摘要:

Coden NPRRDF ISSN 0265-0568 Natural Product Reports A journal of current developments in bio -organic chemistry Volume4 1987 The Royal Society of Chemistry London Natural Product Reports (ISSN 0265-0568) 0 The Royal Society of Chemistry 1987 All Rights Reserved No part of this publication may be reproduced stored in a retrieval system or transmitted in any form or by any means electronic mechanical photographic recording or otherwise without the prior permission of the publishers. Printed in Great Britain by the University Press Cambridge ISSN 0265-0568 NPRRDF 4 1-704 1-1-1-64 (1987) Natural Product Reports A journal of current developments in bio -organic chemistry Volume 4 CONTENTS 1 Centenary Tribute to Sir Robert Robinson (1886-1975) G.Pattenden 3 Robert Robinson (1886-1975) Lord Todd 13 Sir Robert Robinson -His Contribution to Alkaloid Chemistry K. W. Bentley 25 Anthocyanins Brazilin and Related Compounds R. Livingstone 35 Steroids and Synthetic Oestrogens Sir John Cornforth 41 Sir Robert Robinson and the Early History of Penicillin E. P. Abraham 47 Theoretical Organic Chemistry before Robinson C. A. Russell 53 The Development of Sir Robert Robinson’s Contributions to Theoretical Organic Chemistry M. D. Saltzman 61 Electronic Theories of Organic Chemistry Robinson and Ingold J. Shorter 67 Chemistry in Manchester in the Twenties and some Personal Recollections W. Cocker 73 The Dyson Perrins Laboratory in Robinson’s Time M. L. Tomlinson 77 Nature’s Pathways to the Pigments of Life A.R. Battersby (The Robert Robinson Lecture) 89 Amaryllidaceae Alkaloids M. F. Grundon Reviewing the literature published between July 1984 and June 1985 95 Fatty Acids and Glycerides F. D. Gunstone Reviewing the literature published during 1984 and 1985 113 Simple and Complex Lipids Their Occurrence Chemistry and Biochemistry W. W. Christie Reviewing the literature published during 1984 and 1985 129 Phase Behaviour of Binary Mixtures of Membrane Polar Lipids in Aqueous Systems P. J. Quinn Reviewing the literature published between January 1985 and June 1986 139 Chemical and Biochemical Manipulation of DNA and the Expression of Foreign Genes in Micro- organisms J. H. Parish and M. J. McPherson An introduction to the literature of molecular biology 157 The Biosynthesis of C,-C, Terpenoid Compounds D.V. Banthorpe and S. A. Branch Reviewing the literature published during 1985 175 Chemical Systematics P. G. Waterman and A. I. Gray NATURAL PRODUCT REPORTS 1987 CONTENTS 205 Applications of Recombinant DNA in Biotechnology An introduction to literature of selected areas of molecular biology 225 Quinoline Quinazoline and Acridone Alkaloids M. F. Grundon Reviewing the literature published between July 1984 and June 1985 237 Tobacco Isoprenoids I. Wahlberg and C. R. Enzell Reviewing the literature published between 1975 and 1984 277 The Use of Stable Isotopes in Biosynthetic Studies J. C. Vederas Reviewing the literature published between January 1982 and December 1985 339 The Biosynthesis of Polyketides T.J. Simpson Reviewing the literature published between July 1984 and December 1985 377 Monoterpenoids D. H. Grayson Reviewing the literature published during 1984 399 Diterpenoids J. R. Hanson Reviewing the literature published during 1985 415 Indolizidine and Quinolizidine Alkaloids M. F. Grundon Reviewing the literature published between July 1984 and June 1985 423 The Biosynthesis of Plant Alkaloids and Nitrogenous Microbial Metabolites Reviewing the literature published between July 1985 and June 1986 44 1 The Biosynthesis of Porphyrins Chlorophylls and Vitamin B, F. J. Leeper Reviewing the literature published during 1985 471 Book Review Natural Product Chemistry ed. Atta-ur-Rahman Reviewed by E.Haslam 472 Erratum to Quinoline Quinazoline and Acridone Alkaloids M. F. Grundon (Vol. 4 No. 3 p. 225) 473 Natural Sesquiterpenoids B. M. Fraga Reviewing the literature published during 1985 499 Lignans Neolignans and Related Compounds D. A. Whiting Reviewing the literature published between January 1984 and December 1985 527 Pyrrolidine Piperidine and Pyridine Alkaloids A. R. Pinder Reviewing the literature published between July 1985 and June 1986 539 Marine Natural Products D. J. Faulkner Reviewing the literature published between July 1985 and September 1986 577 Pyrrolizidine Alkaloids D. J. Robins Reviewing the literature published between July 1985 and June 1986 591 Recent Progress in the Chemistry of Indole Alkaloids and Mould Metabolites Reviewing the literature published between July 1985 and June 1986 639 Benzenoid and Polycyclic Aromatic Natural Products T.J. Simpson M. J. McPherson and J. H. Parish R. B. Herbert J. E. Saxton Reviewing the literature published during 1984 and 1985 677 p-Phenylethylamines and the Isoquinoline Alkaloids K. W. Bentley Reviewing the literature published between July 1985 and June 1986 703 Book Review Immunology in Plant Sciences ed. H. F. Linskens and J. F. Jackson Reviewed by D. V. Banthorpe I-1 Index of Authors Cited 1-35 Subject Index Nornenclature It is the policy of The Royal Society of Chemistry to en- courage the use of IUPAC and IUB Recommendations on nomenclature. Although many of the appropriate nomen-clature documents will be included in the new edition of the IUB publication ‘Biochemical Nomenclature and Related Documents ’ (to be published by The Biochemical Society London during 1988) a selection of recent Recommenda-tions that will be of particular interest to those who investigate the chemistry occurrence or biosynthesis of natural products includes Nomenclature of tetrapyrroles (Recommendations 1986) Pure Appl.Chem. 1987 59 779-832. Nomenclature and symbols for folic acid and related compounds (Recommendations 1986) Pure Appl. Chem. 1987 59 833-836; Eur. J. Biochem. 1987 168 251-253. Nomenclature of prenols (Recommendations 1986) Pure Appl. Chem. 1987 59 683-4589; Eur. J. Biochem. 1987 167 181-184. Extension of Rules A-1 .1 and A-2.5 concerning numerical terms used in organic nomenclature (Recommendations 1986) Pure Appl.Chem. 1986 58 1693-1696. phe original versions of these Rules are in ‘Nomenclature of Organic Chemistry Sections A B C D E F and H’ 1979 Edition] Nomenclature of glycoproteins glycopeptides and peptidoglycans (Recommendations 1985) Eur. J. Biochem. 1986 159 1-6. ‘Enzyme Nomenclature (Recommendations 1984)’ Supplement 1 Corrections and additions Eur. J. Biochem. 1986 157 1-26. Recommendations for the presentation of thermodynamic and related data in biology (1985) Eur. J. Biochem. 1985 153 4294 34. Nomenclature for incompletely specified bases in nucleic acid sequences (Recommendations 1984) Eur. J. Biochem. 1985 150 1-5 (see also Eur.J. Biochem. 1986 157 1). ‘Enzyme Nomenclature 1984’ (Recommendations of the Nomenclature Committee of the International Union of Biochemistry on the nomenclature and classification of enzyme- catalysed reactions) Academic Press Orlando Florida 1984. Nomenclature and symbolism for amino acids and peptides (Recommendations 1983) Pure Appl. Chem. 1984 56 595-624; Eur. J. Biochem. 1984 138 9-37 (see also Eur. J. Biochem. 1985 152 1 and the Newsletter 1985 of NC-IUB and JCBN ibid. 1985 146 pp. 238 and 239 and the Newsletter 1986 ibid. 1986 154 pp. 485 and 486). Abbreviations and symbols for the description of conformations of polynucleotide chains (Recommendations 1982) Pure Appl. Chem. 1983 55 1273-1280; Eur. J. Biochem. 1983 131 9-15 (see also the Newsletter 1984 of NC-IUB and JCBN Eur.J. Biochem. 1984 138 p. 7). Symbols for specifying the conformation of polysaccharide chains (Recommendations 1981) Pure Appl. Chem. 1983 55 1269-1272; Eur. J. Biochem. 1983 131 5-7. Nomenclature of retinoids (Recommendations 198 I) Pure Appl. Chem. 1983 55 721-726; Eur. J. Biochem. 1982 129 1-5. Symbolism and terminology in enzyme kinetics (Recommendations 1981) Eur. J. Biochem. 1982 128 281-291. Polysaccharide nomenclature (Recommendations 1980) Pure Appl. Chem. 1982 54 1523-1526; Eur. J. Biochem. 1982 126 439441. Abbreviated terminology of oligosaccharide chains (Recommendations 1980) Pure Appl. Chem. 1982 54 1517-1 522; Eur. J. Biochem. 1982 126 433437. Nomenclature of vitamin D (Recommendations 1981) Pure Appl.Chem. 1982 54 1511-1516; Eur. J. Biochem. 1982 124 223-227. Nomenclature of tocopherols and related compounds (Recommendations 1981) Pure Appl. Chem. 1982 54 1507-1510; Eur. J. Biochem. 1982 123 473475. The most recent of the lists of restriction endonucleases and their isoschizomers (compiled by R. J. Roberts) was in Nucleic Acids Res. 1987 15 R189-R217 its predecessors being ibid. 1985 13 r165-r200 and ibid. 1983 11 r 13 5-r 1 67. Natural Product Reports Editorial Board Professor G. Pattenden (Chairman) University of Nottingham Dr D. V. Banthorpe University College London Professor M. F. Grundon University of Ulster at Coleraine Dr J. R. Hanson University of Sussex Dr R.B.Herbert Universi ty of Leeds Professor M. I. Page The Polytechnic Huddersfield Dr T. J. Simpson University of Edinburgh Natural Product Reports is a journal of critical reviews published bimonthly which is intended to foster progress in the study of natural products by providing reviews of the literature that has been published during well-defined periods on the topics of the general chemistry and biosynthesis of alkaloids terpenoids steroids fatty acids and 0-heterocyclic aliphatic aromatic and alicyclic natural products. Occasional reviews provide details of techniques for separation and spectroscopic identification and describe methodologies that are useful to all chemists and biologists who are actively engaged in the study of natural products. Articles in Natural Product Reports are commissioned by members of the Editorial Board or accepted by the'chairman of consideration at meetings of the Board.This journal includes reviews of books relating to natural products. Volumes for review should be sent to the editorial office for which the address is The Royal Society of Chemistry Burlington House London W1V OBN and marked for the attention of Mr B. J. Starkey. Contributors to Volume 4 Abraham E. P. 41 Grundon M. F. 89 225 415 472 Russell C. A. 47 Banthorpe D. V. 157 703 Battersby A. R. 77 Bentley K. W. 13 677 Branch S. A. 157 Christie W. W. 113 Cocker W. 67 Gunstone F. D. 95 Hanson J. R. 399 Haslam E. 471 Herbert R. B. 423 Leeper F. J. 441 Livingstone R. 25 Saltzman M. D. 53 Saxton J. E. 591 Shorter J.61 Simpson T. J. 339 639 Todd Lord 3 Tomlinson M. L. 73 Cornforth Sir John 35 McPherson M. J. 139 205 Vederas J. C. 277 Enzell C. R. 237 Faulkner D. J. 539 Parish J. H. 139 205 Pattenden G. 1 Wahlberg I. 237 Waterman P. G. 175 Fraga B. M. 473 Gray A. I. 175 Grayson D. H. 377 Pinder A. R. 527 Quinn P. J. 129 Robins D. J. 577 Whiting D. A. 499

ISSN:0265-0568    

DOI:10.1039/NP98704FP001

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Robert Robinson (I 886-1 975) Lord Todd Christ’s College Cambridge CB2 36U The Robinson family has been established in Chesterfield Derbyshire since 1794 when William Robinson earlier trained as a draper in Nottingham set up in business there as a manufacturer of surgical dressings. The major development of the family firm (Robinson & Sons Ltd) was due to his grandson William Bradbury Robinson a man of great energy and a tireless inventor who among other things was the first to make a mechanical linting machine to automate the cutting of cotton bandages and to mechanize the production of cardboard pillboxes. W. B. Robinson was married twice first to Elizabeth Lowe (d. 1871) by whom he had eight surviving children and secondly to Jane Davenport (d.1950) who gave him three daughters and two sons. The eldest member of this second family was Robert born on 13 September 1886 at Rufford Farm near Chesterfield and moving with the family to its new home Field House New Brampton when he was 3 years of age. As a member of a family unusually large even for those days and with other branches of the family contributing to the numbers it is not surprising that young Robert had a boisterous childhood and he records in his own autobiography recol- lections of very large reunions at Christmas and on other family occasions. He received his early education in Chesterfield first at Mrs Wilkes’s Kindergarten and then at the nearby Chesterfield Grammar School where he found an inspiring teacher in the headmaster Mr Mansell who seems to have been the first to stimulate his interest in mathematics.At the age of 12 Robert was moved to Fulneck School at Pudsey Greenside about halfway between Leeds and Bradford; there he remained until he entered Manchester University in 1902. The Robinson family were prominent Congregationalists and it may seem odd that Robert should have attended a school run by the Moravian Church in Britain. However Fulneck which had produced inter alios Herbert Asquith had a high reputation and further- more two of Robert’s first cousins had been educated at Neuwied a Moravian school in the Rhineland. Although a majority of the masters at the school were candidates for the Moravian ministry and many boys came from Moravian homes there seems to have been little effort made to convert non-members to the sect and Robert’s period there was comparatively uneventful.His younger brother Victor (1891- 1972) who was later to become chairman and chief architect of the modern development of the family firm and who was always very close to Robert was also at Fulneck and the two brothers in fact overlapped there for a time. It was the habit of the Congregationalist ministers in Chesterfield frequently to visit the Robinson home and hold lengthy discussions on doctrinal matters. These had little interest for the young Robert who inevitably heard some of them when he was at home but the visits had certain positive influences on his career since it was the ministers who introduced him to chess a game which later became a major hobby and who also persuaded his father that he should be sent to university.It is interesting that on leaving school he wished to take up mathematics. However his father was determined that Robert should study something which would be of practical use in the family business; and so in 1902 Robert was despatched to Manchester University to read chemistry. Although attend- ance at a university may have been a novelty in the family the appearance of scientific interest and ability was not ; Robert’s grandfather was locally well known as a naturalist and his father was a not inconsiderable inventor. Robert himself had in his early childhood shown an interest in natural phenomena and he records how as a boy he earned a sovereign for inventing a device for automatically rolling and cutting bandages.Such interests suggest to the writer at least that his talents were more likely to be fully developed through natural science than through mathematics ;certainly natural science benefited greatly from that initial decision to take up chemistry. In 1902 the Manchester Department directed by H. B. Dixon was a major feature of British chemistry and with W. H. Perkin Jr (then 42 years of age) as Professor of Organic Chemistry at the height of his powers it occupied a dominant position at least in that branch of the subject and it rivalled the great German schools until Perkin left for Oxford just before the outbreak of World War I. Among Robinson’s fellow students were men later to acquire fame as chemists -J.L. Simonsen and W. N. Haworth on the academic and C. J. T. Cronshaw on the industrial side. Not all were to remain in chemistry however. A fellow-entrant on the course in 1902 was Ashley Dukes later well known as a playwright and dramatic critic and with his wife Marie Rambert through the Rambert School of Ballet. Robinson records their mutual recognition on matric- ulation because they had each of them captained the cricket 2nd XI in their respective schools (Fulneck and Silcoates) and had each of them as bowlers dismissed the other for a duck in an inter-school match. Although Dukes gave up chemistry after graduation the two remained friends until Dukes’s death in 1959. Another contemporary who left chemistry and later took up academic work in other fields in Canada was Peter Sandiford who shared top place with Robinson in the final honours examination.Sandiford was an ardent Socialist who persuaded Robinson to undergo an uncomfortable tour of Germany in seatless fourth-class railway carriages in order that he should see how the poorer classes in Germany lived and thought ; what conclusions if any the two undergraduates reached are not recorded. In those days the first-year laboratory course was given in the Roscoe Laboratory of the old Manchester Chemical Labora- tories. Some of the old laboratory records have survived including that kept by Norman Smith (later to become Uni- versity Registrar) who was Demonstrator in charge of the elementary laboratory in 1902.It contains the interesting entry ‘Robinson Robert -A good worker but messy.’ In the first year the lecture course which like that in the laboratory dealt with the chemistry of the non-metallic elements was given by H. B. Dixon and in the second G. H. Bailey lectured on metals and with W. A. Bone conducted the practical classes. Bone flamboyant in dress as in language was deeply immersed in his research but the moment of inspiration for Robinson came in the latter part of his second year when he first came in contact with Perkin. According to Robinson Perkin’s course was the high point of the year and he describes it as a miracle of clear exposition; he himself has recorded that it was his attendance at it that finally decided his future career.Robinson was fascinated by the beauty of the organic chemical system and he agreed with Frederick Gowland Hopkins who once declared it to be one of the greatest achievements of the human mind. The third-year course contained advanced lectures on organic chemistry and a special subject -in Robinson’s case the chemistry of dyestuffs -with practical work arranged by J. F. Thorpe in whom he found not only an inspiring teacher but a lifelong friend. Robinson graduated with first class honours in 1905 and entered Perkin’s private laboratory in NATURAL PRODUCT REPORTS 1987 The Manchester chemistry Department in 191 1 (Courtesy of Greater Manchester Museum of Science and Industry). Robert Robinson then an Assistant Lecturer is sitting at the far left and immediately behind him at far left is his great friend Arthur Lapworth.In the middle of the seated row is Professor W. H. Perkin between Chaim Weizmann (in 1948 the first President of Israel) to the left and Professor H. B. Dixon to the right. September of that year as a postgraduate student. During his undergraduate days a great expansion of the Manchester laboratories occurred. In 1902 Dr Edward Schunck bequeathed his laboratory and scientific library at Kersal Moor for the use of the Chemical Department. The building was moved brick by brick from Kersal and re-erected near the existing laboratories being joined to them by a new building containing the Perkin and Dalton Laboratories all of them opened in 1904.A further large addition the John Morley Laboratory was made in 1909 the year before Robinson took his D.Sc. degree. During this period too Robinson had other laboratory facilities for during his first year at university his father built and equipped as a laboratory an extension to the family home at New Brampton. Here the budding chemist certainly carried out a fair amount of experimental work at different times including a synthesis of terebic acid which was successful and a rather grandiose attempt at atom-smashing which was not. On entering Perkin’s research laboratory Robinson’s first task was to prepare ethyl piperonylacetate. Perkin gave him a 5 kg bottle of piperonal adding that he thought it would probably be enough for the purpose.Robinson reported that the permanganate oxidation of piperonal (which was carried out in Winchester quart bottles) was giving lower yields than the analogous oxidation of veratraldehyde whereupon Perkin simply said ‘Do one more oxidation and you will get enough.’ The original intention behind this work-a venture into the coumarin field-was dropped as the results suggested some new lines in the study of the dyewood colouring matter brazilin (and the related haematoxylin). Perkin had already carried out a substantial amount of work on brazilin before taking up the Manchester chair but the problem of its structural elucidation attracted Robinson at once and he plunged himself into the field. He suggested to Perkin a new formula for brazilin based on a reinterpretation of the oxidation of trimethylbrazilin ;he then confirmed its correctness by synthesizing brazilinic acid only to find to his chagrin that the same structure had been proposed a short time earlier on less secure evidence by Werner & Pfeiffer..The chemistry of brazilin was however far from completed and its study continued to occupy some of Robin- son’s attention through almost the whole of his working life. This early work on brazilin almost certainly triggered Robin- son’s lifelong interest in natural colouring matters. It is indeed interesting to see how much of his life’s work had its origin in this Manchester period. To mention but a few examples the germ of his later anthoxanthin studies is to be found in the brazilin work and the chemistry of the substances obtained from brazilein and haematein derivatives by acid treatment led him to the study of pyrylium salts and hence much later to his researches on anthocyanidins and anthocyanins.His work on alkaloids begun with Perkin remained a passion with him as witness his extensive and continuous work on strychnine and brucine and the indole alkaloids in general and this was in turn responsible for the development of his biogenetic theories which have so greatly influenced not only structural studies on natural products but also the experimental study of alkaloid biosynthesis. Already as a research student Robinson was interested in the mechanism of some of the reactions he used and this interest received a powerful stimulus when in 1909 Arthur Lapworth came to Manchester as Schunck Fellow and Senior Lecturer in Inorganic and Physical Chemistry.At the NATURAL PRODUCT REPORTS 1987-LORD TODD same time Robinson who had been University Fellow (1906) and 185I Exhibition Scholar (1907-9) was appointed Assistant Lecturer and Demonstrator and the two struck up a close friendship. During the period between then and 1912 when Robinson went to Sydney they had unlimited opportunity for discussion. At this time Lapworth was obsessed by his theory of alternate polarities and Robinson often stressed to the writer the profound influence which Lapworth had on his thinking and how much the development of his own theoretical ideas owed to those discussions.The contact between the two men established in the period 1909-12 continued until Lapworth’s death in 1941. Of others with whom Robinson formed close friendships in Manchester Chaim Weizmann deserves special mention. He was appointed Lecturer and Demonstrator in the Manchester department in 1906 and was put in charge of the Schorlemmer Laboratory where the practical classes in organic chemistry were conducted. Weizmann soon developed a small research group and among his research students were W. N. Haworth Henry Stephen Maurice Copisarow and Gertrude Maud Walsh (1 886-1 954) who became Robinson’s fiancee and in the early summer of 1912 his wife. Both before and after their marriage the young couple were frequent visitors to the Weizmann home in Palatine Road Didsbury.Over the years the friendship then formed was maintained and Robinson greatly valued his later position as a Governor of the Weizmann Institute of Science in Rehovoth and was proud of his election to its Fellowship. So far this account of Robert Robinson in Manchester might suggest an almost total devotion to the laboratory. True it is that he was in the habit of working there till about 3 a.m. in the company of other night birds like D. L. Chapman (later of Jesus College. Oxford) and Ida Smedley (later of the Lister Institute of Preventive Medicine under her married name Ida Smedley Maclean). But he found time to engage in other interests outside the laboratory. He was fond of music played the piano with more than average skill and was a regular attender of the theatre in all its forms from music hall through Gilbert and Sullivan to serious drama.He played chess avidly and out of doors he spent much time in walking climbing and mountaineering; in these latter pursuits he had the company of Miss Walsh both before and after their marriage for she too was a keen mountain climber. Robinson’s interests in chess and mountaineering played a large part in his life but in order to do them justice further comment on them will be deferred until later. In 1912 the University of Sydney decided to expand its chemical school by creating a second chair in addition to that held by Fawsitt. On the recommendation of Perkin Robinson at that time only 26 years of age was appointed Professor of Pure and Applied Organic Chemistry.Thus little more than six months after their marriage Robert and Gertrude Robinson sailed for Sydney arriving there on 7 February 1913 shortly before the start of the Australian academic year. There both quickly set to work on their researches although a good deal of time must have been spent in organizing lecture courses and practical classes. From the description given in the University of Sydney Calendar for 1914 the course in organic chemistry was very similar in pattern to that in Manchester; Gertrude Robinson was doubtless involved as well as her husband for she held the post of Demonstrator in the session 1913-14. During the short period of Robinson’s stay in Sydney his research was largely devoted to completion and extension of work begun in Manchester but he ventured into a new area when H.G. Smith the great authority on eucalypts drew his attention to this as yet little investigated group. With Smith he published three papers in 1915 one on eudesmin and its derivatives and the others on phenols and esters occurring in some eucalyptus oils. There may indeed have been further work done by him in this field. While in Sydney he had a disastrous fire in his research laboratory in which it is said that he lost not only research specimens but also many of his laboratory records and most of 5 the one thousand pounds worth of chemicals which Perkin had urged him to take to Australia. One of his students in Sydney was T.G. H. Jones later Professor of Chemistry and in due course Vice-Chancellor of the University of Queensland who died in Brisbane a few years ago; we have been unable to trace anyone else with first-hand knowledge of the Robinson period in Sydney. We know from climbing records that Robert and Gertrude made two visits to New Zealand during their sojourn in Sydney but other information about their life there is fragmentary. In 1915 the newly created Heath Harrison Chair of Organic Chemistry in the University of Liverpool was advertised and presumably at Perkin’s instigation Robinson applied. He had by then been little more than two years at Sydney but although he enjoyed Australia it was at that time scientifically remote and an opportunity of returning to England was not to be missed.Although he could not be interviewed the appointing committee were unanimous in their choice. This was not very surprising since in 1914 the British Association for the Advance- ment of Science had held its annual meeting in Australia and many of its members had met Robinson there. As a result quite apart from Perkin’s advocacy he had glowing recommenda- tions from H. E. Armstrong N. V. Sidgwick W. J. Pope and J. F. Thorpe. He took up his new position at Liverpool in January 1916 and there he entered upon a new and very significant phase of his researches on alkaloids. It was here that he carried out his famous synthesis of tropinone from succin- dialdehyde methylamine and acetone in aqueous solution’ and embodied his ideas on biogenesis in a memoir entitled ‘A theory of the mechanism of the phytochemical synthesis of certain alkaloids ’.2 An inspiring leader of an ever-growing research team he was also an outstanding teacher of under- graduates whose lectures given without notes were liberally sprinkled with fascinating asides on some of his own ex-periences.Personally he was rather shy and was regarded by most junior undergraduates as somewhat unapproachable ;but when they did pluck up their courage they found him both kindly and more than willing to help them in their difficulties. During the period 191 5-18 a good deal of work in connection with the war effort was undertaken in Liverpool. The outbreak of war had exposed the weakness of our chemical industry in particular and the need for closer cooperation between the university and industry was recognized in Liverpool and fully supported by Robinson.So it was that close relations were established with British Dyes Ltd a company formed with government money in 1915 to take over the dye-making plant of Read Halliday & Co. at Huddersfield. The research section of the company was planned to operate through ‘colonies’ established in universities where a number of professors of chemistry (Perkin at Oxford Pope at Cambridge and Robinson at Liverpool) were each to have a few chemists ‘at the rate of about E200 p.a. plus university fees’. Although by 1917 Robinson had four chemists in his ‘colony’ who made regular visits to the Huddersfield works it appears that this experiment in devolution was not regarded as very successful from the industry ~tandpoint.~ During the war the fortunes of another dyestuffs firm Levinstein Ltd of Blackley Manchester had become considerably entangled with those of British Dyes Ltd under pressure from Government and in 1919 the two firms merged to become the British Dyestuffs Corporation.The idea of research by means of ‘colonies’ was dropped in favour of properly organized research and development within the com- pany itself. Because of the intense rivalry between the two components however two separate Research Departments were established one at Blackley under Professor A. G. Green F.R.S. previously Professor of Colour Chemistry at Leeds and the other at Huddersfield where Robinson accepted appoint- ment as Director of Research.He left Liverpool at the end of the Autumn Term 1919 to take up his new position although he continued to give some part-time assistance during the rest of the academic year pending the installation of his successor. There is evidence that Robinson did not find his new situation congenial. The intense rivalry between Blackley and Hudders- field which continued despite the fact that they were now part of the same firm certainly did not help matters and when in 1920 it was decided on financial grounds to cut back severely all research activities he resigned in order to become Professor of Organic Chemistry at the University of St Andrews.Yet this short spell in the British Dyestuffs Corporation was by no means unimportant in Robinson’s development. It gave him an insight into and an understanding of the problems of research in industry which not only served him and the various firms to which he later acted as a consultant well but also helped him in guiding the many students who passed through his hands over the years. He also acquired during this period an as- tonishingly comprehensive knowledge of dyestuff chemistry. This was put to good use when following the creation of Imperial Chemical Industries Ltd and the concentration of the research of its Dyestuffs Group at Blackley a consultative committee called the Dyestuffs Group Research Committee (D.G.R.C.) was set up in 1929 with J.F. Thorpe Robert Robinson and I. M. Heilbron as external members. This com- mittee the name of which was changed later to Dyestuffs Division Research Panel (D.D.R.P.) met monthly to consider and discuss with members of the firm’s research laboratories day-to-day research problems as well as policy matters. The writer joined the Committee in 1939 after the death of J. F. Thorpe and recalls vividly not only Robinson’s penetrating insight into the details of the research programmes discussed but his astonishing familiarity with all the technical jargon including the trade names of the dyestuff industry. It is worthy of record too that Robinson was through this activity a major factor in the creation of a medicinal section in the Dyestuffs Group at Blackley and so in the birth of the Pharmaceutical Division of Imperial Chemical Industries Ltd.Robinson re- mained a member of the D.D.R.P. until the commencement of his involvement with Shell Chemicals Ltd in the nineteen-fifties. Robinson took up his new position in St Andrews in the autumn of 1920 as successor to J. C. Irvine who had just resigned as Professor of Chemistry to become Vice-Chancellor of the University. Under the successive guidance of Purdie and Irvine the school of chemistry had become a major centre of carbohydrate studies. W. N. Haworth who had gone there from Manchester as Lecturer in 1912 when Robinson went to Sydney had just left to become Professor at Newcastle and E. L. Hirst was an assistant in the department carrying on carbohydrate research.The new professor who apart from Mrs Robinson brought no research students or collaborators with him very quickly built up a powerful group pursuing research on a variety of lines. Most of these were continuations of already established interests -alkaloids organic reaction mechanisms and natural colouring matters -and some at least were in a crucial phase of development which made the St Andrews period an important one for Robinson and an exciting one for both staff and students. Among those associated with him in alkaloid studies were J. M. Gulland W. 0.Kermack and A. K. Macbeth while D. D. Pratt began the work on anthocyanidins which was later to develop into extensive studies on flower colours both from a chemical and genetic point of view.Miss Ettie Steele who had been a collaborator of Irvine and remained in the professor’s laboratory when Robinson arrived recalls his almost total absorption in research and the marked contrast in this respect between him and his predecessor. E. L. Hirst (de~eased,~ alas since this memoir was written) recalled especially the complete revolution in the attitude to theoretical organic chemistry consequent on Robinson’s arrival. He was already using the Lapworth alternating polarities in his honours lectures and in them he first enunciated his ideas of the aromatic sextet. It is clear from Hirst’s recollections and the records of the St Andrews University Chemical Society of 1922 that the electronic theory of organic chemistry incorporating the ideas of Arthur Lapworth and G.N. Lewis which he advanced a few years later was already developing in his mind. During their stay in St Andrews upon which they always NATURAL PRODUCT REPORTS 1987 looked back with affection the Robinsons did a good deal of walking and climbing in the Highlands but do not seem to have been especially identified with any social activities other than those associated with the Chemistry Department. It was prob- ably something of a wrench to leave St Andrews after so short a stay but when following the retirement of H. B. Dixon Robinson was offered the Chair of Organic Chemistry in Manchester in 1922 he could scarcely have declined not only because of the greater scope the large department there offered but also because of the presence there of his old friend Arthur Lapworth who had taken over the Headship from Dixon.The wheel had so to speak gone full circle and the Robinsons were back in the laboratory in which they had been students. Physically it was virtually unchanged the last major addition having been the Morley extension of 1909. Robinson held the chair in Manchester for six years. They were busy years with a large and growing research school in which one recalls not only names like Wilson Baker and Alexander Robertson but an increasing number of overseas students such as Venkataraman Seshadri Manske and others who now flocked to work with an acknowledged master of his craft. It would be fair however to say that viewed in the context of Robinson’s lifework the Manchester period was essentially one of consolidation rather than of the opening of new fields.Work on strychnine brucine and the morphine group was stepped up and major develop- ment of the anthoxanthins and the first ventures into the anthocyanins occurred while his theoretical views gained in scope and precision. It was only after the virtual completion of the anthocyanin work in Oxford and the appearance of his two definitive lectures on An outline of an electrochemical (electronic) theory of the course of organic reactions in 19325 that major moves into new fields of endeavour occurred. In 1928 Robinson moved from Manchester to become Professor at University College London. Whether this move was the result of a desire to live in London or the result of some disenchantment with Manchester is unknown to the writer for Robinson never discussed it with him but it is not easy to understand on chemical grounds.However the University College interlude was short. In September 1929 W. H. Perkin Jr died in Oxford and almost inevitably Robinson was elected to and accepted the Waynflete Professorship with its ac-companying Fellowship at Magdalen College ;this position he occupied from 1930 until his retirement in 1955. On the face of it the move to Oxford seemed to present no difficulty for Robinson’s major interests -alkaloids and specially strychnine and brucine on the one hand and natural colouring matters on the other -were already the mainstay of Perkin’s research group.But there were problems for any incoming professor. The Oxford Chemistry School was a large one but for various reasons its main growth in the nineteen-twenties had been in the direction of physical chemistry. The majority of college fellows in chemistry had that side of the subject as their main interest and even in the Dyson Perrins Laboratory N. V. Sidgwick T. W. J. Taylor and D. L1. Hammick were heavily oriented to physical aspects of organic chemistry. As a result most of the Oxford undergraduates were channelled in these directions especially during Perkin’s later years when his activity was naturally declining. There was certainly a great new surge in organic chemistry when Robinson arrived but it was to a large extent brought about by the growing influx of doctoral and postdoctoral students from other parts of Britain and from overseas the Oxford men continuing in the main to follow the lines of work being pursued by the Fellows and Tutors of their respective colleges rather than those of the new professor however great his reputation.Robinson had no previous experience of the collegiate system and did not appreciate the delicate balance which existed between college and university; he was interested only in research and was impatient of anything which stood in the way of its progress. So it was that he quickly found himself at odds with the existing arrangements and although this did not prevent him from making the Dyson Perrins Laboratory a world-famous centre NATURAL PRODUCT REPORTS 1987-LORD TODD Professor Sir Robert and Lady (Gertrude) Robinson (Courtesy of Associated Press The Royal Society and A.C. Cooper) of organic chemistry it perpetuated a certain disunity and weakness in the Oxford school which could well have been avoided. Robinson enjoyed his association with Magdalen College but he never became in any way a college man nor had he any great sympathy for the collegiate system at least where chemistry was concerned. The move to Oxford caused little interruption in the research either of Robinson or of his wife who in addition to looking after her family (a daughter Marion b. 1921 and an invalid son Michael b. 1926) spent a great deal of time at the bench mainly on the problems of anthocyanin distribution.She occupied one half of her husband’s private laboratory which abutted on his office on the second floor of the Dyson Perrins Laboratory. Alongside it was a small laboratory occupied by J. Resuggan Robinson’s extremely able technical assistant and beyond that another containing the writer and B. K. Blount from 1931 when they returned to England from Germany until 1934. Our contacts with Robinson during this peak period in his activity were close and frequent for he too spent long hours in the laboratory. There he would visit his research students read or write in his office and have periodical bouts of experimental work. Robinson did not pursue solid experimental studies in the way that his predecessor Perkin did.He confined himself mainly to exploratory experiments usually conducted in test- tubes or boiling-tubes. The author has vivid memories of his awesome method of concentrating ethereal solutions by boiling them in wide-mouthed tubes over a Bunsen burner and igniting the ether vapour as it emerged! Once a test-tube trial of a reaction indicated that something had occurred the follow-up was usually left to a junior colleague. Robinson’s visits to individual research students although inspiring were erratic and depended largely on his somewhat mercurial interest in a particular topic at a given time. So it was that a research student might have spells when he had discussions once or twice a day and others when a week or two could pass without his speaking to Robinson at all.With the writer and B. K. Blount his contacts were probably closer than with any others at this time partly perhaps because of the proximity of their laboratory to his own and a common addiction to crossword puzzles. Each afternoon around four o’clock just as tea was being brewed in beakers Robinson would appear in their laboratory for a united assault on The Times crossword followed often by a discussion on any chemical topic which was currently occupying his mind. In the early part of the Oxford period Robinson enunciated his theoretical views in full and although some topics such as the nitrogenous flower pigments and the leucoanthocyanidins remained ill explored the completion of the major anthocyanin syntheses clearly indicated that the work on anthoxanthins and anthocyanins was approaching its end.Increasingly Robinson’s mind was seeking new fields of endeavour. One such he found when the proposal of Rosenheim and King (1932) of a new carbon skeleton for sterols and bile acids aroused his interest in the steroids. He quickly perceived the flaw in the arguments of these authors and for a short time threatened to take up degradative studies on cholesterol. When a modified and correct structure was proposed later in that year by Wieland and Dane and by Rosenheim and King Robinson had already begun synthetic work aimed at the ring system of oestrone and this effort on the synthesis of substances related to the sterols was sustained in its various aspects until his retirement from the Oxford chair in 1955.The nineteen thirties also saw the appearance of some interesting work on a survey of antho- cyanins and on the genetics of flower colour variation in association with his wife Gertrude Rose Scott-Moncrieff and J. R. Price. The importance of this early contribution to chemical genetics has been largely overlooked. As the years passed Robinson’s services were increasingly sought by outside bodies and he served on many committees. He was knighted in 1939 and in the same year became President of the Chemical Society. On the outbreak of war in September of that year he was at once plunged into a variety of Government activities and served on many bodies concerned with chemical defence and explosives and through the Medical Research Council with chemotherapy.Research in Oxford was much slowed down and what continued was switched to subjects more directly concerned with the war effort e.g. chemical warfare agents and antimalarial drugs. It is probably true to say that none of these evoked great enthusiasm in him and it was only with the advent of penicillin following the work of Florey and Chain that he found a nationally important topic which really aroused his interest. The penicillin studies absorbed most of the time and energy he had available for research during the latter part of the war. After war ended in 1945 Robinson quickly restarted his researches on steroid synthesis in Oxford and returned again with renewed vigour to his old loves strychnine and brucine.But he was not allowed to divest himself of outside responsi- bilities for on St Andrew’s Day in that year he succeeded Sir Henry Dale as President of the Royal Society. This office which he held for five years was peculiarly onerous at that time. The need for science in restoring the ravaged economies of the world was clear the development of the atomic bomb had put a new dimension into the danger of war to mankind as a whole and there was a crying need to restore and amplify the international unity of science and the free dissemination of the results of scientific research. In all these matters Robinson in his capacity as President of the Royal Society played a major r61e. He presided over the Royal Society Empire Scientific Conference in 1946 and the Newton Tercentenary in the same year when representatives of 36 countries in addition to those of the British Commonwealth attended.These were the first two occasions since 1939 on which men of science from different lands had the opportunity of meeting together on an informal footing. Robinson did much to encourage the renewal of contacts with and between scientists in the war-devastated countries of Europe and he was prominent in reactivating the international scientific unions. Among other notable activities were his promotion of the Royal Society Scientific Information Conference in 1948 and his vigorous but alas unsuccessful efforts to create a Science Centre in London a project conceived originally by the previous President Sir Henry Dale.In 1947 Robinson was awarded the Nobel Prize for Chem- istry a richly deserved recognition. The actual citation read ‘for his investigations on plant products of biological importance especially the alkaloids’. Robinson’s work in these fields was without doubt brilliant but when one remembers his contribu- tions to chemical theory and to organic synthesis one feels that it would have been equally or possibly even more appropriate to have said ‘for his outstanding contributions to the entire science of organic chemistry’. For this is in fact the most striking thing about Robert Robinson ;his influence permeated almost the entire science and in the field of synthesis his enduring contribution lies not so much in the synthesis of NATURAL PRODUCT REPORTS 1987 individual natural products as in the stream of brilliant new methods which he produced and which have become part of the fabric of the subject.This is particularly well shown in his studies on steroid synthesis; practically all of the numerous steroid syntheses carried out by other workers rest wholly or partly on synthetic procedures and reactions first explored by Robinson. In 1949 his distinction and his service to science and the nation were recognized by the award of the Order of Merit. He reached the official retirement age in 1951 but remained full of vigour and research ideas. Partly for this reason and partly no doubt in recognition of the heavy inroads on his work by the war and his official responsibilities his tenure of the Oxford chair was extended until 1955 the year in which he was President of the British Association for the Advancement of Science.Two developments during this final phase of his academic career call for special mention -the foundation of a new journal and the beginning of his association with the Shell Company. Shortly before the outbreak of war in 1939 Robinson was with Harold King F.R.S. of the National Institute of Medical Research eager to establish a new journal for organic chemistry in which authors would have the opportunity to write sub- stantial memoirs rather on the lines of the long-established Annalen der Chemie. Efforts to persuade the Royal Society to create for this purpose a Proceedings C came to nought both then and when the idea was resuscitated later.Some years after the war the proposal came up again in a somewhat different form when Dr H. Rosbaud -formerly an editor with the German Springer-Verlag -approached Sir Robert about the possibility of producing such a journal through a commercial publisher. The project thereafter had many vicissitudes owing to doubts in the minds of some chemists about its likely effect on the publications of the Chemical Society and especially to some complex developments among publishing houses which might have been concerned. In the 1950s it came back to life again with the rise of Pergamon Press Ltd under Robert Maxwell. An internationally constituted Editorial Board was set up with Sir Robert Robinson named as Founder and under the name Tetrahedron (originally suggested by R.B. Woodward) the first issue of the new journal eventually appeared in 1957. Mention has earlier been made of Robinson’s long associa- tion with the dyestuff industry and in particular with the committee originally called the Dyestuffs Group Research Committee and later the Dyestuffs Division Research Panel which was advisory to the Dyestuffs Division of Imperial Chemical Industries Ltd and to the developing Pharmaceutical Division. From 1939 until 1949 the D.D.R.P. had three external members R. Robinson I. M. Heilbron and A. R. Todd but in the latter year Sir Ian Heilbron left Imperial College to become Director of the new Brewing Industry Research Foundation.This new position he felt was incompatible with his membership of D.D.R.P. and he accordingly resigned; no new member was appointed. Meanwhile Robinson had added to his industrial connections in the following way. The work of Dr Chaim Weizmann on petroleum cracking largely in collaboration with E. D. Bergmann at the Daniel Sieff Laboratory for Organic Chemical Research at Rehovoth in Isreal (the nucleus of the future Weizmann Institute of Science) gave rise to an industri- ally applicable procedure known as the Catarole Process which although rather rapidly superseded was the operational basis of a company set up under the name Petrochemicals Ltd in this country. This company was established after the last war and a substantial amount of its capital was provided by the Finance Corporation for Industry a government organization which nominated Sir Robert Robinson as an F.C.I.nominee director. This was convenient for him since the company had premises at Partington not far from Manchester and so he found it easy to visit them when attending D.D.R.P. meetings. With the obs- olescence of the Catarole Process however Petrochemicals Ltd ran into financial difficulties and in 1955 it was bought up by Shell. Robinson thereupon severed his connections with I.C.I. Ltd and other industrial companies to which he acted as a NATURAL PRODUCT REPORTS 1987-LORD TODD consultant and upon his retirement from Oxford he became a director of Shell Chemical Co. Ltd with a small laboratory at Egham in which he continued to pursue his alkaloidal and other research with a small group of collaborators.In addition he moved around the Shell research organization in this country and abroad as a consultant. Up to the time of his death he remained in the employ of Shell Chemicals U.K. Ltd and Shell Research Ltd and played an active part in chemistry. Largely as a result of his association with the oil industry he became in his later years very interested in the origin of petroleum and gave a number of public lectures on this topic. So far in this memoir an attempt has been made to set out in something like chronological order the career of Robert Robin- son the scientist. No such account can however convey a full picture of the man.From his career it is easy to recognize his brilliance of mind his restlessness and his great physical and mental toughness. But there were many facets to him which deserve closer mention. He belonged to that rapidly diminishing group of scientists whose interests spread over a wide range beyond their own speciality and extend into music and literature as well. He had an astonishing memory for detail and not only in organic chemistry ;appropriately stimulated he would quote verbatim and with relish long passages from the Ingoldsby Legends or the works of Edward Lear which he had presumably learned as a boy. In matters scientific he had an extraordinary breadth coupled with a penetrating mind which seemed capable of going to the heart of any chemical problem almost instanta- neously.This made argument with him on anything less than a cast-iron case a rather chastening experience the more so as Robinson was never at pains to conceal his real opinion about scientific ideas -or people for that matter. He was capable too of intense concentration on a problem with a corresponding exclusion of everything else from his mind. Thus it was that whereas he could be a delightful companion and a receptive listener there were frequent occasions when he would be so absorbed in his own thoughts as virtually to ignore those around him. This could and frequently did give an impression of remoteness verging on rudeness to strangers and even at times to his own research students. Robinson was nevertheless rather mercurial in his behaviour and could be wholly emotional in his immediate reaction to people and things; this character- istic which got him into hot water from time to time and which frightened those who did not know him well was however an essential part of the man and indeed a source of endearment and of endless anecdotes among his friends.The emotional nature of Robinson’s response to events and his associated impatience with those holding views contrary to his own finds a reflection in his scientific work and helps to explain at once its tremendous scope and its variety. His instinct when confronted with a difficulty in experimental work was to seek at once an alternative route to his objective or even at times to change the objective itself.This contributed positively to the discovery of new reactions but it also led to premature abandonment of synthetic routes that were later shown (often by others) to be practical. This comes out most clearly in his work on steroid synthesis and it helps to explain why Robinson’s name is associated more often with a prodigious number of synthetic reactions and methods than with individual syntheses. Science did not absorb all his restless energy. He did not devote undue time to relaxation from work but when he did he pursued it with an intensity not unlike that which he applied to his science. He and his first wife were keen gardeners and there was always a profusion of flowers in the summer around their Oxford home. Like her he loved music and found solace in it during the dark and lonely days following her death.Introduced to chess in his boyhood Robinson became a first-class amateur player winning the Oxfordshire championship twice and he was President of the British Chess Federation from 1950 to 1953. At the chessboard he was a deep imaginative and observant player and his power of abstract thought already mentioned in connection with his chemistry made him in- dependent of visual aids to play; after his ’ sight failed he continued to play postal chess of a quality astonishing for a man in his eighties. He was attracted by the kriegspiel variant of the game and he was an excellent analyst of chess positions and studies. A bare two years before his death he published a book on the game in collaboration with R.Edwards.6 Robinson’s other great love was for mountains and mountaineering -a love which was much greater and occupied much more of his earlier life than most of his scientific colleagues suspected. Already as a schoolboy he practised rock climbing on crags above his great-grandmother’s native village of Combes near Chapel-en-le-Frith. To what extent he was encouraged in his early climbing pursuits by his stepbrother-in- law J. Morton Clayton a climber of some note and a member of the Alpine Club is uncertain. But it was Clayton who introduced Robert to alpine mountaineering at the age of 17 with a traverse of the Wetterhorn. During his student days and until he went to Sydney in 1912 Robinson did a lot of climbing in Britain and in the Alps.In much of this he was accompanied both before and after marriage by Gertrude a keen climber herself who made her first alpine climbs with him in 191 1. After their return from Sydney and until the beginning of World War I1 the Robinsons spent most of their Christmas and Easter vacations climbing in Britain. This included climbing on rock and gritstone (on snow in winter) as well as fell walking and general mountaineering. Before moving to Sydney Robinson’s summer holidays were spent mainly in the Arolla-Zermatt-Saas Fee area where he climbed almost all the major peaks including the Dent Blanche and the Dufourspitze the highest peak in the Monte Rosa group. On one of these-trips he met Edward Whymper who made the first ascent of the Matterhorn and accompanied him on the walk down from Zermatt to St Niklaus.While at Sydney one of the great attractions was the New Zealand Alps which had been little explored at that time. In the summers of 1913- 15 the Robinsons climbed Mts Wakefield Malte Brun Annette and Footstool and made the first guide-less ascent of Mt Sealy. With Conrad Kain the remarkable Austrian-born guide the Robinsons also climbed the Aiguille Rouge. The next day Robert with Conrad Kain and three others made the second Sir Robert Robinson in the mountains,possibly the North Ridge of Tryfan in North Wales (Courtesy of The Royal Society and A. C. Cooper) Gertrude Robinson on the eastern ridge of the Piz Julier (3385 m) near St Moritz; photograph by Robert Robinson.Date unknown but probably in the 1930s. Some years later the Piz Julier was the last alpine peak climbed by Sir Robert at the age of 70. (Courtesy of Dyson Perrins Laboratory ;identification and informa- tion by Dr Morrin Acheson) grand traverse of Coronet Peak and the first ascent of Mt Meeson which he described as ‘very easy’. After returning to Britain via the Canadian Rockies where only walking proved possible the Robinsons confined them- selves to climbing in the Coolins and the Lake District both in winter and summer until 1920 when a summer in the Pyrenees began an almost unbroken series of alpine climbing holidays until 1939. These were mainly in the Swiss Alps and included ascents of the Eiger Monch and Jungfrau with occasional visits to the French and Italian Alps and a couple of holidays in Norway.The Robinsons enjoyed mountains enormously from every aspect and were both very experienced mountaineers in the widest sense. They had several narrow escapes and on one occasion Robert fell into a crevasse. His companions pulled hard on the rope and when it did not move they thought they were holding him. To their surprise he suddenly appeared having chimneyed out of the crevasse unaided; the rope was frozen in the snow at the lip of the abyss! In all Robinson made over 100 ascents of alpine peaks. His mountaineering activities in more recent years consisted mainly of hill and pass walking. He climbed Piz Julier when he was 70 and his last climb of Table Mountain in South Africa was in 1966.He was elected to membership of the Rucksack Club in 1920 and to the Alpine Club in 1949. To be with Robert in the mountains was to see a new man -humble in the face of Nature and with a capacity for wonder at its majesty which was almost childlike in its simplicity. In 1954 just as he was approaching the end of his tenure in Oxford tragedy struck through the death of his wife Gertrude with whom he had shared all his interests including organic chemistry for over forty years. His loneliness was apparent to NATURAL PRODUCT REPORTS 1987 all his friends but he had the immense good fortune to meet in Stearn Hillstrom a woman who although outwardly quite different in type from Gertrude nevertheless could and did provide the love sympathy and security which he so sorely needed.They were married in 1957 and lived happily together until his death in 1975. Although afflicted by failing eyesight which indeed became virtual blindness in the last few years of his life Robert retained most of his other characteristics including his remarkable knowledge of chemistry his amazing power of concentration and his sense of humour to the very end. How many men could have after the age of 85 devoted the last years of life to the compilation of a two-volume autobiography and in collaboration with E. D. Morgan to the completion of a textbook on organic chemistry published posthumously in 1975?’ Yet this he did and he was actually at work on his memoirs to the very day of his death on 8 February 1975.Such was Robert Robinson -one of the greatest organic chemists and one whose name will live as long as science itself. Honours During his lifetime many honours both public and scientific were showered upon Robert Robinson. He was knighted in 1939 and was awarded the Order of Merit in 1949; he was also a Commandeur de la Legion d’Honneur (France) and a member of the Order of the Rising Sun (Japan). Public honours (as distinct from those directly associated with his research) he was inclined to regard lightly-so much so indeed that his record of them is somewhat sketchy and there may well be some which we have been unable to trace. He took particular pride in the Freedom of his native Chesterfield which he received in 1947 and in the Presidency of the Royal Society (1945-50).During his career he also served as President of the Chemical Society (1939-41) of the Society of Chemical Industry (1958-59) and of the British Association for the Advancement of Science (1955). He was from 1956 an Honorary Fellow of Magdalen College Oxford of which he had formerly been a Professorial Fellow. Other important honours include Medals Davy Royal and Copley Medals (Royal Society); Longstaff Faraday and Flintoff Medals (Chemical Society) ; Hofmann Medal (German Chemical Society) ; Albert Medal (Royal Society of Arts) ;Paracelsus Medal (Swiss Chemical Society) ; Priestley Medal (American Chemical Society) ; Franklin Medal (Franklin Institute of Philadelphia).Honorary Fellowship Membership Associate Membership or Corresponding Membership United Kingdom Biochemical Society Society of Anal- ytical Chemistry Society of Endocrinology Institution of Chemical Engineers Parliamentary and Scientific Com- mittee Royal Society of Edinburgh Royal College of Surgeons Royal College of Physicians (Edinburgh) Royal College of Obstetricians and Gynaecologists. Commonwealth Australian Academy of Science Royal Society of New South Wales Royal Society of New Zealand Indian National Academy of Science Indian Academy of Sciences Indian Chemical Society. Foreign National Academies of United States of America Belgium Denmark France Ireland Japan Norway Rumania Sweden U.S.S.R. New York Academy of Sci- ence American Academy of Arts and Sciences American Philosophical Society and Scientific Academies of Haar-lem Halle Milan Munich Naples and Rome.Honorary member Chemical Societies of Belgium France Poland Japan; Chemists’ Club of New York and Honorary Fellow Weizmann Institute of Science Rehovoth. NATURAL PRODUCT REPORTS 1987-LORD TODD Honorary Degrees D.Sc. -Belfast Bristol Cambridge Durham Liverpool London Nottingham Oxford Sheffield Strathclyde Sydney Wales Delhi Hokkaido Zagreb. D.Pharm.-Madrid Paris. LI.D -Birmingham Edinburgh Glasgow Liverpool Man- Chester St Andrews. D.LI. -Brussels. References 1 R. Robinson J. Chem. Soc. 1917 111 762. 2 R. Robinson J. Chem. Soc. 1917 111 876. 3 W. J. Reader ‘I.C.I. A History Vol. I The Forerunners 1870- 1926’ Oxford University Press London 1970 p. 275. 4 Obituary by M. Stacey and Elizabeth Percival Biogr. Mem. Fellows R. Soc. 1976 22 137. 5 R. Robinson ‘An Outline of an Electrochemical (Electronic) Theory of the Course of Organic Reactions’ Institute of Chem-istry London 1932. 6 R. Robinson and R. Edwards ‘The Art and Science of Chess’ Batsford London 1973. 7 E. D. Morgan and R. Robinson ‘An Introduction to Organic Chemistry’ Hutchinson London 1975.

ISSN:0265-0568    

DOI:10.1039/NP9870400003

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Sir Robert Robinson -His Contribution to Alkaloid Chemistry K. W. Bentley Department of Chemistry Loughborough University of Technology Loughborough Leicestershire LE 7 7 3TU As one who had the inestimable privilege of taking his first steps in research as a Part I1 B.A. student in Oxford forty years ago under the guidance of Sir Robert Robinson it is an honour for me to be invited to survey his contribution to alkaloid chemistry. His work in this field was so extensive so incisive and so important that it is impossible to do it justice in a short contribution; all that I can do is to highlight his most significant work with special reference to three areas. Excluding work on model compounds for comparative reactions and exploratory synthesis in which unsubstituted compounds were used as models Sir Robert published 163 papers on alkaloids over a period of 55 years during the whole of which time he was also making massive contributions to the chemistry of a variety of other natural products and to the development of a rational theory of organic reaction mecha- nisms; throughout all of that time each paper required months of careful experimental work not an hour or two with an n.m.r.spectrometer a gas chromatograph and a mass spectrometer ! The principal challenge and the most extensive continuous work involved the elucidation of the structure of strychnine and its congeners brucine and vomicine published in 54 paper^,^^-'^^ but important work was done on phthalide-isoquinolines,'-18 berbe~ine,'~-~~ tropinone and related alka- loid~,~~-~~ the biogenesis of alkaloid^,^^-^* harmine harmaline and r~taecarpine,"~~~ benzylisoquino-physo~tigrnine,~~-~~ ]ines,63-65 peganine,"6'ji benzophenanthridines 68-79 lycorine,il.'* a variety of indole alkaloid^,'^'-'^^ and the alkaloids of the morphine group.153-1 63 In all of these fields his papers were less numerous than those of other workers but they were in a different class being characterized not only by his skill in planning degradations of the most significant nature but also by razor-sharp logic with which he cut away the misconceptions and confused thinking of others to reveal the real significance of their work so that to the reader it all seemed so simple that he.was left wondering why it had taken so many years to see.Sir Robert wrote all of his own papers with a style of prose composition that makes the Dyson Perrins Laboratory of the nineteen-thirties and -forties OMe OH (1) (2) live on in the pages of the Journal of the Chemical Society of those years. Robert Robinson's first paper on alkaloids' was published in 1907 at the age of 21 and described the synthesis'of hydrastic acid (a key degradation product of hydrastine) ;it was followed two years later2 by a synthesis of cotarnic acid from narcotine. The synthesis of a-gnoscopine which is the racemic form of narcotine (3; R = H) was achieved by mixing cotarnine (1; R = OMe) with meconine (2; R = H) in ethanol,3 but better yields of condensation product were obtained by using iodo- meconine (2; R = I) and nitromeconine (2; R = NO,).However whereas the removal of iodine from (3 ;R = I) gave a- gnoscopine removal of the nitro-group from (3; R = NO,) gave principally a stereoisomer P-gnoscopine. Some years later narcotine was equilibrated with p-narcotine in alkaline solution and it was concluded that a-and P-gnoscopine differ in configuration at the chiral carbon of the lactone ring." Syn- theses of hydrastine from hydrastinine (1 ; R = H) and nitro- and iodo-meconines yielded mixtures of racemic a and P forms;6v l3 the resolution of these led to the correct conclusion that hydrastine (4)differs from narcotine (3; R = H) in its absolute stereochemistry .l4 A much later excursion into the phthalide-isoquinoline field demonstrated Robinson's eagerness to utilize new reagents and new techniques wherever possible.The unprecedented reducing power of lithium aluminium hydride was first reported early in 1948 and of course it had to be applied immediately. Un- fortunately it had to be made from lithium hydride. of which none was available in the Dyson Perrins Laboratory so I found myself heating lithium (with great trepidation!) in a stream of hydrogen. The hydride was formed all right but resembled granite in consistency and reducing it to a fine powder resulted in some rather expensive lithium carbonate. Eventually others obtained the desired reagent; it was used to reduce hydrastine to the diol (5) which was converted into the chiral dihydro- berberinium salt (6) (presumably under the influence of the chiral centres that existed prior to dehydration) and this was converted into berberine (7).lH H&o / OMe 6Me OMe (6) NPR 4 NATURAL PRODUCT REPORTS 1987 0 0Me (10) (11) NH2Me 1 OH OH (14) Me Many years earlier Robinson had participated in the elucida- tion of the structure of berberine [by correctly identifying the key degradation products berberilic acid (8) and berberal (9)ls]and in the first synthesis of a derivative of berberine oxyberberine (12) from the amide-lactone (10) via the phthalide-isoquinoline (I I) which suffered reductive opening of the lactone ring and lactam formation on reduction with zinc and acetic acid.22 (12) (15) + / / / / Me Bo Me The success of the syntheses of narcotine and hydrastine and particularly the ease with which the carbinolamines cotarnine (I ; R = OMe) and hydrastine (1 ; R = H) condensed with a variety of compounds that contained reactive methylene led Robinson to suggest that tropinone (1 5) might be synthesized easily from acetone and the carbinolamine (14) which in turn should be preparable from succindialdehyde (13) NATURAL PRODUCT REPORTS 1987-K.W. BENTLEY (25) I (27) (28) and methylamine. When the dialdehyde methylamine and acetone were allowed to stand together in solution a small (but detectable) amount of tropinone was formed and a 40YOyield was obtained when acetone was replaced by the more reactive acetonedicarboxylic The generality of the process was subsequently demonstrated by using glutaric dialdehyde (which yielded $-pelletierineZ4) maleic dialdeh~de,~~ adipic dialde- h~de,~~ and dialdehydes that contained laevulinic aldeh~de,~’ nitrogen sulphur or selenium.26 It appears from the original paper that the synthesis was not based on biogenetic con-siderations but only on chemical analogy in an attempt to find a simple and cheap synthesis of $-tropine the benzoyl ester of which (tropacocaine) is a local anaesthetic of comparable potency to cocaine.It is clear however that the nature and success of this synthesis were important features in the development of the first rational theories of the biogenesis of alkaloids which were set out in a paper that was received by The Chemical Society on 23 July 1917 only ten days after receipt of the paper in which the synthesis of tropinone is described.This remarkably per- ceptive discourse30 was one of his most important contributions to the chemistry of natural products and remains the foundation of our theories of biogenesis not because many chemists have spent much of their working lives proving that he was essentially right about the origins of alkaloids but because for the first time he showed that complex substances could be built up from simple materials using rational processes for which there are well-known laboratory analogies. Previous suggestions for the formation of alkaloids were unacceptable to him involving as they did processes such as pyrolysis that could not occur in living tissue saying Previous suggestions have no laboratory analogy.It has been assumed that plants have enormously powerful reagents that can cause sub- stances the properties of which have been investigated with con-siderable care to undergo transformations that cannot be induced in the laboratory. To a certain extent especially in regard to oxidation and reduction this must be true but it is probable that this aspect has been exaggerated and that an equally important cause of the variety and complexity of synthesis in plants resides in the highly reactive nature of the substances that function as reactive intermediates. He believed that his synthesis of tropinone summarized the reactions that are involved in the production of the base in plants from the amino acid ornithine and he outlined processes for the biosynthesis of amino acids and alkaloids in which (26) o ( /y OMe OMe ‘linkage of carbon to carbon is traced to two processes only namely the aldol condensation and the very similar con-densation of carbinolamines resulting from the combination of an aldehyde or ketone and ammonia or an amine with substances containing the group -CH-CO-’.Regarding a-amino acids as sources of amines (by decarboxylation) and aldehydes (by oxidation) he proposed the biosynthesis of hygrine (19) and cuscohygrine (20) as resulting from the con- densation of acetone or more likely the equivalent mono-or di-carboxylic acid with the carbinolamine (1 8) which would have been derived from ornithine (16) via the aldehyde (1 7).N-Methylation by the action of formaldehyde and subsequent reduction was regarded as possible at any stage. Oxidation at stages (16) (1 7) or (1 8) would furnish (14) for the synthesis of tropinone; oxidation at (19) could result in the cyclization of hygrine to tropinone (15). As powerful support for these proposals he cited the existence of homologues of hygrine and tropinone namely N-methylisopelletierine (2 1) and ~-pelle- tierine (22) as well as the hemlock alkaloids all of which are clearly derived from lysine and pointed to a plausible origin of nicotine from ammonia formaldehyde and either hygrine or its precursor . The benzylisoquinoline alkaloid norlaudanosoline (25) was represented as originating from the amine (23) and the aldehyde (24) by a Pictet-Spengler cyclization and the condensation of norlaudanosoline at the nitrogen atom with formaldehyde was regarded as causing N-methylation or formation of the tetrahydroberberine (28) system ; the condensation of formaldehyde with both the aromatic nucleus and the nitrogen atom was proposed to give (26) which would subsequently be converted (by oxidation) into the phthalide-isoquinoline hydra- stine (29).The ring-opened system that is found in protopine (27) was regarded as being formed from a tetrahydroberberine by N-methylation and oxidation (using formaldehyde). The postulated biogenesis of morphine was based on an incorrect formula for the alkaloid but following his elucidation of the correct structure (discussed later) he recognized that the alkaloids of this group and the aporphines were derived by alternative oxidative couplings of phenolic benzylisoquinolines.Having produced these remarkable seminal ideas he turned largely to more interesting things leaving the tedium of proof to others his only subsequent involvement being in attempts to achieve the oxidative coupling of benzylisoquinolines to apor-phines (30) and m~rphine.~’-~~ In the laboratory the reagents NATURAL PRODUCT REPORTS 1987 VOH OH (30) (31) Me (33) Me0wM; \ Me0@Me \ (35) (341 Me Me0m\ M Me e (36) (37) Scheme 1 that were used led only to the dibenzopyrrocolinium salt (31) which at that time was a novel structure though its analogues were found to be natural products in 1952.One of the unsolved problems at that time was the structure of harmine. In 1912 he had proved3' the presence of a reactive methyl group in the alkaloid and in 1919 in a beautifully reasoned paper,41 he re-examined the work of others and fundamentally altered the previously proposed structures re- ducing the possibilities to three [(32)-(34)] but with a clear preference for (32) [which was subsequently shown to be corre~t~~-~~] because of a plausible biogenesis from the amino acid t~yptophan.~'**~ Shortly afterwards the course of the N-methylation of harmine [i.e. (32) + (35) + (36) + (37); see Scheme I] was neatly el~cidated,~~.~~ norharman was syn-thesi~ed,~~ and other work on harmaline was rep~rted.~~.~' In the case of some alkaloids the determination of structure was already complete before Robinson became interested in the challenge that was presented by their synthesis.One such alkaloid was physostigmine the synthesis of which was dealt with in a series of papers in 1932-35.53-62 Noreserethole (43) was synthesized from the indolenine (39) and from the oxindole (41) (see Scheme 2) and N-methylation of (42) or of (43) provided a route to eserethole with could readily be converted through the phenol into physostigmine. The most successful commercial synthesis is only a modification of the route from (41). i? OHC 0 + (Fixher) (38) (39) 1 i ii Me iii iv I Me Me (42) (431 Reagents i MeI; ii NH,NH,; iii HBr; iv NH Scheme 2 Robinson also achieved the first synthesis of the ring system of the benzophenanthridine alkaloids with the preparation of (46; R' = OMe R2 = H) which is an isomer of N-demethyl- chelerythrine (46; R' = H R2 = OMe),68 from (44),via (49 as shown in Scheme 3.When attempts to direct cyclization in the chelerythrine position (by a blocking bromine substituent) failed the synthesis of (46; R' = H R2 = OMe) was achieved from the dicarboxylic acid (47) viathe enol-lactone (48) and the lactam (49).69970 Robinson's most extensive and continuous interest in alka- loids was with the elucidation of the complex puzzle of the structure of strychnine and its close relatives on which he published 54 paper^;'^-'^^ thirty se~en~~-l'~ of these appeared in the twenty years 192746 when the correct structure was proposed.This output was modest in numbers compared with that of Leuchs who published over 125 papers but its con- tribution to the solving of the structural problem was immense and crucial. Undoubtedly that solution would have come earlier had not work been suspended and diverted into more im- mediately demanding lines during the war years 1939-45. Strychnine which was known to be an amide was shown to contain a reactive methylene group and hence to contain the system N-CO-CH2.80 It was also shown to be an ap-di- substituted dihydro-indole by the elucidation of the structure of dinitrostrycholcarboxylicacid (50) which is a degradation pro- duct that had been known for thirty years.This was achieved by the conversion of (50) through dinitrostrychol (51) and dinitro-oxindole into dinitroisatin (52)85.91and by the synthesis of the amide of dinitrostrychol (51).94 A penetrating analysis of the work of Leuchs led to the elucidation of the oxidation of strychnine to strychninonic acid and dihydrostrychninonic acid strychninolic acid and strychninolone as involving the trans- formations that are set out in the part-structures (53)-(57) (Scheme 4).84 This elucidation of the train of atoms from the NATURAL PRODUCT REPORTS 1987-K. W. BENTLEY \ OMe / OMe C0,H Me0 \ Me0 \ NH OMe OMe OMe 0 0 (471 (48) (49) Reagents i NH,OH; ii reduction; iii HC0,H; iv POC1,; v Pd/C at 250 “C; vi NH,; vii PC1,; viii H, Pd Scheme 3 0 6 02N C0,H O2”O NO H N4 (50) (52) I01 ___) Strychnine (53) Dihydrost r y chn i n onic acid ( 54) Strychninonic acid (55) OH OH-HO Strychninolone (57) Strychninolic acid (56) Scheme 4 dihydro-indole unit to the basic nitrogen atom represented a of the products with acid when quaternary salts that were substantial clarification of the problem.isomeric with the starting materials were obtained. De-Over the same period studies of the fission of quaternary methylation of these salts gave tertiary bases of the neo series salts shed further light on the environment of the basic nitrogen which gave the same products as strychnine strychnidine atom.Quaternary salts of strychnine strychnidine brucine brucine and brucidine respectively when they were reduced. and brucidine are split by alkoxides by nucleophilic dis-A careful and critical examination of his own work and of placement rather than by eliminati~n.~~. 78*88-90 The double- that of others led Robinsong1 to propose the structure (58) for bond in the alkaloids was shown to have migrated however strychnine as best explaining the mass of data. An alternative since the ring-opening could be smoothly reversed by treatment structure in which there is a 16-17 rather than a 7-17 linkage NATURAL PRODUCT REPORTS 1987 . .. (58) (59) Reagents i Me,SO,; ii MeO-; iii H+ Scheme 5 OH 0 - PhCH 0 Me1 __j PhCHO C-C MeN n n (67) (68) (69) which had been proposed by Leuchs was rejected because Robinson could not accept that strychnine was an unblocked dihydro-indole ;the structure was quickly disproved by showing that N-methyl-sec-@-strychnine [part-structure (62) which is obtained by methylating the carbinolamine $-strychnine (61)] condenses with benzaldehyde and must therefore contain the system -CH,-CO- confirming the presence of the system -CH,-CH-N(b) in ~trychnine.~~.~~ The possibility of an 8-1 7 linkage which would also give a blocked dihydro-indole was briefly considered later,93.104 to accommodate some work of Leuchs (subsequently shown by Robinson to be incorrectlo6) but was never seriously maintained.On the basis of the structure (58) for strychnine the ring- opening by alkoxides (see Scheme 5) was represented as giving (59) which could be recyclized to (60).This representation explained the easy recyclization which was found to be much more difficult after the double-bond had been red~ced'~,'~ but was subsequently found to be untenable when neostrychnine was identified as a vinylamine.'"' Hofmann degradation of dihydrostrychnidine provided re- sults of great significan~e.~~ lo2* lo3*lo5 One of the degradation products was found to recyclize in acid to a mixture of the original quaternary salt (minor component) and an isomer of this which could be demethylated to an isomer of dihydro- strychnidine. This was interpreted as recyclization of the methine base (65) at either end of the double-bond to give the isomeric quaternary salts (64) and (66) for both of which virtually strain-free models could be constru~ted.'~~ lofl It was recognized that either (64) or (66) could represent the strych- nidine skeleton but the five-membered nitrogen-containing ring appeared to be more in accord with the reactions of neostrychnine.Only three enamine structures (67)-(69) are possible for the neo-bases on the basis of formulae (64) and (66). Of these structures the six-membered-ring structure (69) would be oxidized by peracids to a keto-formamide whereas the oxidation product of a derivative of neostrychnine which was clearly a keto-amide resisted hydrolysis during a thirty-hour Clemmensen reduction ; such stability seemed incompatible with a f~rrnamide.~~"~' Only the part-structure (68) seemed to be in accord with these observations.It was at this stage that war interrupted the work and nothing was published between 1939 and 1946 when the skeleton of (66) was seriously proposed in print for the first time107.108 (though it had been advanced at a meeting of the Alembic Club in 1942). Positive evidence of the size of the nitrogen-containing ring was obtained by the oxidation of dihydrostrychninone (70) to carbon dioxide and cuninecarboxylic acid (71) which was readily converted into the y-lactam (72) if heated.log Subsequent studies in the field of Strychnos alkaloids resulted in the elucidation of the structures of vomicine (73 ;R =OH) [by the oxidation of the alkaloid to the keto-acid (74; R = C02H)and the ketone (74; R =H) which were obtained in the same way from N-methyl-sec-@-strychnine (73 ; R =H) and from N-methyl-sec-~-br~cine],"~~ 119 of strychnospermine (75 ; R =OMe) and spermostrychnine (75; R =H) [which were con- firmed by the conversion of the latter into the base (76) NATURAL PRODUCT REPORTS 1987-K.W. BENTLEY 0+u 0JJ Me Qj& 0 028 0 Me 'OAMe (73) (74) (75) Me ( 78) (77) which was also prepared from the Wieland-Gumlich aldehyde (77)],12' and of akuammicine (78).128*1323 134 Robinson's own work was crucial to the solution of the strychnine problem but in one remarkable case all of the evidence existed in the published work of others when he entered the field with a remarkable analysis that penetrated to the heart of the problem and dispersing the confusion deduced an almost completely correct structure to which he made the minor necessary correction two years later on the basis of a single well-chosen experiment.In 1923 the classic paper by Gulland and Robinson on the structure of opened with the words Largely on account of the migration phenomena encountered in the study of this group of alkaloids the morphine puzzle has absorbed the interest of many chemists in two generations and in the case of no other natural product have so many different constitutional formulae been proposed or such a volume of experimental work directed to the elucidation of constitution recorded. It is therefore only because the present authors are convinced that insufficient attention has been paid to certain aspects of the subject that they venture to advance still another suggestion.Starting from a hypothetical structure (79) for dihydro- codeine that was in accord with the facts that were then known about the compound Robinson considered possible structures for codeine that would afford (79) once two hydrogen atoms had been added. Such structures would have to contain a double- bond or an additional ring; since evidence for a double-bond in Me0 1 Ac Me Et CH20H (76) codeine seemed to be lacking an additional carbon-carbon linkage was sought. He then struck right to the heart of the matter the singular significance of which had never been appreciated by other workers.Of the reactions encountered in the study of the chemistry of morphine and its allies none are more remarkable and surprising than those in which an aromatic phenanthrene system and an amino-ethanol deriva- tive are simultaneously produced.. . It is not merely a case of a singular reaction occurring in one or two particular substances ;the process is so common that its cause must be sought in some general property of the morphine structure. The driving force behind the change is doubtless the tendency to produce an aromatic nucleus because the extrusion of the side-chain is never observed independently of the formation of the true phenanthrene derivative. But the obvious consequence has not previously been stated.The formation of the aromatic phenanthrene derivative cannot take place for structural reasons unless the ethanamine side-chain is displaced in favour of a hydrogen atom or a hydroxyl group. Actually the displacement is normally in favour of a hydrogen atom. It is equally clear that the only structural condition which could inhibit aromatic ring formation is that the side-chain is attached to a quaternary carbon atom one of those (13,14) which are shared by two nuclei in the resulting phenanthrene derivative. The structure (80) was therefore proposed for codeine and was shown to rationalize all of the rearrangements of morphine codeine and thebaine for the first time; in particular (a) Freund's two supposedly isomeric tetrahydrodeoxy-codeines could be formulated as arising from alternative openings of the four-membered ring.HO OH HO (79) (80) (81) (b) The transformation of codeine (80) into n codeine (81) could resemble the transformation of geraniol into linalool with a swing of the bridge rather than of a double-bond. (c) a-Methylmorphimethine (82) could isomerize to the stable /?-compound (83) ; Knorr's formula for the ,&isomer was a naphthalene and Wieland's modification (84) would be expected to isomerize to a naphthalene with ease. (d) The structure (80) already contains the skeleton of apomorphine and the production of this base from morphine could be explained by a simple sequence of hydrolysis and dehydration. (e) The formation of thebenine (87) from codeinone (85) could be recognized as involving rotation of the bottom half of the molecule rather than migration of a carbonyl group and could be explained by postulating that the intermediate (86) is Me@ 0 HO HO (82) (83) HO (84) M:&JMe 0 OH (88) (89) NATURAL PRODUCT REPORTS 1987 produced followed by its cyclization in acid.In 1923,of course no theory of reaction mechanisms existed but the proposed process could only operate if the side-chain occupied the 13-9 position; indeed this represented the only evidence that the nitrogen atom is linked to C-9 rather than to C-10 until the synthesis of tetrahydrodeoxycodeine 26 years later. Robinson always felt that this proposal never received sufficient atten- ti~n.'~~ (f)A relationship could be established between the mor- phine alkaloids and those of the benzylisoquinoline group which Robinson had postulated in his early proposals con-cerning biosynthe~is.~~ Robinson rejected the previously held belief that hydroxy- codeinone from thebaine and hydrogen peroxide was an a-hydroxy-ketone and proposed a y-hydroxy-ketone structure.When he showed that this must be @-unsaturated he proposed the structure (88) for it and structures (89) and (90) for codeine and thebaine,'55 which left all of the reactions equally simply explained and the origins of the intermediate (86) from thebaine and codeinone more easily understood. Some people were never able quite to appreciate the logic of these deductions. Even in 1952 H.L. Holmes in the second volume of Holmes and Manske's monograph on 'The Alka- loids ' described Robinson's formulae as 'minor variations ' of those of Knorr and said that the Robinson and Knorr-Wieland formulae 'accommodated all of the experimental facts equally well' which was clearly untrue. In general however the formulae were accepted until twenty-two years later they were challenged and vindicated in a dramatic way which is where literally I came in! In October 1947 Sir Robert received from Lyndon Small of the University of Virginia the prepublication manuscript of a paper in which were described three years of extensive and detailed experimental work from which he had concluded that the formulae of Gulland and Robinson could not explain the reaction of thebaine with Grignard reagents and questioned WI I (90) HO f-Me00" xo (93) (92) (911 NATUKAL PRODUCT REPORTS 1987-K.W. BENTLEY their validity. Robinson knew that they could explain the reaction and had with characteristic generosity presented the explanation to Small for his own use in a visit to the U.S.A. in 1945. All that was needed was one simple proof. So I began work as a D.Phi1. research student by preparing phenyl- dihydrothebaine on Tuesday and Wednesday oxidizing it on Thursday and isolating the key product on Friday. The excitement in the laboratory was infectious; no one could avoid realizing that something interesting was afoot since Sir Robert visited me at the bench nineteen times in four days impatient for the coup de grcice.This came at 4.45 p.m. on the Friday with the determination of melting points and of mixed melting points of samples of 4-methoxyphthalic anhydride and 4-methoxy-N-methylphthalimidethat I had obtained from the oxidation and of authentic materials that had been synthesized by Robinson himself on Thursday and Friday. Four days to prove that he was right twenty-two years before; four days to make Small's paper obsolete weeks before it was published; four days to provide material for his Presidential Address to The Royal Society. That address subsequently published in Nature16" under the title 'An Essay in Correlation Arising from Alkaloid Chemistry' must rank among his finest rationalizations. Appropriately the reaction was shown to be essentially the thebenine transformation [which is set out in modern terms in formulae (90)-(92)] limited by the non-aqueous conditions.In aqueous acid the formation of (92; X = R = H) is followed by its hydrolysis to (86); however in the Grignard reaction (92; X =BrMg R = Me) is stable except to attack by the Grignard reagent which when phenylmagnesium bromide gives phenyldihydrothebaine (93). The intermediate (92; X = BrMg R = Me) has been isolated.162 Sir Robert Robinson's monumental achievements in organic chemistry will surely never be surpassed. They were achieved without any of the spectroscopic crystallographic and com- putational facilities or the vast mass of accumulated back- ground knowledge (much of which he generated) that make life so much easier today.He would not have scorned the use of these facilities indeed he would have embraced them with eagerness and enthusiasm for everything had to be pressed into service in the quest for knowledge. He was one of the giants on whose shoulders we see the distant land. For over five decades he bestrode chemistry like a colossus and for those who had the immense privilege of working for him and with him and for the many who know only his work his name remains like the surge and thunder of the sea. References Phthalide-isoquinoline Alkaloids 1 W. H. Perkin and R. Robinson J. Chem. Soc. 1907 91 1086. 2 W. H. Perkin. R. Robinson and F. Thomas J. Chem. Soc. 1909 95 1977. 3 W. H. Perkin and R.Robinson J. Chem. Soc. 1911 99 775. 4 E. Hope and R. Robinson J. Chem. Soc. 1911 99 1153. 5 E. Hope and R. Robinson J. Chem. Soc. 191I 99 21 14. 6 E. Hope and R. Robinson Proc. Chem. Soc. 1912 28 17. 7 E. G. Jones. W. H. Perkin and R. Robinson J. Chem. SOC.,1912 101 257. 8 E. Hope and R. Robinson J. Chem. Soc. 1913 103 361. 9 G. M. Robinson and R. Robinson J. Chem. Soc. 1914 105 1456. 10 E. Hope and R. Robinson J. Chem. Soc. 1914 105 2085. 11 G. M. Robinson and R. Robinson J. Chem. Soc. 1924 125 827. 12 J. N. Kly and R. Robinson J. Chem.Soc. 1925 127 1618. 13 E. Hope F. L. Pyman F. G. P. Remfrey and R. Robinson J. Chem. SOL..,I93 1 236. 14 M. A. Marshall F. L. Pyman and R. Robinson J. Chem. SOC. 1934 1315. 15 R.Robinson Annu. Rev. Biochem. 1935 4 497. 16 P. W. G. Groenwoud and R. Robinson J. Chem. Soc. 1936 199. 17 R. D. Haworth A. R. Pinder and Sir Robert Robinson Nature (London) 1950 165 529. 18 R. Mirza and Sir Robert Robinson Nature (London) 1950 166 271. Rerberine 19 W. H. Perkin and R. Robinson J. Chem. Soc. 1910 97 305. 20 J. W. McDavid W. H. Perkin and R. Robinson J. Chem. Soc. 1912 101 1218. 21 G. M. Robinson and R. Robinson J. Chem. Soc. 1917 111 958. 22 W. H. Perkin J. N. Riy and R. Robinson J. Chem. SOC.,1925 127 740. Tropinone and Related Alkaloids 23 R. Robinson J. Chem. Soc. 1917 111 762. 24 R. C. Menzies and R. Robinson J. Chem. Soc. 1924 125 2163. 25 B. K. Blount and R. Robinson J. Chem. Soc. 1932 1429. 26 B.K. Blount and R. Robinson J. Chem. SOC.,1932 2485. 27 B. K. Blount and R. Robinson J. Chem. Soc. 1933 1511. 28 G. Barger A. Girardet and R. Robinson Helv. Chim. Acta 1933 16 90. 29 G. Barger R. Robinson and T. S. Work J. Chem. Soc. 1937 711. Biogenesis of Alkaloids 30 R. Robinson J. Chem. Soc. 1917 111 876. 31 R. Robinson and S. Sugasawa J. Chem. Sac. 1931 3163. 32 R. Robinson and S. Sugasawa J. Chem. SOC.,1932 789. 33 R. Robinson and S. Sugasawa J. Chem. Soc. 1933 280. 34 R. Robinson J. Chem. Soc. 1936 1079. 35 Sir Robert Robinson J. Roy. SOC. Arts 1948 96 795. 36 Sir Robert Robinson Naiure (London) 1948 162 524. 37 Sir Robert Robinson Proc. R. Soc. London Ser. A 1951 205 15. 38 Sir Robert Robinson .Structural Relations of Natural Products' The Clarendon Press Oxford 1955.Harmine and Related Alkaloids 39 W. H. Perkin and R. Robinson J. Chem. SOC.,1912 101 1775. 40 W. H. Perkin and R. Robinson J. Chem. Soc. 1913 103 1973. 41 W. H. Perkin and R. Robinson J. Chem. SOC.,1919 115 933. 42 W. H. Perkin and R. Robinson J. Chem. Soc. 1919 115 959. 43 W. H. Perkin and R. Robinson J. Chem. Soc. 1919 115 967. 44 W. 0.Kermack W. H. Perkin and R. Robinson J. Chem. Sac. 1921 119 1062. 45 W. 0.Kermack W. H. Perkin and R. Robinson J. Chem. Soc. 1922 121 1872. 46 W. Lawson W. H. Perkin and R. Robinson J. Chem. Soc. 1924 125 626. 47 H. Nishikawa W. H. Perkin and R. Robinson J. Chem. SOC. 1924 125 657. 48 R. H. F. Manske W. H. Perkin and R. Robinson J.Chem. Soc. 1927 1. 49 R. H. F. Manske and R. Robinson J. Chem. Soc. 1927 240. 50 Y. Asahina R. H. F. Manske and R. Robinson J. Chem. Soc. 1927 1708. 51 H. S. Boyd Barrett W. H. Perkin and R. Robinson J. Chem. Soc. 1929 2942. 52 V. V. S. Iyer and R. Robinson J. Chem. Soc. 1934 1635. Physost igm ine (E.w ine) 53 R. Robinson and H. Suginome J. Chem. Soc. 1932 298. 54 R. Robinson and H. Suginome J. Chem. Soc. 1932 304. 55 H. S. Boyd Barrett and R. Robinson J. Chem. Soc. 1932 317. 56 F. E. King and R. Robinson J. Chem. Soc. 1932 326. 57 F. E. King and R. Robinson J. Chem. Soc. 1932 1433. 58 F. E. King and R. Robinson J. Chem. Sue. 1933 270. 59 F. E. King R. Robinson and H. Suginome J. Chem. Sot.. 1933 1472. 60 F. E. King M. Liguori and R.Robinson J. Chem. Soc. 1933 1475. 61 F. E. King M. Liguori and R. Robinson J. Chem. Soc. 1934 1416. 62 F. E. King and R. Robinson J. Chem. Soc. 1935 755. Benzylisoquinolines 63 J. W. Armit and R. Robinson J. Chem. Soc. 1927 1604 64 Z. Kitasato and R. Robinson J. Chem. Soc. 1932 785. 65 P. C. Young and R. Robinson J. Chem. Soc. 1933 275. Peganine 66 T. M. Reynolds and R. Robinson Nature (London) 1934 134 142. 67 T. M. Reynolds and R. Robinson J. Chem. Sac. 1936 196. 22 Benzophenan1h r idines 68 T. Richardson R. Robinson and E. Seijo J. Chem. Soc. 1937 835. 69 A. S. Bailey and Sir Robert Robinson J. Chem. Soc. 1950 1375. 70 A. S. Bailey Sir Robert Robinson and R. S. Staunton J. Chem. Soc. 1950 2577.Lycorine 71 E. J. Forbes J. Harley-Mason and Sir Robert Robinson Chem. Ind. (London) 1953 946. 72 G. R. Clemo and Sir Robert Robinson Chem. Ind. (London) 1955 1086. Strychnine Brucine and Vomicine 73 W. H. Perkin and R. Robinson J. Chem. Soc. 1910 97,305. 74 G. R. Clemo W. H. Perkin and R. Robinson J. Chem. Soc. 1924 125 1751. 75 F. Lions W. H. Perkin and R. Robinson J. Chem. Soc. 1925 127 1158. 76 G. R. Clemo W. H. Perkin and R. Robinson J. Chem. Soc. 1927 1589. 77 J. M. Gulland W. H. Perkin and R. Robinson J. Chem. Soc. 1927 1627. 78 A. E. Oxford W. H. Perkin and R. Robinson J. Chem. SOC. 1927 2389. 79 R. C. Fawcett W. H. Perkin and R. Robinson J. Chem. Soc. 1928 3082. 80 W. H. Perkin and R. Robinson J.Chem. Soc. 1929 964. 81 J. N. Ashley W. H. Perkin and R. Robinson J. Chem. Soc. 1930 382. 82 K. N. Menon W. H. Perkin and R. Robinson J. Chem. Soc. 1930 830. 83 0.Achmatowicz R. C. Fawcett W. H. Perkin and R. Robinson J. Chem. Soc. 1930 1769. 84 R. Robinson Proc. R. Soc. London Ser. A 1931 130 431. 85 K. N. Menon and R. Robinson J. Chem. Soc. 1931 773. 86 B. K. Blount and R. Robinson J. Chem. Soc. 1931 3158. 87 L. H. Briggs and R. Robinson J. Chem. Soc. 1931 3160. 88 0.Achmatowicz W. H. Perkin and R. Robinson J. Chem. Soc. 1932 486. 89 0.Achmatowicz G. R. Clemo W. H. Perkin and R. Robinson J. Chem. Soc. 1932 767. 90 0.Achmatowicz W. H. Perkin and R. Robinson J. Chem. Soc. 1932 775. 91 K. N. Menon and R. Robinson J. Chem.Soc. 1932 780. 92 W. H. Perkin R. Robinson and J. C. Smith J. Chem. Soc. 1932 1239. 93 B. K. Blount and R. Robinson J. Chem. SOC. 1932 2305. 94 P. Hill and R. Robinson J. Chem. Soc. 1933 486. 95 W. H. Perkin R. Robinson and J. C. Smith J. Chem. SOC. 1934 574. 96 0.Achmatowicz and R. Robinson J. Chem. Soc. 1934 581. 97 L. H. Briggs and R. Robinson J. Chem. Soc 1934 590. 98 T. M. Reynolds and R. Robinson J. Chem. Soc. 1934 592. 99 B. K. Blount and R. Robinson J. Chem. Soc. 1934 595. 100 R. Robinson J. Chem. Soc. 1934 1490. 101 T. M. Reynolds and R. Robinson J. Chem. Soc. 1935 935. 102 0.Achmatowicz and R. Robinson J. Chem. Soc. 1935 1291. 103 0.Achmatowicz P. Lewi and R. Robinson J. Chem. Soc. 1935 1685. 104 H. T. Openshaw and R.Robinson J. Chem. Soc. 1937 941. 105 0.Achmatowicz and R. Robinson J. Chem. Soc. 1938 1467. 106 H. L. Holmes and Sir Robert Robinson J. Chem. Soc. 1939 603. 107 Sir Robert Robinson Experientia 1946 2 28. 108 L. H. Briggs H. T. Openshaw and Sir Robert Robinson J. Chem. Soc. 1946 903. 109 H. L. Holmes H. T. Openshaw and Sir Robert Robinson J. Chem. Soc. 1946 908. 110 H. L. Holmes H. T. Openshaw and Sir Robert Robinson J. Chem. Soc. 1946 910. 111 H. T. Openshaw and Sir Robert Robinson J. Chem. Soc. 1946 912. 112 H. T. Openshaw and Sir Robert Robinson Nature (London) 1946 157 438. 113 Sir Robert Robinson Nature (London) 1947 159 263. 114 R. N. Chakravarti and Sir Robert Robinson J. Chem. Soc. 1947 78. 115 R. N. Chakravarti K.H. Pausacker and Sir Robert Robinson J. Chem. Soc. 1947 1554. NATURAL PRODUCT REPORTS 1987 116 K. H. Pausacker and Sir Robert Robinson J. Chem. Soc. 1947 1557. 117 R. N. Chakravarti and Sir Robert Robinson Nature (London) 1947 160 18. 118 A. S. Bailey and Sir Robert Robinson Nature (London) 1948 161 433. 119 A. S. Bailey and Sir Robert Robinson J. Chem. Soc. 1948 703. 120 K. H. Pausacker and Sir Robert Robinson J. Chem. Soc. 1948 951. 121 Sir Robert Robinson and A. M. Stephen Nature (London) 1948 162 177. 122 Sir Robert Robinson and J. E. Saxton J. Chem. Soc. 1952 982. 123 F.A.L. Anet and Sir Robert Robinson Chem. Ind. (London) 1953 245. 124 Sir Robert Robinson and J. E. Saxton J. Chem. Soc. 1953 2596.125 F.A.L. Anet A. S. Bailey and Sir Robert Robinson Chem. Ind. (London) 1955 944. 126 J. T. Edward and Sir Robert Robinson Tetrahedron 1957 1 29. Strychnospermine and Spermostrychnine 127 F.A.L. Anet and Sir Robert Robinson J. Chem. SOC. 1955 2253. Akuammine Akuammicine and Akuammigine 128 M. F. Milson Sir Robert Robinson and A. F. Thomas Experi-entia 1953 9 89. 129 Sir Robert Robinson and A. F. Thomas J. Chem. Soc. 1954 3479. 130 Sir Robert Robinson and A. F. Thomas J. Chem. Soc. 1954 3522. 131 Sir Robert Robinson and A. F. Thomas J. Chem. Soc. 1955 2049. 132 M. F. Milson and Sir Robert Robinson J. Chem. Soc. 1955 3362. 133 M. M. Janot J. Le Men K. Aghoramurthy and Sir Robert Robinson Experientia 1955 11 343. 134 K.Aghoramurthy and Sir Robert Robinson Tetrahedron 1957,1 172. Calycanthine and Related Alkaloids 135 P. R. Levy and Sir Robert Robinson ‘Festschrift Paul Karrer’ Birkhauser Basel 1948 p. 38. 136 Sir Robert Robinson and H. J. Teuber Chem. Ind. (London) 1954 283. 137 H. F. Hodson Sir Robert Robinson and G. F. Smith Proc. Chem. Soc. 1961 465. Quinamine 138 C. C. J. Culvenor L. J. Goldsworthy K. S. Kirby and Sir Robert Robinson Nature (London) 1950 166 105. 139 G. D. Benz C. C. J. Culvenor L. J. Goldsworthy K. S. Kirby and Sir Robert Robinson J. Chem. Soc. 1950 1130. 140 C. C. J. Culvenor L. J. Goldsworthy K. S. Kirby and Sir Robert Robinson J. Chem. Soc. 1950 1485. Gelsemine 141 M. S. Gibson and Sir Robert Robinson Chem. Znd.(London) 1951 93. Ajmaline 142 D. Mukherji Sir Robert Robinson and E. Schlittler Experi-entia 1949 5 215. 143 F. A. L. Anet D. Chakravarti Sir Robert Robinson and E. Schlittler J. Chem. SOC. 1954 1242. 144 Sir Robert Robinson Chem. Ind. (London) 1955 285. 145 Sir Robert Robinson J. D. Hobson F. A. L. Anet and F. C. Finch Chem. Ind. (London) 1955 285. 146 F. C. Finch J. D. Hobson Sir Robert Robinson and E. Schlittler Chem. Ind. (London) 1955 653. 147 Sir Robert Robinson Angew Chem. 1957 69 40. 148 Sir Robert Robinson ‘ Festschrift Arthur Stoll ’ Birkhauser Basel 1957 p. 457. Yohimbine 149 K. T. Potts and Sir Robert Robinson J. Chem. SOC. 1955 2675. Echitamine 150 D. Chakravarti R. N. Chakravarti R. Ghose and Sir Robert Robinson Tetrahedron Lett.1960 No. 10 p. 10. 151 D. Chakravarti R. N. Chakravarti R. Ghose and Sir Robert Robinson Tetrahedron Lett. 1960 No. 11 p. 25. NATURAL PRODUCT REPORTS 1987-K. W. BENTLEY 152 D. Chakravarti. R. N. Chakravarti R. Ghose and Sir Robert Robinson. Tetrahedron Lett. 1960 No. 12 p. 33. The Morphine Alkaloids 153 J. M. Gulland and R. Robinson J. Chem. Soc. 1923 123 980. 154 J. M. Gulland and R. Robinson J. Chem. Soc. 1923 123 998. 155 J. M. Gulland and R. Robinson Mem. Proc. Manchester Lit. Philos. Soc. 1925 69 79. 156 C. F. van Duin R. Robinson and J. C. Smith J. Chem. Soc. 1926 903. 157 R. S. Cahn and R. Robinson J. Chem. Soc. 1926 908. 158 R. Ghosh and Sir Robert Robinson J. Chem. Soc. 1944 506. 159 Sir Robert Robinson Proc.R. Soc. London Ser. B 1947 132 v-xix. 160 Sir Robert Robinson Nature (London). 1947 160 815. 161 K. W. Bentley and Sir Robert Robinson Esperientia 1950 6 353. 62 K. W. Bentley and Sir Robert Robinson J. Chem. Soc. 1952 947. 63 K. W. Bentley Sir Robert Robinson and A. E. Wain J. Cliem. Soc. 1952 958. 64 Sir Robert Robinson in 'The Chemistry of the Morphine Alka- loids' by K. W. Bentley The Clarendon Press Oxford. 1954 Foreword pp. v-ix.

ISSN:0265-0568    

DOI:10.1039/NP9870400013

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Anthocyanins Brazilin and Related Compounds R. Livingstone Department of Chemical and Physical Sciences The Polytechnic Uuddersfield UD 7 3DH 1 Brazilin 2 0-Trimethylbrazilone 3 Brazilein 4 Brazylium and Benzopyrylium Salts 5 The Synthesis of Deoxytrimethylbrazilone and 0-Trimethylbrazilone 6 The Constitution of Brazilein 7 The Synthesis of Brazilin 8 Haematoxylin 9 Anthocyanidins and Anthocyanins 10 References 1 Brazilin In relating the contributions of Sir Robert Robinson to the chemistry of oxygen heterocycles it must be emphasized that he appeared to have a special regard for the chemistry of brazilin (1). His name is on publications from 1906 until 1974 and on extensive concerned with its chemistry. Robinson's elucidation of the structure of the brazylium ~alts~*~l afforded the background for his later outstanding contributions to the chemistry of anthocyanidins and anthocyanins.Brazilin is obtained from Pernambucu redwood (which contains twice as much as true Brazilwood4) and has the formula C,,H,,0,.5 Before Robinson commenced his studies on brazilin it was known to give a tetra-acety16 and a triacetyl' derivative and to yield brazilein (27) and a CgH604 compound which was believed to be a dihydroxychromone,8 if it was oxidized by Me0 +J OCH CO,H Ro%H F3O\'-/OR MeO-OMe Me000CH2COzH CO H I OH (8) atmospheric oxygen in alkaline sol~tion.~ Oxidationlo of 0-trimethylbrazilin (2) by potassium permanganate resulted in the isolation of brazilinic acid (3) (ClgH180g) 2-carboxy-5- methoxyphenoxyacetic acid (4),metahemipinic acid (9,and brazilic acid (6) (Cl2HI2O6).W.H. Perkin was able to verify the structures of products (4),(5) and (6) and on this evidence suggested structure (7) for brazilin. He correctly recognized the indane and chroman ring systems but his proposed fusion of the rings was incorrect. He also presumed wrongly that brazilin and haematoxylin are secondary alcohols instead of tertiary alcohols. Evidence in support of this indane moiety was the later isolation of 4,5-dimethoxyhomophthalicacid (8) in low yield from the products resulting from oxidation of brazilin with potassium permanganate. l1 Brazilic acid (6) yielded the derivatives that would be expected and if it was warmed with concentrated sulphuric acid it lost water to yield anhydrobrazilic acid (9)' which decomposed (in boiling barium hydroxide solution) to produce /?-(2-hydroxy-4-methoxybenzoyl)propionic acid (10) and formic acid.Condensation of ethyl /?-(2-hydroxy-4-methoxy-benzoy1)propionate (1 1) with ethyl formate in the presence of sodium (see Scheme 1) gave ethyl anhydrobrazilate which on hydrolysis yielded anhydrobrazilic acid (9);12this was the first 3-substituted chromone to be synthesized. At this stage no satisfactory explanation had been given of the products of oxidation of 0-trimethylbrazilin (2)by chromic acid and Perkin had not yet arrived at the correct constitution of brazilinic acid (3) which contained all of the carbon atoms of 0-trimethylbrazilin (2).Robinson was unhappy with Perkin's proposed structure (7) for brazilin; the CH groups in this structure had to become CH groups in the oxidation products. After suggesting an alternative structure (l) he obtained the necessary evidence in support of this structure by elucidating the structure of brazilinic acid (3). He showed it to be a keto-dicarboxylic acid that is reducible to a dihydro-derivative which readily forms a characteristic lactone (12). A small yield of the acid (3) was ob-tained via Friedel-Crafts condensation of ethyl m-methoxy- 1 It (10) 0 + . 1.11 ..t MeOfiOH ucoCH,C H,CO,Et Reagents i HCO,Et Na ; ii hydrolysis Scheme 1 NATURAL PRODUCT REPORTS 1987 MeOqCH2C02H 0 II HC/O'C//O MeOoOCH2C02Et + Me0 It Me0 OMe (13) 0 6 (14) (12) MeOoOMe MeOqMe \ \ \ Meoq..c//o (15) -HC00 C=O --+ (12) + 6 (14) Me0 OMe Me0 OMe (16) (17) (18) R = Me (19) (52) R = Ac OMe (20) R = K (21) R = Ac (22) R = H (18) (24) phenoxyacetate (1 3) and metahemipinic anhydride (14). A better route involved the condensation of resorcinol dimethyl ether (15) with metahemipinic anhydride (14) followed by demethylation of the ortho-methoxy-group and subsequent reduction to the lactone (16). The desired lactone (12) was obtained by addition of the acetic acid residue.13 The necessary evidence for Robinson's proposed structure (1) for brazilin was thus provided but to his great dis-appointment he found that he had been anticipated some years previously by A.Werner and P. Pfeiffer,14 who had suggested structure (1) without any real chemical evidence. As far as Robinson was concerned the evidence that was then available to him was consistent with the suggested structure (I) but at this stage there was nothing to exclude an alternative structure (1 7). However Werner and Pfeiffer had presented a completely 0 OMe (23) (25) wrong conception of the nature of 0-trimethylbrazilone (18) which is a product from the oxidation of 0-trimethylbrazilin (2) by chromic acid. There still remained two outstanding problems concerning the chemistry of 0-trimethylbrazilone (18) and brazilein (19) both of which were oxidation products that could be derived from brazilin.It was originally decided that Robinson would investigate the former and Perkin the latter but in the end both investigations were carried out by Robinson. 2 0-Trimethylbrazilone The oxidation of 0-trimethylbrazilin (2) with chromic acid in acetic acid resulted in the addition of one atom of oxygen and the loss of two atoms of hydrogen; 0-trimethylbrazilone (1 8) 27 NATURAL PRODUCT REPORTS 1987-R. LIVINGSTONE -H (25) v,vi MeOo-";co 'OH \ OMe 2M e O ~ o\cOMe ~ \ / OMe \ / OMe Reagents i Hoesch reaction; ii Me,SO, EtOH NaOH; iii BrCH,CO,Et EtOH NaOEt; iv EtOH NaOEt; v PCl, C6H6; vi AlCl, C6H6 Scheme 2 -Meoq.l& (18) 0 OzN \ OWH HO OH / Q Ho";liH OH 0 0-(27) (28) (29) brazilone (22) was converted into a p-naphthoquinone tri- methoxy-a-brazanquinone (23) which was later synthesized by Me P.C.Johnson and A. Robertson.15 (19) j + Perkin and Robinson'' also elucidated the details of the reaction between 0-trimethylbrazilone (1 8) and sulphuric acid which had been reported earlier by J. Herzig and CO-workers." \ The product which was isomeric with 0-trimethylbrazilone Meo3Me Me0 0 Me0 OMe (1 8) was called @-trimethylbrazilone (24). If this was oxidized with potassium permanganate it yielded 4,5-dimethoxyhomo- phthalic acid (8) and with dehydrating agents it afforded p-anhydrotrimethylbrazilone (25) which was later synthesized by K. W. Bentley and R. Robinson (Scheme 2).lS Another product that was identified by Robinsonlg was that from the reaction between 0-trimethybrazilone (1 8) and con- centrated nitric acid.20 He found that the elements of nitric acid were added to give nitrohydroxydihydro- 0-trimethylbrazilone (26) in nearly quantitative yield.3 Brazilein During this early period Robinson was mainly responsible for (32) providing the evidence for the structure of brazilein (19) which could be obtained by atmospheric oxidation of an alkaline Reagents i Me,SO, KOH H,O; ii heat NaOH H,O; iii heat solution of brazilin (1) or better by oxidation of an alcoholic HC0,H; iv CrO, AcOH solution using iodine.21 Of the four possible structures (19), Scheme 3 (27) (28) and (29) for brazilein the last two were eliminated on the following evidence. was formed.Evidence for its structure and for those of its If brazilein was methylated by dimethyl sulphate (see Scheme derivatives was presented by Robinson over many years. If 0-3) it furnished 0-trimethylbrazilein (30) and the tetramethyl- trimethylbrazilone (1 8) was heated with alcoholic potassium dihydrobrazileinol (31). The former if boiled with sodium hydroxide it lost water to form the potassium salt (20) of a-hydroxide solution afforded the trimethyldihydrobrazileinol anhydrotrimethylbrazilone ; treatment of (20) with acetic an- (32); if this was warmed with formic acid it was dehydrated to hydride gave the acetyl derivative (21). a-Anhydrotrimethyl- regenerate the starting material (30). Methylation of the tri- NATURAL PRODUCT REPORTS 1987 -+ HS0,-+ FeCI (311 L L (33) Reagents i heat H,SO,; ii FeCl, HCI Scheme 4 Me0 OMe (38) (39) i ti 1 (34) Reagents i HCO,H ZnC1,; ii HCI FeCl Scheme 5 L? Me0 OMe (40) methyl derivative (32) yielded the tetramethyldihydrobrazi-leinol (31) which produced 0-trimethylbrazilone (18) if it was oxidized with chromic acid in acetic acid indicating that the tetramethyldihydrobrazileinol (3 1) was derived from either structure (19) or structure (27) thus excluding structures (28) and (29).These considerations served to determine the position of the alcoholic hydroxyl group in brazilin (1) and ruled out for the first time the alternative structure (1 7). Studies relating to the brazylium salts eventually provided the evidence for structure (19) for brazilein.4 Brazylium and Benzopyrylium Salts The action of mineral acids on brazilein (19) resulted in the loss of water and the production of salts of the form BHX for example (33; R = H) and (34; R = H). .Originally these were called isobrazilein salts,22 before the establishment of the theory of oxonium salts and long before the analogy of pyrylium salts with pyridinium salts was understood. Robinson recognized the isobrazilein salts as pyrylium ~alts~.~~ and the cation was called 'brazylium '. If tetramethyldihydrobrazileinol (3 1) was warmed with sulphuric acid methanol and water were elimi- nated to produce 0-trimethylbrazylium hydrogen sulphate (33 ; R = Me) which could readily be converted into O-trimethyl- brazylium ferrichloride (34; R = Me) (see Scheme 4).The ferrichloride (34; R = Me) was also obtained (at a later date) from 0-trimethylbrazylium bromide which had been obtained by treating deoxytrimethylbrazilone (43) with bromine in ace tone. The condensation of salicylaldehyde and its derivatives with ketones was studied by Perkin and Robinson23 in relationship to the preparation of benzopyrylium and brazylium salts and the reaction was later elaborated by Robinson for the synthesis of anthocyanidins and anthocyanins. By using the appropriate derivatives (35) and (36) of salicylaldehyde and indan- 1-one respectively the earlier formula (7) for brazilin was disproved since the ferrichloride (37) was different from that which had been obtained from 0-trimethylbrazilin (2).24 The first synthesis of a substance that contained the skeleton of brazilin (l) namely 0-trimethylbrazylium ferrichloride (34 ; R = Me) was accomplished by Crabtree and Robinson in 1918.25 Veratrylidenepaeanol (38) was catalytically hydro-genated to its dihydro-derivative (39) which was treated with boiling absolute formic acid and zinc chloride and then with ferric chloride in hydrochloric acid (see Scheme 5) to give a ferrichloride that was identical with 0-trimethylbrazylium ferrichloride (34; R = Me).It was not found to be possible to convert the chromone (40) into a brazylium salt hence it was suggested that the mechanism probably involved ring-closure of the starting material to an indene followed by 0-formylation and further ring-closure.5 The Synthesis of Deoxytrimethylbrazilone and 0-Trj met h yIbrazi lone In 1926 Robinson synthesized deoxytrimethylbrazilone (43),26 which was also obtained virtually simultaneously (and by the same method) by Pfeiffer and his collaborators. 27 7-Methoxy-3-veratrylidenechromanone (41)28 was catalytically hydro-genated to a dihydro-derivative (42) which afforded deoxytri- methylbrazilone [O-trimethylanhydrobrazilin](43) when it was cyclodehydrated by heating it with phosphoric anhydride. Catalytic hydrogenation of deoxytrimethylbrazilone (43) yielded its dihydro-derivative which was originally described as 0-trimethybrazilane-a (44)but which is now regarded as a cis-brazilane. It was assumed that the catalytic reduction would be 29 NATURAL PRODUCT REPORTS 1987-R.LIVINGSTONE FeC14-+ FeCl,-“eoq;H 0 Me0 OR 6 Q Eta% Me0 OMe Me0 OMe Meo% Me0 OEt (41) R = Me (421 (47) R = Et Meo% Me0 OR (441 R =Me (51) R =Ac (43) R = Me (48) R = Et (18 1 likely to yield the cis form. The dihydro-derivative (44),upon oxidation with chromic acid gave 0-trimethylbrazilone (1 8). 6 The Constitution of Brazilein The addition of water to the quinonoid group of O-trimethyl- brazilein produced a new phenolic hydroxyl group for which the character was indicated by its ethylation. This O-ethyl- trimethyldihydrobrazileinol was converted [by methods that have already been described for O-tetramethyldihydrobrazi-leinol (3 1)] into an 0-ethyl-dimethylbrazylium ferrichloride of formula (45) or (46).The former would arise if brazilein had structure (27) and the latter if it had structure (19). The study which was completed by MiCoviC and Robinsonz9 by 1937 involved the synthesis of compound (45) (by the method of Crab tree and Robinson 25 from 4’-ethoxy- 2’-hydroxy- 2-vera- trylideneacetophenone) whilst compound (46) was prepared from 3-(3-ethoxy-4-methoxybenzylidene)-7-methoxychroman-one (47) by its conversion into the related deoxyethyldimethyl- brazilone (48) and thence into the brazylium salt (see Section 4). The salt (46) was identical with that which could be derived from 0-trimethylbrazilein thus proving the structure of 0-trimethylbrazilein to be (30) and hence of brazilein to be (19).7 The Synthesis of Brazilin The most obvious route to the synthesis of 0-trimethylbrazilin (2) was by way of deoxytrimethylbrazilone (43) but all attempts to hydrate the double-bond of this substance met with failure. 0-Trimethylbrazilone (1 8) reacted with phenylhydrazine in hot alcoholic with the loss of two atoms of oxygen and the formation of deoxytrimethylbrazilone (43) which was oxidized (in the presence of strong acids) to the brazylium salt. Robinson31 had shown that the reduction of O-trimethyl-brazilone (1 8) by zinc and acetic acid gave a pinacol(49) which was characterized by converting it into the trimethylbrazylium ferrichloride. The synthesis of brazilin (1) depended on the synthesis of a similar un-methylated pinac01.~~ (45) (46) (18) (49) R = Me (50)R = Ac [structure (51) is with (44); structure (52) is with (1811 __+ (52) (50) AcowAc AcQAc 0 (19) Reagents i Zn.EtOH. AcOH Scheme 6 0-Triacetylbrazilone (52) was obtained by the oxidation of 0-tetra-acetylbrazilin by chromic acid and then reduced (by zinc in alcoholic acetic acid) to yield the pinacol (50). The conversion of (50) into (+)-brazilein (19) was achieved when it was subjected to hydrolysis (by an alkali) followed by acidi- fication as shown in Scheme 6. In order to synthesize triacetylbrazilone (52) O-trimethyl- brazilane-a (dihydrodeoxytrimethylbrazilone-a) (44) (which had already been synthesized) was demethylated and the resulting trihydric phenol was acetylated to form the 0-triacetylbrazilane (5l) which was oxidized by chromic acid.The triacetylbrazilone (52) that was thus obtained was identical with the product that had been derived from natural brazilin. This made the (+)-brazilein (19) a synthetic compound. It was reduced by sodium borohydride to (+)-brazilin (l) which was resolved (as its tetra[( +)-menth-1-yloxyacetyl]-derivatives) to afford d-cis-brazilin. A summary of the overall route to (&-)-brazilin (1) is indicated in Scheme 7 and although it was completed in 1955 it was only described by Robinson in 1970.33 Robinson’s last papers on this subject which dealt with the synthesis of brazilin from an indenocoumarin and the reduction of brazilein appeared in 1974.34*35 NPR 4 NATURAL PRODUCT REPORTS 1987 OMe "'0% O'c//O \/ Me0 OMe $2Me0 OMe (53) R'= RZ = H (55) (56) (54) R' =Me RZ = H R' M HO%H O% R'O OR' HO Me0 OMe -0 (57) R' = RZ = Me 159) (60) (58) R'R = -CH,CH,-HO OC6H11 05 (61 1 8 Haematoxylin Haematoxylin (53) (C16H1406) is obtained from logwood extract and contains one more hydroxyl group than brazilin (l) at position 8 of the dihydrobenzopyran moiety.Robinson's studies on the chemistry of haematoxylin ran very much parallel with those on brazilin. Oxidation of the tetramethylhaema- toxylin (54) by potassium permanganate did not yield the analogue of brazilic acid (6) but did afford haematoxylinic acid corresponding to brazilinic acid ;36 on reduction haemat- oxylinic acid gave the lactone (55).It was synthesized by first condensing metahemipinic anhydride with pyrogallol trimethyl ether in the presence of aluminium chloride under conditions that allowed the demethylation of the ortho-methoxy-group. If the product was reduced and then the acetic acid group was introduced it gave the lactone (55).37 If O-tetramethyl-haematoxylin (54) was oxidized with chromic acid it gave 0-tetramethylhaematoxylone (56),38while deoxytetramethyl-haematoxylone (57) and deoxydiethylenehaematoxylone (58) were ~ynthesized~~ by methods that have already been described for the formation of deoxytrimethylbrazilone (43).26 The chem- istry of haematein (59) was found to be similar to that of brazilein (19) and tetramethylhaematoxylium ferrichloride (60) was ~ynthesized.~~ Haematoxylin (53) was synthesized from appropriate starting materials by the same route as had been used for brazilin (1).32,33 9 Anthocyanidins and Anthocyanins Sir Robert Robinson made extensive contributions to the chemistry of the anthocyanidins and anthocyanins and he synthesized the more important examples following the public- c'-OH OH 2Me0 -CH -CO,Et MeOCH,-0 i Ye C-CH-C0,Et ii I 0 OMe oC-" 0 Reagents i Na; ii RCOCl [R = 4-MeOC6H or 3,4-(MeO),C,H,]; iii NaOH H,O Scheme 8 ation of the classic paper by R.W. Willstatter and A. E. Everest in 191 3.14 Willstatter and Everest isolated and characterized cyanin which is the colouring matter from the flowers of corn- flower and discussed the constitution of the anthocyanins in their publication.The anthocyanins are hydroxy-derivatives of 2-phenylbenzopyrylium (flavylium) salts are responsible for the red violet and blue colours of flowers and exist in Nature mostly as glycosides. Willstatter and Everest introduced the parent names which are now used; anthocyanin for the glycosides and anthocyanidins for the aglycons. By extracting the petals of cornflower rose and dahlia with methanolic NATURAL PRODUCT REPORTS 1987-R. LIVINGSTONE OMe OMe OBz I (63) CH,OH OBZ -iii CI -OMe OMe OH (64) (as barium salt) Reagents i HCl EtOAc; ii Ba(OH), MeOH; iii H,SO equiv. to Ba; iv HC1 Scheme 9 CI -OC 6H7 0 (OAC), OBz CI -(66) Reagents i HCl EtOAc; ii NaOH; iii HC1 Scheme 10 hydrogen chloride they obtained cyanin chloride (61).When this was hydrolysed it gave cyanidin chloride (62) which was shown to be a pentahydroxy-2-phenylbenzopyryliumsalt and two molecules of glucose. Other anthocyanins afforded benzo- pyrylium chlorides that contained varying numbers of hydroxy- and methoxy-groups. In the early 1920s Robinson synthesized a number of 3-hydroxy-2-phenylbenzopyryliumsalts including a number of the anthocyanidin type,42 some that were related to chrysin apigenin and lute~lin,~~ pelargonidin and cyanidin chloride and delphinidin In the synthesis of 3- hydroxy-2-phenylbenzopyrylium salts the necessary inter-mediates were acetophenones that were substituted by methoxy- groups both in the nucleus and in the methyl group.Various methods were employed to produce these compounds of which one is illustrated in Scheme 8. Condensation (in ethyl acetate containing hydrogen chlor- ide) of the appropriate intermediate with a protected phloro- glucinaldehyde gave the desired 3-methoxylated 2-phenyl- benzopyryliurn salt which was demethylated (by hydriodic acid) to give the required anthocyanidin. At first it was thought to be necessary to protect all of the nuclear hydroxy-groups and finally to demethylate them. Such a process could clearly not be applied to the synthesis of methyl ethers including the chlorides of peonidin petunidin hirsutidin and malvidin (64). However a technique was developed which allowed the mini- mum of protection and by means of acyl groups only.Robertson and much to their surprise found that the monobenzoylation of phloroglucinaldehyde furnished the 2-benzoyl-derivative (63) thus making possible the synthesis of malvidin chloride (Scheme 9).47 Robinson and his co-workers then synthesized a number of anthocyanins the first being callistephin chloride (66). This had been isolated by Willstatter from a species of aster but was later identified as the anthocyanin of the flowers of scarlet carnations. The two components for the synthesis z.e. 2-0-benzoylphloro-glucinaldehyde (63) and 4’-acetoxy-2-(tetra-O-acetyl-/3-~-glucosy1oxy)acetophenone(65) were combined as indicated in Scheme The intermediate (65) was prepared by the route that is outlined in Scheme 11.Robinson related an interesting concerning the pre- paration of 3’,4’-diacetoxy-2-hydroxyacetophenone, which is the intermediate that was required for the synthesis of chrysan- themin chloride (67).50 2,3’,4’-Trihydroxyacetophenone was carefully acetylated by acetic anydride and sodium acetate in the quantities that would in theory be required for acetylation of two of the three hydroxy-groups. The product that could be isolated by extraction with diethyl ether was probably a mixture of di- and tri-acetyl derivatives. When the ether extract was dried with calcium chloride a considerable amount of pre- NATURAL PRODUCT REPORTS 1987 ;i NaOUC(0) CH OH Reagents i NaOH ;ii Ac,O ;iii tetra-O-acetyl-/3-D-glucosyl bromide Ag,O Scheme 11 (671 oc6H1l O5 (68) R’= RZ= R3 = R4 = H (69) R’ = R3 = R4 = H,R 2 =Me (70) R’ = R3 = H R2 = Me R4 = OMe (71) R’ =R2 = Me R3=H R4= OMe cipitate appeared; this precipitate was collected and when it was treated with water it afforded the pure desired intermediate.Robinson said49 that ‘The formation of this calcium chloride compound was another piece of luck but as Benjamin Franklin declared “Luck is the bonus accruing to industry.” We had certainly worked hard to achieve our objective before we got this unexpected help. ’ Investigations concerning the positions of glucose units in diglucosidic anthocyanins were carried out by P. Karrer who methylated the anthocyanins and then removed the sugar residues by acid hydrolysis followed by degradation of the resulting methylated anthocyanidin by hot dilute alkalis in an atmosphere of hydrogen to give as one of the products a monomethyl ether of phloroglucinol.This method allowed the glucose unit at position 3 to be distinguished from that at position 5 or 7 but it was not possible to distinguish between the latter two. Robinson suggested that the diglucosidic an- thocyanins were 3,5-diglucosides and then obtained con-firmation by synthesizing a number of them including the chlo- rides of cyanin (68) peonin (69) malvin (70) and hirsutin (7 1),51 which were obtained from 2-O-(monoacetyl-~-~-glucosyl)-phloroglucinaldehyde and 3’,4’-diacetoxy-2-(tetra-O-acetyl-P-D-glucosyloxy)acetophenone 2-O-(tetra-O-acetyl-P-~-glu-cosy1)phloroglucinaldehyde and 4’-acetoxy-3’-methoxy-2-(tetra-0-acetyl-P-D-glucosyloxy)acetophenone,2-O-(tetra-O-acetyl-,4-D-gIucosyl)phloroglucinaldehyde and 4’-acetoxy-3’ 5’-dime thoxy -2-( te tra-O- ace tyl -P-D-glucos y1oxy)acet o-phenone and 4-methoxy-2-O-(tetra-O-acety~-~-~-g~ucosyl)-phloroglucinaldehyde and 4’-acetoxy-3’,5’-dimethoxy-2-(tetra-O-acetyl-P-D-glucosyloxy)acetophenone,respectively.10 References 1 R. Robinson in ‘Chemistry of Carbon Compounds’ ed. F. H. Rodd Elsevier Amsterdam 1959 Vol. IVB p. 1005. 2 R. Robinson in ‘Rodd’s Chemistry of Carbon Compounds ’ ed. S. Coffey Elsevier Amsterdam 1977 Vol. IVE p. 427. 3 W. H. Perkin and R. Robinson J. Chem. Soc. 1908 93 489 [see p. 4901. 4 M. Chevreul Ann. Chim. 1808[i] 66 225.5 C. Liebermann and 0. Burg Ber. Dtsch. Chem. Ges. 1876 9 1883. 6 K. Buchka and A. Erck Ber. Dtsch. Chem. Ges. 1885 18 1138. 7 C. Dralle Ber. Dtsch. Chem. Ges. 1884 17 372. 8 C. Schall Ber. Dtsch. Chem. Ges. 1894 27 524 [see p. 5281. 9 C. Schall and C. Dralle Ber. Dfsch. Chem. Ges. 1888 21 3009 [see p. 30171; 1889 22 1547 [see p. 15591; 1892 25 18. 10 A. W. Gilbody W. H. Perkin and J. Yates Proc. Chem. Soc. 1899 15 27 75 241; W. H. Perkin and J. Yates ibid. 1900 16 105 107. 11 W. H. Perkin J. Chem. Soc. 1902 81 1008 [see p. 10281; W. H. Perkin and R. Robinson ibid. 1907 91 1073 [see p. 10821. 12 W. H. Perkin and R. Robinson J. Chem. SOC.,1908 93,489 [see pp. 502 5091. 13 W. H. Perkin and R. Robinson J. Chem. SOC.,1908 93 489.14 A. Werner and P. Pfeiffer Chem. Z. 1904 3 421. 15 P. C. Johnson and A. Robertson J. Chem. Soc. 1950 2391. 16 W. H. Perkin and R. Robinson J. Chem. Soc. 1909 95 381 [see p. 3851; cJ ibid. 1908 93 p. 501. 17 J. Herzig J. Pollak and E. G. Galitzenstein Ber. Dtsch. Chem. Ges. 1904 37 63 1. 18 K. W. Bentley and R. Robinson J. Chem. Soc. 1950 1353. 19 W. H. Perkin and R. Robinson J. Chem. Soc. 1909 95 381 [see p. 3891. 20 A. W. Gilbody and W. H. Perkin J. Chem. Soc. 1902 81 1040 [see p. 10481; J. Herzig J. Pollak and B. Vouk Monatsh. Chem. 1904 25 871. 21 P. Engels W. H. Perkin and R. Robinson J. Chem. Soc. 1908 93 1115. 22 J. J. Hummel and A. G. Perkin J. Chem. Soc. 1882 41 367. 23 W. H. Perkin and R. Robinson J.Chem. Soc. 1907 91 1073; W. H. Perkin R. Robinson and (in part) M. R. Turner ibid. 1908 93 1085. 24 W. H. Perkin and R. Robinson J. Chem. Soc. 1908 93 1 106. 25 H. G. Crabtree and R. Robinson J. Chem. Soc. 1918 113 859. 26 W. H. Perkin and R. Robinson J. Chem. Soc. 1926 941; 1927 2094; 1928 1504. 27 P. Pfeiffer 0.Angern E. Haack and J. Willems Ber. Dtsch. Chem. Ges. 1928 61 839. 28 W. H. Perkin and R. Robinson Proc. Chem. Soc. 1912 28 7. 29 V. M. MiCovid and R. Robinson J. Chem. Soc. 1937 43. 30 J. Herzig and J. Pollak Ber. Dtsch. Chem. Ges. 1905 38 2166; 1906 39 265. 31 W. H. Perkin J. N. RBy and R. Robinson J. Chem. Soc. 1928 1504. 32 F. Morsingh and R. Robinson paper presented at the 14th International Congress of Pure and Applied Chemistry Zurich 1955 (see Congress Handbook p.260). 33 F. Morsingh and R. Robinson Tetrahedron 1970 26 28 1. 34 J. N. Chatterjea R. Robinson and M. L. Tomlinson Tetra-hedron 1974 30 507. 35 R. H. Jaeger P. M. E. Lewis and R. Robinson Tetrahedron 1974 30 1295. 36 W. H. Perkin and J. Yates J. Chem. Soc. 1902 81 235. 37 W. H. Perkin and R. Robinson J. Chem. SOC.,1908 93 489 [see p. 5151. 38 W. Hi Perkin J. Chem. Soc. 1902 81 1057 NATURAL PRODUCT REPORTS 1987-R. LIVINGSTONE 39 W. H. Perkin A. Pollard and R. Robinson J. Chem. SOC.,1937 49. 40 H. G. Crabtree and R. Robinson J. Chem. SOC. 1922 121 1033. 41 R. W. Willstatter and A. E. Everest Ann. Chem. Justus Liebig. 1913 410 189. 42 D. D. Pratt and R.Robinson J. Chem. SOC.,1922 121 1577; 1923 123 745. 43 D. D. Pratt R. Robinson and P. N. Williams J. Chem. SOC. 1924 125 199. 44 D. D. Pratt and R. Robinson J. Chem. Soc. 1924 125 188. 45 D. D. Pratt and R. Robinson J. Chem. SOC., 1925 127 166. 46 A. Robertson and R. Robinson J. Chem. SOC.,1927 1710. 47 W. Bradley and R. Robinson J. Chem. SOC.,1928 1541. 48 A. Robertson and R. Robinson J. Chem. SOC.,1928 1460. 49 R. Robinson ‘Memoirs of a Minor Prophet’ Elsevier Amster- dam 1976 Vol. 1 p. 144. 50 S. Murakami A. Robertson and R. Robinson J. Chem. Soc. 1931 2665. 51 R. Robinson and A. R. Todd J Chem. SOC.,1932 2488 2293 2299.

ISSN:0265-0568    

DOI:10.1039/NP9870400025

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Steroids and Synthetic Oestrogens Sir John Cornforth School of Molecular Sciences University of Sussex Falmer Brighton BN I 9QJ Steroids Synthesis directed at the steroids began at Oxford in 1932 before the structures aimed at were known with certainty; a provisional and incorrect structure for 'ketohydroxyoestrin ' (oestrone) is shown in the first paper of what was to be a series of 53 extending over two decades. The earlier work was all aimed at the 'aromatic' steroids equilenin and oestrone. These posed a simpler stereochemical problem there are only four molecular species corresponding to the structure formula (1) for equilenin and sixteen for oestrone (2) whereas for a true sterol [cholesterol (3)] there are 256. Robinson cast his net wide over the problem exploring new ways to build up the ring system and attacking the difficulties presented by the angular methyl groups.His ingenuity in devising schemes for synthesis had full play and the methods discovered in his laboratory contributed not only to the final achievement but it can be said to nearly all steroid syntheses that have ever been executed. The syntheses in general followed one of two strategical plans (a) to arrive at the four-ring 0 0 HO (1 1 (2 1 system as soon as possible and to modify this or (b) to aim at a tricyclic intermediate containing functions that would allow addition of the fourth ring. The second strategy proved the more fruitful. Plan (a) In the first paper of the series (with G. R. Ramage') ethyl or methyl 4-methoxycinnamate (4) was coupled reductively to two stereoisomeric forms (meso and racemic) of dianisyladipic ester (5).The related acid could be cyclized and reduced to a hexahydrochrysene (6). If this approach had been prosecuted it could have led at least to oestrone but several of the techniques required were still to be invented and the line was abandoned principally because of unpromising yields in the first step. Again condensation of an a-tetralone (7) with 1-acetyl-cyclopentene produced the ring structure of oestrone in a single step.'s3 Later,* it was shown that the dihydro-derivative of the product (8) could be C-methylated to introduce the angular eoMe Me0 \ (6) 0 I 0 NATURAL PRODUCT REPORTS 1987 0 Me0m""' \ (12) 0 0 (18) methyl group thus constructing (9) the complete carbon skeleton of oestrone.The simplicity of this success is balanced by the difficulty of arriving at a substituted ring D. Later,5 an analogue thought to be (10) was constructed but not further elaborated. Later still (with Birch6) the unsaturated ketone (1 1) was made by reaction between 1-acetyl-3,4-dihydro-6-rhethoxy-naphthalene and the lithium enolate of 2-isopropylcyclo-pentanone; but an angular methyl group could not be inserted between rings c and D by methylmagnesium halide in the presence of cuprous halide though this method had succeeded with simpler models.' The third and most ingenious variant was initiated at Robinson's own bench and was announced in a paper' of which he was sole author.Here a furfurylidene derivative (I 3) of a 2-acetylnaphthalene (12) was converted by a known but neglected type of hydrolysis-rearrangement to a diketo-acid (14) cyclized by cold dilute alkali to a cyclopentenone (15). This could be dehydrated before or (with Koebner9) after reduction of the double bond to the tetracyclic structures (16) or (17). The latter was hydrogenated to a stereoisomer (18) of norequilenin methyl ether. Much later (with Birch & JaegerlO) the ketone (18) was methylated to yield the cis-isomer (19) of ( )-equilenin methylation at the angular position being forced by introduc- tion on the other side of the carbonyl group of a blocking group (methylanilinomethylene) removable by hydro1ysis.l' 0 MeO\ / (14) 0 0 (19) Plan (b) Here again the first objective was oestrone and (with Schlitt- 1er12) a satisfactory synthesis of the tricyclic ketone (22) from rn-methoxybenzaldehyde was achieved in 1935 ; by orthodox methods the aldehyde was extended to the keto-ester (20) and this was cyclized first by sodium ethoxide to the dihydro- resorcinol (21) and thence by phosphoric oxide to the ketone (22).Later (with Walke~-'~-~~) the methylated analogue (23) was made similarly and the saturated ketone (24) was made with some difficulty from (22). Further condensation with ethyl oxalate followed by thermal decarbonylation and methy- lation of the ensuing keto-ester gave the key intermediate (25) as a mixture of stereoisomers.Unfortunately the same pro- cedure could not be applied to the unsaturated ketone (22) but the keto-ester (28) was reached by an ingenious modification Friedel-Crafts condensation of the chloride-methyl ester of glutaric acid with methyl m-methoxyphenylbutyrate (26) gave a keto-ester (27) cyclized directly by potassium methoxide to the tricyclic keto-ester (28). In a 'partial synthesis ' (with Litvan16) natural oestrone was degraded to the dicarboxylic acid (29) and built up again by using the Arndt-Eistert synthesis to extend the acetic acid side chain followed by cyclization of the homologous acid (30) to oestrone methyl ether. Thus the conversion of (25) to (29) would complete the synthesis of the oestrone skeleton and the synthesis was pushed NATURAL PRODUCT REPORTS 1987-SIR JOHN CORNFORTH n COzR (20) (21) Me0Q)y \ Me0@\ y (23) CO Me (26) (29) -0 (32) 1 (33) as far as the hydroxydiester (31) obtained by a Reformatski reaction.In fact this approach was vindicated ten years later by Anner and Miescher who achieved the total synthesis of oestrone by improvements in the synthesis of the tricyclic intermediate and by separation of stereoisomers where these were formed. Another crucial discovery of the early years was the ‘Robinson ring extension’ (with du Feu & McQuillin”) a synthesis of cyclohexenones from the enolate salt of a ketone and the methiodide of a Mannich base made from for example acetone formaldehyde and diethylamine.With 2-methylcyclo- hexanone (32) for example the product was an octalone (33) methylated in the angular position. The procedure is successful because methyl vinyl ketone probably the true reactant is formed gradually and in low concentration from the methio- dide. This reaction led to many successful syntheses both at Oxford and elsewhere. n o \ Me0mo (24) (25) PCO,Me C0,Me (27) (30) (31) During the war years work on sterol synthesis could not continue with the same momentum but discoveries were still made that laid the foundations for later success. An approach to the non-aromatic steroids (with Martin18) was explored. From 1-methyl-2-methoxynaphthalene(made readily avail- ablelg by a procedure for nuclear methylation) the tetralone (34) was prepared and elaborated to the tricyclic ketone (36) by the procedure already outlined oxalylation decarbonylation Reformatski reaction dehydration reduction to and separation of the stereoisomers of the diester (35) homologation by the Arndt-Eistert synthesis cyclization and demethylation.This tricyclic ketone was hydrogenated by the novel pro- cedure of catalytic hydrogenation at high temperature and pressure over palladium-strontium carbonate this reduced the aromatic ring without loss of oxygen by hydrogenolysis and reoxidation led to the diketone (37) as a mixture of stereo- isomers. It had been hoped that the ring extension reaction would now lead to stereoisomers of androstenedione (38) because the result with 2-methylcyclohexanone seemed to indicate a predilection for addition to a methine rather than to a methylene group; but in fact the product was shownz0 to be the benzofluorene derivative (39).This check could no doubt have been circumvented in time for example by modifying the interfering carbonyl group before reduction of the aromatic ring; and in parallel work it was shown (with Pinder21.22) that cholestenone (40) could be resynthesized from the ‘ Inhoffen ketone ’ (41) (a degradation product from cholesterol) by conversion into the methylanilinomethylene derivative (42) and reaction at the methine carbon with acrylonitrile hydrolysis then gave the ‘Windaus acid’ (43) which was known to be convertible into cholestenone.Thus the problem of adding ring A to a suitable analogue of (37) was not unsurmountable. However the synthesis ab initio by this plan required many stages and stereochemical control over the proliferation of NATURAL PRODUCT REPORTS 1987 HO $y 0 0P (37) 0 0 (38) (39) QMe Me0 / (441 (451 ROdo"(46) AcO& H OH 0 H (47)R = Me (49)R =H (51) (48)R = H (50) R = AC isomers was poor. Meanwhile work had proceeded on an tetralone (45). The work was resumed at the end of the war and alternative scheme that was to attain the goal. (with J. W. C~rnforth~~.~~) it was shown that this ketone could In 1941 (with J. W. & R.CornforthZ3) a simple method had be methylated in satisfactory yield to the monomethyl ketone been found to make p-tetralones from P-methoxynaphthalenes (46) and that the ring extension reaction with this ketone was by reducing them with sodium and alcohol and hydrolysing the unusually easy no doubt because of its relatively high acidity intermediate enol ethers by dilute acid.1,6-Dimethoxynaph- the tricyclic ketone (47) was formed and was demethylated to thalene (44)was an especially favourable case and it yielded the the phenolic ketone (48). This was hydrogenated via the NATURAL PRODUCT REPORTS 1987-SIR JOHN CORNFORTH (54) (55) ( 56) (57) (58) HO (60) H saturated ketone to the diol (49) which was stereochemically homogeneous. Its monoacetate (50) was now hydrogenated in dioxan at 200 "C/ 150 atm over palladium on strontium car- bonate to a mixture of acetoxy-alcohols (51).The overall yield in the ten stages from 1,6-dihydroxynaphthalenewas 10YO averaging 80% per stage. Chromic oxidation of the product (51) followed by hydrolysis with alcoholic alkali gave a mixture of two hydroxy-ketones (A and B); since these were a-decalones and had suffered an enolizing treatment they could be presumed to be the two possible trans forms (52A) and (52B). As it turned out the one formed in smaller proportion had the configuration (52B) corresponding to natural steroids but the quantities available were sufficient for separation of the isomers (by crystallization of the hydrogen succinates) and resolution of each of them into the optical enantiomers.Each of these four stereoisomers was then treated by a procedure (formylation methylation hydrolysis oxidation) designed to convert them into four 2,13-dimethyl- 1,7-dioxo- perhydrophenanthrenes. One of these (53) from the dextro- rotatory enantiomer of the B hydroxy-ketone was identical in all respects with a degradation product of the bile acid deoxycholic acid. The same diketone (53) was also obtained 0 from a degradation product of cholesterol the 'Koster-Logemann ketone' (54) by Oppenauer oxidation to the un- saturated ketone (55) followed by hydrogenation. These results were useful because the Koster-Logemann ketone was a by-product of the chromic oxidation of cholesteryl acetate dibromide a process used industrially to prepare sex hormones by partial synthesis from cholesterol.Thus if the diketone (53) could be transformed into the Koster-Logemann ketone ample supplies of tricyclic material in the correct stereochemical form would be available to continue the syn- thesis. The conversion into the unsaturated ketone (59 by bromination and dehydrobromination was done elsewhere by Billeter and Miescher while the synthesis was in progress (with Cardwell J. W. Cornforth Holtermann & Duff 26*27). The enol acetate (56)derived from (55) was aminolysed following a procedure of Birch with potassamide in liquid ammonia and the product reduced by lithium aluminium hydride to the diol (57). Preferential protection of the ring A hydroxyl was achieved by tritylation and the trityl ether (58) was oxidized and hydrolysed to yield the ketone (54).Carboxylation of the benzoate of the Koster-Logemann ketone was effected by a method due to Hauser the enolate formed with sodium triphenylmethide was poured on solid NATURAL PRODUCT REPORTS 1987 OH (63) (66) carbon dioxide and the acids were separated and esterified with diazomethane. Two isomers were obtained one of which proved to be the desired keto-ester (59). A Reformatski reaction on this keto-ester gave two stereo- isomeric esters (60) after partial hydrolysis. One of these was hydrogenated esterified acetylated and dehydrated with phos- phoryl chloride and pyridine. The product was hydrogenated and the acetoxy group was replaced by benzoyloxy for ease of identification.This product methyl 3/3-benzoyloxyaetioallo-bilianate (61) proved to be identical with a specimen prepared from cholesterol; comparison was made easier by a charac- teristic double melting point of this substance and identity was confirmed by X-ray crystallography. Completion of the syn- thesis by the usual Arndt-Eistert homologation had already been effected at Oxford and had led to epiandrosterone (62). The missing steps in a formal total synthesis of cholesterol from this steroid were completed and partial synthesis had already connected it with a host of other steroids. The long trail had ended. The preliminary communication of these results in 195126 was coincident with a report of a different synthesis from Woodward’s laboratory and since then many other syntheses have been devised.Unquestionably Robinson was the pioneer of steroid synthesis and progress was made possible over the ground that he broke. As he said2s in his Ramsden lecture (1950) ‘the work of one period supplies the tools for the next ’. Synthetic 0estfoge ns The finding that certain synthetic substances could produce in vivo the effects of the natural oestrogenic hormones was developed in a c01laboration~~-~~ with Dodds & Lawson at the Courtauld Institute of Biochemistry. Analogues patterned on oestradiol (63) but having two phenolic rings were explored. For example the dimethoxyhexahydrochrysene (6) prepared by Ramage & Robinson’ yielded on demethylation a product (64)almost as potent as oestradiol.This work led to the discovery of diethylstilboestrol (65) hexoestrol (66) and dieno- estrol (67) all highly active oestrogens that found pharma- ceutical and other applications. The more active stereoisomeric form of hexoestrol was shown to be the meso form (66) and that of diethylstilboestrol to be the trans-stilbene (65). It is easy to see in this work Robinson’s flair for structural generalization and for developing flexible synthesis. (67) References 1 G. R. Ramage and R. Robinson J. Chem. SOC.,1933 607. 2 W. S. Rapson and R. Robinson J. Chem. SOC.,1935 1285. 3 D. M. Crowfoot W. S. Rapson and R. Robinson J. Chem. SOC. 1936 757. 4 D. A. Peak and R. Robinson J. Chem. SOC.,1937 1581. 5 N.A. McGinnis and R. Robinson J. Chem. SOC.,1941 404. 6 A. J. Birch and R. Robinson J. Chem. SOC.,1944 503. 7 A. J. Birch and R. Robinson J. Chem. SOC.,1943 501. 8 R. Robinson J. Chem. SOC. 1938 1390. 9 A. Koebner and R. Robinson J. Chem. SOC.,1938 1994. 10 A. J. Birch R.Jaeger and R. Robinson J. Chem. SOC.,1945 582. 11 A. J. Birch and R. Robinson J. Chem. SOC.,1944 501. 12 R. Robinson and E. Schlittler J. Chem. SOC. 1935 1288. 13 R. Robinson and J. Walker J. Chem. Sac. 1936 192. 14 R. Robinson and J. Walker J. Chem. SOC.,1936 747. 15 R. Robinson and J. Walker J. Chem. SOC.,1937 60. 16 F. Litvan and R. Robinson J. Chem. SOC.,1938 1997. 17 E. C. du Feu F. J. McQuillin and R. Robinson J. Chem. SOC 1937 53. 18 R. H. Martin and R.Robinson J. Chem. SOC.,1943 491. 19 J. W. Cornforth R. H. Cornforth and R. Robinson J. Chem. SOC.,1942 682. 20 R. H. Martin and R. Robinson J. Chem. SOC.,1949 1866. 21 A. R. Pinder and R. Robinson Nature (London) 1951 167 484. 22 A. R. Pinder and R. Robinson J. Chem. SOC.,1952 1224. 23 J. W. Cornforth R. H. Cornforth and R. Robinson J. Chem. SOC.,1942 689. 24 J. W. Cornforth and R. Robinson J. Chem. SOC.,1946 676. 25 J. W. Cornforth and R. Robinson J. Chem. SOC.,1949 1855. 26 H. M. E. Cardwell J. W. Cornforth S. R. Duff H. Holtermann and R. Robinson Chem. Znd. (London) 1951 389. 27 H. M. E. Cardwell J. W. Cornforth S. R. Duff H. Holtermann and R. Robinson J. Chem. SOC. 1953 361. 28 R. Robinson Mem. Proc. Manchester Lit. Phiios. SOC.,1950 92 125. 29 E. C. Dodds L. Golberg W. Lawson and R. Robinson Nature (London) 1938 141 247. 30 E. C. Dodds L. Golberg W. Lawson and R. Robinson Nature (London) 1938 142 34. 31 E. C. Dodds L. Golberg W. Lawson and R. Robinson Nature (London) 1938 142 211. 32 E. C. Dodds L. Golberg W. Lawson and R. Robinson Proc. R. SOC.London Ser. B 1939 127 140. 33 E. C. Dodds L. Golberg E. I. Griinfeld W. Lawson C. M. Saffer (Jnr.) and R. Robinson Proc. R. SOC. London Ser. B 1944 132 83. 34 E. C. Dodds R. L. Huang W. Lawson and R. Robinson Proc. R. SOC. London Ser. B 1953 140,470.

ISSN:0265-0568    

DOI:10.1039/NP9870400035

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Sir Robert Robinson and the Early History of Penicillin E. P. Abraham Sir William Dunn School of Pathology South Parks Road Oxford OX7 3RE 1 Introduction 2 Early Work in the Sir William Dunn School of Pathology 3 Collaboration with the Dyson Perrins Laboratory 4 The Structure of Penicillin 5 Attempted Chemical Synthesis of Penicillin 6 Conclusion 7 References 1 Introduction As one among the many who have owed much to Sir Robert Robinson and can look back with gratitude to their contact with a great master of classical organic chemistry it is an especial pleasure to join in this Tribute. A facet of Sir Robert’s personality led to certain turbulent episodes in his scientific life. I was then too young and perhaps too timid ever to incur his serious displeasure but I soon became aware of the loyalty and support that he gave to his junior colleagues and of his sense of humour.At a party in the 1930s for graduate students he regaled us with an account of his latest climb in Norway with Gertrude the first Lady Robinson. When they finally reached the top their young Norwegian guide announced to Gertrude ‘Today we have broken three records this is the first time that this mountain has been climbed this year; it is the first time for three years that it has been climbed by a lady and you are by far the oldest lady who has ever climbed it.’ In the nineteen-thirties Professor Robinson obtained a grant from the Rockefeller Foundation to initiate a study of peptides and proteins and I became a member as a D.Phi1.student of a group which he set up for this purpose. He immediately suggested to me the use of the phthalyl group as a protective group in peptide synthesis. A little later when some work had begun on lysozyme he said ‘You should do an electrometric titration go to see Dr Neuberger who does these titrations at University College Hospital ’. This I did and returned to set up a hydrogen electrode. These events had some bearing on later ones. After the outbreak of war in 1939 when I managed to get back to Oxford at the end of a year at Hans von Euler’s Biochemiske Institut in Stockholm the peptide-protein project in the Dyson Perrins Laboratory had come to an end and Robinson told me to go to the Sir William Dunn School of Pathology to see Professor H.W. Florey who he said had an interesting proposal. The proposal was that I should join him and Ernst Chain in an attempt to throw light on the biochemistry of wound shock. The hypothesis on which this study was based soon proved to be untenable but in 1938 Florey and Chain had decided to make a systematic investigation of antimicrobial substances that were known to be produced by micro-organisms; amongst these was penicillin in which Alexander Fleming its discoverer had apparently lost interest for he wrote in 1940 ‘It [penicillin broth] was used in a few cases as a local antiseptic but although it gave reasonably good results the trouble of making it seemed not worth while ’. In the spring of 1940 Florey showed that a very crude preparation of penicillin probably 1 or 2% pure which had been made available by the work of Chain and Norman Heatley with a culture of Fleming’s Penicillium notatum would protect mice from otherwise lethal infections with streptococci and staphylococci when it was injected into the blood stream.This exciting development made it evident that further work on penicillin should have high priority and Florey asked me to join with Chain in an attempt to purify penicillin and study its chemistry. 2 Early Work in the Sir William Dunn School of Pathology What was the position at that time? Others may have observed the action of penicillin produced by Penicillium species long before Fleming’s strange encounter with it in 1928 but of this we shall never now be certain.Clutterbuck Lovell and Raistrick had set out to isolate penicillin in 1932. They had found that it could be extracted into diethyl ether from an acidified aqueous solution but its instability then led them to abandon their work. In March 1940 Heatley introduced the simple and effective step of re-extracting the substance from ether into a neutral aqueous solution but virtually nothing was known about the nature of penicillin except that it was an organic acid. Several factors hampered our initial rate of progress. One was the very small amount of active starting material that was available. Surface cultures of Fleming’s fungus produced only about 0.5 pg of penicillin per millilitre whereas more than 20000 times as much can now be produced by high-yielding strains of Penicillium chrysogenum in deep fermentation.More- over much of the early material was reserved for a small clinical trial in Man at the Radcliffe Infirmary Oxford. Florey rightly regarded this trial as essential to stimulate attempts by pharma- ceutical companies to overcome the then formidable difficulty of producing penicillin on a large scale. The first patient to receive penicillin by injection had a sharp rise in temperature and a rigor but we found that the pyrogens that were responsible for this disconcerting reaction could be removed by chromatography on alumina. It was indeed fortunate that the great mass of impurity like penicillin itself was non-toxic for this enabled the trial to be carried out successfully with material which later turned out to have been only between 7 YOand 1 % pure.An indication of how little penicillin was then available for chemical studies is provided by our failure to obtain any chemical information in 1940 from an experiment with a penicillinase an enzyme which we had discovered in Escherichia coli. The amount of penicillin that we could then use as a substrate was too small for us to detect the acid group which is liberated when penicillin is inactivated by the enzyme. Another reason why progress was much slower than it would be now was clearly the lack of the modern procedures with high resolution for the isolation of a single substance from a complex mixture and for later chemical studies there was no n.m.r.spectroscopy. We were mainly dependent on the classical methods of organic chemistry although sometimes aided by the results of electrometric titrations and by Dorothy Hodgkin’s ability to determine a precise molecular weight by X-ray crystallography and to decide with very small amounts of material whether a degradation product and a synthetic product were identical. However by the end of 1941 Chain and I had obtained a preparation of penicillin that was about 50% pure. We could not assess its purity at the time but its high antibacterial activity against the Oxford staphylococcus evoked from Chain an enthusiastic non sequitur ‘nothing could be as active as this if NATURAL PRODUCT REPORTS 1987 Some members of the Oxford penicillin team in Professor Howard Florey's study in the Sir William Dunn School of Pathology ca.1942 (Courtesy of Sir Edward Abraham). From the left E. P. Abraham Wilson Baker Ernst Chain and R. Robinson. it were not nearly pure'. On the basis of this over-optimistic conclusion our tentative suggestion for the molecular weight for penicillin was too high and corresponded with that of a dicarboxylic acid but we established several of its significant chemical properties. Thus on hot acid hydrolysis it yielded carbon dioxide on inactivation with weak acid and alkali it liberated new ionizable groups and its inactivation in neutral solution was strongly catalysed by heavy metal ions such as Zn2+ Cu2+ and Pb2+. The problems which then faced attempts to produce penicillin in quantity by fermentation together with the realization that the substance would be of value in war medicine provided a powerful stimulus to the idea that penicillin might be more easily obtained by chemical synthesis.One consequence of this was that in 1942 Chain and I began a collaboration with Sir Robert Robinson and Dr Wilson Baker in the Dyson Perrins Laboratory. Some months later this group was joined by John Cornforth and during subsequent years by about fifteen other chemists. 3 Collaboration with the Dyson Perrins Laboratory One of the first questions that Sir Robert asked was whether penicillin contained sulphur. We told him that a year earlier a small amount of sulphur had been found in the relatively crude preparation of penicillin then available but that the micro- analysts had reported that nitrogen was present and sulphur was absent from the much purer preparation we had obtained more recently.' This unfortunate analytical error was not to be corrected until one of the main degradation products of penicillin had been isolated.During 1942 Chain and I found that,~on acid hydrolysis our best preparations of penicillin yielded their nitrogen as am- monium chloride and an amino acid and that the amount of amino-nitrogen that was liberated increased linearly with the antibacterial activity of the preparation. In October 1942 I isolated the amino acid (named penicillamine) in crystalline form2 and showed that it was oxidized by bromine water to a strongly acidic penicillaminic acid.Penicillamine gave a deep blue colour with ferric chloride but none of us realized at the time that this was a characteristic reaction of cysteine. However in July 1943 Dorothy Hodgkin and Wilson Baker pointed out that the C H and N analysis of penicillaminic acid which left a very high oxygen value would not fit a compound that contained only C H N and 0;Wilson Baker then showed that penicillamine after fusion with sodium yielded black silver sulphide on a silver coin. The belated discovery of sulphur3 made it possible to rationalize former puzzling observations and enabled definitive progress to be made.* The lesson from this story is perhaps that one should be wary of accepting a negative result of a single experiment.On attempting to crystallize penicillamine from acetone I had obtained a new crystalline compound. After the presence of sulphur had been recognized it became clear that this was a thiazolidine and that penicillamine was an a-amino-p-thiol amino acid. John Cornforth then deduced that it contained a gem-dimethyl group (and not an ethyl group) attached to the p-carbon atom because it gave a low value for C-methyl group in a Kuhn-Roth estimation; and he proved in the autumn of 1943 by a chemical synthesis involving the addition of benzyl mercaptan to 4-isopropylidene-2-phenyloxazolone, that it was 3-mercapto-~-valine(l).4 In this connection Robinson stated later than he had recalled the synthesis of an intermediate * A ban on the publication of work on the chemistry of penicillin was imposed in Britain and the U.S.A.early in 1943. British reports were then classified as 'Secret' and submitted first to a Penicillin Production Committee of the Ministry of Supply (PEN reports) and later to a Committee on Penicillin Synthesis of the Medical Research Council (CPS reports). American reports were submitted to a Committee for Medical Research in Washington D.C. British libraries in which these reports were deposited after the War are listed in Nature (London) 1947 159 565. NATURAL PRODUCT REPORTS 1987-E. P. ABRAHAM oxazolone from hippuric acid and acetone which had been carried out many years earlier by Simonsen in Manchester. While these advances were being made work by Chain showed that acid hydrolysates of purified penicillin contained an ether-soluble compound which yielded a 2,4-dinitrophenyl- hydrazone as well as the water-soluble penicillamine.Further study of this substance in the School of Pathology and the Dyson Perrins Laboratory showed later that it was an aldehyde with the structure (2); it was named 2-pentenylpenill0aldehyde.~ When the product that was formed on alkaline inactivation of penicillin was treated with mercuric chloride the penillo- aldehyde and CO were liberated and penicillamine precipitated as a mercaptide. Thus it seemed clear that the inactivation of penicillin had yielded a thiazolidine. By July 1943 the use of partition chromatography on silica gel in Imperial Chemical Industries and in the School of Pathology led to penicillin preparations which appeared to be 70-90% pure since they were transformed into a crystalline isomeric product penillic acid in about 75% yield when inactivated at pH 2.This penillic acid had first been isolated earlier in the year by Duffin and Smith in the Wellcome laboratories and soon afterwards by us in Oxford. In August 1943 the Medical Research Council received the exciting news by telegram from the U.S.A. that Wintersteiner MacPhillamy and Alicino at Squibb had crystallized a sodium salt of their penicillin and that it had the composition C,,H,,O~N,SNa. We had been using barium salts during our purification because sodium salts of the amorphous material were extremely hygroscopic but I immediately converted our purest barium salt into a sodium salt and took the latter to Dorothy Hodgkin.When placed on a microscope slide it absorbed water to yield a syrup which set to a mass of crystals.'j The correct formula [(C,,H,,O,N,S),Ba] was then put forward for the barium salt of the Oxford penicillin. It was known (I think from a communication to Sir Robert when he visited America with Sir Ian Heilbron in 1943) that the American penicillin yielded phenylacetic acid on hydrolysis. Thus the American product (benzylpenicillin) differed from the Oxford product (2-pentenylpenicillin) in containing a C,H5- CH,CO group on place of C,H,CO. Shortly afterwards Cook and Heilbron at Imperial College London showed that the pentenylpenicillin could be hydrogenated to yield amylpeni- cillin.The difference between the American and British peni- cillins was shown later to be due to the addition of corn steep liquor containing phenylacetic acid to the American fermenta- tions to stimulate growth of the Penicillium. The Oxford product was then called penicillin F and the American product penicillin G although Chain disliked this nomenclature and used the terms penicillin 1 and penicillin 2. 4 The Structure of Penicillin It was at this time that Sir Robert began to exert a powerful influence on thoughts about the structure of the penicillin molecule. He decided that the carbon dioxide that was liberated from penicillin on acid hydrolysis and also on treatment of alkali-inactivated penicillin with mercuric chloride came from a carboxyl group in the #?-position to the aldehyde group of penilloaldehyde.It followed that the penicillin structure could be derived by removal of the elements of water from the thiazolidine (3) later known as a penicilloic acid. The crucial question was how this should be done. Robinson at once proposed the thiazolidine-oxazolone struc- ture (4) for the Oxford penicillin. A major reason for his conviction that this structure was correct was that it offered an explanation [as indicated by the arrows in structure (5)] of the ready transformation of penicillin at pH 2 into an isomeric penillic acid containing two acid groups and one basic group to which he had assigned the correct structure (6) containing an imidazoline ring.Our finding that penillic acid yielded CO and a more stable penillamine (7) on treatment with mercuric chloride was then readily understandable. Later we (3) (4) (5) H C5Hg H COzH H COzH (8) ?u HH OH H 'C0,H found that a similar fission of the penillic acid ring system occurred in dilute baryta without the loss of CO, to yield isopenillic acid. However in carrying out electrometric titrations of purified penicillin I had been unable to find any evidence for the presence of the weakly basic group that was present in simple thiazol- idines and in a penicilloate. I therefore wrote down the #?-lactam structure (8) containing an N-acylthiazolidine ring and proposed it to Chain. He at. once accepted it and became its strong supporter.After drafting a report on his structures of penillic acid and penicillin for submission to the Penicillin Production Com- mittee Robinson left Oxford for a few days. Chain Baker and I added the p-lactam structure as an alternative to the thiazol- idine-oxazolone and submitted the amended version of the report on 22 October 1943.5 Sir Robert rarely took kindly to suggestions that conflicted with his own. On his return he expressed acute displeasure and sent in a personal addendum stating that 'one of us considers the four-ring structure above somewhat improbable '. He later proposed that the absence of a detectable basic group was due to an interaction between the electron-donating nitrogen of the thiazolidine ring and the electron-deficient carbonyl carbon of the oxazolone but the question of whether such an interaction would be adequate remained.Chain who was no stranger to sustained and vehement argument later engaged in at least one memorable dispute with Robinson on the subject of the thiazolidine-oxazolone struc-ture. Rumour has it that the encounter terminated with Sir Robert throwing an inkpot after Chain’s departing figure but I cannot vouch for the veracity of this story. Whatever the truth the meeting generated no lasting enmity. In a final collection of unpublished memoirs Robinson stated later that Harold King when he became secretary of a newly formed Committee for Penicillin Synthesis (set up by the Medical Research Council at the end of 1943) had proposed to him a p-lactam structure but he did not mention this to us at the time and curiously made no reference to our own proposal in October.Early in 1944 a tricyclic structure (9) for penicillin was suggested independently by Rohrmann (at Eli Lilly in the U.S.A.) and by F. A. Robinson (at Glaxo) and it appeared to find favour with the group at Imperial College. This structure contained the skeleton of penillic acid preformed. Later an ‘azlactol’ structure (10) was proposed by Stodola in the U.S.A. However these structures were not widely accepted. Until 1945 Sir Robert’s thiazolidine-oxazolone structure appeared to have the support of the majority of those in the field including members of the Merck group although the latter mentioned the p-lactam as a possible alternative.One outstanding organic chemist threatened to give up organic chemistry if the p-lactam structure turned out to be correct but fortunately when it came to the point he did not do so. Further products that were obtained from benzylpenicillin in 1944 yielded no decisive evidence for the structure of the penicillin molecule. Thus the Merck group found that benzyl- penicillenic acid which was obtained by treatment of benzyl- penicillin methyl ester with mercuric chlqride in ether showed ultraviolet absorption with Emax at 3 150 A and gave a hydroxy- methyleneoxazolone (11) on alkaline hydrolysis. Their findings were consistent with the oxazolone structure (1 2) but several months later they isolated desthiopenicillin after hydrogenolysis of benzylpenicillin with Raney nickel.This compound was too stable in acid alkali or methanol to contain an oxazolone with no exocyclic double-bond. On the other hand its properties were consistent with the presence of an isolated p-lactam as in structure (1 3). However extensive infrared studies by groups in Britain and the U.S.A. failed to provide decisive evidence for either of the two main structures that had been proposed for penicillin itself. Perhaps the strongest dislike of the p-lactam structure came from the belief based partly on the behaviour of isolated p-lactams that the reactivity of the amide bonds in its p-lactam ring and its N-acyl side-chain would be too low to account for the relative instability of penicillin.Nevertheless in 1944 we brought together further information that was consistent with a /3-lactam structure. For example penicillin was much more stable to mercuric chloride or iodine than were un-acylated thiazolidines including the penicilloates and it yielded a sulphone on oxidation with potassium permanganate without cleavage of the thiazolidine ring. In what he described later as ‘in some measure of the nature of a rationalisation aposteriori’ R. B. Woodward at Harvard deduced that the p-lactam of a fused P-lactam-thiazolidine structure would be much less stable than an isolated p-lactam because amide resonance in the former would be suppressed by the absence of coplanarity and the impediment to the introduction of a double-bond at the bridgehead of a small bicyclic system.He supported this conclusion by an analysis of the heats of formation of an isolated p-lactam an analogous peptide ethyl ester a penicilloate and the methyl ester of benzylpenicillin which were determined at the laboratories of the National Bureau of Standards at Washington ;but controversy continued until May 1945 when an X-ray-crystallographic analysis of the sodium and potassium salts of benzylpenicillin was brought to a successful conclusion by Dorothy Hodgkin and Barbara Rogers-Low. This estab- lished the p-lactam structure beyond doubt and revealed the relative stereochemistry of the molecule as shown by (14) or its mirror image. The distance between the carbon and the nitrogen NATURAL PRODUCT REPORTS 1987 C6H5CH2 LN H 0 0 n H C02Me (11) (12) (13) HH (14) H n H C02H (15) (16) of the lactam bond (1.4 A) was close to that of a normal amide bond.Woodward felt able to reconcile this structure with the conversion of penicillin into an intermediate oxazolone (1 5) during the penicillin-penillic acid rearrangement which ac-counted for the known introduction of non-labile deuterium into the product from the medium. He also proposed that the formation of the oxazolone-containing penicillenic acid in the absence of an external proton source occurred similarly but with transfer of a proton from the nitrogen in the side-chain to either the nitrogen or the sulphur of the thiazolidine ring.Albert Neuberger made a detailed analysis of the dissociation constants of penicillin penicilloates and related compounds and concluded that they were only consistent with a p-lactam structure. On the other hand it seemed that Sir Robert could never bring himself to believe that the p-lactam structure that had been found in the crystal would alone account for the reactivity of penicillin in solution. He preferred to regard this remarkable substance as a mobile tautomeric system of which the p-lactam and oxazolone structures were components with an intermediate such as (16).’ Although the earliest work on the chemistry of penicillin was done in Britain several American institutions particularly Merck Squibb and Pfizer had become actively involved in chemical studies by 1942.A Committee on Medical Research of the Office of Scientific Research and Development had been set up in Washington D.C. in the summer of 1941. Towards the end of 1943 this Committee came to an agreement with the Medical Research Council’s Committee for Penicillin Synthesis in London for the exchange of information in the form of secret reports relating to the problem of penicillin synthesis. However the time that passed before the formal agreements were completed at Government level resulted in much delay in exchanges during 1944. Hence similar observations were made entirely independently in each country. For example the presence of sulphur in the penicillin molecule appears to have been discovered in the same month by the group at Oxford and by Alicino at Squibb.NATURAL PRODUCT REPORTS 1987-E. P. ABRAHAM 5 Attempted Chemical Synthesis of Penicillin During 1944 there was a large increase in the number of those working on the chemistry of penicillin and by 1945 about a thousand chemists in thirty-nine major laboratories were in- volved in a great Anglo-American enterprise which involved a disclosure of information by pharmaceutical companies that would have been inconceivable in times of peace. Penillamine and penicilloates were soon synthesized by the groups at Imperial College and at Oxford. Other penicilloates and penillic acid were synthesized by the group led by Karl Folkers at Merck but the synthesis of penicillin itself proved to be much more difficult than had been expected.Belief in the thiazolidine-oxazolone structure led to many attempts in the United States of America to produce the active molecule by the action of azlactonizing agents (such as acetic anhydride phosphorus trichloride and benzoyl chloride in pyridine) on a variety of penicilloates (17). However the oxazolone that was formed by azlactonization of these com- pounds was unstable and the product that could be obtained was a penicillenic acid containing a 4-heteromethyleneoxazol-one fragment. During 1944 and 1945 a major effort was made on both sides of the Atlantic to synthesize penicillin by the condensation of 4-heteromethyleneoxazolones (18) with penicillamine (1). In Oxford Robinson and Cornforth played a leading role in the synthesis of appropriate oxazolones and major contributions were made by the group of workers at Merck in the United States.Relatively few products were isolated and characterized from the resulting condensations but it appeared that they yielded mainly an inactive penicillenic acid instead of a peni- cillin. In one case we were at first tempted to cry ‘Eureka’ after Lady (Gertrude) Robinson had brought to me an aqueous solution to be tested on a nutrient agar plate that had been seeded with staphylococci. By the following morning it had not merely produced a small clear ring in which no bacterial growth had occurred but also it had obliterated growth on the entire plate. Unfortunately her product was in a strong acetic acid- sodium acetate buffer and the acetic acid was responsible for the powerful antibacterial activity.Nevertheless traces of penicillin-like antibacterial activity were detected by several such procedures.8 The activity that was observed after the condensation in pyridine of peni- cillamine with 2-benzyl-4-methoxymethylene-5-oxazolone was undoubtedly due to ben~ylpenicillin.~ It was destroyed by penicillinase; when the product that had been obtained from sulphur-labelled penicillamine was diluted with pure benzyl- penicillin radioactivity could not be removed by repeated crystallization of the mixture. Finally Du Vigneaud and his colleagues at Cornell University Medical College purified enough material by counter-current distribution between sol- vents to isolate from it a small sample of crystalline sodium benzylpenicillin but the highest yield of penicillin that they obtained from the reaction was less than 0.1 % and their attempts to increase it were unsuccessful.Presumably only a trivial amount of a thiazolidine-oxazolone had escaped inter ah conversion into a penicillenate and had rearranged with acylation of the thiazolidine nitrogen as indicated in structure (19) to yield the p-lactam structure. By 1946 when the Anglo-American enterprise had come to an end one major incentive behind the great war-time effort to synthesize penicillin had disappeared because benzylpenicillin and other penicillins with non-polar side-chains could be produced on a large scale by fermentation of mutant strains of Penicillium chrysogenum in deep aerated cultures.For a few years synthetic work in this field virtually ceased but the problem was then taken up by John Sheehan at the Massa- chusetts Institute of Technology. In the nineteen-fifties he finally succeeded in accomplishing a rational synthesis of penicillin by the introduction of a carbodi-imide as a new reagent for the formation of the amide bond of the p-lactam ring by the use of a trityl protective group (with which oxazolone formation H$ ‘bCO; 0 H (18) H+ )HH (19) could not occur) and by careful attention to stereochemistry. Even so the synthesis could not compete commercially with the astonishingly efficient fermentation. In the Weizmann lectures that Sir Robert gave in 1953 on the structural relations of natural products and the light they might throw on biogenesis he remarked briefly that ‘the structural relations of penicillin have always been sun clear’.The validity of his implied dissection of the penicillin ring system into units of cysteine and valine was established beyond doubt by experiments with isotopically labelled amino acids. However it is now evident that the biosynthetic process differs in kind from the reaction sequences that had been explored hitherto by synthetic organic chemists for the amide group which becomes part of the /?-lactam ring and a valine fragment with the D configuration are introduced into a tripeptide precursor S-L-a-aminoadipoyl-L-cysteinyl-D-vahe [N-(~-5-amino-5-carboxy-pentanoy1)-L-cysteinyl-D-valine] before any ring-closure occurs.6 Conclusion Two further observations would seem to be relevant to this occasion. First the work in Oxford which led to the introduction of penicillin into medicine was initiated mainly because it was thought to be of scientific interest and not because it was expected to reveal substances of clinical value. Secondly the success of this work was due in no small measure to Florey’s belief that pathology would greatly benefit from the importation of chemists and biochemists into a medically oriented depart- ment. Many earlier discoveries of the production of antibiotics by micro-organisms remained sterile because they were made in an environment in which techniques for taking them further were unavailable.Although the outcome of attempts to produce penicillin by total chemical synthesis was disappointing the work on its structure and reactivity in which Sir Robert had such an influential role laid a foundation for the astonishing development of new /?-lactam antibiotics that has occurred in the past three decades. 7 References 1 E. P. Abraham W. Baker E. Chain H. W. Florey E. R. Holi- day and R. Robinson Nature (London) 1942 149 356. 2 E. P. Abraham E. Chain W. Baker and R. Robinson Nature (London),1942 151 107. NPR 4 46 3 E. P. Abraham W. Baker E. Chain and R. Robinson PEN 88 1943 30 July. 4 E. P. Abraham W. Baker E. Chain J. W. Cornforth R. H. Cornforth and R. Robinson PEN 100 1943 4 October. 5 E. P. Abraham W. Baker E. Chain and R. Robinson PEN 103 1943 22 October. 6 E. P. Abraham W. Baker E. Chain and R. Robinson PEN 94 1943 2 September. NATURAL PRODUCT REPORTS 1987 7 Robert Robinson in ‘The Chemistry of Penicillin’ ed. H. T. Clarke J. R. Johnson and Sir Robert Robinson Princeton Uni- versity Press 1949 Vol. xv p. 449. 8 G. M. Robinson E. P. Abraham W. Baker E. Chain and R. Robinson CPS 35 1944 27 March. 9 E. P. Abraham W. Baker E. Chain and R. Robinson CPS 648 1945 26 November.

ISSN:0265-0568    

DOI:10.1039/NP9870400041

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Theoretical Organic Chemistry before Robinson C. A. Russell Department of History of Science and Technology The Open University Walton Hall Milton Keynes MK7 6AA 1 Introduction 2 Problems 2.1 Singularity of Formula 2.2 Unsaturation 2.3 Reactivity 3 New Lines of Attack 3.1 Dynamism 3.2 Dualism 3.3 Divisibility of Valency 4 References 1 Introduction Literally speaking the phrase ‘theoretical organic chemistry ’is a tautology for organic chemistry has always been ‘theoretical ’ in the sense that theory is part of its very nature. One of the first persons to allocate quasi-structural formulae to organic com- pounds wrote in 1858 that ‘the end of chemistry is its theory’;‘ eleven years earlier Frankland had turned to organic chemis- try as relief from clay analysis ‘of little or no theoretical interest’;2 and even before then Berzelius had written of the difference between living and dead matter as a ‘key to the theory of organic ~hemistry’.~ In fact by 1858 part of the problem facing organic chemists was that their subject was littered with competing theories so much so that KekulC’s textbook had to represent one substance (acetic acid) by no less than nineteen different form~lae,~ as shown in Figure 1.Such confusion reflects not the inaccuracy of analytical data but divergent views on ‘atomic weights’ as well as the absence of any agreed theoretical scheme. Fortunately relief was at hand with the advent of valency and structure theories and a unified theory of organic chemistry became possible.From now on ‘theory’ in organic chemistry usually meant one of two things (a) The allocation of correct structures thus incorporating more and more compounds within the one theoretical frame- work. Ironically once this happened such structures became presented as facts rather than theories as when Knorr’s antipyrine which was at first believed to be a quinoline was shown to be a phenyldimethylpyrazolone. Thousands of other examples confirm this as a dominant trend in late nineteenth- century organic chemistry. (b) The opposite of practical organic chemistry. Many authors wrote separate treatises on theoretical and practical organic chemistry reflecting the sheer difficulty and variety of the techniques that had by now become established to say nothing of the educational system in which they played a prominent part.By the year Robinson was born (1886) the simple and familiar axioms of tetravalent carbon catenation ring-forma- tion group function and so on had been firmly coupled with the belief that the properties of an organic substance were a function of its structure alone. This gave to organic chemistry a paradigm of immense elegance and power comparable with that of universal gravitation in cosmology. It was given additional strength by its applicability within the burgeoning chemical industry of European countries above all pre-war Germany. Before 1914 organic chemistry was chiefly distinguished by the immense success of organic synthesis capable of almost C,H,O .. . . . .. . . empirische Formel. C,H,O + HO . . . . . . dualietische Formel. C,H,O . H . . . . . . Wasaerstoffsaure-Theorie. C,H + 0 . . . . . . Kerntheorie. C,H,O,+ HO . . . . . Longchamp’s Ansicht. C,H + H30 . . . . . Graham’s Ansicht. C,H,O,.O HO -. . . . . Radicaltheone. C,H . 0 + HO . . . . . Radicaltheone. c4H3$ 10 . . . . . . . Gerhardt. Typentheorie. 10 . . . . . . . . “ypentheorie (Schiachkoff etc.) C,O +C,H +HO . . . Bercelius’ Paarlingstheorie. H 0 .(C,H,)C, 0 . . . . . K o 1 b e*s Ansicht. H O.(C,H,)C,,O.O . . . ditto Wurtz Men di us. C,O . . . . . . Ge u ther. C1)~2H3[0+ HO . . . . Rochleder. (C H + CO,) + HO . Persoz. C2lH C p H 710 . . . .. Buff. Figure 1 Representations of acetic acid as illustrated in ref. 4. The formulae are based on the premise that the atomic weights of carbon and oxygen are 6 and 8 respectively. indefinite development within the established theory. So true was this that further theoretical advances were neither sought nor expected. It was in that sense that Todd could write.6 ‘Strong and confident in themselves the German organic chemists placed little emphasis on theory and were on the whole unsympathetic to the young and growing science of physical chemistry.’ However there were exceptions and it is these which prompted A. W. Stewart to derogate the synthetic work as of little value (even though he did compare its output with that of the mythical giant Briareos who had 50 heads and 100 hands !) :’ Despite the Briarean efforts of the synthetic school it is safe to say that the latter half of the nineteenth century will be regarded as a time when theoretical speculation played the main part in the development of the subject.Of the hundred thousand organic compounds prepared during that time the majority were still-born and their epitaphs are inscribed in Beilstein’s Handbook. Compared with the great clarifying process which laid the basis of our modern views they weigh but little in the balance. That was written in 1918 and the author recognized a possible charge of ‘bias against the flood of synthetic material which pours chiefly from the German laboratories ’.7 However despite any nationalistic prejudice he was right to stress the fact that theory had not entirely stood still.One can indeed identify a small cluster of problems which remained to vex and tantalize those chemists who had a taste for such things but which were largely ignored by the majority (who had other priorities such as industrial production teaching etc.). It is these problems which may legitimately be taken to be the subject of ‘theoretical organic chemistry ’ a modern term which denotes a generalized study of structures and reactions particularly their mechanistic aspects. In what follows consideration will be given first to three problems that classical organic chemistry could not solve (but had to live with) and then to the development of alternative lines of attack.2 Problems 2.1 Singularity of Formula The most basic article of faith of the structure theory was that a substance was uniquely defined by its structure and therefore each substance had only one structural formula. The difficulty was that one of the most important of all of the organic substances that were studied in the nineteenth century lament- ably failed to conform to this requirement benzene. It was familiar ubiquitous (from coal-tar) and economically crucial for the production of drugs dyes and explosives yet some of its simplest derivatives each appeared to be equally well represented by two formulae most obviously substances such as 1,2-dichlorobenzene. The two familiar Kekule structures highlight a fundamental and then intractable problem.8 Other phenomena seemed to be similar though of consider- ably less importance.Acetoacetic ester for instance appeared to be sometimes eno1ic9 and sometimes ketonic.l0 This time it was more a question of balancing evidence one formula being more likely to be ‘ right’ than the other (for which the supporting data had to be then explained away). Strangely it was one of the founders of structure theory A. Butlerov who encountered some other anomalies. In 1877 he observed that two octenes were obtainable from 2-methyl- propan-2-01 and concluded enigmatically that such molecules ‘will always behave in two isomeric forms’.” In the same year he noted that two series of alkyl derivatives were apparently derived from hydrogen cyanide and for this he suggested that there must be some kind of isomeric change.It must be stressed that (benzene apart) these were problems on the fringes of organic chemistry and the few exceptions were not allowed to undermine faith in the traditional doctrines of structure theory. This was also true of some later examples at a time when structures were depicted as three-dimensional. Cyclohexane might have been expected to exist in two forms (boat and chair) but even if the former was excluded there ought to be two different monosubstituted cyclohexanes. There were not. The very fact that such anomalies were largely disregarded has much to say about the stability of scientific paradigms.12 2.2 Unsaturation A whole cluster of problems centred around the simple pheno- mena of unsaturation.l3Given that there were more ‘bonds ’ on a tetravalent carbon atom than were needed to unite a molecule like ethylene what does one do with those in excess? Kekule who was committed to a doctrine of invariant valency could only indicate them as in some way spare or if they were on adjacent atoms join them together as a double or even a triple bond. Others (e.g. Frankland) spoke of ‘latent atomicities ’ though no one was sure exactly what a ‘spare ’ or ‘latent ’ bond might be. Others again untroubled by Kekule’s presupposi- tions simply joined the carbon atoms with a single bond and left it at that. Related to the problem of ethylene was that of benzene. NATURAL PRODUCT REPORTS 1987 Apart from the apparent identity of 1-2 and 1-6 bonds there was the difficulty with which benzene underwent addition reactions.This was another example of an anomaly that was set aside as insoluble irrelevant or just trivial. For example H. E. Armstrong in his textbook ‘Organic Chemistry’ (in 1880) represents a hexatriene structure yet asserts also the equivalence of positions 1 and 6 and says that the whole is ‘perfectly ~ymmetrical’.’~The author regards multiple bonds as un-important and in his chapter on aldehydes he never once writes a C=O group. Many years later looking back on Victorian controversy he alleges of benzene that ‘only a few pedants were concerned as to details of structure’.15 Had this not been the case theoretical organic chemistry might have blossomed before Robinson was born The other main question about multiple bonds i.e.their reactivity seems to have been largely unrecognized until Baeyer put forth his Strain Theory.16 Probably this reflects a widespread reluctance to think of molecules in terms of mechanical analogies. Otherwise it might have been obvious that a double bond would impart greater not diminished strength. Even after Baeyer the differential reactivities of alkenes and alkynes were largely ignored. 2.3 Reactivity The problem of reactivity (or lack of it) in aromatic and unsaturated molecules by no means exhausted the difficulties. There was the question of variation of group function for instance. Differences in carbonyl behaviour between ketones and aldehydes were well known but inexplicable ;still more was this true of differences with esters.As late as 1911 Perkin and Kipping argued for the structure of acetic acid on the basis of evidence for methyl and hydroxyl groups. Significantly they say nothing of the ‘carbonyl’ group and offer no explanation of the acidity of the -COOH group.17 With hindsight one may well wonder how long such puzzles could go unremarked if not unresolved. Not all were complacent however and A. W. Stewart complained :I8 Instead of attempting to bring their formulae into harmony with the facts organic chemists have been content to drag behind them a lengthening chain of implications which they read into a formula; e.g. in the case of acetone and ethyl acetate we do not distinguish in our formulae between the two carbonyl groups but we mentally interpret the two symbols differently.A further aspect of the problem of reactivity lay in the directive influence of substituents most obviously in the substitution of benzene. The work of Kornerls and others had established the configuration of substitution products and by the mid- 1870s it was obvious that some groups that were already present in the molecule ‘directed’ other groups to the ortho-/ para-positions and other groups directed incoming substituents to the meta-position. Any comprehensive theoretical explana- tion was at that stage out of the question and the best that could be hoped for was a set of empirical rules. Several attempts to link directive power with ‘acidity’ of the directing groups were made by KOrner,lg Hiibner,20 and Noelting.2L Crum Brown22 suggested that if HX were oxidized to HOX in one stage then X would be rneta-directing (he was not then to know of the oxidations of water or ammonia).Elsewhere similar problems of orientation of substituents arose as in the matter of 1,2- versus 1,4-addition to conjugated dienes but here as in aromatic substitution no comprehensive theory was available. Underlying all of these difficulties was a fundamental un- certainty as to the relationship between the reacting molecule and its conventional representation on paper (or even as a three-dimensional model). Kekule had argued that his ‘rational formulae are only reaction formulae and not structural formu- lae ’,23 while Crum Brown distinguished between what he called ‘chemical’ and ‘physical ’ positions of Many years later Stewart wrote of ‘modern formulae and their failings’ observing that they do not explain for example the behaviour NATURAL PRODUCT REPORTS 19874.A. RUSSELL of p-quinone monoxime as p-nitrosophenol and suggesting that more account be taken of the effect of reagents and of physical data.25 3 New Lines of Attack Perhaps the most important single development in organic theory during the reign of classical structure theory was the birth of stereochemistry.26 Its predictive and explanatory power is well known especially in the area of isomerism. Whether at first it helped to foster a deeper understanding of reactivity is another matter.On one hand the newly recognized tetrahedra gave the molecular concept a concreteness that it was in danger of losing in the face of growing atomic scepticism. Incorporated by Baeyer in his famous Strain Theory tetrahedra helped to predict the instability of three- and four-membered rings (and rather unfortunately the reactivity of alkenes). This was one of the first comprehensive physical theories of chemical reactivity. On the other hand the early stereochemical concepts were unable to account for many other outstanding problems not least 1,4-addition ;more seriously they raised new problems as in the decreased reactivity in triple bonds and the non-isolation of isomers that had been predicted for non-planar cyclohexanes.Perhaps that was why at the very end of the century there was an ‘extreme distrust ’of three-dimensional models.27 If the origins of modern theoretical organic chemistry are not to be found in steric concepts they can be much more convincingly located in the fusion of three other ideas none of which however had been very successful on its own. These were dynamism dualism and a critique of the unitary theory of valency. 3.1 Dynamism With the isolated exception of Wilhelmy’s quantitative studies of the inversion of sucrose,28 organic chemistry was not greatly affected by the rise of reaction kinetics until the end of the nineteenth century. That does not mean that the dynamic nature of organic processes failed to excite speculation or comment.The first occasion seems to have been Kekule’s oscillation hypothesis for the benzene The sug- gestion -that the molecule oscillated between the two cyclo- hexatriene forms -was a somewhat desperate attempt to ‘save the phenomena’ and permit only one 1,2-disubstituted benzene. Yet as Armstrong pointed out ‘this oscillation hypothesis never found favour ’.15 The literature abundantly bears this out; thus the idea is not even mentioned by Ladenburg in his ‘History of Chemistry ’,3* and he questioned whether Kekule understood its implication^.^^ There were substantial grounds for scepticism. There were physical reasons. As Michaelis pointed the oscillation hypothesis required the carbon atoms to move further than those of hydrogen and this was generally at variance with the kinetic theory.But the fundamental objections were surely chemical. The fact remained that a duality of formula for one substance was a fundamental violation of the structure theory and who was to say where that might lead? It was preferable with Victor Me~er,~~ to reckon the differences between 1,2- and 1,6-isomers so small as to be undetectable though that itself needed further explanation. Meanwhile the recognition of tautomerism in the 188Os brought a necessary dynamic element (at least to a few areas of chemistry). Laar,34 who coined the name suggested an oscil- lating hydrogen atom as in acetoacetic ester. Knorr thought rather in terms of mobile Jacobson’s concept of ‘desmotropy ’emphasized the existence of both forms which were interconvertible only under certain condition^.^^ Hantzsch and Her~mann~~ limited this to cases of tautomerism where two physical forms were isolable.It is hard to avoid the impression that for all their interest such cases were relegated to the fringes of organic theory and the main development of the subject was little affected. By no means would most chemists have agreed with the view of Schorlemmer (in 1894) that progress now forced chemists ‘to a dialectic treatment of the subject and justified even for molecules the axiom of Heraclitus that everything is in an eternal This expression of a Marxist philosophy of science stands ironically in contrast with the Soviet proscription of resonance structures under Stalin in the 1950s.3.2 Dualism A dualistic view of organic substances can be traced back to Berzelius and even to Lavoisier. The Berzelian notion of positive and negative parts of an organic molecule (as in electrolytes) survived even the traumas of chlorination of acetic acid (when ‘positive ’hydrogen was replaced by ‘negative’ chlorine).39 The dualistic division of compounds into radicals appeared in the new radical theory of the 1840s that was later subsumed under the concept of valency. It was vindicated or so it seemed by the isolation of radicals such as cacodyl ‘ethyl’ [actually butane] et~.~O The proliferation of organic compounds that were mani- festly non-electrolytes and for which the structure could be satisfactorily accounted in terms of simple bond theory did not demand dualistic interpretation.Yet dualism remained as an undercurrent in chemical thought and visibly surfaced in the crisis over aromatic substitution. According to the empirical rules of Hiibner ‘in the replace- ment of hydrogen atoms during the preparation of poly- substituted benzene derivatives the incoming substituents of a negative (acidic) character go to the para-position with respect to the least negative (acidic) substituent already present ’.20 Despite Stewart’s later claim that the ‘nature of the incoming substituent plays a hardly appreciable part in the pr~blem’,~~ here is a clear insight into a polar classification of reagents that persisted from Berzelius right up to Robinson and Ingold.Hubner’s rules incorrectly predicted identical directive effects of chlorine atoms and nitro-groups. In a modified scheme Noelting distinguished between ‘neutral basic or weakly acidic groups’.21 Yet as late as 1930 one commentator could condemn his ideas as also suffering from ‘that curse of chemical nomen- clature -the word “negative” applied to groups ’.41 This ignores the significance of an attempt to formulate however vaguely an electrical (as opposed to electronic) theory of organic chemistry. Others have stressed the vagueness of such ideas of acidity attributing them to Berzeliu~.~~ That this greatest of nineteenth-century chemists should still be blamed in the 1950s is as much a tribute to the persistence of his insights as is their fusion with a third stream of chemical thought that we now consider.3.3 Divisibility of Valency The notion of a constant indivisible valency with unvarying integral values was inherent in Kekult’s thought. Yet even here is some concession in his ‘molecular What held the two components together in tetramethyl-ammonium iodide for example which can be represented as Me3N-MeI? Attacks on this position came from several quarters in the 1880s. In Germany Lossen (in 1880) wrote ethylene as H H and denied the reality of the pre-existent valencies. He wrote that valency is simply a ‘number expressing how many atoms are found in the binding Claus a few months later elaborated a similar thesis.45 H. E. Armstrong went further. Adopting an extreme Berze- lian position he asserted that chemical reaction was ‘reversed electrolysis’and expounded his views in 1885 and (especially) 1888.He agreed with Lossen adding:46 Whatever be the nature of chemical affinity it is difficult to avoid the conclusion that the “charge” of a negative radical especially is rarely if ever given up at once that its affinity is at once exhausted. It would appear that the amount of residual charge -of surplus affinity -possessed by a radical after combination with others depends both on its own nature and that of the radical or radicals with which it becomes associated. Thus a monatomic atom” in reaction was written as -e-+-e-=e==-D H H HZ tetramethylammonium iodide47 was written as H3c\ H,C’ phosphorus and lead were represented as and benzene was drawn“ as It has to be admitted that Armstrong relished a minority position.Speculative aggressive and strongly committed to the radical tradition he remained relatively isolated within British science and his views are hardly typical. Views very similar to his may however be discerned in a later development that marked a milestone in theoretical organic chemistry. In 1899 Thiele postulated ‘an affinity residue or a partial valency ’ in attempting to account for the predominance of 1,4-addition to butadiene that occurs in certain circum~tances.~~ Partial valencies were supposed to exist on unsaturated carbon atoms. If these were part of a conjugated chain there could be a process of mutual satisfaction between those on adjacent atoms leaving only the terminal centres of unsaturation open to attack as in the hydrogenation of butadiene In a similar way the unreactivity of benzene could be explained in terms of total mutual neutralization NATURAL PRODUCT REPORTS 1987 assailed by some on the grounds that this was a retreat from the electrochemical insights that were then developing.Michael observed (in 1899) that the concept of affinity residues fails to account for the orientation of addition (which was begin- ning to be interpreted in polar terms) or for predominant 3,4- addition in some cases [as dibenzylidenepropionic acid PhCH=C(COOH)CH=CHPh].50 Hinrichsen (in 1904) argued similarly,51 while Erlenmeyer (in 190 1) preferred free valencies to partial ones.52 There was a reluctance to multiply hypotheses.However Thiele has been hailed as ‘one of the founders of early theoretical organic chemistry ’.53 An advocate of this polar alternative view A. Michael a ‘negative-positive rule ’ for unsymmetrical ad- ditions. Maximum neutralization is obtained if a negative addendum becomes attached to the more electropositive atom of the unsaturated molecule. This accounts for Markovnikov addition of hydrogen iodide to propylene the methyl group making the central carbon atom more positive. Michael derived this from Ostwald’s dictum that ‘every system tends towards the state whereby the maximum entropy is reached ’. The next major step was taken by Bernard Flur~cheim,~~ who had worked with Werner and Thiele.Based upon Werner’s ideas of maximum disposable affinity his scheme also used Thiele’s insights into conjugation. If two atoms have a strong affinity for each other any addenda will be held by weak affinity forces and an alternation of strong and weak links will arise X-A-B-C -0 Y -AmB-C-D In 1902 Flurscheim applied this to the substitution reactions of benzene YY HSO, M The application was criticized for its inability to explain the ortho-directing power of methyl groups56 and for its suggestion of an absolute distinction between weak and strong Yet Ingold claimed that ‘Flurscheim’s theory was about as correct as it was possible for a pre-electronic theory to be indeed its largely correct form made the task of remoulding it in electronic terms a particularly easy one for others’ adding that he was truly ‘the last of the great pre-electronic builders of the theory of organic chemistry’.58 Flurscheim did not accept the electron into chemistry because he could not see that bonding could be electrostatic.As Ingold ’ also noticed Flurscheim was ‘good at unanswerable arguments ’. It is hard to say when the electron was first introduced into organic chemistry but one of the earliest attempts was made by H. S. Fry.59 Extrapolating from some speculations of J. J. Thomson Fry proposed an ‘electronic isomerism’ in which a molecule XY could have two forms though these were not necessarily separable or isolable + +-x-v = x-Y Similarly carbon could exist in five different states + f+ + -+c+ -c+ -c+ -c-c-+ + --The combination of these states of carbon in benzene leads to six possible electromers as shown in Figure 2.Other variations on this concept were proposed e.g. by Falk and Nelson,6o and attempts were made to apply it by VorlanderG1 o=i=o +-+ H-N-H (though this did not explain the high reactivity of cyclobuta- diene or cyclo-octatetraene). Thiele’s innovation was to apply this concept to unsaturated centres thus combining views like those of Armstrong and of Lossen. His work very quickly became a classic yet he was +-+ + -yqr-+- -.+)A+-+ +-+ + +- +- + -*I + + +- + + NATURAL PRODUCT REPORTS 19874. A. RUSSELL + + -*; + Figure 2 The six possible electromers of benzene.and others as shown in structures (1) and (2). However its extreme dualism repelled many and the last major advance before Robinson had to wait for some years. In 1920 Arthur Lapworth proposed his rule of alternating polarities for conjugated chains :62 Ill II -C=C-C=O and -C=C-CEN +-+-+-+-etc. This was based on earlier recognition (in 1903) of a two-stage nucleophilic attack by cyanide on carbonyl Obviously indebted to the earlier work that has already been described Lapworth then extended his ideas to aromatic substitution as illustrated in structures (3) and (4). Lapworth’s X-Y (3) (4) great contribution was his ‘key-atom’ hypothesis. He pre- supposed a key-atom whose effect is relayed in ‘fullest display ’ down a conjugated chain.But:64 In attaching the -and + signs to the oxygen and carbon atoms no hypothesis is invoked nor is it necessary or even desirable to assume that electrical charges are developed on these two atoms (except perhaps at the actual instant of chemical change). The signs are applied in the first instance merely as expressing the relative polar characters which the two atoms seem to display at the instant of the chemical change in question. He was not far from the polarity signs and curly arrows that soon adorned mechanistic accounts of organic reactions. His own great achievement was nothing less than a synthesis of dualism dynamism and a non-unitary valency theory. This was surely the ultimate if unrealized goal of Berzelius himself.No one else ever came so near to the vision of the great Swedish chemist as did Arthur Lapworth. It had taken nearly a century to happen. Of Lapworth it was once written? It is now seen that this insight into chemical mechanisms and his insistence on the electrochemical point of view at the molecular level. forged a necessary link in the chain of theory which now connects the most diverse phenomena. This was no fulsome tribute from a distant admirer or remote historian. The words are those of Sir Robert Robinson. 4 References 1 A. S. Couper Philos. Mag. 1858 16 (Ser. 4) 104. 2 E. Frankland ‘Sketches from the Life of Edward Frankland’ privately published London 2nd edn. 1902 p. 166. 51 3 J. J. Berzelius ‘Lehrbuch der Chemie’ Dresden 1827 Vol.3 (i) p. 135. 4 A. Kekule ‘Lehrbuch der organischen Chemie ’ Erlangen 186 1 Vol. 1 p. 58. L. Knorr Ber. Dtsch. Chem. Ges. 1883 16 2597. 6 A. R. Todd in Tetrahedron,Suppl. No. 1 ‘The Perkin Centenary London’ Pergamon Press London 1958 p. 91. 7 A. W. Stewart ‘Recent Advances in Organic Chemistry’ Long- mans Green & Co. London 3rd edn. 1918 pp. 1 and xii. 8 C. A. Russell ‘The History of Valency’ Leicester University Press Leicester 1971 p. 254. 9 A. Geuther Jahresber. Fortschr. Chem. 1863 16 323. E. Frankland and B. F. Duppa J. Chem. Soc. 1866 19 395. 11 A. M. Butlerov Ann. Chem. Justus Liebig 1877 189 44 (see p. 76). 12 C. A. Russell in ‘van’t Hoff-le Be1 Centennial’ (ACS Symposium Series No.12) ed. 0.B. Ramsay American Chemical Society Washington D.C. 1975 p. 159. 13 C. A. Russell ‘Early chemical ideas on unsaturation’ in ‘Actes du XII“ Congrks International d’Histoire des Sciences ’ Paris 1968 (publ. 1971) Vol. 6 p. 87. 14 H. E. Armstrong ‘Introduction to the Study of Organic Chem- istry’ Longmans Green & Co. London 2nd edn. 1880 p. 129. H. E. Armstrong Chem. Znd. Rev. 1929 7 914 (see p. 916). 16 A. von Baeyer Ber. Dtsch. Chem. Ges. 1885 18 2278. 17 W. H. Perkin and F. S. Kipping ‘Organic Chemistry’ W. & R. Chambers London 191 1 pp. 159-160. 18 Ref. 7 p. 319. 19 W. Korner Gazz. Chim. Ital. 1874 4 305. H. Hiibner Ber. Dtsch. Chem. Ges. 1875 8 873. 21 E. Noelting Ber. Dtsch. Chem. Ges. 1876 9 1797. 22 A. Crum Brown and J.Gibson J. Chem. SOC.,1892 61 367. 23 Ref. 4 p. 157. 24 A. Crum Brown Trans. R. SOC. Edinburgh 1864 23 707 (see p. 710). Ref. 7 p. 318. 26 0.B. Ramsay ‘Stereochemistry ’ Heyden London 1981 27 A. Lachman ‘The Spirit of Organic Chemistry’ Macmillan New York 1899 p. 45. 28 L. Wilhelmy Ann. Phys. Chem. Poggendorf 1850 81 413 499. 29 A. Kekule Ann. Chem. Justus Liebig 1872 162 77 A. Ladenburg ‘Lectures on the History of the Development of Chemistry since the Time of Lavoisier ’ transl. L. Dobbin Alembic Club Edinburgh 1905. 31 A. Ladenburg Ber. Dtsch. Chem. Ges. 1872 5 322. 32 A. Michaelis Ber. Dtsch. Chem. Ges. 1872 5 463. 33 V. Meyer Ann. Chem. Justus Liebig 1870 156 265; 1871 159 1 (see p. 24). 34 C. Laar Ber. Dtsch. Chem. Ges.1885 18 648; 1886 19 730. L. Knorr Ann. Chem. Justus Liebig 1899 306 332. 36 P. Jacobson Ber. Dtsch. Chem. Ges. 1888,21,2624 (see p. 2628). 37 A. R. Hantzsch and F. Herrmann Ber. Dtsch. Chem. Ges. 1887 20 2801. 38 C. Schorlemmer ‘The Rise and Development of Organic Chem- istry’ ed. A. Smithells Macmillan London 1894 p. 184. 39 C. A. Russell Ann. Sci. 1963 19 136. Ref. 8 p. 21. 41 A. W. Stewart ‘Recent Advances in Organic Chemistry’ Long- mans Green & Co. London 6th edn. 1931 Vol. 1 p. 365. 42 E.g. W. A. Waters ‘Physical Aspects of Organic Chemistry’ Routledge & Kegan Paul London 4th edn. 1950. p. 463. 43 F. A. Kekule Compt. rend. Acad. Sci. 1864 58 510. 44 W. Lossen Ann. Chem. Justus Liebig 1880 204 265 (see p. 284). A. Claus Ber.Dtsch. Chem. Ges. 1881 14 432. 46 H. E. Armstrong Rep. Br. Assoc. Adv. Sci. 1885 55 945 (see p. 960). 47 H. E. Armstrong Philos. Mag. 1888 25 (Ser. 5) 21. 48 H. E. Armstrong Philos. Mag. 1887 23 (Ser. 5) 73 (see p. 108). 49 F. K. J. Thiele Ann. Chem. Justus Liebig 1899 306 87. A. Michael J. Prakt. Chem. 1899 60 467. 51 F. W. Hinrichsen Ann. Chem. Justus Liebig 1904 336 168 (see p. 174). 52 E. Erlenmeyer jun. Ann. Chem. Justus Liebig 1901 316 43. 53 R. Huisgen Proc. Chem. SOC. 1958 210. 54 A. Michael J. Prakt. Chem. 1899 60 286 409. B. Fliirscheim J. Prakt. Chem. 1902 66 321. 56 J. Obermiller ‘Die orientierenden Einflusse und der Benzolkern ’ J. A. Barth Leipzig 1909. 57 A. F. Holleman ‘Die direkte Einfuhrung von Substituenten in den Benzolkern ’ Veit Leipzig 19 10. 58 C. K. Ingold Nature (London) 1955 176 191; J. Chem. SOC. 1956 1087. 59 H. S. Fry Z. Phys. Chem. 1911 76 385 398. 60 K. G. Falk and J. M. Nelson J. Am. Chem. Soc. 1910 32 1637. 61 D. Vorlander Ber. Dtsch. Chem. Ges. 1901 34 1632. NATURAL PRODUCT REPORTS 1987 62 A. Lapworth Mem. Proc. Manchester Lit.Philos. Soc. 1920 64 No. 3 p. 1. 63 A. Lapworth J. Chem. Soc. 1903 83 995. 64 Ref. 62 p. 3. 65 R. Robinson ‘Arthur Lapworth ’ in ‘British Chemists’ ed. A. Findlay and W. H. Mills The Chemical Society London 1947 p. 366.

ISSN:0265-0568    

DOI:10.1039/NP9870400047

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

The Development of Sir Robert Robinson‘s Contributions to Theoretical Organic Chemistry M. D. Saltzman Department of Chemistry Providence College Providence RIO29 18 USA 1 Major Influences on Robinson 2 The Development of an Electronic Interpretation of Organic Reactions 3 The Robinson-Ingold Controversy 4 The General Polar Effect 5 Conclusion 6 References Louis Hammett has written ‘To many physical chemists in the 1920s and early 1930s the organic chemist was a grubby artisan engaged in an unsystematic search for new compounds.. .’.l The work of Sir Robert Robinson (1886-1975) radically changed the perception of non-organic chemists about the nature of organic chemistry. Through his development of an electronic theory of organic reactions Robinson was instru- mental in converting organic chemistry from an art into a science.This work the development of which will be discussed in this paper occupied only a decade and a half of his more than seven decades of active involvement in organic chemistry. Sir Robert in his autobiography ‘Memoirs of a Minor Pro- phet ’,remarked :2 ‘The development of these ideas constituted in the writer’s opinion his most important contribution to knowledge.’ Robinson’s work in theoretical organic chemistry was viewed by himself as an adjunct to his lifelong interest in synthetic chemistry especially as applied to natural products. Who and what were the major influences which shaped Robin- son’s thinking that led to his proposal of a general theory of organic reactions in 1925 and 1926? 1 Major Influences on Robinson The first major influence was William Henry Perkin Jr (1 860- 1929).Through his lectures on organic chemistry during Robinson’s second year (1 903-4) as an undergraduate at Manchester University Perkin ‘decided my future career; I was fascinated by the beauty of the organic chemical ~ystem’.~ Under the tutelage of Perkin Robinson rapidly progressed to the D.Sc. in 1909 and to a staff appointment in the department of chemistry as Assistant Lecturer and Demonstrator. Robin- son’s major work during this period (1909-12) was concerned with the chemistry of brazilin haematoxylin and various alkaloids including berberine. Perkin instilled the love of organic chemistry in Robinson but Perkin had one shortcoming as Robinson wrote:4 He had a simple outlook on the subject which he treated as a system in which parts were related by reactions.However he never paused to consider the underlying mechanism of organic chemical reactions. For him chemistry was still the science for transformation of materials and these could be represented by changes in structural formulae. Synthetic and other reactions could usually be explained by drawing rings around reactive moieties with consequent changes in the binding of bonds. Robinson’s interest in the mechanisms of organic reactions came from his association with Arthur Lapworth (1872-1941). In 1909 Lapworth joined the staff of Manchester University as Senior Lecturer on leaving his lectureship in Goldsmiths’ College London.Lapworth had obtained his DSc. in 1895 while a student at the Central Technical College London where the chemistry department was headed by Henry Edward Armstrong (1848-1937) one of the greatest chemistry teachers in Britain during his career at Central from 1884 until 191 1. A man of unorthodox but novel views Armstrong was very much interested in the theory of organic chemistry. He is perhaps best remembered for his work on aromatic substitution including the centric formula for benzene. It was probably due to this environment that Lapworth acquired his lifelong interest in the theory of organic reactions ; Robinson wrote :5 I had the inestimable advantage of friendship with him and unlimited opportunity for discussion from that time until 1912 when I entered on my first Professorship at the University of Sydney.In the period before 1909 Lapworth had contributed several important advances in theoretical organic chemistry. He had elucidated the mechanism of the addition of hydrogen cyanide to aldehydes ketones and @-unsaturated ketones as well as that of the benzoin condensation. In all of these reactions Lapworth realized that ions play a crucial role. He commented :6 . . .it is to electrolytic dissociation often doubtless in extremely minute amount that the majority of changes in organic compounds may be most probably assigned. This work Robinson believed led Lapworth to propose a general view of how reactivity at one site in a molecule could influence reaction at another site....the addition of hydrogen cyanide to unsaturated ketones suggested that the quality of reactivity of the carbon of a carbonyl group can be transmitted to the ,%carbon of an a,P-unsaturated ketone. If so he may have argued a carbonyl might activate a methylene group through a double bond.’ Lapworth in 1900 reported the reaction of ethyl crotonate with ethyl oxalate in the presence of sodium ethoxide 0 0 II II Et OC -COEt + CH,CH=CH i-COE t NaOEt1 00II It 0 II EtOC-CCHzCH=CHCOEt To Robinson Lapworth’s discovery of this reaction showed the deep insight that Lapworth had into reaction mechanism. During his early association with Robinson Lapworth was developing a system which came to be known as alternating polarities in a chain of atoms.Although Lapworth published his theory only in 1920 Robinson was using these ideas of alternating polarities as early as 1916.8 By assigning + and -signs to atoms according to their relative polarity to each other at the time of chemical change Lapworth devised a scheme to show how these polarities could be transmitted through a chain to effect reaction at a remote site. As Lapworth wrote:g The extension to the influence of the directing or key-atom over a long range seems to require for its fullest display the presence of double bonds and usually in conjugated positions ;consequently the principle must find ample scope in the aromatic series where conjugation is the rule. NATURAL PRODUCT REPORTS 1987 J.L. Simonsen (left) and Arthur Lapworth in the Schunck Laboratory of the Manchester Chemistry Department (Courtesy of Greater Manchester Museum of Science and Industry) A classic example of the application of Lapworth’s system was his explanation of the reactions of the m-and p-methoxy- benzyl bromides :lo QC H pC H CH,Br +-The para-isomer is much more easily hydrolysed to the benzyl alcohol whereas the rneta-isomer is more easily reduced to m-methylanisole. Robinson believed that “Lapworth’s main con- tribution to modern theory was his classification of reagents and his earlier work on reaction mechanisms which were closely inter-related ”.ll Indeed Robinson always used the Lapworth nomenclature of anionoid (electron-donating) and kationoid (electron-accepting) for reagents even after these terms became totally archaic as a tribute to the importance of Lapworth’s work.Table 1 taken from Robinson’s publication ‘Outline of an Electrochemical (Electronic) Theory of the Course of Organic Reactions’,12 in 1932 shows many examples of this scheme of classification. Thus from Lapworth Robinson acquired an interest in reaction mechanisms especially as an aid to his synthetic work and a feeling that for the most part organic reactions proceeded by ionic mechanisms. Robinson was able to return to Man- Chester in 1922 as Professor of Organic Chemistry and to renew his close association with Lapworth. This lasted until 1928 when Robinson made his penultimate move to University Table 1 Lapworth’s classification of reagents Anionoid Electron-donating.Active anions NH,- OH- CN- HC i C- CH(CO,Et),-. Complexes containing unshared electron pairs -NH, -OH,. Reducing agents Fe++ Fe(CN),--etc. Metals as sources of electrons. Kationoid Electron-accepting. Active kations H,O+ $N,+ cotarninium 0 of peroxides ;metallic atoms with incomplete electron shells. Oxidising agents Fe+++ Fe(CN),-- etc. Halogens HNO, HSO, 0,. R (alkyl) in RMghal. R in Rhal or NR,)X. C in C==C as in C,H, C& etc. C in C==O as in CH,O etc. - Neutral atoms and free radicles. College London. G. N. Burkhardt remembers that during this period :13 ...Arthur Lapworth and Robert Robinson not only discussed structure and reactivity and mechanism of reactions in the department but often after lunch they could be seen in a corner of the staff common room covering old envelopes with +and -signs,partial valencies equations diagrams and arrows of many shapes indicating electron drifts and availabilities.A third early influence on Robinson was Johannes Thiele (1865-1918). From his work with Baeyer on aromatic chem- istry Thiele had become aware of the major problems that chemists faced in explaining the chemistry of benzene and NATURAL PRODUCT REPORTS 1987-M. D. SALTZMAN conjugated systems in general. In 1899 Thiele published two papers14 in which he proposed the concept of partial valencies. The chemistry that Thiele studied was the type that fascinated Robinson for many decades that is the reactions of conjugated systems.Thiele suggested that in any double bond the com- bining power of the atoms is not fully used and there is a residual affinity or valency that can be used in reactions. Thiele suggested that in buta-1,Cdiene the partial valencies of the inner two carbons neutralize each other producing an inacti- vated inner double-bond while leaving partial valencies at positions 1 and 4 for reaction C=C-F=? + c=c-c=c I1 I-: IIII 1111 I I Thiele was able to explain the mechanism of the reduction of benzil to benzoin by stannous chloride in alcohol as a 1,4-addition of hydrogen and ketonization of the initially formed enediol HO ' /o Ph-C-C' I 'Ph H When the reaction was carried out in the presence of acetic anhydride zinc dust and hydrochloric acid which provided conditions for the initially formed alcohol to be acetylated as it was produced the formation of equal parts of the cis-and trans-diacetates was found by Thiele.This confirmed his mechanism of the reduction. For benzene Thiele represented the system as *a* 0. *. which showed the equivalence of all positions in benzene. Colin Russell in his definitive 'History of Valency' has written of Thiele:15 'That Thiele had grasped a profound truth about unsaturation in general is widely admitted today. His anticipation of quantum mechanical doctrines is remarkable. ' Robinson states his debt to Thiele as follows in discussing the development of his ideas :2 The starting point was the theory of partial valency which differed from the well known views of J.Thiele in an important respect. Thiele suggested that an unsaturated atom possesses a partial or residual valency in addition to those normally represented by ordinary bonds. My idea was that of bonds themselves being split and thus providing partial valencies. Using the idea of partial valency and Lapworth's insight into the polarization in a chain of atoms Robinson was to make his first contributions to theoretical organic chemistry beginning in 1916. These contributions would later be converted to an electronic basis in 1922. As Robinson wrote in 1917:16 The logical application of schemes of partial dissociation simple and conjugated of addition and decomposition by making and breaking of partial valencies and of redistribution of affinity demands the con- sideration of these questions of polarity and leads to a system of mechanism of reactions which appears to be capable of including the representation of chemical changes of the most varied type and the present authors are not acquainted with any examples of reactions the course of which cannot be illustrated in the manner implied.A few examples of the application of these ideas are shown below. What is particularly important about these examples is that they show Robinson's insight concerning conjugation. Conjugation is the transfer of a free partial valency to an adjacent atom or to the end of a chain of atoms -it is the explanation of action at a distance in a molecule." In the case of butadiene (an example involving an even number of atoms) and its reaction with bromine Robinson presented the following rationale 4- For the behaviour of ethyl p-aminocrotonate (a system con- sisting of an odd number of atoms) in its reaction with methyl iodide the following rationale for the formation of the products was offered 0 0 II Me -C =CH -COEt + -Me-C GCH II -COEt II The role of partial valencies was extended by Robinson to molecular rearrangements.A theory of partial valencies obviously offers a scope for the explanation of such changes which it may plausibly be assumed are in all cases due to an initial ring formation by the aid of fractional valencies. Robinson offered a rationale for the Wagner-Meerwein re-arrangement of borneol to camphene and he stated 'that a very large number of molecular changes particularly in the terpene series can be brought under the above generalisation '.I* The heart of Robinson's proposal was the formation of an intermediate of the type shown below for systems ax Y I I,R~ R-C-C I '$ R' -+-'R' For the rearrangement of borneol to camphene we have $H2--! A.J. Birch19 believes that this rationalization in 1920 shows a type of delocalization and is a precursor of the proposal that was made in 1939 by C. L. Wilsonz0 of the non-classical carbo- cation for the rearrangement of camphene hydrochloride to isobornyl chloride. 2 The Development of an Electronic Interpretation of Organic Reactions Robinson’s early work involved a non-electronic approach.As he wrote in 1922:21 Whilst all these theories and their corresponding devices of symbol- isation have proved serviceable as working hypotheses the connecting link in the form of a common physical basis is lacking.. . This of course was the electron and the theory of bonding as presented by G. N. Lewis and Irving Langmuir. Lewis in 1916 had proposed the electron-pair concept of bonding as well as the concept of the ‘group of eight ’ as the driving force for the bonding of the elements of the first two rows of the Periodic Table.22 Lewis’s paper was rather brief and he did not dwell on its applications to organic systems in any detail. Due to Lewis’s involvement in the war effort and his interest in other research areas he did not pursue his original theory further when he returned to civilian life.However Irving Langmuir in a series of twelve papers and an extended series of lecture tours (both at home and abroad) greatly expanded on Lewis’s original ideas and showed their applicability to all elements.23 Langmuir introduced the term ‘octet’ for the ‘group of eight’ of Lewis as well as the terms ‘covalency ’ and ‘electrovalency’. One of Langmuir’s speaking engagements was at the Edin- burgh meeting of the British Association for the Advancement of Science in 1921 which Robinson attended. Robinson im- mediately seized upon the insights that had been offered by Langmuir and was able to convert his previous work involving partial valencies to an electronic basis.With his colleague W. 0.Kermack (of the Royal College of Physicians Edin- burgh) Robinson published in 1922 a landmark paper ‘An Exploration of the Property of Induced Polarity of Atoms and an Interpretation of the Theory of Partial Valencies on an Electronic Baskz4 This was one of the first successful ap- plications of Lewis-Langmuir theory to organic chemistry and in it we see many of the insights that were to become part of Robinson’s general theory of organic reactions. One of Robinson’s major insights was the mobility of octets which could be transmitted through a chain. Experience has shown that the alternating effect is transmitted but feebly by saturated atoms whereas it may be discerned at the end of long chains wholly comprised of unsaturated atoms.This is easy to understand in view of the fact that unsaturated atoms share more electrons in common than saturated atoms. There will be a greater mobility of electrons and the octets when formed will have some units at least which are not subject to restraint a condition which tends to stability.25 Several of the most interesting examples from this paper are presented below. For the reactions of hexatrienes Robinson represents this conjugated system using the now familiar curved arrow to show electron movement and the electromerk effect 3 NATURAL PRODUCT REPORTS 1987 On an electronic basis the reaction of crotonic ester with methyl iodide then becomes H H I I Me-C=C-CO Et Me -C -C -CO Et 1% (rNY CH .___) I1 I +NHz CH 12 1-The mobility of the electron pair on nitrogen in unsaturated systems Robinson realized was the cause of the reduced basicity of aromatic amines as compared to aliphatic amines and also certain nitrogen-containing heterocycles.One of the most significant aspects of the paper in 1922 was the electronic interpretation of aromaticity. Robinson repre- sented the benzene ring as . CH CH CH ... CH. .CH ..CH *. .me in which he assumes that in a conjugated system a stable arrangement is for two atoms to share three electrons. The relation to the Kekule formula is seen to be a remarkably close one and to involve the movement of electrons not from atom to atom but merely to new position in three octets.If therefore the benzene molecule is in fact as many chemists have assumed subject to vibrations and in a dynamic condition a relatively insignificant rearrangement is required in order to pass from one KekulC formula to the other.26 When Robinson tried to use this notation for naphthalene and anthracene he found that :27 ...it is impossible that both the central quaternary atoms in naphthalene or more than two such atoms in anthracene can be surrounded by stable electron systems. Therefore Robinson believed that the a-position in naphthalene and positions 9 and 10 in anthracene were by default intensely positive thus leading to the enhanced reactivity in substitution of these positions.The treatment of pyridine was simply an extension of the explanation for benzene and thus its aromaticity was easily rationalized. The basicity of pyridine as contrasted to pyrrole resulted naturally from the electronic formulae that were assigned to these compounds by Robinson. The feeble basicity of pyrrole was accounted for by the need for the unshared pair of electrons on nitrogen to complete the sextet. In 1925 Robinson introduced the term ‘aromatic sextet’ to denote the six-electron system that explained the unique pro- perties of benzene. To represent this unique unit Robinson introduced the notation of a circle inscribed in the ring The circle in the ring represents the view that six electrons in the benzene molecule produce a stable association which is responsible for the aromatic character of the substance.’’ CH iCH:CH,~CH:CH *d 0’ :CH -In 1932 in a lecture Robinson took note of Huckel’s work in P+ *d the following comment :z9 Recently it has been claimed that the aromatic sextet can be theoretically justified and derived on modem mathematical-physical theories.The C-alkylation of aminocrotonic esters is explained by first showing the general reaction of a conjugated amine with hydrogen chloride Robinson by this time had his own doubts concerning the sextet for in the same lecture he remarked? The ‘aromatic sextet’ is not a vital part of the theory and severe self- r 1’ :CIt R:N::C:C:R3 .. f! ** .. R:N:C::C:R3 ...*R2 .. *.4 HCL criticism might even suggest that it is a phantasy.. .in the meantime the KekulC formula is entirely satisfactory for the illustration of the reactions of benzenoid substances. NATURAL PRODUCT REPORTS 1987-M. D. SALTZMAN Robinson never showed any real interest in quantum chem- istry. This may have been the result of erroneous conclusions that had been reached in the early applications when the calculations produced results that were completely contradicted by the chemical facts. Todd and Cornforth have written:30 Robinson’s estrangement from quantum theory was a very sad thing. There can be no doubt that he could have mastered the relevant parts of it not only without difficulty but also without any real effort had he so wished.Had he done so theoretical organic chemistry would probably have followed a very different course. 3 The Robinson-lngold Controversy Much of Robinson’s theoretical work after 1922 was confined to aromatic chemistry and was the result of an often bitter polemical argument with C. K. Ingold (1893-1970) concerning the mechanism of aromatic substitution. The human dimen- sions of this controversy are the subject of an accompanying paper in this issue by John Shorter. A brief review of its theoretical basis as well as the chemistry that was involved in the controversy follows. In 1925 Ingold began to publish a series of papers entitled ‘The Nature of the Alternating Effect in Carbon Chains’,31 which used as the basis of its discussion the theories of Bernard Flurscheim (1 874-1955).In 1902 Flur~cheim,~~ utilizing Wer- ner’s theories of variable valency in conjunction with Faraday’s conception of tubes of force in space proposed that a sub- stituent on an aromatic ring could by its nature affect differently the various positions in the aromatic ring. This produced what Flurscheim called a redistribution of chemical affinity around the ring thus leading to either ortho-/para- or meta-substitution with respect to the initial substituent Functionalities that produce a strong affinity demand at carbon atom 1 to which they were bonded would leave carbons 2,4 and 6 with much free affinity thus leading to ortho- or para-substitution. A group that had only a weak affinity demand at carbon atom 1 created free affinity at carbons 3 and 5 thus producing meta- substitution.Flurscheim represented the situation in an aro- matic ring by the use of thick lines for large affinity demand and thin lines for small affinity demand and this convention was adopted initially by Ingold. An arrow was used at the atoms where free affinity was available. Two pertinent examples are CH By use of this conception of variable valency Flurscheim in essence proposed a system for propagating electrical effects within a molecule. He was never able to translate these electrical ideas to an electronic basis (as Robinson had already done for his in 1922) and thus his important early insights have never received proper recognition among the majority of chemists.During the period between 1924 and late 1925 Ingold seems not to have reached the level of sophistication in terms of electronic theory that Robinson had. Ingold believed that Robinson was still thinking in terms of the alternate variable valencies of 1920 and not in terms of Lewis-Langmuir theory. Ingold considered that Flurscheim’s ideas were superior to those of Robinson and also of Lapworth and thus issued a challenge:33 Crucial and also simple cases in which the two hypotheses inevitably lead to opposite predictions are not easily devised; but it is only by experiments on cases of this kind that an insight into the nature of the alternating effect can be gained. For his test Ingold picked the chemistry of nitrosobenzene. The nitroso-group as a substituent would according to Flur- scheim’s theory place a small affinity demand at carbons 2,4 and 6 due to a large demand at carbon 1 leading to ortho-/para- substitution.Ingold believing that Robinson’s thinking was dominated by polarity considerations alone with little import- ance being attached to electronic effects in conjugated systems proposed then that meta-substitution would be predicted by Robinson’s theory. The crux of the argument is shown in these diagrams from Ingold’s paper N = key atom free affinity in o-/p-positions =-NO group is o -/p -direct ive +-+ -0’ = key atom -’-m-carbon atoms are negative :.NO group is m-directive Robinson quickly replied to this challenge writing The reactions of nitrosobenzene and its derivatives have recently been much discussed and in this short note it is proposed to consider the manner in which an electronic theory of conjugation can be applied to this remarkable group of substances and with special reference to the association of the nitroso-group with an unsaturated system.Using the basic principle of the conservation of octets Robinson saw that in nitrosobenzene it was the nitrogen atom with its unshared pair of electrons in conjugation with the aromatic ring which was responsible for the orientation in substitution. Robinson classified the type of conjugated system in nitrosobenzene as a ‘crotenoid’ system (later called hetero- enoid) after the chemistry of crotenate esters. The general tendency to acquire a more even distribution of valency operates in the crotenoid types to facilitate polarization according to the annexed scheme [below] in which arrows represent the changes in the valency functions of electrons necessary to preserve the Thus para-substitution will also occur as predicted (and found) by Ingold.The chemistry of ethyl /3-aminocrotonate is another example of a heteroenoid system. Robinson also realized that the weakness of aniline as a base and the enhanced acidity of phenol were the result of these compounds being also hetero- enoid systems In addition to aromatic substitution nitrosobenzene (in the form of its p-diethylamino-derivative)also undergoes a facile reaction with hydroxide ion to produce p-nitrosophenol.This reaction is the result of this compound belonging to a class of conjugated systems that Robinson named katioenoid (originally called crotonoid). In his system electromeric changes could occur in a manner opposite to those in heteroenoid systems. Thus for p(diethy1amino)nitrosobenzene the reaction is repre- sented as Katioenoid systems were also involved in the chemistry of addition to ap-unsaturated carbonyl systems as for example the reaction of ammonia with mesityl oxide Me 0 I II ?. d Me-C-CH2-CMe I NH3 NH2 To pick nitrosobenzene as a test was a fatal mistake for Ingold. The net result is that nitrosobenzene is useless for diagnosis of polarities but can be used to determine the situation of the most reactive centre of a molecule with which it can be brought into combination...It cannot be too strongly emphasised that the application of what are loosely called ‘the polarity theories ’ demands first consideration of the situation of the conjugated systems.. .of three types which may be called butadiene crotenoid and ~rotonoid.~~ Robinson was to categorize six different classes of conjugated system in a subsequent paper appearing in 1926.36 These six categories of systems two of which have just been discussed are shown in Table 2. Table 2 Conjugated systems Name Type Polarization no Pol yenoid c=c-c=c c=c-c=c 1 ‘-3 0 Heteroenoid -0-C =C -0-c=c I I c -0 -c-c=o fs. Katioenoid c=c-c=o I 0-c-0 ‘3 0 Neutralized 0-c=o 0 fs. 0-c-c=o o=c-c=o Quinonoid 0 0-c-0-c-0 c-c-0-o=c-c=c-c =o I H-O-C=O R A Dissociating I HrC-CC=O(3.systems H-C-C=O -\ I I H-C-C=C NATURAL PRODUCT REPORTS 1987 An interesting example of a neutralized system is shown in the chemistry of 4-bromo-5-nitroveratrole. In the nitration of 4-bromo-5-nitroveratrole,the nitro-group diminishes the directive power of the methoxyl (b) in the p-position to a greater extent than that of a (a) in the rn-position and therefore the latter induces substitution apparently abnormally ortho to nitro~yl.~’ The basis of Robinson’s analysis was that in certain systems heteroatoms that donate their free electron can have that effect neutralized. Thus for example in the case of amides the free electron pair from nitrogen is taken by the carbonyl oxygen and this is the reason for the failure of the amide group to function as a strong base.In the case of 4-bromo-5-nitro-veratrole the interposition of an even number of unsaturated carbon atoms can produce the conditions for a neutralized system for methoxyl (b) and nitration occurs ortho to methoxyl (4 0 The reduced acidity of anisic acid is easily explained once one realizes that this molecule contains a neutralized conjugated system In the comparison of the reactivity of benzil and p,p- diethoxybenzil we see effects of a quinonoid compared to a neutralized system. In benzil the quinonoid system leads to high reactivity whereas in the diethoxy-derivative incorpora- tion of the ethoxy-group produces a neutralized system which diminishes the reactivity of the carbonyl group These represent only several examples of the many diverse organic reactions that Robinson was able to explain by his classification of conjugated systems in which electromeric ._ change can occur.38 4 The General Polar Effect One of Robinson’s other most important contributions was his studies of the general polar effect and its application to conjugated systems.This line of research was stimulated by the discussion in 1925 between Ingold and Robinson concerning the correct mechanistic interpretation of aromatic substitution involving ’onium- type compounds. Robinson reported in 192639 how the mobility of octets in conjugated systems could be influenced by polar effects.In a series of papers dealing with the nitration of catechol ethers and quinol ethers Robinson was able to assess these effects. The experiments involving the catechol ethers are particularly interesting because they show the ability of Robinson to design a very simple experiment that would yield the maximum of information. These ethers which can be classified as heteroenoid systems upon nitration could yield a mixture of isomers; the extent to which one isomer dominated would give a clue as to the effect of R versus methyl in terms of electron movement HNO RO RO NATURAL PRODUCT REPORTS 1987-M. D. SALTZMAN Table 3 Relative directive powers of alkoxyl groups OR R Relative directive power 100 135 128 150 123 The oxygen by means of its free electrons increases its covalency with the ring C (process a).C recovers its normal covalency by giving up correspondingly electrons to C (process b) (ortho substitution) or by relinquishing C,C co-valency electrons to C,Cy (process c). C must then relinquish C,C covalency electrons *to the sole use of C (process d) (para substitutlon). In the activated form the oxygen is positively charged and is exhibiting oxonium ~haracter.~' R-The results that Robinson obtained for what he called 'directive power' were as shown in Table 3. In the quinol ethers where methoxyl helps the substituent OR to place the nitro-group ortho to it the results were OC,H (164); OC,H (180); OC,H (186). It was recognized that if oxygen acquired a negative or positive charge the activation of the aromatic ring would be greatly affected.Thus the reactivity of a series of oxygen functionalities follows in the order 0 due to the decreasing availability of the electron pair on oxygen. In nitrogen functionalities the order would be OH Me2.+ > Me-C-N Me3i< '4 > Conjugation occurs by virtue of electron displacements which produce an alternating polar effect as an inevitable consequence of the laws of valency operating in relation to changes in co-valency. Electronic displacements which do not involve co-valency changes require no alternation and may be continuous but diminishing in degree along a chain.. .Such displacements should occur in almost all types of mole- cules and will be propagated by electrostatic ind~ction.~~ The inductive effect a name coined by Ingold in 1926 had previously been described by G.N. Lewis in 1916 and its effect was dramatically demonstrated in the addition reactions of alkenes by Howard Lucas in a series of papers appearing in 1924 and 1925.42 Lucas had shown that in ally1 chloride the addition of HBr produces 1-bromo-3-chloropropane as the only product Robinson proposed that the inductive effect in combination with conjugation was the reason for the variation in strengths of carboxylic acids. Since a carboxyl group was a member of the class of dissociative conjugated systems the effect of R as electron-donating or -withdrawing would therefore affect the degree of dissociation of the oxygen-hydrogen bond.Robinson then turned his attention to the inductive effect in aromatic systems in which conjugation of the group was not possible. Three cases were distinguished and the effects of the appropriate substituents were discussed. B C Case A Case B Case C In Case A the substituent being electron-donating the flow of electrons favours ortho-/para-substitution. An alternative statement is that the ring carbon atom around which the density of electrons is greatest most easily becomes the positive end of a conjugated polarised complex. The applications will be obvious -toluene and tert-butylbenzene are in the same In the case of group B which has a strong attraction for electrons it is easy to see in a general way that the circumstances are reversed but in order to make the argument clear we take an extreme instance such that B has a definite positive charge.The electrical field emanating from B then produces positive electrification in diminishing degree over the portion of the molecule represented. One consequence is that all displacements of electrons in activation will tend to be towards B and this inhibits para sub~titution.~~ The action of a positive pole thus favours meta-substitution as would therefore any electron-withdrawing group. In the case of such groups as carboxy carbonyl and trichloromethyl in which it had been shown that carbon has positive character these would also be meta-directing. This theory seems to harmonise better than any other which has been advanced with the facts of substitution in polycyclic aromatic groups....44 Case C represented a situation in which the group could at times be electron-donating or -withdrawing. Robinson felt that the donating aspect would be dominant because this provided a favourable opportunity for activation ;the electron- withdrawing aspect of the group would inhibit substitution in any case. The halogens represent a good example of substituent groups of Class C. Case B provided the most interesting examples since it was at the centre of the bitter polemic between Robinson and Ingold in 1925. Ingold had reported that dibenzylmethylamine upon nitration in 95% nitric acid produces as the major products the ortho- and para-isomer~.~~ N,N-Diacetylbenzyl-amine was reported to produce the meta-isomer.These results were in line with Ingold's continued use of the alternating affinity. Robinson realized that under the reaction conditions that had been used the tertiary amine must be in the form of its 'onium salt. The amide being much less basic would still be found to a great degree as the free compound. Thus the former should fit a type of system of Class B and the latter a system of Class A. Robinson performed the appropriate experiments and found indeed that Ingold had obtained the wrong results.46 Nitration of benzyltrimethylammonium nitrate produced nearly 90 YO of the meta-isomer ; N,N,N-trimethylanilinium nitrate had been previously shown to give 100% of the meta-isomer.Robinson predicted that P-phenylethyltrimethyl- ammonium and y-phenylpropyltrimethylammonium would give lesser amounts of the meta-isomer as the effect of the positive pole would fall off very rapidly with distance. Ingold did the appropriate experiments and found the percentages to be 19 and 5 respectively.*' In further experiments involving phosphorus antimony and arsenic salts that were bound directly to the aromatic ring or as benzyl compounds similar 60 results were obtained as Robinson had predicted and an example is NMe3NO CH,N Me N0 CH CH NMe3N03 I I IZ PMe X C H2P Me3X I I The work with benzylamine convinced Ingold that the use of alternating affinities was not sufficient to explain all aspects of aromatic substitution.Thus in Part V48of his series on ‘The Nature of the Alternating Effect in Carbon Chains’ appearing in mid-1926 Ingold discussed his results in terms of electronic displacements in conjugated systems. In this paper Ingold introduced the idea of the permanence of polarization in a molecule due to the electromeric effect of Robinson. In the carboxylamide group the nitrogen atom will necessarily con- stitute the positive end of the betaine linking and thus forms arise which.. .would be expected to diminish the tendency towards op-sub~titution.~~ This was the forerunner of Ingold’s proposal of mesomerism which was made in 1934.50 Robinson was able to solve the anomaly of the rneta-directive ability of the sulphonic acid group by the insight that the sulphur atom has a high electron affinity thus making it electropositive.The sulphonic acid functionality falls into a type of system of Class B. The possibility that the sulphonic acid group is meta-directive for the same reason that the ammonium-salt group is meta-directive would become a probability if it could be shown that the effect is produced when a saturated carbon atom separates the sulphur atom from the benzene nucleus.. . .51 The nitration of benzylsulphonic acid produced approximately 10% of the rneta-isomer as was predicted theoretically. Further proof was the nitration of benzylsulphonyl chloride where the sulphur atom is now much more electropositive (due to the presence of the chlorine). In this experiment the rneta-isomer constitutes at least 40% of the product mixture.A series of nitration experiments involving aromatic sul- phones which was reported by Twist and Smiles52 in 1925 provides an example of Class B and Class A effects operating in a single molecule i( CH3 CH,+CH S0,CH The incorporation of methyl groups reduces the electropositive nature of sulphur resulting in somewhat less rneta-product. 5 Conclusion By 1927 Robinson’s interest in theoretical matters seems to have waned. A. J. Birch has offered perhaps the best explana- tion for this :19 He liked the broad imaginative sweep of ideas and having made a general point to his satisfaction would depart to new creative areas. He felt that he had solved a problem in principle with a general suggestion and was impatient of the exacting and often boring experimental work then required to develop it quantitatively.This he left to others notably Ingold. NATURAL PRODUCT REPORTS 1987 In the brief period of less than fifteen years Robinson had almost single-handedly revolutionized organic chemistry and moved it away from being an art in the direction of an exact science. 6 References 1 L. P. Hammett J.Chem. Educ. 1966 43 464. 2 R. Robinson ‘Memoirs of a Minor Prophet’ Elsevier Amster- dam 1976 Vol. 1 p. 184. 3 Ref. 2 p. 17. 4 Ref. 2 p. 25. 5 Ref. 2 p. 71. 6 A. Lapworth J. Chem. SOC.,1901 79 1265. 7 R. Robinson in ‘British Chemists’ ed. A. Findlay and W. H. Mills The Chemical Society London 1947 p. 360. 8 R. Robinson Mem.Proc. Manchester Lit. Philos. SOC.,1920,64 No. 4 p. 1. 9 A. Lapworth Mem. Proc. Manchester Lit. Philos. SOC.,1920 64 No. 3 p. 1. 10 A. Lapworth and J. B. Shoesmith J. Chem. Soc. 1922 121 1391. 11 Ref. 7 p. 363. 12 R. Robinson ‘Outline of an Electrochemical (Electronic) Theory of the Course of Organic Reactions’ Institute of Chemistry London 1932 p. 13. 13 G. N. Burkhardt ‘Structure Properties and Mechanisms of Carbon Compounds some developments 1898-1939’ unpub- lished manuscript. 14 J. Thiele Ann. Chem. Justus Liebig 1899 306 87 125. 15 C. A. Russell ‘The History of Valency’ Leicester University Press Leicester 1971 p. 241. 16 G. M. Robinson and R. Robinson J. Chem. SOC.,1917 111 962. 17 Ref. 8 pp. 34. 18 Ref.8 pp. 6-1 1. 19 A. J. Birch J. Proc. R. SOC.N.S. W. 1976 109 152. 20 T. P. Nevell E. DeSalas and C. L. Wilson J. Chem. SOC.,1939 1188. 21 W. 0.Kermack and R. Robinson J. Chem. Soc. 1922 121 428. 22 R. E. Kohler Hist. Stud. Phys. Sci.,1971 3 343. 23 R. E. Kohler HistStud. Phys. Sci. 1974 4 39. 24 W.O. Kermack and R. Robinson J. Chem. SOC. 1922 121 427. 25 Ref. 24 p. 432. 26 Ref. 24 p. 437. 27 Ref. 24 p. 438. 28 J. W. Armit and R. Robinson J. Chem. SOC.,1925 127 1604. 29 Ref. 12 p. 10. 30 Lord Todd and J. W. Cornforth Biogr. Mem. Fellows R. SOC. 1976 22 467. 31 C. K. Ingold J. Chem. SOC.,1925 127 513. 32 For details of Flurscheim’s life and work see C. K. Ingold J. Chem. SOC.,1956 1087. 33 Ref. 31 p. 514. 34 R.Robinson Chem. Ind. Rev. 1925 3 456. 35 Ref. 34 p. 457. 36 J. Allan A. E. Oxford R. Robinson and J. C. Smith J. Chem. SOC.,1926 401. 37 J. N. R5y and R. Robinson J. Chem. SOC.,1925 127 1618. 38 See Ref. 12 for an extensive discussion of the classes of conjugated systems and the chemistry associated with them. 39 J. Allan A. E. Oxford R. Robinson and J. C. Smith J. Chem. Soc. 1926 376 383 392 401. 40 Ref. 36 p. 402. 41 Ref. 36 p. 404. 42 H. J. Lucas and A. Y. Jameson J. Am. Chem. SOC.,1924 46 2475; H. J. Lucas and H. W. Moyse ibid. 1925 47 1459. 43 Ref. 36 p. 409. 44 Ref. 36 p. 410. 45 E. L. Holmes and C. K. Ingold J. Chem. SOC.,1925 127 1800. 46 H. R. Ing and R. Robinson J. Chem. Soc. 1926 1655. 47 F. R. Goss W. Hanart and C. K. Ingold J. Chem. SOC.,1927 250; C. K. Ingold and I. S. Wilson ibid. p. 810. 48 C. K. Ingold and E. H. Ingold J. Chem. Soc. 1926 1310. 49 Ref. 48 p-1311. 50 C. K. Ingold Chem. Rev. 1934 15 250. 51 A. C. Bottomley and R. Robinson J. Chem. SOC.,1927 2785. 52 R. F. Twist and S. Smiles J. Chem. Soc. 1925 127 1248.

ISSN:0265-0568    

DOI:10.1039/NP9870400053

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Electronic Theories of Organic Chemistry Robinson and Ingold J. Shorter Department of Chemistry The University Hull HU6 7RX May I say at the outset that in preparing this paper I have been greatly indebted to the article on this topic which Dr Martin Saltzman wrote for the Journal of Chemical Education in 1980; also to the memoirs of Dr G. N. Burkhardt retired Senior Lecturer of the University of Manchester;2 and finally to the section on theoretical chemistry in the Biographical Memoir of Sir Robert Robinson written by Lord Todd and Sir John Cornforth. Why is it necessary to include a paper on ‘Electronic Theories of Organic Chemistry Robinson and Ingold’ in our Centenary Tribute? There are two principal reasons. In the first place we cannot ignore the fact that when the basic electronic theory of organic chemistry is presented today the general approach and the terminology that is employed are derived from Sir Chris- topher Ingold rather than Sir Robert Robinson.I will give some obvious examples. Nowadays we do not classify reagents as anionoid or cationoid as Robinson did following Lapworth ; we use rather the corresponding terms that were introduced by Ingold nucleophiles and electrophiles.Thus if you give a lecture in a Perkin Division symposium and in it you refer to the ‘anionoid reactivity’ of benzene you will certainly be met by blank stares whereas everyone will know what you mean if you speak of ‘electrophilic aromatic substitution ’. Similarly it would be unwise to use most of the terms in Robinson’s classification of conjugated systems all those words ending in enoid.You might get away with polyenoid but few people would immediately realize what you meant by heteroenoid or katio-enoid. These terms did not last largely because Ingold did not find them useful. Thus we cannot pretend that the form of electronic theory that was pioneered by Robinson is still in use today but the theory that was developed by Ingold at around the same time has endured. We ought to appreciate what brought about this state of affairs. To find the second reason why we need the present paper we should turn to Robinson’s autobiography ‘Memoirs of a Minor Prophet ’ particularly Volume 1 Chapter XI ‘Develop-ment of an Electronic Theory’.4 This opens with a sentence which has surprised many readers ‘The development of these ideas constituted in the writer’s opinion his most important contribution to knowledge.’ However we shall be more con- cerned now with the later part of this chapter where Robinson devotes several pages to his relations with Ingold particularly in the mid-1920s. I will quote two passages which reveal Robinson’s feelings fifty years later towards the end of his life. After describing some quite amicable correspondence with Ingold he writes When the promised paper by Ingold and Ingold [ref. 444 appeared there was nothing in it which could justify a claim to novelty of outlook. The monograph which Ingold eventually wrote [ref. 51 was based essentially on the theories which I had advanced a short time earlier and which had been contested in the controversy which took place largely in the correspondence columns of Chemistry and Industry.I regret very much the necessity to point out that every device was used to give the readers of this book [i.e. ref. 51 the impression that the electronic theories advocated were original and had relatively small beginnings in the earlier work of Lapworth and myself. ’ A few lines further on Robinson continues I am touching this question of acknowledgment as he was apt to include a necessary reference to Lapworth or myself in a large number of references so that any idea that our contributions were original or specially applicable to the matter in hand was well and truly buried.That these and other devices were successful has been proved to me on numerous occasions for example when I have lectured in the United States and had (sic.) been told that the idea I mentioned in the course of my talk had already been advanced in the monograph of Ingold. Robinson obviously felt very deeply about all this and in presenting our Centenary Tribute to him we can hardly ignore the situation which involves the fate of what he regarded as ‘his most important contribution to knowledge’. The origins of the Robinson-Ingold troubles are clearly visible in the controversy in Chemistry and Industry [Review] which is referred to by Robinson in one of the passages I quoted above. We will spend some time taking a look at the salient features of this controversy.Early in 1923 Chemistry and Industry Review‘ became a vehicle for the discussion of the new electronic theory of valency and of the theoretical aspects of organic chemistry. These topics featured frequently at the monthly meetings of The Chemical Society at Burlington House. Summaries of the papers that were read and of the ensuing discussion were reported in Chemistry and Industry Review the following week. These reports stimulated letters to the Editor and occasionally there appeared a longer article from one of the main par- ticipants. It was a very involved and controversial discussion. It seems to have started with a meeting of The Chemical Society on 15 March 1923 when Professor T. M. Lowry read a paper on ‘The Polarity of Double Bonds’; this was duly reported in the issue of Chemistry and Industry Review for 23 March along with additional matter that had been provided by Lowry in reply to points that had been raised at the meeting.’ The discussion continued on a small scale during the rest of 1923 with pertinent items appearing in about six issues.These included a report on the conference of The Faraday Society at Cambridge in mid-July on the ‘Electronic Theory of Val- ency’.8v9 The discussion gathered momentum through 1924 with about eighteen issues containing relevant items. It reached its peak in 1925 when about thirty issues of Chemistry and Industry Review were involved but in the issue of 15 January 1926 the correspondence was closed by editorial fiat in the following words :lo Discussion of alternate polarities and kindred topics is of great importance and we hope the letters we have published in these columns have cleared away a considerable mass of misapprehensions.We are however obliged to wait for a period before dealing with the subject again; a proportion of our readers fails to understand the whole of the arguments without a mental effort which is made unwillingly. Letters were banned but reports of meetings of The Chemical Society continued so that a few more issues in 1926 relate to the discussion. There was a small overspill into 1927 but by that time the fires of controversy had really gone out as we shall see. Many chemists made some contribution to the discussion but there were five major participants whose contributions largely generated the controversy.Let me give a short profile of each of these in order of decreasing age. First there was Arthur Lapworth,” the senior Professor of Chemistry at Manchester (Faculty of Science) who in 1923 was 51 years of age. He had been a pupil of H. E. Armstrong and was distin- guished for his researches in camphor chemistry and his pioneer- ing studies of the kinetics and mechanism of organic reactions in solution. Secondly we have T. Martin Lowry,12 Professor of NPR 4 NATURAL PRODUCT REPORTS 1987 From left to right [above] Dr Arthur Lapworth ca. 1913 (Courtesy of Dr G. N. Burkhardt); Professor T. Martin Lowry in the early 1920s (Courtesy of the Department of Physical Chemistry Cambridge University); Dr Bernard Flurscheim aged 57 (Courtesy of Dr C.H. Flurscheim) ; [below] Professor Robert Robinson ca. 1922; Dr C. K. Ingold ca. 1921 (Courtesy of the Department of Chemistry University College London) Physical Chemistry at Cambridge 49 in 1923. He had much in common with Lapworth having also been a pupil of Armstrong and-having worked on camphor; this work had led him to make important studies of optical activity and mutarotation. Next we have Bernard Fliirscheim,13 also 49 in 1923; he was not as is sometimes supposed of some central European nationality but was English. He had however studied on the Continent with Werner and with Thiele. He was of independent means and rarely if ever did a paid job but worked in a private laboratory at his home in Hampshire.By 1923 he was well known for contributions to theoretical organic chemistry stretching back over 20 years. Fourthly we come to Robert Robinson who had moved in 1922 from St Andrews to Manchester to join Lapworth as the more junior Professor; in 1923 he was 37 years old. Robinson had been a student at Manchester with W. H. Perkin and had got to know Lapworth in 1909 when the latter had come to Manchester as a Senior Lecturer. By 1923 Robinson already had a great reputation as a synthetic and natural product organic chemist with about one hundred publications to his name. Finally we have Christopher K. Ingold,14 by far the youngest of the five being 30 years of age in 1923. He was then a lecturer at Imperial College under Professor Jocelyn Thorpe with whom he had served a long apprenticeship over about a decade.He was already fairly distinguished in 1924 he joined Lapworth Lowry and Robinson as a Fellow of The Royal Society and succeeded Julius B. Cohen in the Chair of Organic Chemistry at Leeds. His chemical interests were largely derived from Thorpe and were in the synthesis and structure of organic compounds and especially in tautomerism. By 1923 he had over 30 papers to his credit and was starting to publish at a great rate. I have already described the discussion of theoretical organic chemistry in Chemistry and Industry Review as ‘involved ’. This was partly because a variety of different topics got introduced. The principal topic was the directive effects of substituents on aromatic substitution but other aspects of the influence of structure upon reactivity appeared from time to time; for example tautomerism.l5 Occasionally there were also periph- eral discussions which tended to raise the temperature of the NATURAL PRODUCT REPORTS 1987-J. SHORTER controversy. Thus in 1923-4 there was a vigorous disputation between Lowry and Ingold (who was backed up by Thorpe) as to the exact role of water molecules in the mutarotation of glucose.16 In 1924 there was also a brief excursion into the theory of structural effects on optical activity which at that time was a very obscure subject.” Professor David Boyd from Southampton who had taught Ingold as an undergraduate was prominent in this and also played a minor role in the main event.However the main reason why the discussion got very involved and controversial was that each of the five principal participants was advocating his own peculiar theoretical ap- proach. Lowry was very much supporting the attempt to understand organic chemistry through the new electronic theory of valency; it was he who had organized the meeting of The Faraday Society at Cambridge in 1923.’ Lapworth had long since devised a pre-electronic but electrochemical theory of organic chemistry which he had applied with some success. It is usually referred to as the theory of alternating polarities.18 By 1923 he had made little progress in translating it into terms involving electron-pair bonds probably because he was worried by the lack of a model that would be acceptable to physicists.Robinson on the other hand was enthusiastically engaged in translating into electronic termslg his earlier theories involving partial valencies and conjugation. 2o The professors at Man- Chester however found that their theoretical approaches had much common ground; while they did not agree in every detail they avoided public discussion of such differences and thus always appeared to be batting on the same side. Flurscheim’s views had developed on rather different lines.21 There was an electrical aspect to his theoretical approach but his theory had had its origins early in the century and he refused to accept that bonding in organic molecules had anything to do with electrons.His approach is usually described as the theory of alternating afinities. In postulating an alternation Flurscheim’s and Lapworth’s theories appeared to have some- thing in common but disagreements arose in practice because the two theories sometimes led to diametrically opposite conclusions. What were Ingold’s views on theories of organic chemistry? It is probably fair to say that in 1923 he was not greatly interested in theoretical organic chemistry. He is not reported as having spoken at the meeting of The Faraday Society at Cambridge and possibly was not even present.’ J. F. Thorpe his chief was certainly there and expressed great scepticism about what was going on; according to him there had been no great advance in theoretical organic chemistry since van’t H~ff.~~ This view was of course hotly contested by Robinson and others However later in the year Thorpe took the same line in a review2‘ of the fourth edition of J.B. Cohen’s ‘Organic Chemistry for Advanced Students’ and early in 1924 the Editor of Chemistry and Industry Review commented on the printed proceedings of the Faraday Society meeting as follows :25 The impression left on our minds -probably an inaccurate one -is that Thorpe and Ingold believe that in organic chemistry we do not know much more of the fundamentals than that the carbon atom is tetrahedral in its grasp and that it is no good talking gaily about the different kinds of valency and pretending we do. There is thus some evidence that in 1923-24 Ingold shared Thorpe’s scepticism.Certainly during 1924-25 when the con- troversy was well under way and Ingold was participating vigorously he sometimes tried to give the impression that he held no particular brief for any of the contending theories.26 More often however during most of the controversy he appeared to be a strong supporter of Flurscheims’s theory of alternating affinities and was often strongly critical of Lap- worth’s theory of alternating polarities and the electronic theories of Lowry and of Robinson. As we shall see it was only early in 1926 that Ingold embraced electronic theories of organic chemistry. 63 It would be quite impossible in this paper to follow all of the intricacies of the controversy in Chemistry and Industry Review.I shall try to convey briefly some idea of the tone of the discussion and then to indicate several matters which caused particular problems as between Lapworth and/or Robinson on the one hand and Ingold on the other. The discussion was often very heated and there were many occasions on which a participant complained that his views were being misunderstood or misrepresented by another partici- pant. Some things were said or written which were probably very difficult for the victim to forgive or forget when the controversy was long over. For instance Lapworth was nor- mally the most urbane of men but he seems on occasion to have become exasperated with Ingold and to have treated him as a rather stupid and ignorant boy.Thus he began a criticism of one‘ piece of Ingold’s work with the words ‘It is almost incredible that the authors have not yet realised.. .’27 Indeed Ingold may well have felt that Lapworth and Robinson were ganging up against him. During the period of the controversy Ingold presented some fourteen pertinent papers at meetings of The Chemical Society more than from all of the other four main participants put together. On these occasions both Lap- worth and Robinson were often in the audience poised to enter the fray. If they could not attend a particular meeting they submitted their views in writing on the basis of the summary that had been circulated and their statements were read out by the Secretary at the start of the discussion.And of course there was often a follow-up in the correspondence columns of Chemistry and Industry Review. An allegation that was sometimes made was that one of the participants was ‘shifting his ground ’; this was naturally always vigorously denied by the participant in question. It is difficult now to tell how much ground-shifting really went on. Certainly it sometimes seemed to fairly innocent bystanders that some of this was occurring. Thus at the meeting of The Chemical Society on 19 June 1924 Professor G. T. Morgan complained that it was difficult to get at close quarters with a theory the exponents of which continually shifted their ground.28 In so far as Lapworth and Flurscheim were severally defending moribund theories it seems probable that they were shifting ground from time to time.It was also quite natural that as the electronic theory developed some changes of view or emphasis would occur. What is quite clear is that by late 1925 many British chemists were tired of the controversy; the foreclosure by the Editor of Chemistry and Industry Review in January 1926 was no doubt welcomed by many.l0 Just before this occurred Professor H. E. Armstrong tabled a motion at a meeting of the Council of The Chemical Society which read :29 That henceforth the absurd game of chemical noughts and crosses be tabu within the Society’s precincts and that following the practice of the Press in ending a correspondence it be an instruction to the Officers to give notice ‘That no further contributions to the mystics of Polarity will be received considered or printed by the Society ’.The motion found no seconder but had no doubt expressed what many people were feeling ! I want now to highlight a few matters which caused particular trouble as between Ingold on the one hand and Lapworth and/or Robinson on the other. In 1924 Ingold initiated work on systems that he considered would provide critical tests as between Flurscheim’s theory and the theories of Lapworth and Robinson. Ingold submitted this work to The Chemical Society in a series of papers under the general title ‘The Nature of the Alternating Effect in Carbon Chains’. Part I of the series concerned the directing influence of the nitroso-group in aromatic substit~tion.~~ This was read at a meeting on 18 December 1924.31 Ingold had predicted from Flurscheim’s theory that the nitroso-group would be ortho-/ para-directing and from either Lapworth’s or Robinson’s theory it would be meta-directing like the nitro-group.By experiment it was found to be ortho-/para-directing thus 5-2 apparently confirming Flurscheim’s theory and disproving the others. Lapworth and Robinson however had no difficulty in showing that their theories also were able to explain this result but the argument dragged on for months.32 Ingold also got into difficulties over other work which he did with nitrosobenzene. During 1922 and 1923 with various co- workers Ingold had studied the addition reactions of nitroso- benzene with various unsaturated compounds and had claimed that the products contained four-membered rings.Early in 1924 he asserted that the nature of the products indicated a reaction mechanism that was contrary to what would have been predicted by applying Lapworth’s theory of alternating p~larities.~~ Lapworth in association with G. N. Burkhardt and other co-workers repeated these experiments and found that Ingold and his colleagues had misidentified the products which did not contain four-membered rings at‘ all. The reactions when properly formulated were entirely in accord with Lapworth’s theory. The results were outlined in Chemistry and Industry Review for 27 March 1925,34 and were subsequently published35 in the Journal of the Chemical Society but they played no further part in the controversy for Ingold refrained from public comment.Part 11 of Ingold’s series on alternating effects dealt with the directing influence of the a-methoxyvinyl group -C(0Me)= CH2.36 As with the nitroso-group this was supposed to be a test case and the outcome was similar. When the paper was read to a meeting of The Chemical Society on 19 February 1925 Robinson and Lapworth sent statements to show how they would deal with Ingold’s results.37 We come now to a rather complicated and important part of the story involving the mononitration of tertiary benzylamines and their salts. I have space to give only a very oversimplified account of what happened to another of Ingoid’s critical tests. Ingold predicted that the free amine would be nitrated in the meta-position and the salt in the ortho- and/or para-position.Part 111 of the series on alternating effects,3s which was read to a meeting of The Chemical Society on 21 May 1925,39 contained results that appeared to confirm the prediction. Robinson ad- NATURAL PRODUCT REPORTS 1987 Ingold did not see the change in quite that way and in reply he indicated that ‘in the formulation of their own view much benefit had been derived from the consideration both of Flurscheim’s theory and Robinson’s. Since many important principles of Flurscheim’s theory had now been reproduced in electronic language it could not be sweepingly described as having been abandoned. ’One imagines that this was interpreted by the audience as a courteous gesture to Flurscheim whom he appeared to be deserting.It must have seemed to those present that the long controversy was over. In fact a much larger problem as between Robinson and Ingold was only just beginning. With Ingold it turned out to be not so much a case of ‘If you can’t beat them join them’ but ‘If you can’t beat them take them over ’. To appreciate what happened we must first return to the earlier part of 1925 when Robinson was preparing for publication a series of studies on the relative directing powers of certain groups in aromatic substitution. In connection with this he thought it useful to present a coherent account of the basic ideas of his electronic theory which were scattered in bits and pieces in various publications or not published at all.This was designed as Part IV of the series in the names of Allan Oxford Robinson and Smith,46 and it was read to a meeting of The Chemical Society on 18 June 1925.47 Ingold was present and made some complimentary remarks in the discussion. Maybe this was the beginning of his conversion! Later in the year Robinson sent Ingold a copy of the finalized manuscript which was ultimately published along with other Parts early in 1926.46 In mid-February 1926 Ingold returned the manuscript to Robinson with an appreciative covering letter which is quoted in Robinson’s autobi~graphy.~~ Shortly before return- ing the manuscript to Robinson Ingold had sent off to The Chemical Society the group of papers44 which he presented at the meeting on 6 May 1926,49 and to which I have already referred.Robinson always believed that the paper by Allan Oxford Robinson and Smith46 was of great influence on Ingold although Ingold never clearly acknowledged this. Indeed he tended to give the impression that the ideas and mitted that he would have predicted the opposite ~rientation.~~ views in Parts IV to VII of ‘The Nature of Alternating Effect in In the following months he and Dr H. R. Ing re-examined the systems that were involved in Part 111 of Ingold’s series. In Chemistry and Industry Review for 1 January 1926 they were able to announce that Ingold had got it the wrong way round:41 the free amines were nitrated at ortho- and para- positions and their salts at a meta-p~sition.~~ The issue of 15 January 192643 contained the expected letters in reply from Ingold and from Flurscheim naturally conceding as little ground as possible but in that very issue the Editor closed down the correspondence.1° Thereafter we can only trace what happened through the reports of meetings of The Chemical Society and the final versions of the papers in the Journal of the Chemical Society.However probably unbeknown to the Editor of Chemistry and Industry Review the fires of the controversy were dying down. It seems probable that Ingold’s experience of having several times been shown to be wrong in one way or another had at last begun to have an effect on him. Whatever the exact reason his views of theories of organic chemistry underwent a remarkable change during the first few months of 1926.On 6 May 1926 (actually in the middle of the General Strike) he presented parts IV to VII~~ of ‘The Nature of the Alternating Effect in Carbon Chains’ at a meeting of The Chemical and talked quite happily about the shifts of electrons that were caused by substituents the tendency of atoms to achieve octets of electrons and so on and he drew molecular pictures involving curly arrows. In a communication to the meeting,45 Robinson had stated that ‘the views now adopted by Ingold and his collaborators differed in no fundamental respects from those already advanced at various times by Lapworth and by himself. The advocacy of non-polar theories of alternation so characteristic a feature of the Parts I 11 and 111 of this series had now been abandoned and this development was welcomed.’ Carbon Chains’ had largely been arrived at independently of Robinson. Since 1924 Ingold had contributed the carbocyclic section to Annual Reports on the Progress of Chemistry. Ingold’s Report for 192650 differs markedly in general style and content from the Reports for 1924 and 1925. It contains about 20 pages on Orienting Effects in Benzene Substitutions and on certain related matters. This would have been written early in 1927. It is a fairly comprehensive survey referring to many papers that had been published before 1926 with a good deal on his own work and some account of Robinson’s. We cannot doubt that to Robinson and Lapworth it seemed that he had got the balance wrong.Very significantly too he took the opportunity to begin tidying up and changing the terminology of electronic theory. Thus he introduced the term ‘tautomeric effect’ to describe conjugative shifts of electrons and the term ‘inductive effect ’ to describe the propagation of the non-conjugative movement of electrons. These he represented by the symbols T and I respectively to which were attached ‘plus’ or ‘minus’ signs to indicate whether the influence of a given group had a promoting or an impeding effect on aromatic substitution reactions such as nitration. This was a foretaste of what was to come in the next few years. In his contributions to the Annual Reports for 19275’ and 192852 Ingold also devoted much space to various aspects of electronic theory.However the most important development of this time was Ingold’s initiation of a large research pro- gramme devoted to the study of systems that were ripe for the application of electronic theory which was done more and more in his own way. Between 1927 and 1931 Ingold published 63 papers.14 Almost all of them were physical organic in character with much application of electronic theory. During the same years Robinson published 83 papers3 Almost all of NATURAL PRODUCT REPORTS 1987-5. SHORTER them were concerned with natural products or classical synthetic organic chemistry; not more than about ten of them dealt with electronic theory to any considerable extent. In about 1931 Robinson seems to have realized that the electronic theory was slipping away from him and he tried to make his contribution more widely known but unfortunately rather special and limited publications were involved.Thus in 1932 he gave two lectures to the Institute of Chemistry on an ‘Outline of an Electrochemical (Electronic) Theory of the Course of Organic Reactions’. The printed version of these lectures contained one reference to Ingold among its 68 citations.53 It was distributed to several thousand members of the Institute but most of these lived in Britain. Few copies would have reached the USA or Continental Europe. He tried to deal with the latter through French and German versions which were produced for the 4th Solvay Conference54 and Ahrens S~mrnlung,~~ respectively.In 1934 he again wrote a fairly general account this time for the Jubilee Volume of the Journal of the Society of Dyers and Colo~rists,~~ which was a very obscure publication for the chemical world in general. By coincidence there also appeared in 1934 Ingold’s very substan- tial article in Chemical Reviews on ‘Principles of an Electronic Theory of Organic Reactions’.57 This was widely read through- out the world particularly of course in the United States of America. Of its 44 citations just one was to ‘Robinson et al. ’ (meaning Allan Oxford Robinson and Smith)46 although there were several to Lapworth and to Flurscheim. Of course by 1934 there had been considerable real progress since 1926 not merely changes in terminology and Robinson had not participated in this to any great extent.For instance the concept of ‘mesomerism ’ or ‘resonance ’ had become very important and while Robinson had had a glimmering of the idea back in 1925 its full development had only come with the application of wave mechanics. In the period from the mid- 1930s to the mid-l940s progress in electronic theories was somewhat held up by World War 11. Even so by the time Robinson made one more effort to set the record straight in his Faraday Lecture of 1947 his presentation appeared antique and the purpose of his lecture was probably not understood by most of his audience. The printed version in the Journal of the Chemical Society5s is in fact an excellent summary of the development of electronic theory of organic chemistry as it seemed to him.In the 1930s and 1940s many authors of papers or books who wished to expound or apply electronic theory faced a dilemma. They were aware that Robinson had developed an electronic theory before Ingold but the trouble was that this was not the form of electronic theory that they wished to use. What many of them did was to make passing reference to Robinson by citing the lectures to the Institute of Chemistry53 or perhaps the paper by Allan Oxford Robinson and Smith,46 and then to refer to (and use) Ingold’s publications particularly his article in Chemical review^.^' H. B. Watson’s book ‘Modern Theories of Organic Chemistry’ which was first published in 1937 is a good example of this It is of interest that W.A. Waters’ ‘Physical Aspects of Organic Chemistry ’ (first pub- lished in 1935 60) makes Robinson’s contributions much more prominent. Waters’ approach was much more historical ; his book was produced under T. M. Lowry’s patronage. Of course authors in the next generation in the 1950s onwards knew even less of Robinson’s contributions and from 1953 Ingold’s ‘Structure and Mechanism in Organic Chemistry’5 became the natural point of reference for discussions of electronic theory of organic chemistry. In this paper I have tried to show in outline why Ingold’s version of the electronic theory is used today rather than Robinson’s and why Robinson felt so deeply about this. In the space that is available I have had to omit many relevant points.In particular I have not been able to discuss certain matters that bear on Robinson’s relations with Ingold which I have recently discovered through examining the Robinson archives at The Royal Society. There is correspondence between Thorpe Robinson and Ingold in July 1926,61 and an unpublished manuscript by Robinson from early 1938.62 When this story is told Ingold inevitably appears in a somewhat unfavourable light. I want therefore to make it clear that this does not diminish the enormous importance of Sir Christopher Ingold’s contributions to the advancement of physical organic chemistry. His further development of elec-tronic theory from 1926 must properly be counted as one of his great achievements. Much of what he did by way of revising electronic theory as it was when he took it over has proved to be for the best even though some of the changes that he introduced seemed to Robinson to be undesirable or un-necessary.It is not the ‘takeover ’,as such that is to be criticized but the manner in which Ingold appears to have set about it. What he did has sometimes been described as ‘piracy’ and Robinson himself obviously supposed that Ingold was acting in a calculated way. It could be however that this is an over- simplified view and that there was an element of inadvertence in what Ingold did. After Ingold had embraced electronic theory he may well have thought of himself as going back to first principles and working it all out in his own way. In particular he certainly regarded himself as translating the valuable parts of Flurscheim ’s theory of alternating affinities into electronic Further his choice of the term ‘tautomeric effect’ for the conjugative electronic shift shows that he regarded his own work with Thorpe on tautomerism as contributing to electronic theory.By the time Ingold had thought about it all a great deal and had devised new terms and symbols Robinson seemed to him to be just one of a number of scientists who had at various times contributed important ideas which constituted the strands that he brought together and wove into a more comprehensive theory of organic chemistry. I think we should also remember that by the standards of the day Ingold’s publication rate was very high; from 1923 to 1931 it averaged about thirteen papers a year.It is perhaps understandable if he was not always as careful as he ought to have been in relating his own work to other people’s and in choosing appropriate references. I must confess that I find the public discussion of the disagreements of these two great British chemists not long departed from us somewhat distasteful and embarrassing. It has however been a necessary exercise to set Robinson’s contribution to electronic theory in proper perspective. Such a discussion may also serve to remind us that chemistry does not just happen; it is made by real people who in varying degree show not only admirable virtues but often show very human failings as well. References and Notes M.D. Saltzman J. Chem. Educ. 1980 57 484. G. N. Burkhardt ‘Arthur Lapworth and Others’ unpublished memoirs ; copies are deposited in the University Libraries at Manchester and Hull England. Lord Todd and Sir John Cornforth Biogr. Mem. Fellows R. SOC. 1976 22 415. (The section on Theoretical Chemistry is pp. 465- 478.) R. Robinson ‘Memoirs of a Minor Prophet’ Elsevier Amsterdam 1976 Volume 1. C. K. Ingold ‘Structure and Mechanism in Organic Chemistry,’ Cornell University Press Ithaca New York 1953. From 1923 the Journal of the Society of Chemical Industry was divided into two sections one of which was called Chemistry and Industry Review. Volume 42 of J. SOC. Chem. Ind. contained Volume 1 of Chem. Ind. Rev. In 1932 the title was shortened to Chemistry and Industry.This has sometimes led to confusion. In this article all references to this journal are given the abbreviation for the title from 1932 onwards as Chem. Ind. (London); year and page are cited but without the volume number. T. M. Lowry Chem. Ind. (London) 1923 302. The additional matter is on pp. 304-5. Chem. Ind. (London) 1923 771. 9 The full account of this meeting is in Trans. Furuduy SOC.,1923 19 450 et seq. 10 Chem. Ind. (London) 1926 44. 11 Obituary notice by R. Robinson Obit. Not. Fellows R. SOC. 1947 5 555. 12 Obituary notice by Sir William Pope Obit. Not. Fellows R. SOC. 1938 2 287. 13 Obituary notice by C. K. Ingold J. Chem. SOC. 1956 1087. 14 Obituary notice by C. W. Shoppee Biogr. Mem.Fellows R. SOC. 1972 18 349. 15 J. F. Thorpe and C. K. Ingold Chem. Ind. (London) 1923 612. 16 Chem. Ind. (London) 1923 656 1136; 1924 9; 1925 281. 17 Chem. Ind. (London) 1924 851 917 1010 1214 1239. 18 A. Lapworth J. Chem. SOC. 1922 416. 19 W. 0.Kermack and R. Robinson J. Chem. SOC. 1922 427. 20 R. Robinson Mem. Proc. Munchester Lit. Philos. SOC.,1920 64 No. 4 p. 1. 21 B. Flurscheim Trans. Chem. SOC.,1909 718; 1910 84. 22 Ref. 9 p. 527. 23 Ref. 9 p. 528. 24 J. F. Thorpe Chem. Ind. (London) 1923 1 168. 25 Chem. Ind. (London) 1924 27. 26 C. K. Ingold Chem. Ind. (London) 1924 1057; 1925 258. 27 A. Lapworth Chem. Ind. (London) 1925 563. 28 Chem. Ind. (London) 1924 664. 29 Chem. Ind. (London) 1925 1050. (I am grateful to Dr R. B. Moyes for verifying this event in the Minutes of the Council of The Chemical Society).30 C. K. Ingold J. Chem. SOC.,1925 513. 31 Chem. Ind. (London) 1924 1297. 32 See especially R. Robinson Chem. Ind. (London) 1925 456. 33 C. K. Ingold and S. D. Weaver J. Chem. SOC. 1924 1456. 34 A. Lapworth Chem. Ind. (London) 1925 336. 35 G. N. Burkhardt and A. Lapworth J. Chem. SOC. 1925 1742. For personal recollections of this work see ref. 2. 36 C. K. Ingold and E. H. Ingold J. Chem. SOC.,1925 870. 37 Chem. Ind. (London) 1925 227. 38 C. K. Ingold and E. L. Holmes J. Chem. SOC.,1925 1800. 39 C. K. Ingold Chem. Ind. (London) 1925 563. 40 R. Robinson Chem. Ind. (London) 1925 639. 41 R. Robinson Chem. Ind. (London) 1926 9. 42 H. R. Ing and R. Robinson J.Chem. SOC. 1926 1655. 43 Chem. Ind. (London) 1926 43. 44 (a) E. L. Holmes and C. K. Ingold J. Chem. SOC. 1926 1305; (b) C. K. Ingold and E. H. Ingold ibid. p. 1310; (c) E. L. Holmes and C. K. Ingold ibid. p. 1328; (d) E. L. Holmes C. K. Ingold and E. H. Ingold ibid. p. 1684. 45 Chem. Ind. (London) 1926 356. NATURAL PRODUCT REPORTS 1987 46 J. Allan A. E. Oxford R. Robinson and J. C. Smith J. Chem. SOC.,1926 401. 47 Chem. Ind. (London) 1925 659. 48 Ref. 4 p. 219. 49 The papers were received by The Chemical Society on 10 February 1926. 50 C. K. Ingold Annu. Rep. Prog. Chem. 1926 23 1 12. 51 C. K. Ingold Annu. Rep. Prog. Chem. 1927 24 106. 52 C. K. Ingold Annu. Rep. Prog. Chem. 1928 25 111 53 R. Robinson ‘Outline of an Electrochemical (Electronic) Theory of the Course of Organic Reactions’ Institute of Chemistry London 1932 52 pp.54 R. Robinson ‘Quelques aspects d’une theorie electrochimique du micanisme des riactions organiques ’ Quatrieme Conseil de Chimie de 1’Institut Solvay Brussels 1932 pp. 423489. The report of the ensuing discussion opened by Ingold occupies pp. 490-501. (I am grateful to Dr Marie-Franqoise Ruasse of the University of Paris VII for the gift of a copy of this item.) 55 R. Robinson ‘Versuch einer Electronentheorie organisch-chemischer Reaktionen ’ (Sammlung chemischer und chemisch- technischer Vortrage begrundet von F. B. Ahrens) Ferdinand Enke Stuttgart 1932 76 pp. (I am grateful to Professor Dr Christian Reichardt of the University of Marburg for the gift of a copy of this item.) 56 R.Robinson J. SOC.Dyers Colour. 1934 Jubilee Issue p. 65. 57 C. K. Ingold Chem. Rev. 1934 15 225. 58 R. Robinson J. Chem. SOC. 1947 1288. 59 H. B. Watson ‘Modern Theories of Organic Chemistry’ Oxford University Press London 1937. 60 W. A. Waters ‘Physical Aspects of Organic Chemistry’ Rout- ledge and Kegan Paul London 1935. 61 Robinson Archives (The Royal Society London) item D33. 62 Robinson Archives (The Royal Society London) item B208. This manuscript is in the form that was required for a paper to be submitted for publication in J. Chem. SOC. and was probably prepared in late February 1938. It is devoted to arguing for the priority of Lapworth and Robinson’s contributions over those of Ingold. It appears from the Minutes of the Publications Committee ofThe Chemical Society that this paper was received by the Society. It was expected that Ingold would wish to reply so it was agreed ‘to allow each author to publish one paper to be seen by the other author before publication’. The Minutes contain no further explicit reference to this matter. Whatever the explanation may be Robinson’s paper with (or without) a reply from Ingold never appeared in J. Chem. SOC. (I am grateful to the Librarian of The Royal Society for access to the Robinson archives and to the Librarian and Dr Ivor Williams of The Royal Society of Chemistry for examination of the records of The Chemical Society.)

ISSN:0265-0568    

DOI:10.1039/NP9870400061

出版商:RSC    

年代:1987

数据来源: RSC

摘要:

Chemistry in Manchester in the Twenties and some Personal Recollections W. Cocker Department of Chemistry Trinity College Dublin 2 Ireland 1 Introduction 2 H. B. Dixon 3 A. Lapworth 4 Robert Robinson 5 Laboratories 6 Postgraduate Research Students 7 References 1 Introduction When the decade [1920-291 opened universities were still feeling the effects of four years of war during which period there were few undergraduate and postgraduate students. During the war members of the staff in the chemistry department who were not on active military service were called upon to assist the war effort in the chemical industry. For example Professor H. B. Dixon was Deputy Inspector of High Explosives for the Manchester area. Manchester was not unique in this respect.Research in the war period was thus curtailed. Moreover with the opening of the decade there was a large influx of under- graduates which created great demands on the time of the staff and on the available accommodation. Table 1 shows the student bulge which occurred in the early years of the twenties. After 1923 the numbers of students graduating settled down for a number of years to about 25 per year. In spite of all the difficulties research soon got under way and during the decade about 250 publications emanated from the chemistry department in the Faculty of Science (‘Owens’). A significant number also came from the department of technological chemistry of the Faculty of Technology (now UMIST). The publications covered a wide span of chemistry (Table 2) and while the research groups of Professors Lapworth and Robinson contributed the majority of the papers other staff and their research groups were responsible for about a hundred.The twenties were indeed golden years in the life of a distinguished department. It was a decade when the under- standing of organic reaction mechanisms advanced at times haltingly and the chemistry of natural products blossomed. 2 H.B. Dixon Important changes in the staff took place during the decade. Until 1922 H. B. Dixon was Sir Samuel Hall Professor and Director of the Lab0ratories.l Initially he was a classical scholar of Christ Church Oxford but the College authorities were induced by Dr. A. Vernon Harcourt to transfer Dixon to his care.This was a move which conferred great benefit upon chemistry; Dixon was later to become Bakerian Lecturer of The Royal Society (1893) and Royal Medallist (1913). It was with Harcourt that Dixon started work on the rate of chemical change between solutions of hydrogen peroxide and hydriodic acid a piece of classical physical chemistry. Later he turned to the study of gaseous explosions and amongst other things showed that a rigorously dried mixture of carbon monoxide and oxygen in stoicheiometric proportions could not be induced to explode by applying an electric spark. He studied the rates of gaseous explosions and this work was continued when in 1886 he followed Sir Henry Roscoe as Professor of Chemistry in Owens College. Here he built up a strong research school and was active until the day of his death in 1930.He Table 1 Numbers of students graduating in chemistry (in the Faculty of Science) in the years 1920-23 Year Number 1920 32 1921 59 I922 81 1923 57 Table 2 Research interests of members of staff in the chemistry department of the Faculty of Science 1920-29 H. B. Dixon A. Lapworth R. Robinson W. Baker D. H. Bangham G. N. Burkhardt F. P. Burt C. Campbell B. A. M. Cavanagh F. C. Challenger F. Fairbrother D. C. Henry J. B. M. Herbert D. H. Hey J. E. Myers A. Robertson H. Stephen Propagation of flame and explosions ; ignition of gases Chemistry of camphor and its derivatives; mechanisms of organic reactions with a thermodynamic approach Chemistry of alkaloids; plant colouring matters including synthesis ; mechanisms of organic reactions particularly as applied to aromatic substitution Synthesis of chromones flavones Surface chemistry of metals graphite Organic reaction mechanisms Sorption of gases on surfaces Ignition of gases by explosion waves Molecular thermodynamics Organic derivatives of Bi Sb and S; microbiological reactions Electroendosmosis of organic liquids against glass; colloid chemistry Colloid chemistry Sorption of gases on crystal surfaces Synthesis of physiologically active bases Physico-chemical periodicity Synthesis of glucosides Syntheses using Hoesch reaction ; new method of synthesis of aldehydes In addition to these members of staff there were a number of senior postgraduate workers in the Department during the decade.Mention may be made of W. Bradley M. G. Evans (who later joined the staff) S. J. Folley R. D. Haworth H. R. Ing A. E. Oxford T. R. Seshadri J. C. Smith J. B. Speakman and K. Venkataraman. Special mention must be made of Mrs G. M. Robinson (later Lady Robinson) who was engaged in the synthesis of long-chain aliphatic compounds. devised a method of photographing the movement of flames in gaseous explosions. Those who were undergraduates in the twenties will remember the bangs and crashes which came from a laboratory in the basement of the Roscoe Laboratory. Here explosive. mixtures of gases were subjected to adiabatic com- pression in a steel cylinder the piston of which was forced in by a falling weight.Outside this work the accurate determination of the atomic weight of chlorine by Dixon and Edgar,* using a specially designed apparatus was considered to be a classic. Dixon had many distinguished students about a dozen of whom were elected to Fellowship of The Royal Society. These included W. N. Haworth R. Robinson and J. L. Simonsen who as research students of W. H. Perkin jun. worked on NATURAL PRODUCT REPORTS 1987 University of Manchester Chemistry Department doctoral group of 1925,with Sir Henry Miers (Vice-Chancellor) and Professor Robinson (Courtesy of Dr G. N. Burkhardt). Members of the group include F. Fairbrother (sitting at far left) and G. N. Burkhardt (third from right in the back row) who devoted their entire professional lives to Manchester and J.C. Smith (second from right in the back row) who migrated to Oxford and spent many years as a colleague of Robinson in the Dyson Perrins Laboratory. adjacent benches. It was in the research atmosphere that was created by H. B. Dixon and W. H. Perkin jun. that Robert Robinson became an undergraduate in 1902. 3 A. Lapworth On Dixon’s retirement in 1922 Arthur Lapworth became Sir Samuel Hall Professor and Director of Laboratories. The holder of this Chair was primarily responsible for physical and inorganic chemistry but was head of department. This move led to the invitation to Robert Robinson to return to his alma muter as Professor of Organic Chemistry.Thus in 1923 two outstanding chemists came together. The writer had the great privilege of being a student and pupil of and private assistant to Professor Lapworth and a student of Professor Robinson. Before going to Manchester in 1909 as Senior Lecturer in Inorganic and Physical Chemistry Arthur Lapworth had already made his name for his interpretations of the mechanisms of the Claisen acetoacetic ester reaction of the formation of benzoin and of cyanohydrins and of the Knoevenagel reaction. His mechanisms have required little subsequent modification. He had also made significant contributions to the chemistry of camphor work which he continued for a time after becoming Professor of Organic Chemistry in 1913 following the move of Professor W.H. Perkin jun. to Oxford. Another contender for the organic Chair was Dr Chaim Weizmann. During his early years as Professor Lapworth worked on the pungent principle of ginger3 and on the chemistry of capsaicin. In his final paper4 in the series on camphor he described the synthesis of homocamphor. A number of papers in which synthetic methods were described appeared in the early twenties e.g. the reduction of emulsified nitro-compounds5 and the direct acetalization of aldehydes,6 using ammonium chloride as catalyst. Lapworth knew many useful experimental ‘tips’; for example he advised the writer to use a concentrated aqueous solution of sodium salicylate to separate alcohols from mixtures with non-alcoholic compo~nds.~ In nearly all of his projects there was an underlying theoretical interest e.g.in his work on the formation of y-alkylidene derivatives from ethylidenemalonic esters,8 the for- mation of y-oxalyl derivatives of PP-and @-dimethylacrylic acid^,^ and the direct combination of ethylenic hydrocarbons with hydrogen sulphites in the presence of kieselguhr to give sulphonic acids.1° In his obituaryll of Arthur Lapworth Robert Robinson wrote When in the early Manchester days one discussed synthetical projects with Lapworth it was quite clear that he had some unusual private way of deciding whether they would ‘go’ or not. It turned out to be a scheme of alternating polarities in a chain of atoms and the theory was published in 1920. Although somewhat hidden in the Memoirs of the Manchester Literary and Philosophical Society [ref.121 the paper evoked much interest and not a little criticism. In the Manchester paper,12 Lapworth wrote The writer originally fell into the habit of labelling the atoms in reactive molecules with + and -signs as the result of his applications of the ionic theory to the reactions of carbon compounds and especially to those of ketones and allied carbonyl compounds. ..It must be empha- sised however that in attaching the + and -signs to the oxygen and carbon atoms no hypothesis is invoked nor is it necessary or even desirable to assume that electrical charges are developed on these two atoms (except perhaps at the actual instant of chemical change). The signs are applied in the first instance merely as expressing the relative polar characters which the two atoms seem to display at the instant of the chemical change in question.NATURAL PRODUCT REPORTS 1987-W. COCKER An example was Lapworth pointed out that ‘...the whole order of alternating polarities is determined by the oxygen atom or atoms.. .The extension of the influence of the directing or key atom over a long range seems to require for its fullest display the presence of double bonds and usually in conjugated positions.. .’ Another example which illustrates Lapworth’s use of the theory of induced polarities was given by Robinson to the writer’s class in 1927. It involves the behaviour of the o-and p-methoxybenzyl bromides (1) and m-methoxybenzyl bromide (2).Here the key atom is the oxygen of the methoxy-groups. Lapworth and ShoesmithI3 showed by experiment that the ortho- and para-isomers were more readily hydrolysed than the meta-isomer while the reverse was the case in their reactions with hydrogen. iodide the meta-isomer being the most reactive. These differences in properties are in accord with Lapworth’s theory. -0Me OMe -L + $H2-Br At the time there was some criticism that Lapworth had used the Manchester Memoirs for his important paper but in so doing he followed John Dalton and moreover it is unlikely that The Chemical Society would have allowed such freedom with a paper that lacked an experimental section. In 192214 the principle of his earlier paper was broadened. The ideas that had been expressed by Lapworth led in 1925-26 to a long and sometimes vitriolic correspondence in the pages of Chemistry and Industry Review in which B.Fliirscheim C. K. Ingold A. Lapworth T. M. Lowry and R. Robinson took part. Lapworth who was a sensitive person must at times have been deeply hurt. It was a correspondence which created more heat than light ;it was brought to an end by the Editor of Chemistry and Industry Review in 1926 in the following paragraph Discussion of alternate polarities and kindred topics is of great importance and we hope the letters we have published in these columns have cleared away a considerable mass of misapprehensions. We are however obliged to wait for a period before dealing with the subject again; a proportion of our readers fails to understand the whole of the arguments without a mental effort which is made unwillingly.C. K. Ingold who must have misunderstood Lapworth and apparently believed that Lapworth always attached a -sign to oxygen attempted to prove by experiment that on this basis the theory of alternate polarities did not always hold. (The writer remembers that A. Lapworth once observed to him that (3) CH,-C (CO,Et), II 0 -NPh PhN-(4) (5) heal/[ -H,OI PhN=C=C(CO,Et -D PhNHC(O)CH(CO,Et) (6) 1 ‘Professor Ingold is very clever in devising experiments to prove his point of view.’) In the case of nitrosobenzene Ingold15 believed that Lapworth would attach a -sign to the oxygen atom and thus that he would predict that this compound should react with methylenemalonic ester (3)16 to yield the four-membered cyclic compound (4).It was however claimedI6 that compound (5) was formed and in support of this claim it was said that (5) failed to react with potassium permanganate and that it did not either produce a colour with ferric salts or form a copper salt but that when it was heated it decomposed to afford the acetanilide derivative (6). In other words the oxygen of nitrosobenzene should be given a + sign. In reply to Ingold’s criticism Lapworth” pointed out that oxygen is not the key atom in all circumstances and that he was surprised that anyone should think so. Moreover he had never considered the case of nitrosobenzene which was a bad example to take.In fact G.N. Burkhardt and A. LapworthlE showed that the product of the reaction between (3) and nitrosobenzene was not a four-membered-ring compound but the nitrone (7); it gave a positive colour reaction with Fe3+ gave a colour with copper acetate and was oxidized by potassium permanganate in acetone. These workers prepared the nitrone (7) by an alternative method namely the condensation of phenylhy- droxylamine with hydroxymethylenemalonic ester (8). + -+-+ -+ H2C=C[C(0)OCH,CH312 + PhN=O PhN(OH) -CH=C(COZEt 1 (3) HOCH=C(C02Et)z + PhNHOH + PhN=CH-CH(CO,Et), I + 0 (7) Two other examples of the condensation of nitrosobenzene with unsaturated compounds were similarly dealt with by Lapworth.lg Robert Robinson entering the fray showedz0 in an elegant fashion that the nitroso-group can be polarized in both directions.Its presence causes nitrosobenzene to be nitrated in the ortho-and para-positions with no meta-substitution (crotenoid) but pnitroso(dialky1amino)benzenes react with hydroxide ion the dialkylamino-group being displaced by OH (crotonoid). At the time the controversy tended to overshadow Lap- worth’s many other contributions to reaction mechanism in particular his classification of reagents and groups. In-itially12 he referred to groups as basylous (e.g. NH,) if they tend to lower the acidity of a molecule or as acylous (e.g. MeCO) if they have the opposite effect. The terms later became anionoid and cationoid and they implied that the groups were re-spectively donors and acceptors of electrons.Later C. K. Ingold used the terms nucleophilic and electrophilic and these have had the greater acceptance. The writer still thinks that Lapworth’s terms are the more comprehensible. During his occupancy of the Sir Samuel Hall Professorship Lapworth lectured to the first-year honours students. The writer joined this class in 1925. The course ranged widely over general chemistry and his lectures were liberally illustrated by experiments which were impeccably performed by the Chief Steward Mr A. F. Edwards (these days he would be known as a laboratory manager). Lapworth spent an appreciable amount of time on the subject of flame which was not surprising in view of Dixon’s interest in the subject. Crystallography was dealt with in great detail being of great interest to Lapworth an interest going back to his early research days.He communicated this interest to his research students who were directed to take NATURAL PRODUCT REPORTS 1987 An informal group in the Manchester Chemistry Department ca. 1913 but several members were still on the staff well into the 1920s. The occasion was some celebration for the Laboratory Steward A. F. Edwards (possibly a special birthday). He is in the front row holding his present between Professor H. B. Dixon to the left and E. C. Edgar to the right. Mrs Edwards is standing behind and to the right of her husband; the little girl sitting between Chaim Weizmann and Professor Dixon the boy in the Eton collar and the young man sitting next to him are the Edwards children.Mrs Dixon is standing behind her husband between C. Campbell to the left and Arthur Lapworth to the right; J. E. Myers is at the far right of this row. (Courtesy of Dr G. N. Burkhardt) lectures in the crystallography department. The chemistry of the non-metals was dealt with in two or three lectures. The writer remembers Lapworth’s lectures as stimulating though at times his voice was less audible than it might have been. He dealt with essential principles and certainly did not give a catalogue of facts. Professor Lapworth was a perfectionist. He could not bear sloppiness either in speech or behaviour; one’s bench had to be kept in a pristine condition. The writer well remembers a little homily on the subject which ended with the remark that a chemist should be able to carry on research while wearing ‘tails’ without doing damage to them.Later when the writer was Lapworth’s private assistant he was advised to wear a stiff white collar. Lapworth was also very particular about the use of the English language. In the twenties chemical compounds were frequently referred to as ‘bodies’ by some chemists. The writer did this on one occasion when describing his current findings to Lapworth and was chided with the remark ‘I see no corpses in this laboratory ’. Professor Lapworth’s visits to his research students were regular and daily; indeed when work was prospering he made two visits per day. His expositions of points of principle and especially of theory were illuminating even though his actions could be off-putting.He kept a flat tin of tobacco in one waistcoat pocket and a packet of cigarette paper in another. While dealing with some theoretical point he took out both and made a sort of cigarette with tobacco in the middle third of the paper. When he lit the ‘cigarette’ there was a half-inch flare at one end and an unburnable soggy mess at the other. 4 Robert Robinson Robert Robinson’s work is described elsewhere in the Centenary Tribute but it is fitting here to draw attention to the massive number of publications (about 100) which appeared from his research group during his five years (1923-28) as Professor of Organic Chemistry in Manchester. He completed syntheses of most of the anthocyanidins and made headway with syntheses of anthocyanins.Work continued in the alkaloid field on reactions of diazo-ketones on the biological oxidation of tryptophan and on the mechanism of the Fischer indole synthesis and many contributions were made to the under- standing of organic reaction mechanisms particularly in the field of aromatic compounds. The paper by Allan Oxford Robinson and Smith21 was a classic in its time. Robinson lectured to the final-year honours class. The writer was a member of this class in 1927-28 this being Robinson’s final session before going to University College London. He gave two courses one of which a general course was attended by all students; the other -Higher Organic Chemistry -was attended by the organic ‘specialists’.A corresponding course in physical chemistry was available to those students who were more interested in this branch of chemistry. The general course dealt largely with heterocyclic systems and with natural prod- ucts that contain these. He ranged widely over this chemistry throwing in sidelights and experimental ‘tips’ that had been derived from his vast knowledge of organic chemistry. The ‘specialist ’ course consisted of one term of dyestuffs’ chemistry. The remainder of the session dealt with organic reaction NATURAL PRODUCT REPORTS 1987-W. COCKER The No. 2 Roscoe Laboratory of the Manchester Chemistry Department (Courtesy of Greater Manchester Museum of Science and Industry) mechanisms. Robinson’s lectures had something for everyone -facts for those who were so interested and inspiration as well for the intending research students.Some of the lectures that were given by Professor Robinson are still vivid in the writer’s mind. One lecture on imidazoles (then named glyoxalines) included Pyman’s synthesis of histi- dine. This was very relevant since F. L. Pyman had just vacated the Chair of Technological Chemistry. In another lecture Robinson described the synthesis of harmaline,22 which was very topical since the description of this work had appeared only a few months earlier. He took the opportunity to describe the Japp-Klingemann method of formation of phenylhydraz- ones in some detail and Gowland Hopkins’ of harman by the reaction of tryptophan with ferric chloride in ethanol.He observed that this work materially facilitated the constitutional studies of harmaline in that it located the pyrrole nucleus. In the same lecture he digressed to describe the work of Ing and Man~ke~~ on the decomposition of phthalimides with hydrazine. On another occasion he also demonstrated his test for weak bases,25 such as alcohols esters and ketones. In this test he used a solution of the weak base in light petroleum to which he added a concentrated solution of ferric chloride in hydrochloric acid. Three layers were formed; the top layer contained base in petroleum the middle (green) layer contained the salt and the bottom layer the ferric chloride reagent. Acid- stable weak bases e.g. camphor can be isolated from mixtures by forming the ferric chloride salt which can be decomposed by adding water.Robinson’s large-scale method of preparation of sodium amalgam and that of acetonedicarboxylic acid from citric acid were spectacular and very effective and safe in competent hands. In the twenties students of chemistry were expected to have a knowledge of dyestuffs. In his lectures Robinson described the various types starting from picric acid and nitronaphthols through the azo range indigoids and thioindigoids to anthra- quinones. The writer remembers that he brought into the lecture theatre Rowe’s ‘Colour Index’,2s which at that time consisted of a single volume. In each lecture he paged through the Index without apparently finding what he wanted. He closed the book with a bang and started to lecture.To the impressionable student this action was an effective demonstration of his knowledge of the subject. Robinson’s lectures on reaction mechanism were very com- prehensive. He covered a good deal of history and many facets of the subject e.g. Sugden’s parachor Thiele’s partial valency theory and the work of Flurscheim Ingold Lapworth and himself. He spent some time on describing his views on aromaticity and especially on the aromatic ~extet.~’ He used this concept to explain the difference in the basicity of pyrrole and pyridine pointing out that in the former the ‘basic’ electrons of the nitrogen atom were used to complete the sextet but not in the case of pyridine. These were novel ideas at the time.One of the unsolved questions of that period was why a halogen that is attached to the aromatic nucleus induces ortho-and para-nitration of the nucleus while it increases the acidity of acetic acid. These were pre-resonance days. The class was very sceptical about some of the theories that Robinson had on reaction mechanism and asked for a special tutorial to discuss them. It never materialized. The writer also remembers that Robinson was very scathing about the work of some others. In one lecture he made a remark such as ‘Dr X should really be associated with this work but the only thing that Dr X should be associated with is the effect of boot leather’. In 1927 Professor Robinson was only 41 years of age. He was at the height of his powers and his lectures were full of energy enlightenment and novelty.5 Laboratories Practical work was a very important part of the course in chemistry. Students pursuing this course had their own private benches in each of the three years. They started their first-year practical work in either the Dalton or the No. 1 Roscoe Laboratory where they were given a grounding in preparative inorganic chemistry and in qualitative inorganic analysis. During that year the writer learned how to prepare anhydrous chlorides of both metals and non-metals by a variety of routes. He also analysed dozens of mixtures of salts. One term was spent in the Metallurgy Department. In the second year students progressed to the No. 2 Roscoe Laboratory where they carried out both gravimetric and volumetric analysis and learned the importance of accuracy.One term was also given over to physical chemistry. The Dalton and Roscoe Laboratories were erected in 1872 and were similar to laboratories in other colleges and uni- versities in being lofty church-like structures. In the third year students progressed to the organic lab- oratories namely the Schorlemmer Laboratories (built in memory of Carl Schorlemmer who was the first Professor of Organic Chemistry in Britain) and the Morley Laboratories which were built in 1909. The latter consisted of a teaching laboratory (for 36 students) a suite of research laboratories a private laboratory a room for the Professor of Organic Chemistry and a store.The benches were extremely well equipped. Each had outlets for gas water steam and electricity and had built-in vacuum pumps. The steam baths were a great boon for undergraduates and research workers alike. The writer remembers that as an undergraduate he spent 20 hours per week in the laboratory developing skills in preparative methods and organic analysis. Dr Alexander Robertson was the member of staff in charge of the Morley Laboratory in 1927-28. Dr William Bradley later Professor of Colour Chem- istry at Leeds University was engaged in research on the bench behind the writer’s. 6 Postgraduate Research Students Research students were directed to take lectures (without examinations) in two subjects each year outside their own subject. One could choose as one wished the purpose being to widen one’s outlook.In the writer’s case the subjects were crystallography electrometallurgy physiological chemistry (with H. S. Raper) and psychology. The oral examinations for the Ph.D. degree were public. They were well advertised in the University and there was usually a fairly large attendance of students who would later have to undergo the examination. They were held in a large room with the candidate (and blackboard) at one end and the external and internal examiners at the other end. Professors Robinson and Lapworth were the writer’s examiners. It was a very friendly examination. NATURAL PRODUCT REPORTS 1987 The writer has dealt with chemistry in the twenties in ‘Owens’. During that same period there was a vigorous department of chemistry in the Faculty of Technology.Until 1927 F. L. Pyman occupied the Chair of Technological Chemistry. He had a large group of workers engaged on the chemistry of amidines and glyoxalines [imidazoles] and there were other members of staff engaged in research in applied chemistry. Professor James Kenner followed F. L. Pyman but his research interests in Manchester rightly belong to the thirties. The writer is greatly indebted to Dr G. N. Burkhardt with whom he commenced research for much of the information which appears in this article. 7 References 1 A photograph of H. B. Dixon can be found in his obituary notice J. Chem. Soc. 1931 3350. 2 H. B. Dixon and E. C. Edgar Philos. Trans. R. Soc.London Ser. A 1905 205 169. 3 A. Lapworth and F. A. Royle J. Chem. Soc. 1919 115 1109. 4 A. Lapworth and F. A. Royle J. Chem. Soc. 1920 117 743. A. Lapworth and L. K. Pearson J. Chem. Soc. 1921 119 765; R. D. Haworth and A. Lapworth ibid. p. 768. 6 R. D. Haworth and A. Lapworth J. Chem. Soc. 1922 121 76. 7 W. Cocker A. Lapworth and A. Walton J. Chem. Soc. 1930 440. 8 L. Higginbotham and A. Lapworth J. Chem. Soc. 1922 121 2823. 9 L. Higginbotham and A. Lapworth J. Chem. SOC. 1923 123 1325. I. Kolker and A. Lapworth J. Chem. Soc. 1925 127 307. 11 R. Robinson J. Chem. SOC.,1947 989. 12 A. Lapworth Mem. Proc. Manchester Lit. Philos. Soc. 1920,64 No. 3 p. 1. 13 A. Lapworth and J. B. Shoesmith J. Chem. Soc. 1922 121 1391.14 A. Lapworth J. Chem. SOC.,1922 121 416. C. K. Ingold J. Chem. Soc. 1924 125 87. 16 C. K. Ingold and S. D. Weaver J. Chem. Soc. 1924 125 1456. 17 A. Lapworth Chem. Ind. Rev. 1924 2 1294. 18 G. N. Burkhardt and A. Lapworth J. Chem. SOC. 1925 127 1742. 19 G. N. Burkhardt A. Lapworth and E. B. Robinson J. Chem. SOC.,1925 127 2234; G. N. Burkhardt A. Lapworth and J. Walkden ibid. p. 2458. R. Robinson Chem. Znd. Rev. 1925 3 456. 21 J. Allan A. E. Oxford R. Robinson and J. C. Smith J. Chem. Soc. 1926 401. 22 R. H. F. Manske W. H. Perkin,jun. and R. Robinson J. Chem. Soc. 1927 1. 23 F. G. Hopkins and S. W. Cole J. Physiol. 1903 29 451. 24 H. R. Ing and R. H. F. Manske J. Chem. SOC.,1926 2348. R. Robinson J. Chem. Soc. 1925 127 768. 26 F. M. Rowe ‘Colour Index’ The Society of Dyers and Colourists Bradford 1st edn 1924. 27 J. W. Armit and R. Robinson J. Chem. Soc. 1925 127 1604.

ISSN:0265-0568    

DOI:10.1039/NP9870400067

出版商:RSC    

年代:1987

数据来源: RSC