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Selected Contributions to Chemistry from 1880 to 1980

Curator: Larry H. Bernstein, MD, FCAP

 

FUNDAMENTALS OF CHEMISTRY – Vol. I  The Contribution of Nobel Laureates to Chemistry

– Ferruccio Trifiro

http://www.eolss.net/sample-chapters/c06/e6-11-01-04.pdf

This chapter deals with the contribution to the development of chemistry of all the Nobel Prize winners in chemistry up to the end of the twentieth century, together with some in physics and medicine or physiology that have had particular relevance for the advances achieved in chemistry. The contributions of the various Nobel laureates cited are briefly summarized. The Nobel laureates in physics dealt with in this chapter are those who made important contributions to ard the understanding of the properties of atoms, the development of theoretical tools to treat the chemical bond, or the development of new analytical instrumentation. The Nobel laureates in medicine or physiology cited here are those whose contributions have been in the area of using chemistry to understand natural processes, such as the physiological aspects of living organisms through electron and ion exchange processes, enzymatic catalysis, and DNA-based chemistry. Eight areas of thought or thematic areas were chosen into which the contributions of the Nobel laureates to chemistry can be subdivided.

  1. The Properties of Molecules

4.1. The Discovery of Coordination and Metallorganic Compounds

4.2. The Discovery of New Organic Molecules

4.3. The Emergence of Quantum Chemistry

  1. The Dynamics of Chemical Reactions

6.1. Kinetics of Heterogeneous and Homogeneous Processes

6.2. The Identification of the Activated State

  1. The Understanding of Natural Processes

8.1. From Ferments to Enzymes

8.2. Understanding the Mechanism of Action of Enzymes

8.3. Mechanisms of Important Natural Processes

8.4. Characterization of Biologically Important Molecules

  1. The Identification of Chemical Entities

9.1. Analytical Methods

9.2. New Separation Techniques

9.3. The Development of New Instrumentation for Structure Analysis

The Nobel Prize in Chemistry: The Development of Modern Chemistry

by Bo G. Malmström and Bertil Andersson*

http://www.nobelprize.org/nobel_prizes/themes/chemistry/malmstrom/

Introduction

1.1 Chemistry at the Borders to Physics and Biology

The turn of the century 1900 was also a turning point in the history of chemistry. A survey of the Nobel Prizes in Chemistry during this century provides a view toward important trends in the development of Chemistry at the center of the sciences, bordering onto physics, which provides its theoretical foundation, on one side, and onto biology on the other. The fact that chemistry flourished during the beginning of the 20th century is intimately connected with fundamental developments in physics.

In 1897 Sir Joseph John Thomson of Cambridge announced his discovery of the electron, for which he was awarded the Nobel Prize for Physics in 1906. It took a number of years before its relevance to chemistry was seen. In 1911 Ernest Rutherford, who had worked in Thomson’s laboratory in the 1890s, formulated an atomic model, which depicted a cloud of electrons circling around the nucleus. Rutherford had received the Nobel Prize for Chemistry in 1908 for his work on radioactivity.

In Rutherford’s atomic model the stability of atoms was at variance with the laws of classical physics. Niels Bohr from Copenhagen brought clarity to this dilemma in the distinct lines observed in the spectra of atoms, the regularities of which had been discovered in 1890 by the physics professor Johannes (Janne) Rydberg at Lund University. This was the basis for Bohr’s formulation (1913) of an alternative atomic model. Only certain circular orbits of the electrons are allowed. In this model light is emitted (or absorbed), when an electron makes a transition from one orbit to another. For this, Bohr received the Nobel Prize for Physics in 1922

Gilbert Newton Lewis next suggested in 1916 that strong (covalent) bonds between atoms involve a sharing of two electrons between these atoms (electron-pair bond). Lewis also contributed fundamental work in chemical thermodynamics, and his brilliant textbook, Thermodynamics (1923), written together with Merle Randall, is counted as one of the masterworks in the chemical literature. Lewis never received a Nobel Prize.

However, important work was published in the 1890s, considered by the first Nobel Committee for Chemistry (see Section 2). Three of the Laureates during the first decade, Jacobus Henricus van’t Hoff, Svante Arrhenius and Wilhelm Ostwald, are generally regarded as the founders of a new branch of chemistry, physical chemistry. Fundamental work was also recognized in organic chemistry and in the chemistry of natural products, which is clearly reflected in the early prizes. Further, the Nobel Committee, recognized the border towards biology in 1907, with the prize to Eduard Buchner “for his biochemical researches and his discovery of cell-free fermentation”.

  1. The First Decade of Nobel Prizes for Chemistry

So much fundamental work in chemistry had been carried out during the last two decades of the 19th century that a decision for the first several prizes was not easy.  In 1901 the Academy had to consider 20 nominations, but no less than 11 of these named van’t Hoff, who was selected. van’t Hoff had already established the four valences for the carbon atom in his PhD thesis in Utrecht in 1874, foundation work for  modern organic chemistry. But the Nobel Prize was awarded for his later work on chemical kinetics and equilibria and on the osmotic pressure in solution, published in 1884 and 1886.

In his 1886 work van’t Hoff showed that most dissolved chemical compounds give an osmotic pressure equal to the gas pressure they would have exerted in the absence of the solvent. An apparent exception was aqueous solutions of electrolytes (acids, bases and their salts), but in the following year Arrhenius showed that this anomaly could be explained, if it is assumed that electrolytes in water dissociate into ions. Arrhenius had already presented the rudiments of his dissociation theory in his doctoral thesis, which was defended in Uppsala in 1884 and was not entirely well received by the faculty. It was, however, strongly supported by Ostwald in Riga, who, in fact, travelled to Uppsala to initiate a collaboration with Arrhenius. In 1886-1990 Arrhenius did work with Ostwald, first in Riga and then in Leipzig, and also with van’t Hoff in Berlin. Arrhenius was awarded the Nobel Prize for Chemistry in 1903,  and he was also nominated for the Prize for Physics (see Section 1).

The award of the Nobel Prize for Chemistry in 1909 to Ostwald was chiefly in recognition of his work on catalysis and the rates of chemical reactions. Ostwald had in his investigations, following up observations in his thesis in 1878, shown that the rate of acid-catalyzed reactions is proportional to the square of the strength of the acid, as measured by titration with base. His work offered support not only to Arrhenius’ theory of dissociation but also to van’t Hoff’s theory for osmotic pressure. Ostwald was founder and editor of Zeitschrift für Physikalische Chemie, the publication of which is generally regarded as the birth of this new branch of chemistry.

Three of the Nobel Prizes for Chemistry during the first decade were awarded for pioneering work in organic chemistry. In 1902 Emil Fischer, then in Berlin, was given the prize for “his work on sugar and purine syntheses”. Fischer’s work is an example of the growing interest biologically important substances, and was a foundation for the development of biochemistry. Another major influence from organic chemistry was the development of chemical industry, and a chief contributor here was Fischer’s teacher, Adolf von Baeyer in Munich, who was awarded the prize in 1905 “in recognition of his services in the advancement of organic chemistry and the chemical industry, … ” His contributions include, in particular, structure determination of organic

Ernest Rutherford [Lord Rutherford since 1931], professor of physics in Manchester, was awarded the Nobel Prize for Chemistry in 1908. In his studies of uranium disintegration he found two types of radiation, named α- and β-rays, and by their deviation in electric and magnetic fields he could show that α-rays consist of positively charged particles. He had received many nominations for the Nobel Prize for Physics (see Section 1).

In 1897 Eduard Buchner, at the time professor in Tübingen, published results demonstrating that the fermentation of sugar to alcohol and carbon dioxide can take place in the absence of yeast cells. Louis Pasteur had earlier maintained that alcoholic fermentation can only occur in the presence of living yeast cells. Buchner’s experiments showed unequivocally that fermentation is a catalytic process caused by the action of enzymes, as had been suggested by Berzelius for all life processes. Because of Buchner’s experiment, 1897 is generally regarded as the birth date for biochemistry proper. Buchner was awarded the Nobel Prize for Chemistry in 1907, when he was professor at the agricultural college in Berlin. This confirmed the prediction of his former teacher, Adolf von Baeyer: “This will make him famous, in spite of the fact that he lacks talent as a chemist.”

  1. The Nobel Prizes for Chemistry 1911-2000

3.1 General and Physical Chemistry

The Nobel Prize for Chemistry in 1914 was awarded to Theodore William Richards of Harvard University for “his accurate determinations of the atomic weight of a large number of chemical elements”. In 1913 Richards had discovered that the atomic weight of natural lead and of that formed in radioactive decay of uranium minerals differ. This pointed to the existence of isotopes, i.e. atoms of the same element with different atomic weights, which was accurately demonstrated by Francis William Aston at Cambridge University, with the aid of an instrument developed by him, the mass spectrograph. For his achievements Aston received the Nobel Prize for Chemistry in 1922.

One branch of physical chemistry deals with chemical events at the interface of two phases, for example, solid and liquid, and phenomena at such interfaces have important applications all the way from technical to physiological processes. Detailed studies of adsorption on surfaces, were carried out by Irving Langmuir at the research laboratory of General Electric Company, who was awarded the Nobel Prize for Chemistry in 1932, the first industrial scientist to receive this distinction.

Two of the Prizes for Chemistry in more recent decades have been given for fundamental work in the application of spectroscopic methods (Prizes for Physics in 1952, 1955 and 1961) to chemical problems. Gerhard Herzberg, a physicist at the University of Saskatchewan, received the Nobel Prize for Chemistry in 1971 for his molecular spectroscopy studies “of the electronic structure and geometry of molecules, particularly free radicals”. The most used spectroscopic method in chemistry is undoubtedly NMR (nuclear magnetic resonance), and Richard R. Ernst at ETH in Zürich was given the Nobel Prize for Chemistry in 1991 for “the development of the methodology of high resolution nuclear magnetic resonance (NMR) spectroscopy”. Ernst’s methodology has now made it possible to determine the structure in solution (in contrast to crystals; cf. Section 3.5) of large molecules, such as proteins.

3.2 Chemical Thermodynamics

The Nobel Prize for Chemistry to van’t Hoff was in part for work in chemical thermodynamics, and many later contributions in this area have also been recognized with Nobel Prizes.  Walther Hermann Nernst of Berlin received this award in 1920 for work in thermochemistry, despite a 16-year opposition to this recognition from Arrhenius. Nernst had shown that it is possible to determine the equilibrium constant for a chemical reaction from thermal data, and in so doing he formulated what he himself called the third law of thermodynamics. This states that the entropy, a thermodynamic quantity, which is a measure of the disorder in the system, approaches zero as the temperature goes towards absolute zero. van’t Hoff had derived the mass action equation in 1886, with the aid of the second law which says, that the entropy increases in all spontaneous processes [this had already been done in 1876 by J. Willard Gibbs at Yale, who certainly had deserved a Nobel Prize].  Nernst showed in 1906 that it is possible with the aid of the third law, to derive the necessary parameters from the temperature dependence of thermochemical quantities. Nernst carried out thermo-chemical measurements at very low temperatures to prove his heat theorem. G.N. Lewis (see Section 1.1) in Berkeley extended these studies in the 1920s and his new formulation of the third law was confirmed by his student, William Francis Giauque, who extended the temperature range experimentally accessible by introducing the method of adiabatic demagnetization in 1933. He managed to reach temperatures a few thousandths of a degree above absolute zero and could thereby provide extremely accurate entropy estimates. He also showed that it is possible to determine entropies from spectroscopic data. Giauque was awarded the Nobel Prize for Chemistry in 1949 for his contributions to chemical thermodynamics.

The next Nobel Prize given for work in thermodynamics went to Lars Onsager of Yale University in 1968 for contributions to the thermodynamics of irreversible processes. Classical thermodynamics deals with systems at equilibrium, in which the chemical reactions are said to be reversible, but many chemical systems, for example, the most complex of all, living organisms, are far from equilibrium and their reactions are said to be irreversible. Onsager developed his so-called reciprocal relations in 1931, describing the flow of matter and energy in such systems, but the importance of his work was not recognized until the end of the 1940s. A further step forward in the development of non-equilibrium thermodynamics was taken by Ilya Prigogine in Bruxelles, whose theory of dissipative structures was awarded the Nobel Prize for Chemistry in 1977.

3.3 Chemical Change

The chief method to get information about the mechanism of chemical reactions is chemical kinetics, i.e. measurements of the rate of the reaction as a function of reactant concentrations as well as its dependence on temperature, pressure and reaction medium. Important work in this area had been done already in the 1880s by two of the early Laureates, van’t Hoff and Arrhenius, who showed that it is not enough for molecules to collide for a reaction to take place. Only molecules with sufficient kinetic energy in the collision do, in fact, react, and Arrhenius derived an equation in 1889 allowing the calculation of this activation energy from the temperature dependence of the reaction rate. With the advent of quantum mechanics in the 1920s (see Section 3.4), Eyring developed his transition-state theory in 1935 which showed that the activation entropy is also important. Strangely, Eyring never received a Nobel Prize (see Section 1.2).

In 1956 Sir Cyril Norman Hinshelwood of Oxford and Nikolay Nikolaevich Semenov from Moscow shared the Nobel Prize for Chemistry “for their researches into the mechanism of chemical reactions”.  A limit in investigating reaction rates is set by the speed with which the reaction can be initiated. If this is done by rapid mixing of the reactants, the time limit is about one thousandth of a second (millisecond). In the 1950s Manfred Eigen from Göttingen developed chemical relaxation methods that allow measurements in times as short as a thousandth or a millionth of a millisecond (microseconds or nanoseconds). The methods involve disturbing an equilibrium by rapid changes in temperature or pressure and then follow the passage to a new equilibrium. Another way to initiate some reactions rapidly is flash photolysis, i.e. by short light flashes, a method developed by Ronald G.W. Norrish at Cambridge and George Porter (Lord Porter since 1990) in London. Eigen received one-half and Norrish and Porter shared the other half of the Nobel Prize for Chemistry in 1967. The milli- to picosecond time scales gave important information on chemical reactions. However, it was not until it was possible to generate femtosecond laser pulses (10-15 s) that it became possible to reveal when chemical bonds are broken and formed. Ahmed Zewail (born 1946 in Egypt) at California Institute of Technology received the Nobel Prize for Chemistry in 1999 for his development of “femtochemistry” and in particular for being the first to experimentally demonstrate a transition state during a chemical reaction. His experiments relate back to 1889 when Arrhenius (Nobel Prize, 1903) made the important prediction that there must exist intermediates (transition states) in the transformation from reactants to products.

Henry Taube of Stanford University was awarded the Nobel Prize for Chemistry in 1983 “for his work on the mechanism of electron transfer reactions, especially in metal complexes”. Even if Taube’s work was on inorganic reactions, electron transfer is important in many catalytic processes used in industry and also in biological systems, for example, in respiration and photosynthesis.

3.4 Theoretical Chemistry and Chemical Bonding

Quantum mechanics, developed in the 1920s, offered a tool towards a more basic understanding of chemical bonds. In 1927 Walter Heitler and Fritz London showed that it is possible to solve exactly the relevant equations for the hydrogen molecule ion, i.e. two hydrogen nuclei sharing a single electron, and thereby calculate the attractive force between the nuclei. A pioneer in developing such methods was Linus Pauling at California Institute of Technology, who was awarded the Nobel Prize for Chemistry in 1954 “for his research into the nature of the chemical bond …” Pauling’s valence-bond (VB) method is rigorously described in his 1935 book Introduction to Quantum Mechanics (written together with E. Bright Wilson, Jr., at Harvard). A few years later (1939) he published an extensive non-mathematical treatment in The Nature of the Chemical Bond, a book which is one of the most read and influential in the entire history of chemistry. Pauling was not only a theoretician, but he also carried out extensive investigations of chemical structure by X-ray diffraction (see Section 3.5). On the basis of results with small peptides, which are building blocks of proteins, he suggested the α-helix as an important structural element. Pauling was awarded the Nobel Peace Prize for 1962, and he is the only person to date to have won two unshared Nobel Prizes.

α-helix   Pauling’s α-helix

α-carbon atoms are black, other carbon atoms grey, nitrogen atoms blue, oxygen atoms red and hydrogen atoms white; R designates amino-acid side chains. The dotted red lines are hydrogen bonds between amide and carbonyl groups in the peptide bonds.

Pauling’s VB method cannot give an adequate description of chemical bonding in many complicated molecules, and a more comprehensive treatment, the molecular-orbital (MO) method, was introduced already in 1927 by Robert S. Mulliken from Chicago and later developed further. MO theory considers, in quantum-mechanical terms, the interaction between all atomic nuclei and electrons in a molecule. Mulliken also showed that a combination of MO calculations with experimental (spectroscopic) results provides a powerful tool for describing bonding in large molecules. Mulliken received the Nobel Prize for Chemistry in 1966.

Theoretical chemistry has also contributed significantly to our understanding of chemical reaction mechanisms. In 1981 the Nobel Prize for Chemistry was shared between Kenichi Fukui in Kyoto and Roald Hoffmann of Cornell University “for their theories, developed independently, concerning the course of chemical reactions”. Fukui introduced in 1952 the frontier-orbital theory, according to which the occupied MO with the highest energy and the unoccupied one with the lowest energy have a dominant influence on the reactivity of a molecule. Hoffmann formulated in 1965, together with Robert B. Woodward (see Section 3.8), rules based on the conservation of orbital symmetry, for the reactivity and stereochemistry in chemical reactions.
3.5 Chemical Structure

The most commonly used method to determine the structure of molecules in three dimensions is X-ray crystallography. The diffraction of X-rays was discovered by Max von Laue in 1912, and this gave him the Nobel Prize for Physics in 1914. Its use for the determination of crystal structure was developed by Sir William Bragg and his son, Sir Lawrence Bragg, and they shared the Nobel Prize for Physics in 1915. The first Nobel Prize for Chemistry for the use of X-ray diffraction went to Petrus (Peter) Debye, then of Berlin, in 1936. Debye did not study crystals, however, but gases, which give less distinct diffraction patterns.

Many Nobel Prizes have been awarded for the determination of the structure of biological macromolecules (proteins and nucleic acids). Proteins are long chains of amino-acids, as shown by Emil Fischer (see Section 2), and the first step in the determination of their structure is to determine the order (sequence) of these building blocks. An ingenious method for this tedious task was developed by Frederick Sanger of Cambridge, and he reported the amino-acid sequence for a protein, insulin, in 1955. For this achievement he was awarded the Nobel Prize for Chemistry in 1958. Sanger later received part of a second Nobel Prize for Chemistry for a method to determine the nucleotide sequence in nucleic acids (see Section 3.12), and he is the only scientist so far who has won two Nobel Prizes for Chemistry.

The first protein crystal structures were reported by Max Perutz and Sir John Kendrew in 1960, and these two investigators shared the Nobel Prize for Chemistry in 1962. Perutz had started studying the oxygen-carrying blood pigment, hemoglobin, with Sir Lawrence Bragg in Cambridge already in 1937, and ten years later he was joined by Kendrew, who looked at crystals of the related muscle pigment, myoglobin. These proteins are both rich in Pauling’s α-helix (see Section 3.4), and this made it possible to discern the main features of the structures at the relatively low resolution first used. The same year that Perutz and Kendrew won their prize, the Nobel Prize for Physiology or Medicine went to Francis Crick, James Watson and Maurice Wilkins “for their discoveries concerning the molecular structure of nucleic acids … .” Two years later (1964) Dorothy Crowfoot Hodgkin received the Nobel Prize for Chemistry for determining the crystal structures of penicillin and vitamin B12.

Crystallographic electron microscopy was developed by Sir Aaron Klug in Cambridge, who was awarded the Nobel Prize for Chemistry in 1982. Attempts to prepare crystals of membrane proteins for structural studies were unsuccessful, but in 1982 Hartmut Michel managed to crystallize a photosynthetic reaction center after a painstaking series of experiments. He then proceeded to determine the three-dimensional structure of this protein complex in collaboration with Johann Deisenhofer and Robert Huber, and this was published in 1985. Deisenhofer, Huber and Michel shared the Nobel Prize for Chemistry in 1988. Michel has later also crystallized and determined the structure of the terminal enzyme in respiration, and his two structures have allowed detailed studies of electron transfer (cf. Sections 3.3 and 3.4) and its coupling to proton pumping, key features of the chemiosmotic mechanism for which Peter Mitchell had already received the Nobel Prize for Chemistry in 1978 (see Section 3.12). Functional and structural studies on the enzyme ATP synthase, connected to this proton pumping mechanism, was awarded one-half of the Nobel Prize for Chemistry in 1997, shared between Paul D. Boyer and John Walker (see Section 3.12).

3.6 Inorganic and Nuclear Chemistry

Much of the progress in inorganic chemistry during the 20th century has been associated with investigations of coordination compounds, i.e., a central metal ion surrounded by a number of coordinating groups, called ligands. In 1893 Alfred Werner in Zürich presented his coordination theory, and in 1905 he summarized his investigations in this new field in a book (Neuere Anschauungen auf dem Gebiete der anorganischen Chemie), which appeared in no less than five editions from 1905-1923. . Werner showed that a structure for compounds in which a metal ion binds several other molecules (ligands), all the ligand molecules are bound directly to the metal ion. Werner was awarded the Nobel Prize for Chemistry in 1913. Taube’s investigations of electron transfer, awarded in 1983 (see Section 3.3), were mainly carried out with coordination compounds, and vitamin B12 as well as the proteins hemoglobin and myoglobin, investigated by the Laureates Hodgkin, Perutz and Kendrew (see Section 3.5), also belong to this category.

Much inorganic chemistry in the early 1900s was a consequence of the discovery of radioactivity in 1896, for which Henri Becquerel from Paris was awarded the Nobel Prize for Physics in 1903, together with Pierre and Marie Curie. In 1911 Marie Curie received the Nobel Prize for Chemistry for her discovery of the elements radium and polonium and for the isolation of radium and studies of its compounds, and this made her the first investigator to be awarded two Nobel Prizes. The prize in 1921 went to Frederick Soddy of Oxford for his work on the chemistry of radioactive substances and on the origin of isotopes. In 1934 Frédéric Joliot and his wife Irène Joliot-Curie, the daughter of the Curies, discovered artificial radioactivity, i.e., new radioactive elements produced by the bombardment of non-radioactive elements with a-particles or neutrons. They were awarded the Nobel Prize for Chemistry in 1935 for “their synthesis of new radioactive elements”.

Many elements are mixtures of non-radioactive isotopes (see Section 3.1), and in 1934 Harold Urey of Columbia University had been given the Nobel Prize for Chemistry for his isolation of heavy hydrogen (deuterium). Urey had also separated uranium isotopes, and his work was an important basis for the investigations by Otto Hahn from Berlin. In attempts to make transuranium elements, i.e., elements with a higher atomic number than 92 (uranium), by radiating uranium atoms with neutrons, Hahn discovered that one of the products was barium, a lighter element. Lise Meitner, at the time a refugee from Nazism in Sweden, who had earlier worked with Hahn and taken the initiative for the uranium bombardment experiments, provided the explanation, namely, that the uranium atom was cleaved and that barium was one of the products. Hahn was awarded the Nobel Prize for Chemistry in 1944 “for his discovery of the fission of heavy nuclei”, and it can be wondered why Meitner was not included. Hahn’s original intention with his experiments was later achieved by Edwin M. McMillan and Glenn T. Seaborg of Berkeley, who were given the Nobel Prize for Chemistry in 1951 for “discoveries in the chemistry of transuranium elements”.

The use of stable as well as radioactive isotopes have important applications, not only in chemistry, but also in fields as far apart as biology, geology and archeology. In 1943 George de Hevesy from Stockholm received the Nobel Prize for Chemistry for his work on the use of isotopes as tracers, involving studies in inorganic chemistry and geochemistry as well as on the metabolism in living organisms. The prize in 1960 was given to Willard F. Libby of the University of California, Los Angeles (UCLA), for his method to determine the age of various objects (of geological or archeological origin) by measurements of the radioactive isotope carbon-14.

3.7 General Organic Chemistry

Contributions in organic chemistry have led to more Nobel Prizes for Chemistry than work in any other of the traditional branches of chemistry. Like the first prize in this area, that to Emil Fischer in 1902 (see Section 2), most of them have, however, been awarded for advances in the chemistry of natural products and will be treated separately (Section 3.9). Another large group, preparative organic chemistry, has also been given its own section (Section 3.8), and here only the prizes for more general contributions to organic chemistry will be discussed.

In 1969 the Nobel Prize for Chemistry went to Sir Derek H. R. Barton from London, and Odd Hassel from Oslo for developing the concept of conformation, i.e. the spatial arrangement of atoms in molecules, which differ only by the orientation of chemical groups by rotation around a single bond. This stereochemical concept rests on the original suggestion by van’t Hoff of the tetrahedral arrangement of the four valences of the carbon atom (see Section 2), and most organic molecules exist in two or more stable conformations.

The Nobel Prize for Chemistry in 1975 to Sir John Warcup Cornforth of the University of Sussex and Vladimir Prelog of ETH in Zürich was also based on research in stereochemistry. Not only can a compound have more than one geometric form, but chemical reactions can also have specificity in their stereochemistry, thereby forming a product with a particular three-dimensional arrangement of the atoms. This is especially true of reactions in living organisms, and Cornforth has mainly studied enzyme-catalyzed reactions, so his work borders onto biochemistry (Section 3.12). One of Prelog’s main contributions concerns chiral molecules, i.e. molecules that have two forms differing from one another as the right hand does from the left. Stereochemically specific reactions have great practical importance, as many drugs, for example, are active only in one particular geometric form.

Organometallic compounds constitute a group of organic molecules containing one or more carbon-metal bond, and they are thus the organic counterpart to Werner’s inorganic coordination. In 1952 Ernst Otto Fischer and Sir Geoffrey Wilkinson independently described a completely new group of organometallic molecules, called sandwich compounds in which compounds a metal ion is bound not to a single carbon atom but is “sandwiched” between two aromatic organic molecules. Fischer and Wilkinson shared the Nobel Prize for Chemistry in 1973.

3.8 Preparative Organic Chemistry

One of the chief goals of the organic chemist is to be able to synthesize increasingly complex compounds of carbon in combination with various other elements. The first Nobel Prize for Chemistry recognizing pioneering work in preparative organic chemistry was that to Victor Grignard from Nancy and Paul Sabatier from Toulouse in 1912. Grignard had discovered that organic halides can form compounds with magnesium. Sabatier was given the prize for developing a method to hydrogenate organic compounds in the presence of metallic catalysts. The prize in 1950 was presented to Otto Diels from Kiel and Kurt Alder from Cologne “for their discovery and development of the diene synthesis”, developed in 1928, by which organic compounds containing two double bonds (“dienes”) can effect the syntheses of many cyclic organic substances.

The German organic chemist Hans Fischer from Munich had already done significant work on the structure of hemin, the organic pigment in hemoglobin, when he synthesized it from simpler organic molecules in 1928. He also contributed much to the elucidation of the structure of chlorophyll, and for these important achievements he was awarded the Nobel Prize for Chemistry in 1930 (cf. Section 3.5). He finished his determination of the structure of chlorophyll in 1935, and by the time of his death he had almost completed its synthesis as well.

Robert Burns Woodward from Harvard is rightly considered the founder of the most advanced, modern art of organic synthesis. He designed methods for the total synthesis of a large number of complicated natural products, for example, cholesterol, chlorophyll and vitamin B12. He received the Nobel Prize for Chemistry in 1965, and he would probably have received a second chemistry prize in 1981 for his part in the formulation of the Woodward-Hoffmann rules (see Section 3.4), had it not been for his early death.

The Nobel Prize for Chemistry in 1984 was given to Robert Bruce Merrifield of Rockefeller University “for his development of methodology for chemical synthesis on a solid matrix”. Specifically, the synthesis of large peptides and small proteins.

3.9 Chemistry of Natural Product

The synthesis of complex organic molecules must be based on detailed knowledge of their structure. Early work on plant pigments was carried out by Richard Willstätter, a student of Adolf von Baeyer from Munich (see Section 2). Willstätter showed a structural relatedness between chlorophyll and hemin, and he demonstrated that chlorophyll contains magnesium as an integral component. He also carried out pioneering investigations on other plant pigments, such as the carotenoids, and he was awarded the Nobel Prize for Chemistry in 1915 for these achievements. Willstätter’s work laid the ground for the synthetic accomplishments of Hans Fischer (see Section 3.8). In addition, Willstätter contributed to the understanding of enzyme reactions.

The prizes for 1927 and 1928 were both presented to Heinrich Otto Wieland from Munich and Adolf Windaus from Göttingen, respectively, at the Nobel ceremony in 1928. These two chemists had done closely related work on the structure of steroids. The award to Wieland was primarily for his investigations of bile acids, whereas Windaus was recognized mainly for his work on cholesterol and his demonstration of the steroid nature of vitamin D. Wieland had already in 1912, before his prize-winning work, formulated a theory for biological oxidation, according to which removal of hydrogen (dehydrogenation) rather than reaction with oxygen is the dominating process.

Investigations on vitamins were recognized in 1937 and 1938 with the prizes to Sir Norman Haworth from Birmingham and Paul Karrer from Zürich and to Richard Kuhn from Heidelberg. Haworth did outstanding work in carbohydrate chemistry, establishing the ring structure of glucose. He was the first chemist to synthesize vitamin C, and this is the basis for the present large-scale production of this nutrient. Haworth shared the prize with Karrer, who determined the structure of carotene and of vitamin A. Kuhn also worked on carotenoids, and he published the structure of vitamin B2 at the same time as Karrer. He also isolated vitamin B6. In 1939 the Nobel Prize for Chemistry was shared between Adolf Butenandt from Berlin and Leopold Ruzicka (1887-1976) of ETH, Zurich. Butenandt was recognized “for his work on sex hormones”, having isolated estrone, progesterone and androsterone. Ruzicka synthesized androsterone and also testosterone.

The awards for outstanding work in natural-product chemistry continued after World War II. In 1947 Sir Robert Robinson from Oxford received the prize for his studies on plant substances, particularly alkaloids, such as morphine. Robinson also synthesized steroid hormones, and he elucidated the structure of penicillin. Many hormones are of a polypeptide nature, and in 1955 Vincent du Vigneaud of Cornell University was given the prize for his synthesis of two such hormones, vasopressin and oxytocin. Finally, in this area, Alexander R. Todd (Lord Todd since 1962) was recognized in 1957 “for his work on nucleotides and nucleotide co-enzymes”. Todd had synthesized ATP (adenosine triphosphate) and ADP (adenosine diphosphate), the main energy carriers in living cells, and he determined the structure of vitamin B12 (cf. Section 3.5) and of FAD (flavin-adenine dinucleotide).

3.10 Analytical Chemistry and Separation Science

A prize in analytical chemistry was given to Jaroslav Heyrovsky from Prague in 1959 for his development of polarographic methods of analysis. In these a dropping mercury electrode is employed to determine current-voltage curves for electrolytes. A given ion reacts at a specific voltage, and the current is a measure of the concentration of this ion.

The analysis of macromolecular constituents in living organisms requires specialized methods of separation. Ultracentrifugation wad developed by The Svedberg from Uppsala a few years before he was awarded the Nobel Prize for Chemistry in 1926 “for his work on disperse systems” (see Section 3.11). Svedberg’s student, Arne Tiselius, studied the migration of protein molecules in an electric field, and with this method, named electrophoresis, he demonstrated the complex nature of blood proteins. Tiselius also refined adsorption analysis, a method first used by the Russian botanist, Michail Tswett, for the separation of plant pigments and named chromatography by him. In 1948 Tiselius was given the prize for these achievements. A few years later (1952) Archer J.P. Martin from London and Richard L.M. Synge from Bucksburn (Scotland) shared the prize “for their invention of partition chromatography”, and this method was a major tool in many biochemical investigations later awarded with Nobel Prizes (see Section 3.12).

3.11 Polymers and Colloids

The Svedberg who received the Nobel Prize for Chemistry in 1926, also investigated gold sols. He used Zsigmond’s ultramicroscope to study the Brownian movement of colloidal particles, so named after the Scottish botanist Robert Brown, and confirmed a theory developed by Albert Einstein in 1905 and, independently, by M. Smoluchowski. His greatest achievement was, however, the construction of the ultracentrifuge, with which he studied not only the particle size distribution in gold sols but also determined the molecular weight of proteins, for example, hemoglobin. In the same year as Svedberg got the prize the Nobel Prize for Physics was awarded to Jean Baptiste Perrin of Sorbonne for developing equilibrium sedimentation in colloidal solutions, a method which Svedberg later perfected in his ultracentrifuge. Svedberg’s investigations with the ultracentrifuge and Tiselius’s electrophoresis studies (see Section 3.10) were instrumental in establishing that protein molecules have a unique size and structure, and this was a prerequisite for Sanger’s determination of their amino-acid sequence and the crystallographic work of Kendrew and Perutz (see Section 3.5).

3.12 Biochemistry

The second Nobel Prize for discoveries in biochemistry came in 1929, when Sir Arthur Harden from London and Hans von Euler-Chelpin from Stockholm shared the prize for investigations of sugar fermentation, which formed a direct continuation of Buchner’s work awarded in 1907. With his young co-worker, William John Young, Harden had shown in 1906 that fermentation requires a dialysable substance, called co-zymase, which is not destroyed by heat. Harden and Young also demonstrated that the process stops before all sugar (glucose) has been used up, but it starts again on addition of inorganic phosphate, and they suggested that hexose phosphates are formed in the early steps of fermentation. von Euler had done important work on the structure of co-zymase, shown to be nicotinamide adenine dinucleotide (NAD, earlier called DPN). As the number of Laureates can be three, it may seem appropriate for Young to have been included in the award, but Euler’s discovery was published together with Karl Myrbäck, and the number of Laureates is limited to three.

The next biochemical Nobel Prize was given in 1946 for work in the protein field. James B. Sumner of Cornell University received half the prize “for his discovery that enzymes can be crystallized” and John H. Northrop together with Wendell M. Stanley, both of the Rockefeller Institute, shared the other half “for their preparation of enzymes and virus proteins in a pure form”. Sumner had in 1926 crystalized an enzyme, urease, from jack beans and suggested that the crystals were the pure protein. His claim was, however, greeted with great scepticism, and the crystals were suggested to be inorganic salts with the enzyme adsorbed or occluded. Just a few years after Sumner’s discovery Northrop, however, managed to crystalize three digestive enzymes, pepsin, trypsin and chymotrypsin, and by painstaking experiments shown them to be pure proteins. Stanley started his attempt to purify virus proteins in the 1930s, but not until 1945 did he get virus crystals, and this then made it possible to show that viruses are complexes of protein and nucleic acid. The pioneering studies of these three investigators form the basis for the enormous number of new crystal structures of biological macromolecules, which have been published in the second half of the 20th century (cf. Section 3.5).

Several Nobel Prizes for Chemistry have been awarded for work in photosynthesis and respiration, the two main processes in the energy metabolism of living organisms (cf. Section 3.5). In 1961 Melvin Calvin of Berkeley received the prize for elucidating the carbon dioxide assimilation in plants. With the aid of carbon-14 (cf. Section 3.6) Calvin had shown that carbon dioxide is fixed in a cyclic process involving several enzymes. Peter Mitchell of the Glynn Research Laboratories in England was awarded in 1978 for his formulation of the chemiosmotic theory. According to this theory, electron transfer (cf. Sections 3.3 and 3.4) in the membrane-bound enzyme complexes in both respiration and photosynthesis, is coupled to proton translocation across the membranes, and the electrochemical gradient thus created is used to drive the synthesis of ATP (adenosine triphosphate), the energy storage molecule in all living cells. Paul D. Boyer of UCLA and John C. Walker of the MRC Laboratory in Cambridge shared one-half of the 1997 prize for their elucidation of the mechanism of ATP synthesis; the other half of the prize went to Jens C. Skou in Aarhus for the first discovery of an ion-transporting enzyme. Walker had determined the crystal structure of ATP synthase, and this structure confirmed a mechanism earlier proposed by Boyer, mainly on the basis of isotopic studies.

Luis F. Leloir from Buenos Aires was awarded in 1970 “for the discovery of sugar nucleotides and their role in the biosynthesis of carbohydrates”. In particular, Leloir had elucidated the biosynthesis of glycogen, the chief sugar reserve in animals and many microorganisms. Two years later the prize went with one half to Christian B. Anfinsen of NIH and the other half shared by Stanford Moore and William H. Stein, both from Rockefeller University, for fundamental work in protein chemistry. Anfinsen had shown, with the enzyme ribonuclease, that the information for a protein assuming a specific three-dimensional structure is inherent in its amino-acid sequence, and this discovery was the starting point for studies of the mechanism of protein folding, one of the major areas of present-day biochemical research. Moore and Stein had determined the amino-acid sequence of ribonuclease, but they received the prize for discovering anomalous properties of functional groups in the enzyme’s active site, which is a result of the protein fold.

Naturally a number of Nobel Prizes for Chemistry have been given for work in the nucleic acid field. In 1980 Paul Berg of Stanford received one half of the prize for studies of recombinant DNA, i.e. a molecule containing parts of DNA from different species, and the other half was shared by Walter Gilbert from Harvard and Frederick Sanger (see Section 3.5) for developing methods for the determination of the base sequences of nucleic acids. Berg’s work provides the basis of genetic engineering, which has led to the large biotechnology industry. Base sequence determinations are essential steps in recombinant-DNA technology, which is the rationale for Gilbert and Sanger sharing the prize with Berg.

Sidney Altman of Yale and Thomas R. Cech of the University of Colorado shared the prize in 1989 “for their discovery of the catalytic properties of RNA”. The central dogma of molecular biology is: DNA –> RNA –> enzyme. The discovery that not only enzymes but also RNA possesses catalytic properties have led to new ideas about the origin of life. The 1993 prize was shared by Kary B. Mullis from La Jolla and Michael Smith from Vancouver, who both have given important contributions to DNA technology. Mullis developed the PCR (“polymerase chain reaction”) technique, which makes it possible to replicate millions of times a specific DNA segment in a complicated genetic material. Smith’s work forms the basis for site-directed mutagenesis, a technique by which it is possible to change a specific amino-acid in a protein and thereby illuminate its functional role.

  1. Concluding Remarks

The first eighty years of Nobel Prizes for Chemistry outlines the development of modern chemistry. The prizes cover a broad spectrum of the basic chemical sciences, from theoretical chemistry to biochemistry, and also a number of contributions to applied chemistry. Organic chemistry dominates with no less than 25 awards. This is not surprising, since the special valence properties of carbon result in an almost infinite variation in the structure of organic compounds. Also, a large number of the prizes in organic chemistry were given for investigations of the chemistry of natural products of increasing complexity, and have lead to pharmaceutical development .

As many as 11 prizes have been awarded for biochemical discoveries. The first biochemical prize was already given in 1907 (Buchner), but only three awards in this area came in the first half of the century, illustrating the explosive growth of biochemistry in recent decades (8 prizes in 1970-1997). At the other end of the chemical spectrum, physical chemistry, including chemical thermodynamics and kinetics, dominates with 14 prizes, but there have also been 6 prizes in theoretical chemistry. Chemical structure is a large area with 8 prizes, including awards for methodological developments as well as for the determination of the structure of large biological molecules or molecular complexes. Industrial chemistry was first recognized in 1931 (Bergius, Bosch), but many more recent prizes for basic contributions lie close to industrial applications.

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Curated/reported by : Aviral Vatsa PhD, MBBS

Based on : S Moncada et al

It was in 1980 that Furchgott & Zawadzki first described endothelium- dependent relaxation of the blood vessels by acetylcholine. Further studies in 1984 revealed that other factors such as bradykinin, histamine and 5-hydroxytryptamine release endothelium derived relaxing factor (EDRF), which can modulate vessel tone. EDRF was shown to stimulate soluble guanylate cyclase and was inhibited by haemoglobin. In 1986 it was demonstrated that superoxide (O2) anions mediated EDRF inactivation and that the inhibitors of EDRF generated superoxide (O2) anions in solution as a mean to inhibit EDRF. It was later established that all compounds that inhibit EDRF have one property in common, redox activity, which accounted for their inhibitory action on EDRF. One exception was haemoglobin, which inactivates EDRF by binding to it. In 1987 Furchgott proposed that EDRF might be nitric oxide (NO) based on a study of the transient relaxations of endothelium-denuded rings of rabbit aorta to ‘acidified’ inorganic nitrite (NO) solutions and the observations that superoxide dismutase (SOD, which removes O2) protected EDRF. Till then NO was not known to be produced in mammalian cells. In 1988 Palmer et al could detect NO production both biologically and chemically by chemiluminescence. The following year in 1989 the enzyme responsible for NO production, NO synthase, was discovered and L-arginine:NO pathway was proposed.

Roles of L-arginine:NO pathway

By 1987 it was proposed that NO is generated in tissues other than endothelium. Hibbs et al and Marletta et al proposed that NO was generated by macrophages. Moreover release of EDRF was demonstrated in cerebellar cells following activation with N-methyl-D- aspartate (NMDA ). Both noradrenergic and cholinergic responses are ‘controlled’ by the nitrergic system so that the release of NO (e.g., during electrical field stimulation) counteracts and dominates the response to the noradrenergic or cholinergic stimulus (Cellek & Moncada, 1997). Mechanism of penile erection was unveiled by the studies on nitrergic neurotransmission that led to therapeutic intervention. Selective damage of nitrergic nerves in disease states was proposed as a potent mechanism of pathophysiology. Broadly three areas of research based on three isoforms of NOS came into being;

  • cardiovascular
  • nervous
  • immunology

Identification of NG-monomethyl-L-arginine (L-NMMA) as an inhibitor of the synthesis of NO lay the basis of future research into investigating the role of NO in biological systems. In 1989 it was demonstrated that intravenous infusion of L-NMMA resulted in increase in blood pressure that was reversible by infusing L-arginine. NO was thus implicated in constantly maintaining blood vessel tone. eNOS knockout studies showed a hypertensive phenotypes in the animal models and over expression of eNOS led to lowering of the blood pressure. Furthermore, eNOS activation was attributed to phosphorylation of a specific tyrosine residue in the enzyme.

NO and Mitochondria 

https://pharmaceuticalintelligence.com/2012/09/16/nitric-oxide-has-a-ubiquitous-role-in-the-regulation-of-glycolysis-with-a-concomitant-influence-on-mitochondrial-function/

NO reacts with some of the complexes of the respiratory chain, and inhibits mitochondrial respiration – this is a well accepted notion. Initially it was believed that the target for NO was soluble guanylate cyclase, which in vasculature would lead to elevation of cGMP that eventually results in NO mediated vasodilatation and platelet aggregation inhibition. In 1994, another potential target, cytochrome c oxidase, for inhibitory effects of NO was discovered. This was a reversible effect, in competition with oxygen concentrations. Increases in NO production were also shown to inhibit cellular respiration irreversibly by selectively inhibiting complex I . Hence in 2002 it was proposed that this might be a mechanism through which cell pathology was initiated in certain conditions. Furthermore, NO was proposed to be implicated in the activation of the grp78-dependent stress response , via modulating calcium-related interaction between mitochondria and endoplasmic reticulum . This host defence mechanism might also have role in vasculature. Further evidence was provided in 2003 to link the role of NO in mitochondrogenesis and thus indicating that NO might be involved in the regulation of the balance between glycolysis and oxidative phosphorylation in cells.

NO and Pathophysiology

Lack of NO: By 2000, NO was established as a haemostatic regulator in the vasculature. Its absence was implicated in pathological states such as hypertension and vasospasm. These pathophysiological states share a common beginning of endothelial dysfunction, which has low NO production as one of its characterstic features. This dysfunction has been observed prior to the appearance of cardiovascular disease in predisposed subjects with family history of essential hypertension and atherosclerosis. The most likely mechanism for endothelial dysfunction is that of a reduced bioavailability of NO . The mechanism of this aspect is discussed elsewhere on this site. Protection against reduction of NO bio-availability in the vasculature is a vital therapeutic target and is extensively explored. This can be achieved by the use of antioxidants and/or augmentation of eNOS expression. In 2003 statins were shown to increase the production of endothelial NO in endothelial cell cultures and in animals by the reduction of oxidative stress or by increasing the coupling of the eNOS. It was way back in 1994 that oestrogen was shown to increase both the activity and expression of eNOS. In addition, more recently in 2003, oestrogen was shown to reduce the breakdown of available NO.

Excess of NO: In 2000 it was shown that NO produced from iNOS in vasculature is involved in extensive vasodilatation in septic shock. Later it was demonstrated that inhibition of mitochondrial respiration is an important component of the NO-induced tissue damage. This inhibition of respiration, which is initially NO-dependent and reversible, becomes persistent with time as a result of oxidative stress . Such metabolic hypoxic states where in tissues cannot utilise available oxygen due to NO, could also contribute to other inflammatory and degenerative conditions. An obvious therapeutic target for reducing NO production in such conditions would be L-NMMA. L-NMM was tested in a clinical trial for septic shock in 2004. The results were however disappointing probably due to the blanket reduction in NO production from other NOS enzymes there by having deleterious effects on the treatment group. More specific inhibitors for NOS forms are being investigated for in different disease states.

In conclusion, the L-arginine: NO pathway has had a major impact in many areas of research, specially vascular biology. A lot has been understood about this pathway and its interactions, therapeutic targets are being aggressively investigated, but further investigations are required to delineate further the role of NO in human health and disease.

Further Reading

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1760731/?tool=pubmed

Nitric Oxide and Platelet Aggregation

Inhaled NO in Pulmonary Artery Hypertension and Right Sided Heart Failure

Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

Nitric Oxide in bone metabolism

Nitric oxide and signalling pathways

Rationale of NO use in hypertension and heart failure

Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Nitric Oxide has a ubiquitous role in the regulation of glycolysis -with a concomitant influence on mitochondrial function

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Author/Curator: Aviral Vatsa PhD, MBBS

Nitric oxide (NO) is of extreme biological interest due to its wide range of physiological functions in almost all the human systems. For long it has been of vital interest to chemists, environmental scientists, metallurgists and other domains. It is only recently that the world of biology has discovered the ubiquitous presence of this small molecule in human body and the scientific exploration of its effects has grown ever since. It was only in 1980s that three different groups demonstrated that NO is indeed produced by mammalian cells and that NO has specific biological roles in the human body. These studies highlighted the role of NO in cardiovascular, nervous and immune systems. In cardiovascular system NO was shown to cause relaxation of vascular smooth muscle cells causing vasodilatation, in nervous system NO acts as a signalling molecule and in immune system it is used against pathogens by the phagocytosis cells. These pioneering studies opened the path of investigation of role of NO in biology. In 1998, three scientists, Robert F Furchgott, Louis J Ignarro, and Ferid Murad, were awarded Nobel Prize for their discoveries concerning ‘nitric oxide as a signalling molecule’.

Since then hundreds and thousands of publications have appeared in the scientific literature. These studies have attributed a wide range of biological functions to NO. A few important examples are:

  • toxic free radical causing injury to proteins, lipids and DNA
  • mediator of synaptic plasticity
  • intercellular neuronal signalling molecule
  • pro and anti inflammatory molecule
  • role in cell degeneration and ischaemia-reperfusion injury
  • role in atherosclerosis and inherited motor disorders
  • role in bone remodelling

The above list is by no means exhaustive, but it gives an idea about the ubiquitous involvement of NO in human systems.

Since NO has been implicated in various disease states, it has also been a prime target to achieve therapeutic benefits. Efforts are ongoing to investigate the therapeutic potential of NO in cardiovascular diseases, sepsis and shock, respiratory ailments, neuronal disease and bone conditions…just to name a few.

Although a lot of progress has happened in our understanding of this small molecule since its discovery, but still there are many challenges that the researchers face today while investigating NO. These are primarily because NO is metabolised very quickly (<5 sec) and it can difuse freely across cellular membranes owing to its chemical structure. This is the precise reason why it can act as a potent signaling molecule across systems in the first place. New techniques are appearing to delineate the role of NO at sub-cellular level and have promising potential to aid NO research in the future.

In the future posts on this topic I will strive to cover different aspects of NO physiology and its role in various disease conditions, techniques for NO detection, signaling mechanism etc.

Sources:

1. The nature of endothelium-derived vascular relaxant factor

Nature 308, 645 – 647 (12 April 1984); doi:10.1038/308645a0

T. M. Griffith, D. H. Edwards, M. J. Lewis, A. C. Newby & A. H. Henderson

2. Nitric oxide: physiology, pathophysiology, and pharmacology.

Pharmacological Rev June 1991 43:109-142

S Moncada, R M Palmer, and E A Higgs

3. Introduction to EDRF research.

J Cardiovasc Pharmacol.1993;22 Suppl 7:S1-2.

Furchgott RF

4. http://www.nobelprize.org/nobel_prizes/medicine/laureates/1998/illpres/

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