New Horizons in Organic Chemistry: SynopsisAuthor(s): Alexander ToddSource: Notes and Records of the Royal Society of London, Vol. 16, No. 1, The TercentenaryCelebrations (Apr., 1961), pp. 77-80Published by: The Royal SocietyStable URL: http://www.jstor.org/stable/530768 .

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NEW HORIZONS IN ORGANIC CHEMISTRY

Tercentenary Lecture delivered by Sir Alexander Todd, F.R.S., at 2.30 p.m. on Wednesday 20 July at the Royal Institution

SYNOPSIS

T HERE have been two definitions of organic chemistry. The original definition, due to Berzelius (ca. I800), was 'the chemistry of substances

found in living matter.' The second, commonly ascribed to Gmelin, appeared first about fifty years later, when more was known about the peculiarities of the substances found in living matter-the 'organic' substances as distinct from the 'inorganic' substances-and was simply 'the chemistry of the carbon com-

pounds.' Each of these definitions is defensible, but neither is wholly satis-

factory, since the first is too restricted and the second is, in certain respects, too general. A very large number of known carbon compounds are of purely synthetic origin and do not, as far as we are aware, occur in living matter, but it is undoubtedly true that the study of substances which are found in living organisms has provided most of the major stimuli to the advance of organic chemistry for almost a hundred years, and there is little reason to believe that this will not continue to be the case in the future. After all, it was Pasteur's work on the tartaric acids from wine that led to the van't Hoff-Le Bel theory of the tetrahedral carbon atom, the anthraquinone dyestuffs stem from Graebe and Liebermann's work on alizarin from madder root, and work on poly- merization and plastics goes back to the studies of Harries on natural rubber.

Many other examples could be quoted, but I shall mention only one more because it is less well known than it should be. It was the work of Windaus on the natural sterols which caused Hiickel to develop his theoretical studies on stereoisomerism in fused ring systems; through these studies, important enough in themselves, developed in due course the modem concept of dyna- mic stereochemistry of cyclic structures which has had such a profound influence over a very large area of organic chemistry.

The direct study of substances present in living matter-broadly described as natural products-in the sense of their structural elucidation and total

synthesis in the laboratory, has been a dominant feature of organic chemistry only during the twentieth century. That it was not so dominant before that time can be readily understood, for, without an extensive knowledge of

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carbon chemistry, the relatively complex natural products could not be success- fully investigated. The nineteenth century was, indeed, essentially the period during which the necessary facts of carbon chemistry and the techniques of experiment were developed to the point at which natural product chemistry could be tackled with real prospect of success. This is not to say that natural products were wholly neglected in the nineteenth century; the medical importance of natural drugs ensured that some attention was paid to them, and, indeed, it was through such work in this period that physiological chemistry and, in due course, biochemistry developed. Today, with the moder development of natural product chemistry, it is interesting to see how the rather artificial demarcation between organic chemistry and biochemistry is again becoming blurred-and with considerable advantage to both sciences.

Not only science as a whole, but individual sciences, tend to advance irregularly on a broad front, and during any one phase of development there are always individual investigators who stand apart and who break new ground or see new vistas not apparent to others at the time. For this reason it is difficult -and particularly so with recent events-to put precise dates to changes in scientific patterns. But in broad terms it would seem that during the first thirty years or so of this century most organic chemists dealing with substances occurring in living matter were preoccupied almost entirely with the structure of compounds, while the biochemists were interested essentially in their func- tions. During this period, and subsequently, the organic chemists developed their methods of degradation and synthesis to a high degree of perfection and, aided by the introduction of new physical methods of analysis, they have taken them to the point at which the total synthesis of substances as complex as cholesterol, strychnine, chlorophyll, and a number of the nucleotide co- enzymes, has been realized in the laboratory. But since the mid-thirties, slowly at first, but later with increasing rapidity, interest has been moving to a study of structure in relation to function among natural products.

It is this which has taken organic chemistry much closer to biology than it has ever been before. Equally, of course, it is the increasing realization that function must be considered in relation to structure that is bringing the bio- chemists closer to their organic chemical colleagues. The way in which organic chemical, biochemical-and also biophysical-studies interact and illumine one another has been one of the features of recent scientific advances in a variety of fields of biological interest, and it seems fitting to try to illustrate some of the new vistas that are opening up by giving a brief outline of what has been developing in a few fields apparently diverse from a biological view- point, but which have a common organic chemical thread. It would, of

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course, be possible to choose a series of random topics to illustrate new hori- zons, but it is perhaps more instructive to choose a small group where the chemical background is common. I confess that it is also more interesting to me to choose one where the common background is one with whose develop- ment I have been associated, without in any way claiming any special virtue for it over other areas of organic chemistry. For this reason I would like to discuss some features of the chemistry of the organic phosphates and their relevance to wider problems.

It has long been known that organic phosphates are invariable constituents of living organisms and that they play a variety of roles involving, for example, energy transfer and the facilitation of both synthetic and degradative processes in biological systems. Just how and why they do so and why phos- phate residues should occur in such complex molecules as those of, e.g., the nucleic acids and the phospholipids, has been in the past very much less clear. Until quite recently, organic chemists had paid very little attention to the synthesis or to the study of the chemical behaviour of organic phosphates, and in the absence of knowledge on these matters much careful biochemical work remained without a satisfactory interpretation. My own interest in this field was aroused just about twenty years ago when, stimulated through an interest in vitamin chemistry, I was attracted to the study of nucleotide coenzymes- the active forms of a number of vitamins-and the nucleic acids. This caused us to develop, first in Manchester and then in Cambridge, a large group of investigations into the chemistry of organic derivatives of phosphoric and the polyphosphoric acids. Of the many interesting aspects of these investigations I shall discuss only three to illustrate my general theme-the alkaline hydrolysis of phosphates, the dealkylation of phosphates by anionic (nucleophilic) fission, and the development of phosphorylating agents from phosphates by oxidative processes. The main features of these three topics will be developed and their connexion with other problems explained. The broad overall picture given can be briefly summarized as follows:

(a) It was the realization of the factors governing the relative stability of different types of simple phosphate esters that enabled Brown and Todd in 1951 to interpret the accumulated experimental observations on nucleic acid behaviour and to propound the general theory of the chemical structure of the nucleic acids and so open the way to the subsequent remarkable developments in the biophysical and genetic fields associated with the functions ofdeoxyribo- nucleic and ribonucleic acids through the work of Watson and Crick, Wilkins, Kornberg, Ochoa, and many others. All this work opens new vistas in the understanding of some of the fundamental processes in living cells, and

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also presents new challenges to the organic chemist in the field of synthetic and analytical work.

(b) The elucidation of the mechanism of biosynthesis of the terpenoids and the steroids by Cornforth, Bloch, Lynen, and others is one of the most

fascinating pieces of chemical work done in recent years. The active inter- mediate involved in the synthetic processes used to this end by living organ- isms is an organic phosphate and the mechanism is strictly paralleled by laboratory studies on the disruption of allyl and benzyl phosphates by nucleophilic reagents. Here a knowledge of phosphate chemistry has given an

explanation of the mechanism of a biosynthetic process. (c) The way in which quinol phosphates act as powerful phosphorylating

agents under oxidative conditions (Clark, Kirby, and Todd) suggests an

explanation for the function of the important coenzymes of the ubiquinone or coenzyme Q group isolated and studied by Morton and others, and may provide the key to an understanding of the vitally important oxidative phos- phorylation processes in biological systems.

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