this porphin nucleus, in which, in each of the four pyrrole rings, the two carbon atoms most distant from the nitrogen atom are each linked with an atom of hydrogen. He also showed that, in all naturally occurring porphyrins, these hydrogen atoms are replaced by substitution groups (methyl, ethyl, vinyl, and so on). The possible permutations are therefore considerable.

In 1926 Fischer discovered porphyrin syntheses, and he synthesized over 130 isomers. It was recognized that the iron atom in hemin was situated at the center of the porphin nucleus. He studied the substance ooporphyrin, a constituent of the spots on the eggs of certain birds. He found it identical with the protoporphyrin previously described by Kämmerer, and by introducing iron complexly into it Fischer produced hemin. By a short-term putrefaction of hemoglobin he produced protoporphyrin; and by putrefaction carried on for several months he produced deuterohemin, from which he obtained deuteroporphyrin by splitting off the iron.

By the mild reduction of hemin the substance called mesoporphyrin had previously been obtained. Fischer found that, by decarboxylating mesoporphyrin, etioporphyrin was formed, and he determined that etioporphyrin contained four methyl and four ethyl groups. He then found that, by introducing four methyl and four ethyl groups into the porphin nucleus, etioporphyrin was obtained. But, depending on the position assumed by these residues as side chains in the porphin nucleus, this introduction could be effected in four different ways. He synthesized these four etioporphyrins and related them to the ooporphyrins. He then turned to a study of the mesoporphyrins and found that there were 15 possible isomers. He synthesized 12 of the 15. He found also that mesoporphyrin IX was identical with the mesoporphyrin obtained from hemin. Further, mesoporphyrin IX was derived from etioporphyrin III, and the arrangement of the side chains in hemin was thus determined.

Fischer next determined the formula for deuteroporphyrin and synthesized that substance. By the introduction of iron, deuterohemin was obtained, and by a complex process two acetyl residues were introduced into the latter, producing diacetyl-deuterohemin. Partial reduction of diacetyl-deuterohemin yielded hematoporphyrin, and from it protoporphyrin was produced by the removal of two molecules of water. On the introduction of iron into protoporphyrin, a synthetic hemin was produced that was indistinguishable from natural hemin obtained from hemoglobin. Fischer completed this synthesis in 1929.


Structure of Chlorophyll

Meanwhile Fischer had also been working on chlorophyll. During his career he wrote nearly 130 papers on that subject. Richard Willstätter had shown about 1912 that plants contain two chlorophylls: chlorophyll a and chlorophyll b. From chlorophyll he obtained three different porphyrins, and from these etioporphyrin, which he considered identical with the etioporphyrin obtained from hemoglobin. Fischer started his researches here, and from the three porphyrins he obtained two distinct etioporphyrins. He synthesized very many isomers, and he converted pyroporphyrin into his mesoporphyrin IX. He then worked on the substance phylloerythrin, found in the gastrointestinal tract of ruminants. He showed that it is a porphyrin and that it exhibited an atypical linkage of two of the pyrrole nuclei. It was known that chlorophyll contains magnesium, and Fischer determined that the magnesium atom was situated at the center of the porphin nucleus.

Even with the lead that phylloerythrin gave Fischer, it required many years to enable him to put forward his formula for the structure of chlorophyll a, a formula which seems to be correct. This formula is notable not only for the atypical linkage of two of the pyrrole nuclei, but also for the presence of two surplus hydrogen atoms in 7-and 8-positions, and of a very complex phytyl group in the 7-position. He found that the formula for chlorophyll b is the same as that for chlorophyll a, except that in the former a formyl group replaces the methyl group in pyrrole ring II of the latter.


Bile Pigments

All Fischer's important work on this subject was done during the last few years of his life. Although the pigments biliverdin and bilirubin had been known for nearly a century, when Fischer began his investigations practically nothing was known of their chemical composition. He showed that, whereas the molecule of the porphyrins consists of four pyrrole rings linked by four carbon linkages to form a closed ring (the porphin nucleus), the molecule of a bile pigment is the same except that it lacks one of the carbon linkages. The pigment molecule can therefore be regarded either as an open ring or as a linear chain of four pyrrole nuclei linked by three carbon linkages. Fischer worked out the structural formulas for both biliverdin and bilirubin. In 1942 he synthesized biliverdin, and in 1944 he effected the even more difficult synthesis of bilirubin.


Later Life

Fischer was not only a superb research chemist but also a very fine administrator of a research institute, and he was extremely popular with his staff and students. He was a keen mountaineer, skier, and motorist, despite the fact that as a young man he had suffered from serious surgical tuberculosis. In addition to innumerable scientific papers Fischer was the author, with two colleagues, of a standard work on pyrrole chemistry, Die Chemie des Pyrrols (3 vols., 1934-1940).

The title of Privy Councilor (Geheimrat) was conferred on Fischer in 1925. He received the Liebig Memorial Medal in 1929 and the Davy Medal in 1937. In 1936 Harvard University conferred on him an honorary doctorate. He died in Munich on March 31, 1945.


Further Reading on Hans Fischer

There is a biography of Fischer in Nobel Lectures, Chemistry, 1922-1941 (1966), which also contains his Nobel Lecture. For the chemical background to Fischer's work see P. Karrer, Organic Chemistry (trans. by A. J. Mee, 4th ed. 1950). See also C. W. Carter, R. V. Coxon, D. S. Parsons, and R. H. S. Thompson, Biochemistry in Relation to Medicine (3d ed. 1959), and A. White, P. Handler, and E. L. Smith, Principles of Biochemistry (3d ed. 1964, and later editions).