Advances in Carbohydrate Chemistry, Volume 6

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ADVANCES IN CARBOHYDRATE CHEMISTRY VOLUME 6

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Advances in

Carbohydrate Chemistry Edited by SIDNEYM. CANTOR

CLAUDES. HUDSON

i

National Institutes o Health Bethesda, M a r y and

American Sugar Refining company Philadelphia, Pennsylvania

Associate Editors for the British Isles MAURICESTACEY STANLEY PEAT The Universitl) Birmingham, England

University College of North Wales Bangor, Caernarvonshire, Wales

Board of Advisors WILLIAML. EVANS HERMANN0. L. FISCHER E. L. HIRST R. C. HOCKETT

W. W. PIGMAN C. B. PURVES J. C. SOWDEN ROYL. WHISTLER

M. L. WOLFROM

VOLUME 6

1951 ACADEMIC PRESS INC., PUBLISHERS NEW YORK, N. Y.

Copyright 1951, by ACADEMIC PRESS INC. 125 EAST2 3 STREET ~ ~ NEWYORK10, N. Y.

All Rights Reserved No part of this book may be reproduced in any form, by photostat, microfilm, or any other means without written permission from the publishers. Librarv of Congress Card Catalog Number (45-11351)

PRINTED I N THE UNITED STATES OF AMERICA

CONTRIBUTORS TO VOLUME 6

ELLIOTT P. BARRETT, Baugh and Sons Company, Philadelphia, Pennsylvania D. J. BELL,The University of Cambridge, Cambridge, England WILLIAMA. BONNER,Department of Chemistry, Stanford University, California SIDNEYM. CANTOR, Research and Development Division, American Sugar Refining Company, Philadelphia, Pennsylvania W. L. EVANS, Ohio State University, Columbus, Ohio HEWITTG. FLETCHER, JR., National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Bethesda, Maryland E. L. HIRST,Chemistry Department, The University, Edinburgh, Scotland ROGERW. JEANLOZ,Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts ROBERT ELLSWORTH MILLER,Research and Development Division, American Sugar ReJining Company, Philadelphia, Pennsylvania F. H. NEWTH, Department of Chemistry, University College of North Wales, Bangor, North Wales RICHARD'E. REEVES,Southern Regional Research Laboratory, Bureau of Agricultural and Industrial Chemistry, New Orleans, Louisiana D. D. REYNOLDS, Eastman Kodak Company, Rochester, New York NELSONK. RICHTMYER, National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Bethesda, Maryland JOHNC. SOWDEN, Washington University, Saint Louis, Missouri E. A. TALLEY, Eastern Regional Research Laboratory, U . S. Department of Agriculture, Philadelphia, Pennsylvania

V


EDITORS’ PREFACE We regret to report the death of our esteemed collaborator, Dr. Edmund George Vincent Percival, Reader in Chemistry, the University of Edinburgh, Scotland, on September 27th, 1951, a t the age of forty-four. The importance of his contributions to the progress of carbohydrate research is universally recognized; his ability in teaching and his friendliness endeared him to a wide circle of students and colleagues, who mourn his passing. His aid to this publication, both as a contributor and as a member of its Board of Advisors, is here recorded with deepest appreciation. In addition to the usual author and subject indexes for volume 6, there is included also a cumulative subject index for the preceding five volumes. This cumulative index is offered particularly to research workers as an aid in tracing matters back to the original publications in specialized journals. We are pleased to announce that Dr. M. L. Wolfrom will rejoin the editorial staff, beginning with volume 7. THEEDITORS C. S. H. S. M. C. Bethesda, Maryland Philadelphia, Pennsylvania

Vii


CONTENTS CONTRIBUTORS TO VOLUME6 . . . . . . . . . . . . . . . . . . . . . . .

v

EDITORS’ PREFACE . . . . . . . . . . . . . . . . . . . . . . . . . . .

vii

Obituary of Walter Norman Haworth

.

BY E L. HIRST.Chemistry Department. The University. Edinburgh. Scotland

1

The Methyl Ethers of D-Galactose BY D. J. BELL. The University of Cambridge. Cambridge. England

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. Starting-materials for Preparing Tetramethyl Derivatives . . . . . . I11 Starting-materials for Preparing Trimethyl Derivatives . . . . . . . . IV Starting-materials for Preparing Dimethyl Derivatives . . . . . . . . V. Starting-materials for Preparing Monomethyl Derivatives . . . . . . V I . Monomethyl-D-Galactoses . . . . . . . . . . . . . . . . . . . . . VII . Dimethyl-D-Galactose8 . . . . . . . . . . . . . . . . . . . . . . . VIII . Trimethyl-D-Galactoses . . . . . . . . . . . . . . . . . . . . . . I X . Tetramethyl-D-Galactoses . . . . . . . . . . . . . . . . . . . . .

. .

11 12 . 12 . 13 . 14 14 16

.

19

22

The Synthesis of Oligosaccharides

.

BY W . L EVANS.Ohio State University. Columbus. Ohio. D . D . REYNOLDS. Eastman Kodak Company. Rochester. New York. AND E. A . TALLEY. Eastern Regional Research Laboratory. U . S. Department of Agriculture. Philadelphia. Pennsylvania

I. Introduction . . . . . . . . . . . . . . I1 Historical Development . . . . . . . . . I11. Reaction Type . . . . . . . . . . . . . I V. Conclusion . . . . . . . . . . . . . . . V. Table of Glycosyl Halides . . . . . . . . V I Table of Compounds of Alcoholic Type . . VII. Table of Oligosaccharides. . . . . . . . .

.

.

. . . . . . . . . . . . .

27 31 . . . . . 35 . . . . . 65 . . . . . 66 . . . . . . 67 . . . . . 70

. . . . . . . . . . . . .

. . . . . . . . . . . . . . . . . . . . . . . .

. . . . . . . . . . . . . . . .

The Formation of Furan Compounds from Hexoses

.

BYF. H NEWTH.Department of Chemistry. University College of North Wales. Bangor. North Wales

I . Introduction . . . . . . . . . . . . . . . . . . . . . I1. Furan Compounds Derived from Hexoses . . . . . . . . I11. Furan Derivatives from Hexose Acids . . . . . . . . . IV. Possible Mechanisms of Formation of Furan Derivatives . V. 5-Hydroxymethylfurfural . . . . . . . . . . . . . . . . ix

. . . . . . . . . . . . .

83 84

. . . . . . . 89 . . . . . . . 91 . . . . . . 96

X

CONTENTS

Cuprammonium-Glycoeide Complexes BYRICHARD E. REEVES,Southern Regional Research Laboratory, Bureau of Agricuttural and Industrial Chemistry, Agricultural Research Administration, U.S. Department of Agriculture, New Orleans, Louisiana

....

.

I. Introduction . . .. .... ......... ..... 11. The Cuprammonium-Glycol Reaction . . . . . . . . . . . . . . . . 111. Spatial Requirements for Complexing , . . . . . . . . . . . . . . . IV. Correlations between Reaction with Cuprammonium and Other Reactions of Carbohydrates . . . . . . . .... . . V. Cuprammonium Complexes and the Structure of Polysaccharides . . . . VI. Cuprammonium Complexes and the Shape of Pyranoside Rings. . . . . VII. Appendices. . . . . . . . . . . , . . . . . . . . . . . . .

.. .... ..

. ...

...

108 109 110 113 116 122 131

The Chemistry of Ribose BY ROGERW. JEANLOZ, Worcester Foundation for Experimental Biology, Shrewsbury, Massachuseits AND HEWITT G. FLETCHER, JR., National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Public Health Service, Federal Security Agency, Bethesda, Maryland I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . 135 11. Ribose.. . . . . . . . . . . . . . . . . . . . . . . . . . 136 111. Ribose Derivatives . . . . . . . . . . . . . . . . . . . . . . . . 140

..

.

The 2-(Aldo-polyhydroxyalkyl)benzimidazoles BY NELSONK. RICHTMYER, National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Public Health Service, Federal Security Agency, Bethesda, Maryland

..

.

I. Introduction . . . . ... ,......... . 11. Quinoxalines and Benzimidazoles from Aldoses . . . . , . 111. Benaimidazoles from Aldonic Acids . . . . . . . . . . . IV. Tables. , . . . . . . . . . . . . . . . . . . . . .

.

. . . . . . . . . . . . . . . . . . . . . . . .

175 176 180 198

Trends in the Development of Granular Adsorbents for Sugar Rehing BY ELLIOTT P. BARRETT,Baugh and Sons Company, Philadelphia, Pennsylvania I. Introduction . . , . . . . . . . . . . . . . . . . . . . . . 205 11. Factors Affecting the Depurative Powers of Adsorbents . . . , . . . . 214 111. Adjustment of Adsorbent Properties to Adsorbent Functions . . . . . . 225

..

.

Acoritic Acid, a By-product in the Manufacture of Sugar BY ROBERT ELLSWORTH MILLEBAND SIDNEY M. CANTOR, Research and Development Division, American Sugar Refining Company, Philadelphia, Pennsylvania I. Introduction ............ .,..... 231 11. Physical Properties of Aconitic Acid. . . . . . . . . . . . . . . . . 234 111. Analytical Estimation of Aconitic Acid. . . . . . . . . . . . . . . . 236 IV. The Recovery of Aconitic Acid in the Manufacture of Sugar . . . . . . 239 V. Chemistry and Uses of Aconitic Acid. , . . . . . . 244

..

.

. .. ..... .

.....

xi

CONTENTS

Friedel-Crafts and Grignard Processes in the Carbohydrate Series

BY WILLIAMA. BONNER.Department of Chemistry. Stanford University. California I. I1. I11. IV. V.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . Processes Catalyzed by Aluminum Chloride . . . . . . . . . . . . . . Applications of the Grignard Reaction . . . . . . . . . . . . . . . . Addendum on the Anomeric Configuration of p-D-Glycopyranosylbenzenes Physical Properties of Products from Friedel-Crafts and Grignard Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

251 252 261 282 284

The Nitromethane and 2-Nitroethanol Syntheses

BY JOHN C. SOWDEN.Washington University. Saint Louis. Missouri I . Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. Some Reactions of Nitroparaffins . . . . . . . . . . . . . . . . . I11. Early Attempts to Condense Nitromethane with Aldose Sugars . . . . IV . Carbohydrate C-Nitroalcohols . . . . . . . . . . . . . . . . . . . . V. C-Nitrodesoxy Sugars and C-Nitrodesoxy Inositols . . . . . . . . . . VI . The Acetylated Carbohydrate C-Nitroolefins . . . . . . . . . . . . VII . The 2-Nitroethanol Synthesis of Higher-Carbon Ketoses . . . . . . . ERRATA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

291

. 293 . 297 299 . 310 . 313 . 316

319

FOR VOLUMES 1-5 . . . . . . . . . . . . . . . 321 CUMULATIVE SUBJECTINDEX

AUTHOR INDEX FOR VOLTJM~6 . . . . . . . . . . . . . . . . . . . . . .

409

FOR V o ~ u m 6. SUBJECTINDEX

422

. . . . . . . . . . . . . . . . . . . . .


WALTERNORMAN HAWORTH 1883- 1950 By the sudden death of Sir Norman Haworth on the 19th of March, 1950, the world lost a most distinguished organic chemist who had exercised a profound influence on scientific research and on education. Walter Norman Haworth, the second son and fourth child of Thomas and Hannah Haworth, was born at Chorley in the North West of England on March 19, 1883. His father was manager of Rylands’ factory a t Chorley and after attending the local school until the age of fourteen he joined his father and began to learn the trade of linoleum design and manufacture. It was soon evident, however, that these activities could not satisfy the young man, whose interests in chemistry had been awakened through the use of dyestuffs in his work, and he found means to continue his education under a tutor in the neighboring town of Preston. He persisted in this despite active discouragement from his family and in due course passed the entrance examination of the University of ManChester. He entered the Chemistry Department of that University in 1903, when he became a pupil of W. H. Perkin, Jr., then at the height of his powers and director of one of the major schools of research in Britain. Haworth took first-class honors in chemistry in 1906 and after three years of research with Perkin he was awarded an 1851 Exhibition Scholarship which enabled him to proceed to Wallach’s laboratory a t Gottingen. His outstanding ability earned him the doctor’s degree after only one year of study in Germany, and he returned to Manchester as a Research Fellow. In 1911, a t the end of the minimum time permissible, he was awarded the D.Sc. degree of Manchester for his work on terpenes. I n the same year he became Senior Demonstrator in Chemistry under Sir Edward Thorpe in the Imperial College of Science and Technology, where he gathered experience in teaching and continued his researches on terpenes. The following year, 1912, when he was appointed to a lectureship in the University of St. Andrews, was of special importance for his future career. He then made acquaintance with the new ideas in carbohydrate chemistry initiated by Purdie and Irvine, whose work had opened up a way for the exploration of the structural chemistry of the sugars. The atmosphere of the research laboratory of St. Andrews was exciting and stimulating with Irvine as director and Purdie still a frequent visitor and a powerful influence. The importance of the problems to be 1

2

WALTER NORMAN HAWORTH

solved was clear and Haworth, realizing that it was impossible to do justice to two major fields of research, gradually relinquished work on the terpenes and concentrated his efforts on the carbohydrates. Shortly afterwards, however, the adven.t of World War I put an end to academic research and Haworth took an active part in the organization of the St. Andrews laboratories for the production of fine chemicals and drugs. In 1919 a return to academic research became possible and the laboratories were filled with an eager crowd of undergraduate and postgraduate students. The carbohydrate investigations were renewed wit,h vigor and Haworth’s special concern at this stage was with the structure of the disaccharides. He developed this work with intense energy but, in addition, he took a full part in the social life of St. Andrews where he made many friends, and he found much pleasure in exploring the less accessible parts of the Highlands of Scotland, partly on foot and partly by motorcycle. It was no surprise to his friends when in 1920 he was invited to the Chair of Organic Chemistry at Armstrong College, Newcastle-upon-Tyne, in the University of Durham. Phillips Bedson, who was at that time head of the department, retired in 1921 and Haworth succeeded to the directorship. For the first year or two problems of accommodation and organization required urgent attention, but work on the oligosaccharides was continued steadily and a start was made on the study of the sugar carbonates. During the early part of his professorship at Armstrong College, Haworth lived in Hatfield College in the Durham Division of the university, making many friends in Durham and Newcastle and doing much t o promote cordial relationships between the two divisions of the university. In 1922 he married Violet Chilton Dobbie, daughter of the late Sir James Dobbie, LL.D. F.R.S. She, together with their two sons, survives him. Professor and Mrs. Haworth found a house in the pleasant district to the north of Newcastle bordering on the Town Moor and here their many visitors were received with a gracious and friendly hospitality which made each occasion memorable. A further move came in 1925 when Haworth succeeded Gilbert Morgan as Mason Professor of Chemistry and Director of the Chemistry Department in the University of Birmingham. He now found himself at the head of a large and active school of chemistry housed in spacious laboratories at Edgbaston. Several experienced post-graduate workers moved with him to Birmingham and the change involved comparatively little dislocation in his research effort. The school at Birmingham grew rapidly and from this time on included an increasing number of post-graduate workers who were attracted to Haworth’s laboratories to gain experience in carbohydrate research.


3

For the first few years a t Birmingham, the Haworths had their home at Berkswell, in the heart of the country, some thirteen miles east of the city. Their Elizabethan house formed an ideal setting for the hospitality they so generously offered to their friends and colleagues both from this country and from abroad. After some eight years Haworth began to find the daily motor journeys unduly tiring and he decided t o move to a district within easier range of the University. With the assistance of Philip Haworth, his architect brother, he designed and built a house about five miles to the south of Edgbaston, in a delightful situation overlooking the Worcestershire plain. Every modern device for comfort and ease of working was incorporated in the design which combined most happily modern convenience with dignity of proportion and good taste in decoration and furnishing. The laying out. of the grounds provided Haworth with one of his greatest interests and delights. His knowledge of architecture was of great service when a major university building problem required his attention. It had been clear for some years that the Chemistry Department needed considerable expansion and a generous gift from A. E. Hills enabled this to be carried out. The new buildings, which were set alongside the original Chemistry Department, were constructed on the most modern lines for teaching and research in organic chemistry and were formally opened in 1937 by the President of the Royal Society, Sir Gowland Hopkins. Haworth had always lived and worked a t high intensity and shortly after the completion of the new laboratory a breakdown in health occurred which gave cause for much anxiety. He made a good recovery, however, and was ready to play a strenuous and responsible part in the direction of chemical research during the war. The end of the war brought him little relief from pressure of work and responsibility. The rapid increase in the number of undergraduate and post-graduate students resulted in difficult problems of staffing and accommodation, and the call on his services by societies and government departments remained almost as heavy as it was during the war. In 1946 he undertook an extensive tour in the United States of America and Canada in the course of which he attended the Starch Round Table at Estes Park, Colorado, and lectured to the American Chemical Society. He particularly enjoyed this tour which enabled him to renew personal contact with C. S. Hudson whom he had first met a t the tenth Conference of the International Union of Chemistry a t Liege in 1930, and whose friendship he greatly valued. Two years later, in 1948, he reached the age of sixty-five and, although still at the height of his powers, he retired from the Chair a t Birmingham that he had held with such distinction for twenty-three years. The severance from Birming-

4


ham University affected him strongly but it was a source of satisfaction to him to feel that the carbohydrate research school which he had founded there would continue under the leadership of one of his pupils (Professor Maurice Stacey, F.R.S.) and that active centers of carbohydrate research directed by others of his former pupils were established in many universities including Edinburgh (Dr. E. G. V. Percival and the writer), Bangor, North Wales (Professor S. Peat, F.R.S.), Bristol (Dr. J. K. N. Jones), and Minnesota (Professor F. Smith). Retirement, however, brought him little relaxation of effort ; his advice continued to be sought, and he served on many Boards and Committees. He was appointed to represent the Royal Society at the seventh Pacific Science Congress in New Zealand in February 1949 and, in addition to attendance at the meetings, Sir Norman and Lady Haworth visited many university centers in Australia and New Zealand. The tour, which involved the delivery of lectures in Sydney, Adelaide, and Melbourne, gave him special pleasure and it was in every respect a great success. After his return from Australia he continued his active interest in carbohydrate chemistry, and on the 15th of March, only a few days before his death, he presided over a Chemical Society Committee on Carbohydrate Nomenclature. He appeared to be in excellent health and spirits and conducted the meeting with his customary speed and precision, but a few days later his health failed and he died, without pain or suffering, on March 19, 1950. Kaworth’s reputation as a leading worker in the carbohydrate field was securely established when he moved to Birmingham, and the record of the twenty-five years from 1925 to 1950 brought increasing recognition of his great work. Awards and honors by British and Foreign Societies and Academies came to him with ever-increasing speed during this period. He became a Fellow of the Royal Society (London) in 1928. In 1930 he took a prominent part in the tenth Conference of the International Union of Chemistry at LiBge, and in 1932 he lectured before a crowded meeting of the German Chemical Society in Berlin. I n the following year he received the Longstaff Medal of the Chemical Society jointly with Sir James Irvine. He was the recipient also of the Davy Medal of the Royal Society (1934) and the same Society’s Royal Medal (1942). He was the first British organic chemist to be awarded the Nobel Prize, an honor which he shared in 1937 with Professor P. Karrer. He was an honorary graduate of many Universities including Cambridge (Sc.D.), Queen’s University, Belfast (D.Sc.), Oslo (D.Sc.), and Zurich (D.Sc.). Among the recognitions which he appreciated most highly was the honorary LL.D. degree which he received from the University of Manchester in 1947. He was an honorary member of many foreign


6

societies and academies (Haarlem, Brussels, Munich, Vienna, Finland, Dublin, and the Swiss Chemical Society). He was President of the Chemical Society (London) during the difficult years 1944-46, and VicePresident of the Royal Society (1947), and in the University of Birmingham he held the office of Dean of the Faculty of Science and acted as Vice-principal of the University for the period 194748. It was a source of deep gratification to all who knew him when in 1947 he received the honor of a Knighthood in recognition of his work. It is impossible to give details of his services t o science through active membership of Boards, Committees, and Councils, but brief reference may be made to his share in building up the work of the Colonial Products Research Council and the Rubber Producers Research Association. During the war he was Chairman of the Chemical Panel in Britain which dealt with atomic energy research, and, a t the time of his death, he was Chairman of the Chemical Research Board of the Department of Scientific and Industrial Research. He took a deep interest in the Advances in Carbohydrate Chemistry and was one of the members of the Executive Committee which arranged for the publication of the first volume. Great as were his achievements and his influence in the world of science he will be remembered by those who knew him even more for other aspects of his character and personality. Foremost among these were the kindliness and thoughtfulness for others which he possessed in such marked degree. He was extremely reticent about himself and his own affairs, and his innumerable acts of kindness were carefully hidden, becoming known only by chance to any but the recipients. All who knew him valued his wise council and admired the uncompromising straightforwardness of his dealings and his loyalty to all who worked with him. On the one hand he expected those associated with him to work with the same intensity of purpose that he himself displayed, and on the other he invariably took a keen personal interest in the welfare and activities of all members, past and present, of his laboratory. He had many interests and had travelled widely. He had a deep knowledge of the classics of English literature and, throughout his life, he was interested in paintings and furniture, the points which concerned him most being the design and beauty of the article as a whole rather than the technical details. He never spared himself in his attention t o the minutest details of the running of his department. In lectures he was a master of clear and dignified expression, and his writings revealed the same polished lucidity, well shown in his classical book “The Constitution of Sugars” (1929), and in his scientific papers. Perhaps his most striking attribute was a capacity for leadership which inspired his colleagues and research workers to an almost passionate enthusiasm for

6


the tasks assigned t o them and gave them a determination to solve the problems irrespective of their difficulty. Few men have possessed this quality so markedly and have combined with it the ability t o visualize a great plan of research and carry it through without digressions on irrelevant side issues. The publications on the chemistry of the carbohydrates which emanated from Haworth’s laboratories number well over 300. They are couched in a lucid but highly compressed style and the discoveries they record dominate every aspect of the subject. It is clearly impossible to attempt a summary of this immense effort in a short article and the utmost that can be attempted is to direct attention to a few of the major achievements. A fuller appreciation of his life and work, including a bibliography of his published papers, will be found in the Obituary Notices of the Royal Society of London (1951), and a memoir will appear also in the Journal of the Chemical Society. In one of the earliest of his papers on carbohydrate chemistry Haworth described the use of methyl sulfate and aqueous sodium hydroxide for the preparation of the methyl ethers of sugars. This discovery was of fundamental importance and the method remains to this day a standard procedure for methylation, applicable both to monosaccharides and to complex polysaccharides. While working in the St. Andrews laboratories he applied this technique to the elucidation of the structures of the disaccharides. The method adopted was t o subject the fully methylated sugar (for example, octamethyl lactose) to hydrolysis, whereby a tetramethyl and a trimethyl sugar were obtained, the position of the free hydroxyl group in the latter indicating the point of junction of the two sugar residues in the original disaccharide. Considerable insight into the structure of certain disaccharides was obtained in this way. For example, octamethyl lactose gave 2,3,6-trimethyl-~-glucose and normal tetramethyl-D-galactose, while octamethyl cellobiose yielded the same trimethyl-D-glucose together with normal tetramethyl-D-glucose. Fully methylated sucrose on the other hand gave rise to normal tetramethy1-Dglucose and to the tetramethyl derivative of the so-called y-D-fructose. In no case, however, could these experiments provide a final answer to the structural problem. At that time a 1,4 or y-oxide ring structure was accepted for the normal sugars and the determination of the ring structure present in the tetramethyl “y”-o-fructose proved to be an extremely formidable task which took many years of patient work to resolve. A new approach to the disaccharide problem was necessary when the ring present in the normal stable forms of the methyl glycosides was shown to be the 1,5-and not the lJ4-oxide, evidence for which was contributed by Haworth through his masterly studies of the y- and I-lactones


7

of methylated gluconic acids. On the one hand the ring structure in the residue which gave rise to the tetramethyl hexose was now clear but the isolation of a 2,3,6-trimethyl hexose left open two possibilities, namely a 1,4-oxide ring and a linkage through C5 or a C4 linkage with a 1,boxide ring. The problem was solved by an ingenious development of the methylation method. I n the case of maltose the sugar was first of all oxidized to maltobionic acid, which on methylation yielded methyl heptamethylmaltobionate. The latter on hydrolysis gave 2,3,4,6-tetramethyl-~glucose and 2,3,5,6-tetramethyl-~-gluconicacid. These observations established the structure of maltose unambiguously as 4-[a-D-ghlCOpyranosyll-D-glucopyranose. By similar series of experiments the structures of lactose (4-[,3-~-galactopyranosyl]-~-glucopyranose), and cellobiose (4-[,3D-glucopyranosyl]-D-glucopyranose) were definitely established, and by suitable modifications of procedure structures were assigned t o gentiobiose (6-[@-~-glucopyranosyl]-D-g~ucopyranose) and melibiose (6-[a-D-galactopyranosyll-~-glucopyranose)and to the trisaccharide raffinose. The fructose portion of sucrose resisted attack for some years. Then it became clear that the ring present in the tetramethyl “7”-D-fructose was of the 1,4 or butylene oxide variety and that it was lJ3,4,6-tetramethyl-D-fructofuranose, one of the clearest experimental proofs of this being the oxidative degradation of tetramethyl “y ”-D-fructose to 2,3,5trimethyl-D-arabonic acid. These results established the nature of the two rings present in sucrose and when cognizance was taken of other observations they enabled the structure a-D-glucopyranosyl p-D-fructofuranoside to be put forward for this important disaccharide. Simultaneously with this work many other lines of investigation were being pursued in Haworth’s laboratories. At Armstrong College he had commenced a study of the sugar carbonates, derivatives of special utility in synthetic work on account of their stability towards acid reagents, in contrast with the isopropylidene derivatives, which unite with similarly situated hydroxyl groups, but are extremely susceptible to acid hydrolysis. These carbonates were of great service in the preparation of pure samples of the methyl glycofuranosides. Another major preoccupation of the Birmingham laboratories in the early days of Haworth’s directorship was a wide survey of the rinisystems present in the “ y ” and normal forms of the methyl glycosides. As this progressed it became possible to make comprehensive generalizations which greatly simplified many aspects of sugar chemistry. The stable glycosides possessed 6-membered rings whereas 5-membered rings were present in the “y” sugars. In view of their respective relationships t o

8


pyrane and furane Haworth coined the names pyranose and furanose, now in general use to designate sugar structures. Once these fundamental structural features had been determined the way was open for structural investigations covering every aspect of carbohydrate chemistry. Reference may be made to work on glycols, the preparation of the disaccharides 4-glucosido-mannose and 4-galactosido-mannose from cellobial and lactal respectively (with repercussions on the application of Hudson’s isorotation rules in the mannose series), and to the extensive investigations into the chemistry of the anhydro sugars, leading to a chemical proof of the stereochemistry of glucosamine. When it became clear that the so-called hexuronic acid isolated by SzentGyorgyi from the adrenal cortex was in reality vitamin C, workers in the Birmingham laboratories, using the techniques of carbohydrate research, were enabled t o establish its structure and very shortly afterwards Haworth and his collaborators synthesised it from L-xylosone by the hydrogen cyanide method and by the direct action of nitric acid on L-sorbose. This work was noteworthy in being the first occasion on which a natural vitamin had been obtained synthetically. It was followed up by a comprehensive investigation of the chemistry of ascorbic acid and of many synthetic analogues. Yet another group of researches on simple sugars was concerned with the transformation of sucrose into products of industrial and medicinal importance. On the whole, however, the tendency was to press forward into the important but little explored fields of the polysaccharides as soon as the requisite fundamental knowledge of the monosaccharides became available. Thus it came about that an increasing proportion of the workers at Birmingham devoted their time to structural investigations on cellulose, starch, glycogen, inulin, hemicelluloses, plant gums, and bacterial polysaccharides. A great stimulus to this work was given by the development of the end-group method for the investigation of polysaccharides. This was first applied to cellulose, where it involved the quantitative separation of one part (or less) of tetramethyl glucose from some 200 parts of other methylated glucoses. This work gave chemical proof of the long chain structure of cellulose and it was followed by a detailed survey of the changes in structure and chain length when cellulose is subjected t o chemical treatment. Chemical proof was given of the presence of the maltose structure in starch; the high proportions of end groups in starch and glycogen, indicating highly ramified structures, were established, and later on attention was directed t o methods for the separation of the amylose and amylopectin components of starches and to enzymatic transformations


9

of these materials, culminating in the discovery of the &-enzyme responsible for the formation of branched chains of a-linked D-glucose residues and in the use of this enzyme for the synthesis of amylopectin. Many pioneer structural investigations were carried out in other groups of polysaccharides, notably on inulin, on the xylan from esparto, on the mannan from yeast and on a series of bacterial polysaccharides; amongst the latter were included somatic and lipoid-bound polysaccharides from M . tuberculosis. Noteworthy also was the work on the dextran produced by strains of Leuconostoc, which is showing great promise as a blood plasma substitute. Soon after the beginning of World War I1 Haworth was asked to undertake work on the chemistry of uranium and its compounds and several teams of workers were organized for this purpose in the Birmingham laboratories. Important investigations on organic fluorine compounds were also carried out. In due course Haworth was appointed Chairman of the Chemical Panel of what became known as the Tube Alloys project and in this capacity he carried a particularly heavy burden until the end of the war. During the three years from 1945 until his retirement from the Chair of Chemistry at Birmingham, work in the carbohydrate field was resumed with all the former intensity, and when he left the laboratories in 1948 researches were in progress covering almost every branch of sugar chemistry. E. L. HIRST


THE METHYL ETHERS OF D-GALACTOSE BY D. J. BELL The University of Cambridge, England

CONTENTS Introduction.. . . . . . . . . . . . . . . ......... Starting-materials for Prepari Starting-materials for Preparing Trimethyl Derivatives. . . . . . . . . . . . . . . . . Starting-materials for Preparing Dimethyl Derivatives. . . . . . . . . . . . . . . . . Starting-materials for Preparing Monomethyl Der tives.. . . . . . . . . . . . . Monomethyl-D-Galactoses.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. 6-Methyl-~-Galactose... . . . . . . . . . . . . . . .................. 2. 4-Methyl-~-Galactose.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. 3-Methyl-~-Galactose.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4. 2-Methyl-~-Galactose.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Characterization of Monomethyl-D-Galactoses . . . . . . . . . . . . . . . . . . . . VII. Dimethyl-D-Galactose5 ............................... 1. 2,3-Dimethyl-~-G ............................... 2. 2,4-Dimethyl-~-Galactose,. . . . . . . . . . . . ......... 3. 2,6-Dimethyl-~-Galactose. . . . . . . . . . . . . . 4. 3,4-Dimethyl-~-Galactose.. . . . . . . . . . . . . 5. 4,6-Dimethyl-~-Galactose. . . . . . . . . . . . . . 6. Characterization of Dimethyl-D-Galactoses. . . . . . . . . . . . . . . . . . . . . . . VIII. Trimethyl-D-Galactoses.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. 2,3,4-Trimethyl-~-Galactose, .,. ............................. 2. 2,3,5-Trimethyl-~-Galactose. ... 3. 2,3,6-Trimethyl-n-Galactose. ..... 4. 2,4,6-Trimethyl-~-Galactose. . . . . . 5. 3,4,6-Trimethyl-~-Galactose. . . . . . 6. Characterization of Trimethyl-D-Galactoses. . . . . IX. Tetramethyl-D-Galactoses.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. 2,3,4,6-Tetramethyl-~-Galactose. .............................. ............................... 2. 2,3,5,6-Tetramethyl-~-Galactose. 3. Characterization of Tetramethyl-D-Galactoses . . . . . . . . . . . . . . . . . . . .

I. 11. 111. IV. V. VI.

11

12 13 14 14 14 14 15 15 17

19 19 19

22 22 24 24

I. INTRODUCTION The basic principles concerned with the preparation of partially methylated derivatives of D-galactose and D-glucose are identical. Since Bourne and Peat' have already provided a full discussion of these principles in connection with the latter sugar it would serve no useful purpose merely to re-enumerate their statements. It must be pointed out, however, that in the case of D-galactose, with only two exceptions, synthetic operations have always commenced with derivatives of the (1) E. J. Bourne and S. Peat, Advances in Carbohydrate Chem., 6 , 145-190 (1950).

11

12

D. J. BELL

pyranose form of the sugar. Apart from 2,3,5,6-tetramethyl-~-galactofuranose and 2,3,5-trimethyl-~-ga~actofuranose, no methylated derivative possessing a furanose ring has so far been isolated or synthesized. Moreover, the benzylidene, isopropylidene and trityl derivatives of D-galactose, as well as certain of their partially substituted products at present known, all possess the pyranose ring. Acyclic galactose ethers are not considered in this article. It is therefore sufficient to consider the relatively large number of pyranose derivatives methylated, wholly or in part, in the positions 2, 3, 4 and 6 and the two methylated furanose forms that have been mentioned. 11. STARTING-MATERIALS FOR PREPARING TETRAMETHYL DERIVATIVES The 2,3,4,6-tetramethyl-~-galactopyranose was obtained as early as 1904 by the full methylation of the methyl a- or p-n-galactopyranosides, followed by acid hydrolysis of the products.'" was accurately charThe 2,3,5,6-tetramethyl-~-galactofuranose acterized in 1924-27 and was prepared by the acid hydrolysis of fully methylated a,p methyl D-galactofuranoside. lb

111. STARTING-MATERIALS FOR PREPARING TRIMETHYL DERIVATIVES It is clear for galactopyranose derivatives that methylation of three specific hydroxyl groups out of those on carbon atoms 2, 3, 4 and 6 can be expected only in those instances where the derivative carries a substituent at one alone of these positions, thus masking a particular hydroxyl group. Obviously, such derivatives fall in the four categories of single masking at carbon atoms 2, 3, 4 and 6 , respectively, the remaining three hydroxyls in each case being free. Starting-materials that fall in this classification are noted as follows. Selective trimethylation at positions 2, 3 and 4 is obtainable by the and 8-" D-galactouse of (a) the 6-trityl derivatives of the methyl pyranosides or 6-trity~-~-ga~actopyranose~ itself, (b) the l16-anhydroj3-~-galactopyranose,~J'~~ ( e ) the methyl p-D-galactopyranoside 6-nitrate,' and ( d ) the methyl 6-tosyl-a-~-galactopyranoside.~~~ (la) J. C. Irvine and A. Cameron, J . Chem. Soc., 86, 1071 (1904). (lb) W. N. Haworth, D. A. Rue11 and G . C. Westgarth, J . Chem. SOC.,126, 2468 (1924). (2) F. Smith, J . Chem. SOC.,1724 (1939). (2a) A. Miiller, Ber., 64, 1820 (1931).. (3) B. Kelferich, L. Moog and A. Junger, Ber., 68, 872 (1925). (4) F. Micheel, Ber., 62, 687 (1929). (5) R. M. Hann and C. S.Hudson, J . Am. Chem. SOC.,65, 484 (1941). (6) Edna M. Montgomery, N. K. Richtmyer and C. S. Hudson, J . Am. Chem. Soc., 66, 3 (1943). (7) J. W. H. Oldham and D. J. Bell, J . Am. Chem. SOC.,60, 323 (1938). (8) H. Ohle and H. Thiele, Ber., 66, 525 (1933). (9) D. J. Bell and S. Williamson, J . Chem. Soc., 1196 (1938).

THE METHYL ETHERS O F D-GALACTOSE

13

Selective trimethylation at positions 3 , 4 and 6 has been accomplished by starting with the 1,2-isopropylidene-~-ga~actopyranose.~~ The methyl 2-tosyl-~-~-galactopyranoside~~ could also be used although no instance has so far been recorded. Selective trimethylation a t positions 2, 3 and 6 has not been accomplished because no suitable starting material is known having free hydroxyls at these three positions and having those at 4 and 5 masked. The supposed 1,3-anhydro-~-galactopyranose, the structure of which was assigned from the fact that it is not oxidized by periodate,12 would have supplied a starting material for 2,4,6-trimethyl-~-galactose,but subsequent investigationlZ8has shown that its full methylation and the subsequent hydrolysis of the product yields 2,3,5-trimethyl-~-galactose (see also page 21), proving that this galactosan is actually l16-anhydroa-D-galactofuranose. Its resistance t o periodate apparently results from the trans-position of its hydroxyl groups at positions 2 and 3 in a tworing structure. Similar resistance to periodate oxidation was found in t,he case of 1,6-anhydro-~-~-glucofuranose, l z ba glucosan which proved to yield 2,3,5-t~methyl-~-glucofuranoseby methylation, followed by acid hydrolysis. IV. STARTING-MATERIALS FOR PREPARING DIMETHYL DERIVATIVES In these instances two of the hydroxyl groups 2, 3, 4 and 6 need to be free and two masked. No derivatives of galactopyranose that meet this condition and could yield a 2,4-dimethyl or a 3,6-dimethyl galactose are known. For the production of each of the remaining dimethy1-Dgalactopyranoses an appropriately masked starting-material is available. From methyl 2,3-dibenzyl-~-~-galactopyranoside~~ 4,6-dimethyl-~-galactose has been obtained; 3,4-dimethyl-~-galactose results by appropriate treatment of methyl P-D-galactopyranoside, 2,G-dinitrate;l42,6-dimethyl~-galactose~*g from methyl 3,4-isopropylidene a - l 6 and p-D-galactopyranosides14 and 2,3-dimethyl-~-galactose from methyl 4,6-benzylidene a-16 and p-D-galactopyranosides. (10) P.A. Levene and G. M. Meyer, J . Biol. Chem., 64, 473 (1925). (11) J. S.D.Bacon, D. J. Bell and H. W. Kosterlite, J . Chem. Soc., 1248 (1939). (12) R. M.Hann and C. S. Hudson, J . Am. Chem. Soc., 63,2241 (1941). (12a) B. H. Alexander, R. J. Dimler and C. W. Mehltretter, J . Am. Chem. Soc., in press (1951). (12b) R. J. Dimler, €1.A. Davis and G. E. Hilbert, J. Am. Chem. SOC.,68, 1377 (1946). (13) J. S. D. Bacon, D. J. Bell and J. Lorber, J . Chem. Soc., 1147 (1940). (14) J. S. D. Bacon and D. J. Bell, J. Chem. SOC.,1869 (1939). (15) R. G. Auk, W. N. Haworth and E. L. Hirst, J . Chem. Soc., 1012 (1935). (16) G.J. Robertson and R. A. Lamb, J . Chem. Soc., 1321 (1934).

14

D. J. BELL

V. STARTING-MATERIALS FOR PREPARING MONOMETHYL DERIVATIVES I n these substances three of the four hydroxyl groups at positions 2, 3, 4 and 6 should be masked and only the remaining one free for methylation. Suitable starting-materials are known for three of the possible four types, the unknown type being a substance that could yield a 4-methyl-~-galactose. 6-Methyl-~-galactosehas been prepared from 1,2:3,4-diisopropylidene-~-galactose, l7 3-Methyl-~-galactose from and 2-methylmethyl 4,6-benzylidene-2-tosyl-cr-~-galactopyranos~de~~~~~ D-galactose from methyl 3,4-isopropylidene-6-tosyl-a-~-galactopyranosidegand also from 1,6-anhydro-3,4-isopropylidene-~-~-galactopyranose, 2o methyl 3,4-isopropylidene-~-~-galactopyranoside 6-nitrate17methyl 3-benaoyl-4,6-benzylidene-a-~-galactopyranoside,~~ and methyl 3-t0syl-a-~~ and P-D-galactopyranosides.2 2

VI. MONOMETHYL-D-GALACTOSES 1. 6-Methyl-D-Galactose

This sugar was first prepared by Freudenberg and Smeykal17 by methylating the free hydroxyl group of “diacetone galactose.” The constitution assigned to the sugar rested upon the following main arguments: (a) the sugar forms an osazone without loss of methyl radicals, ( b ) oxidation by nitric acid does not produce a derivative of galactosaccharic acid containing no methoxyl, ( c ) the strong probability that diacetone galactose must possess either the 1,2,3,4-(pyranose) or 1,2,5,6(furanose) diisopropylidene structure. It is now clear that the 1,2,3,4 structure was correctly assigned since &acetone D-galactose can be oxidized to diacetone-D-galacturonic acid. 6-Methyl-~-galactose has also been prepared by methylation of a diisopropylidene-D-galactose dibenzyl mercaptal by Pacsu and Trister.22a (See section on 4-methylD-galactose, page 15.) 2. 4-Methyl-~Calactose This sugar has not so far been synthesized. A monomethyl-Dgalactose, isolated from the hydrolysis products of methylated damson gum, is considered by Hirst and Jones,2s on good evidence, to be the (17) K.Freudenberg and K. Smeykal, Ber., 69, 100 (1926). (18) A. C.Maehly and T. Reichstein, HeEu. Chim. Acta, 80, 496 (1947). (19)F. Reber and T. Reichstein, Heh. Chim. Acta, 28, 1164 (1945). (20) D.McCreath and F. Smith, J . Chem. SOC.,387 (1939). (21) M. Gyr and T. Reichstein, Helu. Chirn. Acta, 28, 226 (1945). (22)E.Sorkin and T. Reichstein, Helu. Chim. Acta, 28, 1 (1945). (224 E.Pacsu and S. M. Trister, J . A m . Chem. SOC.,62,2301 (1940). (23) E.L. Hirst and J. K. N. Jones, J . Chem. Soc., 506 (1946).


15

4-methyl derivative. An osazone was prepared, apparently identical with the known 4-methyl-~-galactosazone obtained from 2,4-dimethylD-galactal and the sugar itself showed no downward rotation-change in cold methanolic hydrogen chloride, indicating substitution in position 4. It should be noted that the “4-methyl galactose” described in TollensElsner’s “Kurzes Handbuch der Kohlenhydrate ” (4th Edition, p. 344) is, in fact, 6-methyl-~-galactose, as shown by Munro and PercivaLZ4

3. S-Methy 1-DGalactose Reber and Reichstein,19*’8by partial tosylation of methyl 4,6-benzylidene-a-D-galactopyranoside followed by chromatography of the crude product, succeeded in preparing crystalline methyl 2-tosyl4,6benzylidene--a-D-galactopyranoside. The corresponding @-compoundwas prepared through the 3-carbethoxy derivative of methyl 4,6-benzylidene8-D-galactopyranoside. On methylation, each 2-tosyl glycoside yielded the corresponding 3-methyl ether and these, after treatment with sodium amalgam in methanol and water, were respectively converted into the methyl 3-methyl-4,6-benzylidene-a- and P-D-galactopyranosides. I n the case of the P-compound, catalytic reduction removed the benzylidene radical and methyl 3-methyl-@-~-galactopyranoside was produced. The free 3-methyl-n-galactose, obtained from the methyl 3-methyl-@-~galactopyranoside, is crystalline and forms a monomethyl osazone identical with that prepared from 2,3-dimethyl-~-galactose.~~~~ Since this sugar differs from 2-methyl-~-galactose, which is the only possible alternative that could be formed by this method of synthesis, its constitution is clearly established. 4. 2-Methyl-D-Galactose Oldham and Bell7 obtained this sugar in crystalline form by methyla6-nitrate, foltion of methyl 3,4-isopropylidene-~-~-galactopyranoside lowed by stepwise removal of the substituent radicals. Shortly afterwards McCreath and Smith20 obtained the identical substance by methylation of 3,4-isopropylidene-l1G-anhydro-~-galactose followed by removal of the isopropylidene radical to give 2-methyl-l,G-anhydro-~galactose, which was then hydrolyzed to yield the free sugar. The constitution of 2-methyl-~-galactose follows from the fact that treatment with phenylhydrazine yields ~-galactosazone.7.20 5. Characterization of & f o n o m e t h y h ~ a ~ a c t o s e s

As an aid to workers who may have need to identify a monomethylgalactose there are recorded in Table I appropriate data and references. (24) J. Munro and E. G. V. Percival, J . Chem. Soc., 640 (1936).

16

D. J. BELL

TABLEI Monomethyh-Cfalactoses and Some of Their Characteristic Derivatives Melting point, "C

Compound

147-149 145-148 anilide methyl a-D-glycopyranoside methyl P-D-glycopyranoside 2-Methyl-~-galactonicacid amide lactone 3-Methyl-a-~-galactose phenylosazone methyl P-D-glycopyranoaide

4(?)-Methyl-p-~-galactose phenylosazone

165 liquid 131-132 liquid liquid 144-147 178-194 200 176-1 79 liquid 207 150 147-150 148-1 50 128 113-114

6-Methyl-~-galactonicacid lactone

liquid

Rotation solvent f53t52t49-

+86.2 +94

+so

-

t180 tl.7

7 20 23 20, 23 9

7

t27 -27-24 t 1 5 0 . 6 - 108.r -17.2

-

-

t31.9 t63.5 -6.2-

References

+92

-

t 1 4 4 + +77 A, 5780) t137- +77 - 4 3 4 -40

23 23 19 19 19 7, 16, 22a 19 22a 23 23 24a 27 71 22a 24

VII. DIMETHYL-D-GALACTOSES 1. I,J-Dimethyl-D-Galactose

First synthesized by Robertson and Lamb,lB this sugar is known only as a liquid. The simple route followed by these authors consisted in methylating the free hydroxyl groups of methyl 4,6-benzylidene-a-~galactopyranoside. Graded hydrolysis removed first the benzylidene radical to give methyl 2,3-dimethyl-a-D-galactopyranoside and this was then hydrolyzed to yield the free sugar. Oldham and Bell' subsequently obtained a crude preparation by way of the crystalline methyl 2,3dimethyl-4,6-benzylidene-~-~-galactopyranoside. Repeated attempts by Bell and Williamson and by Bell and Greville (unpublished) have failed to obtain this sugar in crystalline form. By methylation of methyl 5,6(24a) E. G. V. Percival and G. G. Ritchie, J . Chem. Soc., 1765 (1936).


17

isopropylidene-P-D-galactofuranosideand subsequent hydrolysis, Pacsu and Trister228obtained an amorphous sugar apparently identical with the substance of Robertson and Lamb.I6 The constitution of the sugar follows from these points: (a) Treatment with phenylhydrazine eliminates ( b ) the sugar, dissolved in methanolic one of the two methyl groups;7Js.22a hydrogen chloride, displays a change in rotation from positive t o negative, indicating the presence of a free hydroxyl group in position 4;16( c ) 2,6dimethyl-D-galactose, which is crystalline and the constitution of which is pro~ed,~ isJnot ~ identical with this 2,3-dimethyl-~-galactose. 2. 2,.4-Dimethyl-~-Galactose This sugar has not been prepared synthetically. It is, however, a frequent constituent of the hydrolysia products of methylated polysaccharides containing galactose radicals, for example plant gums26 and the so-called galactogen of the albumin glands of the snail Helix pomatia.27g28

The constitution of 2,4-dimethyl-~-galactose follows from the work of F. Smith.2 Oxidation (HOBr) of the sugar formed dimethyl-Dgalactonic acid lactone which mutarotated in the manner characteristic of a &lactone, indicating that position 5 was unsubstituted in the sugar, and that probably the hydroxyl group of position 4 was methylated. When the methyl glycoside of the sugar was subjected t o complete methylation, followed by acid hydrolysis of the product, the well-known 2,3,4,6-tetramethyl-~-galactosewas obtained, showing that the dimethyl sugar was a derivative of D-galactose and that its position 5 was unsubstituted. The amide prepared from the lactone of the dimethylgalactonic acid showed a negative Weerman reaction, hence there was methylation a t position 2. This was further indicated by the formation, from the sugar, of a monomethyl osazone. Oxidation of the sugar with nitrir acid produced a dimethyl-D-galactosaccharic acid, proving that position 6 was unsubstituted. 3. 2,6-Dimethyl-~-Galactose The easily prepared 3,4-isopropylidene derivatives of the a and p methyl-D-galactopyranosides form the starting points of the s y n t h e ~ i s . ~ . ~ Methylation of either substance, followed by hydrolytic removal of first the isopropylidene and then the glycosidic methyl radicals leads t o crystalline 2,6-dimethyl-~-galactose. Since the above mentioned syn(25) D. J. Bell, J . Chem. Soc., 692 (1945). (26) See numerous papers by F. Smith, by J. K. N. Jones, and by E. L. Hirst, and

their collaborators, in the Journal of the Chemical Society. (27) E. Baldwin and D. J. Bell, J. Chem. SOC.,1461 (1938). (28) D. J. Bell and E. Baldwin, J. Chem. SOC.,125 (1941).

18

D. J. BELL

theses were recorded, this sugar has been isolated from the hydrolysis products of a methylated polysaccharide from Gigartina stellata by Dewar and PercivaLZ9 Discrepancies between the melting points found for various specimens led Bellaoto reexamine the synthesis of this sugar. Several preparations of what was undoubtedly 2,6-dimethyl-~-galactoseall showed melting points lower than that originally recorded by Oldham and Bell.' It was therefore suggested that the original specimen contained a higher proportion of the pure p-form than any samples obtained at a later date, but L. Hough and J. K. N. Jones, in a personal communication to the writer, state that they have now obtained the sugar in the form of a hydrate, m. p. 109". The constitution of 2,6-dimethyl-~-galactosehas been adduced in several ways. The simplest and most conclusive proof is afforded by periodate oxidation^.^^^^^ The free sugar on oxidation by 10, a t pH 7.5 (phosphate buffer) forms no formaldehyde, indicating substitution in position 6. On treatment of the crystalline methyl p-D-glycopyranoside with NRIOI, one mole of 1 0 4 - is reduced, indicating the presence of two adjacent hydroxyl groups; this evidence coupled with the fact that treatment of the sugar with phenylhydrazine yields 6-monomethyl-~-galactosazone leaves no doubt as to the manner of the substitution. 4. S,Q-Dirnethyl-~-Galactose

This sugar was prepared by Bacon and Bell32 by first masking the free hydroxyls (2 and 6) of methyl 3,4-isopropylidene-p-~-galactopyranoside by esterification with the relatively stable and non-migratory nitrate radical. It was found possible preferentially to hydrolyze the isopropylidene radical and leave the nitrate groups in situ. Methylation of the resulting methyl p-D-galactopyranoside 2,6-dinitrate, followed by de-esterification and hydrolysis of the glycosidic methyl, yielded 3,4-dimethyl-~-galactose. The constitution assigned to this sugar follows mainly from the facts that it failed to form a furanoside on treatment with cold methanolic hydrogen chloride and also that the crystalline amide of the corresponding galactonic acid gave a positive Weerman reaction, indicating that the sugar possessed an unsubstituted hydroxyl in position 2. Later work,31 involving periodate oxidation with liberation of formaldehyde, confirmed the absence of a 6-methyl radical. (29) (30) (31) (32)

E. T. Dewar and E. G. V. Percival, J . Chem. SOC.,1622 (1947). D. J. Bell, J . Chem. SOC.,692 (1945). D. J. Bell, J . Chem. SOC.,992 (1948). J. S. D. Bacon and D. J. Bell, J . Chem. SOC.,1869 (1939).

THE METHYL- ETHERS OF D-GALACTOSE

19

5 . 4,6-Dimethyl-~Galactose

The synthesis of this sugar presented certain technical problems. While the obvious starting material was either of the methyl 4,6-benzylidene-pgalactopyranosides it was quite clear that neither carboxylic nor sulphonic nor nitric esters could be used for temporary masking of hydroxyls 2 and 3. However, satisfactory results were obtained when the benzyl radical was employed. Thus it proved easy to prepare ; this substance after methylamethyl 2,3-dibenzyl-/3-~-galactopyranoside tion followed by reductive removal (sodium in ethanol) of the benzyl radicals and hydrolysis of the glycosidic methyl, gave 4,6-dimethyl-~galact0se.3~ The constitution assigned to the sugar followed from the following arguments : ( a ) Treatment with phenylhydrazine yielded a dimethyl galactosazone identical with that derived from 2,4,6-trimethylD-galactose ( q . v . ) ; ( b ) the ditosylated glycoside did not react with sodium iodide in acetone; (c) the sugar, in presence of methanolic hydrogen chloride, showed polarimetric behavior characteristic of a sugar substituted in position 4. 6. Characterization of Dimethyl-D-Galactoses As an aid to workers who may have need to identify a dimethylgalactose there are recorded in Table I1 appropriate data and references.

VIII. TRIMETHYL-D-GALACTOSES 1 . 2,S14-Trimethyl-~-Galactose

The first synthesis of 2,3,4-trimethyl-~-galactose, which had previously been isolated from the hydrolysis products of methylated galactosans, was achieved by McCreath and F. Smith.20 1,6-Anhydro-~galactopyranose, treated with dimethyl sulphate and alkali, underwent easy methylation and the resulting crystalline 2,3,4-trimethyl-l16anhydro-D-galactopyranose was conveniently hydrolyzed t o the free sugar hydrate. The synthesis of this substance was also effected by F. Smith.2 Methyl 6-trityl-a-~-galactopyranoside, in acetone solution, was treated six times with dimethyl sulphate and sodium hydroxide solution. The imperfectly methylated material thus obtained was then subjected to two treatments with methyl iodide and silver oxide. The necessity for so many treatments with methylating reagents emphasizes the difficulty of etherifying a glycoside substituted by the trityl radical in position 6. Subsequent to removal of the trityl radical, the methyl 2,3,4-trimethyl(33) J. S. D. Bacon, D. J. Bell and J. Lorber, J . Chem. SOC.,1147 (1940).

20

D. J. BELL

TABLE I1 Dimethyl-D-Galactoses and Some of Their Characteristic Derivatives Melting Rotation Compound [alD point, “C solvent 2,3-Dimethyl-~-galactose liquid CHC18 tll t 8 0 .9 Hz0 f 5 7 - 3 +lo5 HzO methyl 0-D-glycopyranoside liquid -10.7 CHCl, 4-23.0 H2 0 methyl a-D-glycopyranoside liquid CHCla 4-173.7 f167 CHCls t210 HzO anilide 130-131 f 1 1 9 . 4 EtOH 128-129 154-155 -57 (20 min.) + +12 EtOH 2,4-Dimethyl-@-o-galactose 103 f 2 2 + +85.6 HzO monohydrate 100-103 t 8 5 . 7 HzO methyl &D-glycopyranoside 165-166 :ero Hz0 f142 methyl a-o-glycopyranoside 105 HzO anilide 216 214-216 2,4-Dimethyl-o-galactonic acid 113 lactone f 1 6 2 . 2 - +52.6 HzO 167 amide 4-59 HzO 165 phenylhydrazide 183 2,6-Dimethyl-f3-~-galactose 128-130 f 4 6 . 8 4 +87.5 HzO 106-108 f 4 5 - 3 +88 Ha0 119- 120 f 4 8 4 +87 HzO 1090 monohydrate methyl 0-o-glycopyranoside 73-75 -24 CHCls 72 - 22 CHCls t2 HzO anilide 121- 122 CzHsOH t15 2,6-Dimethyl-~-galactonic acid lactone -49 + -24 liquid HzO amide 154-155 t 4 6 HzO phen ylhydrazide 140 -44.8 140 CzHsOH 3,4-Dimethyl-o-galactose 164-166 t 9 5 4 $117 HzO methyl b-D-glycopyranoside 102- 103 - 9 . 1 CHCls 3,4-Dimethyl-~-gaIactonic acid lactone liquid t 8 9 + +7 HzO amide 172-174 4,6-Dimethyl-or-~-ga~actose 131-133 11334 +76.9 Ha0 phenylosazone 160-162 -51+ -21CzHsOH 159-160 158 methyl 8-o-glycopyranoside 140 -41.5 CHCls a L. Hough and J. K. N. Jones. (Private communication.) (34) E. G. V. Percival and J. C.Somerville, J . Chem. Soc., 1615 (1951). (34a) D. J. Bell and G. D. Greville, J . Chem. Soc., in the press (1951).

12efer-

ences 16 22a 34a 34a 34a 16 34a 34a 16 22a 34a 2 27 2 2 2 27

2 2 27 2 7 30 29 30 29 30 28 29 29 29 29 30 32 32 32 32 33 33 9 34 33

-

THE METHYL ETHERS OF D-GALACTOSE

21

a-D-galactopyranoside was purified by distillation and from the product thus obtained, after hydrolytic elimination of the glycosidic methyl, 2,3,4-trirnethyl-~-galactose crystallized as a hydrate. By drying the hydrate over phosphorous pentoxide an anhydrous crystalline product was obtained. The structure of 2,3,4-trimethyl-~-galactose had previously been proved by Challinor, Haworth and H i r ~ on t ~the ~ following grounds: (a) Oxidation (HOBr) of the sugar yielded a lactone showing the characteristic behavior of a &lactone; ( b ) oxidation (HNO3) of the lactone yielded a trimethyl derivative of D-galactosaccharic acid. Hence the methyl groups must occupy positions 2, 3 and 4. 2. 2,3,6-Trimethyl-~-Galactose This sugar has been synthesized, in an impure state, by Luckett and Smith.36 The stages were as follows: Crude mixed a and p forms of methyl-D-galactofuranosides were tritylated in position 6 and the resulting amorphous product methylated to yield the amorphous 2,3,5trimethyl ether. This was then converted by stepwise removal of the trityl group and the glycosidic methyl into crude 2,3,5-trimethyl-~galactose. The amorphous sugar can, however, be oxidized to give a crystalline lactone; this substance yields a characteristic crystalline amide and a phenylhydrazide. Recently, Alexander, Dimler and Mehltretter12“ have obtained this 2,3,5-trimethyl-~-galactose by the (see page 13) and have methylation of 1,6-anhydro-a-~-galactofuranose identified the sugar by oxidation to a crystalline lactone which yielded a crystalline amide and phenylhydrazide ; all three of the substances proved to be identical with those synthesized by Luckett and Smith. 3. 2,3,6-Trimethyl-~-Galactose So far as can be ascertained, this sugar has not yet been synthesized.

It has, however, been isolated from the hydrolysis products of the methylated derivatives of two interesting polysaccharides formed by certain Penicillia when grown on synthetic media with D-glucose as sole carbon source. The first of these, “varianose,” contains D-galactoe radicals linked 1 to 4. 37 The second polysaccharide, “galactooarolose,” is so far unique in containing radicals linked 1 to 5 and is therefore based ~ constitution of this sugar has been on a furanoside s t r u c t ~ r e . ~The established as follows: (a) Oxidation by HOBr yielded a crystalline l a c t ~ n e , ~identical ~ , ~ ~ with the Crystalline trimethyl-7-D-galactonolactone previously obtained by Haworth, Hirst and StaceySgon partial “(35) S. W. Challinor, W. N. Haworth and E. L. Hirst, J . Chem. SOC.,258 (1931). (36) Sybil Luckett and F. Smith, J . Chem. Soc., 1114 (1940). (37) W.N. Haworth, H. Raistrick and M. Stacey, Biochem. J . , 29, 2668 (1935). (38) W.N. Haworth, H. Raistrick and M. Stacey, Biochem. J . , 81, 640 (1937). (39) W.N. Haworth, E. L. Hirst and M. Stacey, J . Chem. Soc., 2481 (1932).

22

D. J. BELL

methylation of 7-D-galactonolactone and to which the structure of the 2,3,6-trimethyl derivative was tentatively assigned, and identical amides were also obtained from the trimethyl lac tone^;^^^^^^^^ (b) Haworth, Raistrick and Staceya7further showed that the hydroxyl of position 4 was unsubstituted in the sugar, using conventional methods. 4. 2,4,6-Trimethyl-~-Galactose

This sugar was first isolated from the hydrolysis products of methylated agar by Percival and S o m e r ~ i l l e . ~Its ~ synthesis was effected by Bell and Willia~nson,~ starting with either the a- or b-forms of methylD-galactopyranoside. (The original paper should be consulted for the synthetic routes.) The structure of 2,4,6-trimethyl-~-galactose was established as follows:a4 (a) The trimethyl sugar yielded a crystalline dimethyl osa~one;(b) oxidation (HOBr) yielded a lactone which mutarotated in the manner characteristic of a b-lactone; (c) the rotation of the sugar, in methanolic hydrogen chloride, was characteristic of a galactose derivative substituted in position 4; (d) oxidation by HNOa failed t o produce a trimethyl derivative of galactosaccharic acid. Final confirmation of the structure of this sugar, which was the first of a number indicating the natural occurrence of the 1-3 linkage in galactosans, was obtained by the above-mentioned synthesis. 5. SJQ,6-Trirnethy~-~-Galactose

Levene and Meyer,lo by methylation of 1,2-isopropylidene-~-galactopyranose, obtained a sirupy trimethyl-D-galactose which was apparently the 3,4,6-derivative. The reasons for assigning the above quoted structure were fairly obvious: (a) The monoacetone compound, obtained from diacetone galactose, which has a free hydroxyl group in position 6, is non-reducing; (b) the lactone obtained by HOBr oxidation of the free sugar displays a rotation change characteristics of the b-lactones of aldonic acids. No crystalline derivatives are known. 6. Characterization of Trimethyl-DGalactoses As an aid to workers who may have need to identify a trimethylgalactose there are recorded in Table 111appropriate data and references.

IX. TETRAMETHYL-D-GALACTOSES 1. d,~,Q,6-Tet~amethyl-~-Ga~actose

This sugar is conveniently obtained by complete methylation of either the a- or &form of methyl D-galactopyranoside, followed by acid hydrolysis. Its constitution has followed from the fact that its oxida-

23


TABLE 111 Trimethyl-D-Galactoses and Some of Their Characteristic Derivatives ~

Compound

Melting point, "C

2,3,4-Trirnethyl-a-~-galactose monohydrate 80 86 anilide 167 169 2,3,4Trimethyl-~-galacton~c acic lactone Iiquid phenylhydrazide 2,3,5-Trimethy~-~-ga~actose

2,3,5-Trimethyl-~-galactonic acid lactone amide phenylhydradde 2,3,6-Trimethyl-~-galactose 2,3,6-Trimethyl-~-galactonic acid lactone

165-167 175-176 liquid liquid

90 90 152 162-163 144 liquid

101 99 97-98

methyl @-D-glycopyranoside hemihydrate methyl a-D-glycopyranoside anilide 2,4,&Trimethyl-~-galactonicacid lactone amide 3,4,6-Trimethyl-~-galactose 3,4,6-Trimethyl-~-galactonicacid lactone

+152+ +150+

+114 4-114

+80+ +I9 +134+ 4-24

-

-5 -8 -37+

-35

-32

+3 4-5 f 18 4-87

References

2 20 2 20 35 2 35 20 36 12a 36 12a 36 12a

36 39 -

+163.9 -92+ -38

39 38 40 37 39 34 9 9 23 23 9 41

liquid

4-152- +50 f74 -43

34 34 10

liquid

+6+

10

-

phenylhydrazide 2,4,6-Trimethyl-or-~-galactose

Rotation solvent

135 104-105 102-105 11 1-1 12 102 83-85 73-74 179 Liquid

167

- 4 0 4 -28 -32.9+ -21.3 -30.6 (h, 5780) -

+124 + +93 +124+ $90.4 -40.9 4-18 -

+20

(40) E. Pacsu, S. M. Trister and S. W. Green, J. Am. Chem. SOC.,61,2444 (1939). (41) E.L. Hirst and J. K. N. Jones, J . Chem. Sac., 1482 (1939).

24

D. J. BELL

tion yields a lactone that mutarotates as a 6-lact0ne.~~~ There have been several subsequent confirmations of the structure of this sugar, one of the most direct of which is the proof through periodate oxidationd2 that the a- and p-forms of methyl-D-galactoside that supply the startingmaterial are indeed pyranosides. The complete methylation of lactose, 4 3 m e l i b i o ~ e ~and * * ~various ~ polysaccharide~,~~ followed by acid hydrolysis, yields this tetramethyl-D-galactose as one of the products, indicating terminal D-galactopyranose moities in these sugars and polysaccharides. As this sugar rarely appears crystalline it is most readily identified as its anilide. 2. 6,3,6,6-Tetrarnethyl-~-Galactose The liquid methyl galactoside obtained by cold treatment of D-galactose with methanolic hydrogen chloride was methylated by Haworth, Rue11 and Westgarthlb to yield a levorotatory product. This was hydrolyzed by 0.02 N hydrochloric acid to give a liquid tetramethyl sugar which was also levorotatory. The constitution of this was deduced to be furanose since oxidation (HOBr) yielded a liquid lactone having the properties of a y-1actone.de 3. Characterization of Tetramethyl-D-Galactoses

As an aid to workers who may have need to identify a tetramethylgalactose there are recorded in Table IV appropriate data and references. (41a) W. N. Haworth, E. L. Hirst and D. I. Jones, J . Chem. SOC.,2428 (1927).

(42) E. L. Jackson and C. S. Hudson, J. Am. Chem. SOC.,69, 994 (1937). (43) W. N. Haworth and Grace C. Leitch, J . Chem. SOC.,llS, 188 (1918). (44) W. Charlton, W. N. Haworth and W. J. Hickinbottom, J. Chem. SOC.,1527 (1927). (Ma) W. N. Haworth, J. V. Loach and C. W. Long, J . Chem. SOC.,3146 (1927). (45) J. K. N. Jones and F. Smith, Advances i n Carbohydrate Chem., 4, 243-291 (1949). (46) W. N. Haworth, E. L. Hirst and J. A. B. Smith, J . Chem. Soc., 2659 (1930).

25


TABLEI V Tetramethyl-D-Galactosesand Some of Their Characteristic Derivatives

Compound

Melting point, "C

2,3,4,6-Tetramethyl-~-galactose liquid a-pyranose form anilide

72 192 192 195-196

methyl a-glycopyranoside liquid methyl P-glycopyranoside 48-49 2,3,4,6-Tetramethyl-~-galactonic acid amide 121 Glactone liquid

Rotation aolvent

- 109.5" +62.6 +go. 0 +142--, +118 -77- +37.7 -83-t +41 -

+190 +18.7

References

la la

la 41a,44a,47 44a,48 43 49 50 50

-

+35.7 +156-+ +26.1

-

52 41a

(14 hrs.)

+166.5--,$26.2

51

(21 hrs. eqnilib.)

+153 +lo1 +96 +128 p henylhydrazide 135-137 2,3,5,6-Tetramethyl-~-galacliquid tose 2,3,5,6-Tetramethyl-~-galactonic acid liquid 7-Lactone

-

46 46 46 46 41a

lb

-21.2

-

-

-27.1 + -25.2

lb

(12days)

-34 - 13 -11

46 46 46

(47) H.H.Schlubach and K. Moog, Ber., 66, 1957 (1923). (48) J. C. Irvine and D. McNicoll, J . Chem. Soc., 97, 1449 (1910). (49) E. Baldwin and D. J. Bell, J . Chem. SOC.,1461 (1938). (50) D. J. Bell, J . Chem. Soc., 1543 (1940). (51) H.D. K.Drew, E. H. Goodyear and W. N. Hrtworth, J . Chem. Soc., 1237 (1929). (52) J. Pryde, E. L. Hirst and R. W. Humphreys, J . Chem. Soc., 127, 348 (1925).


THE SYNTHESIS OF OLIGOSACCHARIDES BY W. L. EVANS,

D. D. REYNOLDSAND E. A. TALLEY

The Ohio State University, Eastman Kodak Company, Eastern Regional Research Columbus, Ohio Rochester, New York Laboratory, U. S. Department of Agriculture, Philadelphia, Pennsylvanaa

CONTENTS I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27 1. Definition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28 2. Linkage Types. .. .......... . . . . . . . . . 28 11. Historical De ............................................. 111. Reaction Type.. ......... 1. Formation of the OligosaccharideLmkage. . . . . . . . . . . . . . . . . . . . . . . . . a. Enzymatic Syntheses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . b. Action of Dehydrating Agents.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . c. Koenigs-Knorr Reaction. . . . . . . . . . . . . . . . ............... d. Addition to Compounds of Ethylene Oxide e . .. . . . . . . . . . . . e. Alkali Salt Elimination.. ................................... 2. Alteration of the Oligosaccharide Linkage. . . . . . . .

31 35 36 39 41 50 51

a. The Lobry de Bruyn and van Ekenstein Rearrangement c. The Aluminum Chloride Rearr d. The Hydrogen Fluoride Rearr e. The Pyridine Rearrangement. .

57

......................

60

Conclusion.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............. Table of Glycosyl Halides.. . . Table of Compounds of Alcoholic Type. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Table of Oligosaccharides.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

65

g. The Wohl-ZemplBn Degradation IV. V. VI. VII.

........

. . . . . . . . . . . . . 58 . . . . . . . . . . . . . 59

67 70

I. INTRODUCTION The synthesis of oligosaccharides has played an important part in the development of carbohydrate chemistry. In the early days, the laboratory workers were interested mainly in preparing those compounds which normally resulted from living processes. They proved that a so-called “vital force” was not necessary for the production of these 27

28

W. L. EVANS, D. D. REYNOLDS AND E . A. TALLEY

important substances. Later the emphasis shifted t o the development and use of methods of synthesis which indicated the structures of the compounds thus formed. These later workers were able to prove or confirm the structures of various saccharides occurring in nature and to synthesize compounds of known structure for further studies of the chemistry of this important group. 1. Definition The name oligosaccharide was suggested by Helferich, Bohm and Winkler’ for the simpler, crystalline compound sugars which are formed from two or more molecules of monosaccharides, i.e., those compounds formed from n molecules of monosaccharides by the elimination of n - 1 molecules of water. Oligo- is a combining form from the Greek b h y o s meaning few; thus the name literally means composed of a few saccharides. The oligosaccharides are the carbohydrates intermediate between the monosaccharides and the polysaccharides. They may be defined as those polymers of monosaccharides where the value of n is a definite small whole number while the polysaccharides are those polymers where n is very large and relatively indefinite. The value of n for the oligosaccharides has been limited provisionally to a maximum of six by Tollens and ElsnerJ2and by Beilstein.8

2. Linkage Types Since monosaccharides contain one potential or actual carbonyl group and one or more hydroxyl groups, the linkage between the monosaccharide units of an oligosaccharide may be of three different types.2 The first, or trehalose type of union, may be thought of as having been formed by the elimination of water between the hydroxyl groups of the hemiacetal forms of two monosaccharide molecules. The resulting compound is non-reducing since the reducing groups of both monosaccharide units have taken part in the union. In this case, both of the carbon atoms forming the linkage are attached to two oxygen atoms, the one forming the linkage and the other the ring oxygen (formulas are shown below). Well known examples are the trehaloses and sucrose. The second, or typical acetal type of union, may be thought of as having been formed by the elimination of water between the hydroxyl group of the hemiacetal form of one monosaccharide and an alcoholic hydroxyl group on the second monosaccharide. In this case only one of the car(1) B. Helferich, E. Bohm and 5. Winkler, Ber., 68, 989 (1930). (2) B. Tollens, “Kurees Handbuch der Kohlenhydrate,” revised by H. Elsner. Johann A. Barth, Leipzig, 4th ed., p. 416 (1935). (3) F. K. Beilstein, “Handbuch der Organischen Chemie,” (F. Richter, editor). Julius Springer, Berlin, 4th ed., vol. 31, p. 2 (1938).

29

THE SYNTHESIS OF OLIQOSACCHARIDES

bon atoms forming the linkage is attached t o two oxygen atoms. The compound resulting from this type of union shows reducing power unless the reducing group of the second monosaccharide is blocked by some other substituent, such as by the formation of a glycoside. Well known examples are cellobiose, gentiobiose, maltose and lactose. The third, or true ether type, may be thought of as having been formed by the elimination of water between two alcoholic hydroxyl groups on different monosaccharide molecules. Neither of the carbon atoms forming this linkage is attached to two oxygen atoms. In this type both of the reducing groups may remain active. Until recently this type of linkage existed in theory only but now Gilbert, Smith and Stacey4 have united two hexose units in this unusual manner. Conceivably all three types of linkages could be present in one oligosaccharide; in fact, both of the first two types are present in gentianose, raffinose and melezitose. The different types of union may be illustrated by the equations given below. Open chain (Fischer projection) formulas will be used in CHiOH

/Ipo\ I\ OH HO \I H / H

?A!-:-: H

I/

H

'

H OH a-D-Glucopyranose

V-I/

__._ I\ _H_ _ HO

.___ HjO __ \-

I

HnoH H OH &D-Fructofuranose

+

H HOH~C/O>.~ H > L o - \ H

pl\

I/

\I

/

I/

+ Hz0 CHIOH

H OH OH H Sucrose (a-D-glucopyranosyl &D-fructofuranoeide) First Type HC=O

/i

1

CHzOH

H I/ \ OHH

HO

H

HOH&/

H

HC=O

+ Water H

I\

H

H HzhH D-Glucose

HAOH (4-EB-~-galactopyranosyl]-D-glucose) ' Water Second Type (4) Violet E. Gilbert, F. Smith and M. Stacey, J . Chem. I ~ O C . , 622 (1946).

+ B-D-Galactopyranose = Lactose

+

30

W. L. EVANS, D. D. REYNOLDS AND E. A. TALLEY

HC=O

HC=O

HC=O

HC=O

HbOH

HboH

HAoH

HboH

H d H

+iiidH

HobH

,:/HAOH

, '

=

HoAH

AH

+HIO

8 /&OH HAOH;: HAOH HAOH I H 2 b :6xi H J O H HzA HiCOH HAOH D-Galactose + D-Glucose = 6-~-Galnctose3-~-glucoseether + Water HO H

~

P

Third Type

this chapter wherever the ring structure is unknown or is not stabilized. Otherwise the Haworth type formulas will be used. In actual practice, as will be apparent later, the formation of these linkages is not as simple as is implied by the equations given above. In most cases the groups which one does not wish to react must be blocked by some easily removable grouping which is stable to the reaction conditions required for the formation of the linkage. The linkage itself is not usually formed by the simple elimination of water. 3. Nomenclature A committee of the American Chemical Society5 has published a provisional set of rules for carbohydrate nomenclature but these do not cover all questions relating to the naming of oligosaccharides. A number of different systems have been used in the literature for these compounds. In this paper the authors will follow as far as possible the usage suggested by the committee for monosaccharide derivatives. The generic form glycosyl is used t o denote the residue left from a glycose when the uncombined hemiacetal hydroxyl is detached from a cyclic modification of an aldose or a ketose. The syl ending is used only where the union occurs through the potential carbonyl group. For the trehalose type of union, one monose will be given the ending syl and the other the ending side, although the union is not quite that present in a typical glycoside such as methyl D-glucoside. In general, numbers will not be necessary for the trehalose type. For example, sucrose may be called either a-D-glucopyranosyl p-D-fructofuranoside or p-D-fructofuranosyl a-D-glucopyranoside. In naming an oligosaccharide of the typical acetal type, the monosaccharide furnishing the carbonyl group for the linkage is given the syl ending. Its name is preceded by the number of the hydroxyl group of the second sugar t o which the carbonyl group is attached. For example, lactose will be called 4-(P-~-galactopyranosyl)D-glucose. In this case the galactose furnished the carbonyl group for the union, which is that of a mixed acetal, and the alcoholic hydroxyl ( 5 ) Chem. and Eng. News, 26, 1623 (1948).

THE SYNTHESIS O F OLIGOSACCHARIDES

31

group of the union was attached to carbon 4 of the glucose portion. The usual methyl p-lactoside would be methyl 4-(~-~-galactopyranosyl)8-D-glucopyranoside. The ether type of disaccharide will be named as a mixed ether, and numbers will be used to indicate the hydroxyl groups between which the union occurs; thus the intermediate compound of Gilbert, Smith and Stacey4 will be named 6-(1,2 :3,4-&isopropylidene-~galactose) 3-( 1,2 :5,6-diisopropylidene-~-glucose) ether.

4. Scope This review will be limited to crystalline compounds or those for which crystalline derivatives have been prepared, since only the crystalline basis furnishes a firm foundation for structural carbohydrate investigations. Certain degradation methods are included because of their usefulness in structural determinations. No procedures are included, however, for the preparation of oligosaccharides from natural sources either by direct isolation or by hydrolysis of substances of higher molecular weight. A short historical sketch is given first. Therein are discussed the syntheses of some of the more common, naturally occurring oligosaccharides. Further information is given in the discussions of the individual methods which follow. These are arranged more or less in historical order except where they are grouped according to type. A few typical examples will be included in each discussion but where the number for a given method is large the compounds concerned will be grouped in tables containing melting points and optical rotations. The literature is covered to approximately the end of 1949.

11. HISTORICAL DEVELOPMENT Early in the development of carbohydrate chemistry it was learned that mineral acids would split polysaccharides into monosaccharides. Later work has shown that this is a pseudo equilibrium process and can be partially reversed if the conditions are correct. Musculus6 is reported to have applied this method in the first successful experiment leading to the synthesis of sirupy polymeric carbohydrates from glucose. The method is of historical interest only since the reaction is very complex. It has been estimated’ that 104 possible trisaccharides might be formed by treating various methylated derivatives of D-glucose with hydrochloric acid. Fischer’s “isomaltose ” synthesiss is important, although the product was a mixture, because it gave evidence that a synthesis did take place and also because the conditions under which it was carried out are similar to those occurring during the preparation of glucose from (6) Referred to by E. Fischer, B e y . , 23, 3687 (1890). (7) H. Frahm, Ann., 666, 187 (1943).

32


starch. The mother liquors (“Hydrol”)* left after the glucose has been crystallized would be expected to contain “isomaltose.”@ Gentiobiose, 6-(p-D-glUCOpyranOSyl)-D-ghCOSe, has been isolated as the crystalline octaacetate from the product prepared according to Fischer’s directions and from “hydrol.”lo The first case in which the preparation of a new sugar was used to distinguish between two possibilities in the structure of a naturally occurring sugar, was the preparation of 3-(p-~-galactopyranosyl)-~arabinose by Ruff and Ollendorff.” The new sugar was obtained by the oxidation of calcium lactobionate. It was split by acids into D-galactose and D-arabinose. In a similar manner wlyxose was prepared from calcium galactonate. The fact that D-arabinose was obtained instead of D-lyxose when the disaccharide from the lactobionate was hydrolyzed confirmed Fischer’s1ls conclusion that the aldehyde group was present in the D-glucose portion of lactose rather than in the D-galactose portion, as had been inferred tentatively by Lobry de Bruyn and Van Ekenstein.llb The reversibility of the splitting of glycosides and oligosaccharides by enzymes was first pointed out by Hi11,12 but it remained for Bourquelot and his coworkers to develop it into a practical method for the preparation of oligosaccharides. Theyls were able to synthesize gentiobiose, and thus to isolate directly for the first time a natural disaccharide which had been prepared synthetically. It was prepared by the action of bitter almond extract on D-glucose. This synthesis, in which the p-glucosidase of almonds was the active enzyme, showed that the configuration of the disaccharide linkage was beta but the point of attachment of the p-glucosyl unit was not indicated. It was also definite proof that enzymes could synthesize oligosaccharide linkages in vitro as well a~ in vivo. A true chemical synthesis of specific oligosaccharides had to await the discovery of monosaccharide derivatives that were suitable as starting (8) G. R. Dean and J. B. Gottfried, Advances in Carbohydrate Chem., 6, 132 (1950). (9) The name isomaltose has now been applied specifically to 6-(or-~-glucopyranosyl)&glucose obtained from the hydrolyzates of dextran and of starch. Cf. M. L. Wolfrom, L. W. Georges and I. L. Miller, J. Am. Chem. Soc., 71, 125 (1949) and Edna M. Montgomery, F. B. Weakley and G. E. Hilbert, ibid., 71, 1682 (1949). (10) H. Berlin, J. Am, Chem. Soc., 48, 1107, 2627 (1926). (11) 0. Ruff and G. Ollendorff, Ber., 33, 1798 (1900). ( l l a ) E. Fischer, Ber., 21, 2631 (1888); E. Fischer and J. Meyer, ibid., 22, 361 (1889). (llb) C. A. Lobry de Bruyn and W. Alberda van Ekenstein, Rec. trao. chim., 18, 147 (1899). (12) A. C. Hill, J. Chem. SOC.,73, 634 (1898); 83,578 (1903). (13) E. Bourquelot, H. HBrissey and J. Coirre, Compt. rend., 167,732 (1913); and J . pharm. chim., [7], 8, 441 (1913).


33

materials. Some method had to be found which would limit the number of possibilities in a given reaction. Purdie and Irvine14 were the first to use blocking groups for this purpose. Their choice was necessarily restricted at that early time to employment of the methyl group to block the positions which they wanted to remain inactive, and the methyl group in the carbohydrate ethers is not easily removed. Fischer and DelbrUckI5 were the first to use the more satisfactory acetyl group for this purpose. The acetate thus obtained is stable under many of the reaction conditions and yet it is easily removed by saponification. Also the acetates of sugars in general are moderately easily crystallized and purified. Only the derivatives suitable for the preparation of the trehalose type of oligosaccharides were available until Helferich and his coworkers16began their researches on the trityl ethers of carbohydrates. This work led the way to the synthesis of gentiobiose, the first oligosaccharide of natural origin to be isolated in a pure state through a true chemical synthesis. The trityl group reacts preferentially with the primary hydroxyl groups of carbohydrates and can be easily removed after acetylation, leaving the primary hydroxyls free and the remainder blocked with acetyl groups. The chemical synthesis of gentiobiose definitely showed that the linkage was between carbon six of one glucose molecule and carbon one of the other, and although it was not readily apparent at the time, the method that was used showed that the configuration of the linkage was beta. The synthesis of gentiobiose was the first of a long series of directed syntheses of oligosaccharides, many of which did not occur in nature. These syntheses depended on the development of a series of suitable derivatives having only one free hydroxyl group. But with all the progress in the development of syntheses of oligosaccharides, the most common disaccharide, sucrose, still challenges the carbohydrate chemist to supply a wholly chemical synthesis. At the time that gentiobiose was synthesized, it was becoming apparent that sucrose was a D-glucopyranosyl D-fructofuranoside although it was not definitely known what the full configuration of the linkage was. At about this time Irvine and his coworkers17 and Pictet and Vogel18 reported sirupy derivatives of D-fructofuranose. In fact it seemed that the sucrose problem had been solved, for Pictet and Vogel also presented a report18 that they had syn(14) T. Purdie and J. c. Irvine, J . Chem. SOC.,87, 1022 (1905). (15) E. Fkcher and K. Delbriick, Ber., 42, 2776 (1909). (16) (a) B. Helferich, L. Moog and A. Jiinger, Ber., 68, 872 (1925); (b) cf. B. Helferich, Advances in Carbohydrate Chem., 3, 79 (1948). (17) J. C. Irvine, J. W. H. Oldham and A. F. Skinner, J . SOC.Chem. Ind., (London), 47, 494 (1928). (18) A. Pictet and H. Vogel, Helv. Chim. Acta, 11,436 (1928);Ber., 63,1418 (1929).

34


thesized it. However, other workers were not able to duplicate their result^'^-^^ and subsequently their report of the synthesis was withdrawn.22 Later workers obtained only isosucrose octaacetate. Although Binkley and Wolfrom21were able to separate control mixtures of sucrose and isosucrose octaacetates readily by chromatographic techniques they could not isolate any sucrose octaacetate. Following the work of Helferich and his coworkera,l6 a number of oligosaccharides were synthesized where the union was formed through the primary hydroxyl group. In the case of the hexoses, for example, the union was through carbon six. A number of the more important naturally occurring oligosaccharides, however, are united through carbon four of one hexose unit. Although Helferich and his coworkers16b*28 it had not been well had isolated 1,2,3,6-tetraacetyl-@-~-glucopyranose, characterized and thus could not be used for an unequivocal synthesis of oligosaccharides linked through carbon four. This type of synthesis had to wait until Hudson and his coworkers24prepared 1,6-anhydro-2,3isopropylidene-p-D-mannopyranose from the pyrolysis products of so-called vegetable ivory. This derivative was shown very definitely to have a free hydroxyl group at the fourth carbon, which was the only free hydroxyl group present. The 1,6-anhydro ring can be split with concurrent acetylation, after the oligosaccharide union through carbon four is formed, t o give a compound containing an acetylated mannose unit. A short time later the next step was carried out; cellobiose and lactoseas were synthesized, although the secondary hydroxyl at carbon four is much less reactive than the primary hydroxyls and mannose is not a unit in either sugar. In each case, the epimer of the natural disaccharide was synthesized first and then rearranged (see page 57). Although sucrose has not been synthesized by strictly chemical means, its synthesis has been accomplished by the use of enzymes from living organisms. 2e An enzyme from the bacterium Pseudomonas saccharophila Doudoroff was allowed to act on D-glucose-1-phosphate in the presence of D-fructose. This synthesis gives little information about (19) G. Zemplbn, and A. Gerecs, Ber., 62, 984 (1929). (20) J. C. Irvine and E. T. Stiller, J . Am. Chem. SOC.,64, 1079 (1932). (21) W. W. Binkley and M. L. Wolfrom, J . Am. Chem. SOC.,68, 2171 (1946). (22) A. Pictet, Helv. Chim. Acta, 16, 144 (1933). (23) B. Helferich and W. Klein, Ann., 460, 219 (1926). (24) A. E. Knauf, R. M. Hann and C. S. Hudson, J . Am. Chem. SOC.,68, 1447 (1941). (25) W. T. Haskins, R. M. Hann and C. S. Hudson, J . Am. Chem. SOC.,64,1289, 1862 (1942). (26) W. Z. Hassid, M. Doudoroff and H. A. Barker, J . Am. Chem. Soe., 66, 1416 (1944).

THE SYNTHESIS OF OLIGOSACCHARIDES

35

the structure of sucrose, but it does indicate how sucrose might be synthesized in nature. Of the common sugars, only those containing the sucrose and the maltose type linkages still challenge the carbohydrate chemist to obtain them by a true chemical synthesis. Some of the difficulties have been indicated for the synthesis of the sucrose linkage, which is also present in raffinose and gentianose. No good method exists for forming the alpha linkage of maltose although the Zemplh modification of the KoenigKnorr reaction tends to produce this linkage. In addition t o the usual difficulties, reaction is much slower with the secondary hydroxyl group involvedz4than with the primary hydroxyl encountered in most of the successful syntheses. 111. REACTION TYPE One may visualize the formation of new oligosaccharides by three different types of reactions. First, a new linkage may be formed between monosaccharides or smaller oligosaccharide units or both. These new linkages may be formed in the sense indicated earlier (pages 28-30) or by the substitution of one monosaccharide for another. Second, a linkage in an existing oligosaccharide may have its configuration changed. This type of reaction is well-known in the case of the simple glycosides but until recently it had not been accomplished with an oligosaccharide. Third, a monosaccharide unit may be changed in some way. This may be a rearrangement or shift in structure, or a change in the carbon chain length; in fact almost any method for converting one monosaccharide into another may be useful if it does not attack the oligosaccharide linkage. A number of methods will be described where the configuration at one or more carbon atoms becomes reversed or where the carbon chain of an oligosaccharide unit is shortened, but so far no one has produced an oligosaccharide by lengthening the carbon chain; for example, no one has converted a pentose unit into a hexose unit while the former was linked to another monosaccharide unit. However, a step in such a type of synthesis has been made by Hann and Hudson,268who prepared acid from crystalline 5-(~-~-galactopyranosy1)-~-gluco-~-guZo-heptonic lactose by the cyanohydrin synthesis. 1. Formation of the Oligosaccharide Linkage As mentioned earlier (page 31), the first attempts to form a new oligosaccharide linkage were by the use of acid catalysts. Although this method has been attempted by ~ t h e r s Purdie , ~ ~ ~and ~ ~Irvine'4 ~ came nearest to success. They obtained what was probably a mixture of (26a) R. M. Hann and C. S. Hudson, J . Am. Chem. Soc., 68, 1390 (1934). (27) H. H. Schlubach and E. Liihrs, Ann., 647, 73 (1941).

36


octamethyl trehaloses by the action of hydrogen chloride on a benzene solution of 2,3,4,6-tetramethyl-~-glucose.The use of enzymes was more successful and furthermore somewhat less complicated mixtures are obtained. The enzymes catalyze the formation of the linkage with only one configuration, instead of both as in the case of acids. a. EnzymaticSyntheses.-The report by Hi1112of the isolation of maltose and “revertose” as phenylosazones was the first step in the development of the enzymatic syntheses. In this case a 40% solution of D-glucose was treated with the yeast enzyme a-glucosidase. Fischer and Armstrong28 reported the isolation of another disaccharide phenylosazone, but the next important step in the development was the work of Bourquelot and his coworkers. They29Jodemonstrated that the same rotational equilibrium was obtained if one mixed methyl 8-D-glucopyranoside with water and emulsin or if a corresponding amount of D-.glucose and methanol were used: methanol

emulsin + D-glucose F=== methyl 8-D-glucopymnoside water

As might be expected, a large excess of methanol caused the point of equilibrium to shift toward the formation of methyl glucopyranoside. By application of this principle, a series of aliphatic and cyclic @-D-glucopyranosides were prepared, using the appropriate alcohols. A similar series of a-D-ghcopyranosides could be prepared using an a-glucosidase instead of emulsin. These findings were applied to the synthesis of genti~biose’~ by the action of bitter almond extract (8-glucosidase) on D-glucose : HC=O

HC=O

HboH 2

HOAH HAOH

H

-

DGlucose

+ Hz0

emulsin A

Gentiobiose

The factors that might be involved in the syntheses were discussed by Bourquelot and Bridela’ on the view that several different enzymes were acting concurrently; a t the present time it appears t o be general opinion that one enzyme, @-D-glucopyranosidase, causes the set of syntheses of (28) E.Fischer and E. F. Armstrong, Ber., 96, 3144 (1902). (29) E.Bourquelot and M. Bridel, J . pharm. chim., [7]6, 13,56, 193 (1912). (30) E. Bourquelot, J . pharm. chim., [7]10, 361,393 (1914). (31) E.Bourquelot and M. Bridel, Compl. rend., 168, 253 (1919).

THE SYNTHESIS OF OLIGOSACCEARIDES

37

beta linkages, and another enzyme, a-D-glucopyranosidase, the syntheses of alpha linkages. Studies on the reactions have indicateda2 that the syntheses of cellobiose and gentiobiose follow the law of mass-action if allowance be made for the displacement of the equilibrium between a-D-glucose and p-D-glucose either by solvent or by concentration of the solution, and also for the concentration of the actual activated form of D-glucose. The amount of a-D-glucose in the equilibrium mixture was reported to be increased by a corresponding increase in the concentration of the disaccharide used, or by the addition of acetone. Kinetic studies indicated that gentiobiose was formed from two moles of 0-D-glucose while cellobiose arose from one mole of p- and one mole of a-D-glucose. Later have used the action of emulsin on a solution of D-glucose as the basis of a method submitted for the practical preparation of gentiobiose. Since the starting material is readily obtainable, the low yield (about 1 % of the theoretical based on the D-glucose taken) is not serious. Although a true chemical synthesis of sucrose is still lacking, an enzymatic synthesis has been a c c ~ m p l i s h e d ,as ~ ~mentioned on page 34. Doud0roff3~was able to isolate from the bacterium Pseudomonas saccharophila Doudoroff a phosphorylase which catalyzed the reversible reaction: Sucrose

+ inorganic phosphate % a-D-glucopyranosyl phosphate + D-fructose

By applying the reverse reaction Hassid, Doudoroff and B a r k e + ~ were ~~ able to prepare and isolate synthetic crystalline sucrose for the first time. According to the analysis of the reaction mixture, about 20% of the theoretical amount of sucrose was formed. Evidence was presented which indicates that when the a-D-glucopyranosyl phosphate condenses with the D-fructose, the a-configuration is not altered and the D-glucose in the sucrose molecule is of the a-type. The same enzyme preparation was found to have no action on t r e h a l ~ s e m , ~a ~l t~~~s~e , ~ ~ * ~ ~ raffinose,a5 glycogen35 or starch.35 Attempts to substitute phosphoric esters of D-fructose for D-fructose met with no success, nor could any reaction be observed between D-fructose and maltosyl phosphate.38 However, when either L-sorbose or D-xyloketose was substituted for (32) I. Vintilescu, C. N. Ionescu and A. Kizyk, Bull. soc. chim. Roumania, 17, 283 (1935); Chem. Abstracts, 80, 71304 (1936). (33) B. Helferich and J. Leete, Org. Syntheses, 22, 53 (1942). (34) See the reviews by (a) I. Levi and C. B. Purves, (Advances i n Carbohydrate Chem. 4, 1 (1949)) and (b) W. 2.Hassid and M. Doudoroff (ibid., 6, 29 (1950)) for more complete discussions of biochemical syntheses in the sucrose series. (35) M. Doudoroff, J . Biol. Chem., 161, 351 (1943). (36) H. A. Barker, W. Z. Hassid and M. Doudoroff, Science, 100, 51 (1944). (37) M. Doudoroff, N. Kaplin and W. 2. Hassid, J . Biol. Chem., 148, 67 (1943). (38) M. Doudoroff, W. Z. Hassid and H. A. Barker, Science, 100, 315 (1944).

38

W.

L.

EVANS, D. D. REYNOLDS AND E. A. TALLEY

D-fructose, reaction occurred in the same manner as with the sucrose synthesis and the resulting &saccharides, a-D-glucopyranosyl a-L-sorbofuranoside'g and a-D-glucopyranosyl ~-~-xyloketofuranos~de~~~ were isolated. The early work of Hassid and his group, discussed above, might seem to indicate that only D-glucose derivatives of ketoses might be formed and that these were all of the sucrose type and non-reducing. That this is not true, is shown by results they obtained later with an aldose, ~-arabinose.41-4s The product ,3-( a-~-glucopyranosyl)-~-arabinopyranose, is a reducing sugar and thus has a free potential aldehyde group. The corresponding ketose derivative, a-D-glucopyranosyl L-maboketoside, was also ~ynthesised;4~ it resulted from the action of the sucrose phosphorylase of Paeudomonas saccharophila Doudoroff on a mixture of a-D-glucose-1-phosphate and L-araboketose and it is therefore reasonable to infer from the method of its production that it is a - ~ glucopyranosyl a-~-araboketofuranoside.~~~ HOHiC

CHIOH

I\

H//AOH\

p"

T//

O'\Y

p0y y-I/ \ H

H /

H

H OH OH OH cY-D-Glucopyranosyl a-baraboketofuranoside

Later it was found that other monoses could be exchanged directly for D-fructose in the sucrose molecule. First, sucrose labelled with C14 in the D-fructose portion was prepared by the action of the Pseudomonas saccharophila enzyme on ordinary sucrose and CI4 labelled ~-fructose.44 Subsequently D-fructose has been exchanged in the same manner for other monoses, for example, ~ - s o r b o s e . ~Thus ~ new oligosaccharides may be prepared by exchanging one monose for another through the action of this ensyme without the use of,the phosphate intermediate, (39) W. 2. Hassid, M. Dhdoroff, H. A. Barker and W. H. Dore, J . Am. Chem. SOC.,67, 1394 (1945). (40) W. Z. Hassid, M. Doudoroff, H. A. Barker and W. H. Dore, J . Am. Chem. Soc., 68, 1465 (1946). (41) W. Z. Hassid, M. Doudoroff and H. A. Barker, Arch. Biochem., 14,29 (1947). (42) M. Doudoroff, W. 2. Hassid and H. A. Barker, J . Biol. Chem., 168, 733 (1947); W. 2. Hassid and M. Doudoroff, Advances in Enzymology, 10, 123 (1950). (43) W. 2. Hassid, M. Doudoroff, A. L. Potter and H. A. Barker, J . Am. Chem.

Soc., 70, 306 (1948). (44) H. Wolochow, E. W. Putnam, M. Doudoroff, W. 2. Hassid and H. A. Barker, J . Biol. Chem., 180, 1237 (1949). (45) W. 2. Hassid, Paper presented before the Division of Sugar Chemistry and Technology, Am. Chem. Soc., April (1950).

39


Syntheses using enzymes as catalysts give rather low yields. The main value of the method lies in its similarity to the processes probably occurring in nature. I n its present stage of development, the synthesis does not immediately indicate the hydroxyl groups between which the linkage occurs. This must be determined by other methods and several good examples of these may be found in the papers of Hassid and his coworkers. b. Action of Dehydrating Agents.-As indicated earlier, the simplest imaginable method for the formation of oligosaccharide linkages is by the direct elimination of water between two hydroxyl groups. Possibly this may happen in some cases with enzymes but in the enzymatic syntheses by Hassid and his coworkers the mechanism is not of this simple type. Acid catalysis may lead to the direct elimination of water between two monosaccharide units. In any case the addition of some agent which would effectively remove the water formed, would be expected to eliminate the tendency toward hydrolysis. Fischer and Delbruck'6 were the first to use a dehydrating agent to remove the elements of water directly in the synthesis of oligosaccharides: CHzOAc

I

OAc

H

CHZOAC

I

H

I

OAc

OAc

I

H

A chloroform solution of 2,3,4,6-tetraacetyl-p-~-g~ucopyranose was treated with phosphorus pentoxide to give a 2% yield of an isotrehalose octaacetate which gave the amorphous free sugar after deacetylation. Three different trehaloses, differing in the configuration of the union, can exist according to theory and might result from this reaction, namely, a,a-trehalose, a,p-trehalose and p,p-trehalose. The cy,a variety occurs in nature and was originally discovered in ergot by Wigge1-5.~~ It has not yet been synthesized. On the basis of calculations of rotations by HudsonJ4' the isotrehalose of Fischer and Delbruck was p,p-trehalose, in impure form. (46) H. A. L. Wiggers, Ann., 1, 173 (1832). (47) C. 8. Hudson, J . Am. Chem. Soc., 88, 1571 (1916).

40


A number of years later, Schlubach and Maurer4*tried a number of modifications with the idea that an acid catalyst might cause the alpha configuration to predominate and give them the natural trehalose, since alkaline catalysts seemed to give the beta derivatives. They first tried treating a benzene solution of the D-glucose tetraacetate with hydrogen chloride, then tried an addition of calcium chloride, and they also melted the glucose tetraacetate with and without zinc chloride, but in no case could an a,a-trehalose derivative be isolated. Their trehalose, after complete methylation, had quite different properties from the natural octamethyl trehalose which they also prepared. Later a number of other oligosaccharides of trehalose type were prepared.49 A trehalose, assigned the alp-configuration on the basis of Hudson’s rules of i s o r ~ t a t i o nwas , ~ ~ prepared in 15% yield by treating a toluene solution of D-glucose tetraacetate first with zinc chloride and then with phosphorus pentoxide. GakhokidzeS0-S2has reported the synthesis of disaccharides by the dehydration technique, using unusual intermediates. The first was c h l 0 r i d e ~ ~by . 6 ~treat~ prepareds3 from 3,4,6-triacetyl-p-~-glucopyranosyl ment with silver acetates4 to give 1,3,4,6-tetraacetyl-~-g~ucopyranose.~~ A mixture of the latter with 2,3,4,6-tetraacety~-~-glucopyranose in dry chloroform was treated first with zinc chloride and then with phosoctaphorus pentoxide to give 2-(~-~-glucopyranosyl)-~-glucopyranose which has been reportedls2S61 acetate. A 2-(~-galactosyl)-~-galactose, may have been prepared in the same way. The second intermediate,51 1,2-isopropylidene-4,6-benzylidene-~-glucopyranose,was prepared by treating D-glucose with benzaldehyde in the presence of zinc chloride and then with dry acetone and anhydrous copper sulfate. The product, the structure of which was reported to have been checked by methylation, was mixed with 2,3,4,6-tetraacetyl-~-glucoseand treated as above to give, after removal of the blocking groups, 3-(~-glucopyranosyl)-~glucose. (The glucosyl union is reported to have the alpha configuration but no evidence is given to support the assignment.) H. H. Schlubach and K. Maurer, Ber., S8, 1178 (1925). H. Vogel and H. Debowska-Kurnicka, Helv. Chim. Acta, 11, 910 (1928). A. M. Gakhokidze, J . Gen. Chem. ( U . S . S . R.), 11, 117 (1941). A. M. Gakhokidze, J . Gen. Chem. ( U . S. S . R.), 16, 1923 (1946). A. M. Gakhokidze, Trudy Tbilis Uchitel. Znst. (Transactionsof Tbilis Teachers’ Institute (U.S. 8. R . ) ) , 2, 146 (1941). (53) W. J. Hickinbottom, J . Chem. SOC.,1676 (1929). (53a) P. Brigl, 2. physiol. Chem., 116, 1 (1921). (54) In the experimental part of the paper,60 silver carbonate was mentioned as the reagent but the amounts used agree for silver acetate which also is given as the reagent in the introduction of the paper. (55) Cf.E. Hardegger and J. de Pascual, Helv. Chim. Acta, 81, 281 (1948), for a discussion of the configuration at carbon atom one. (48) (49) (50) (51) (52)

41


As shown by the examples given, the action of dehydrating agents does not give any information as to the configuration of the oligosaccharide linkage formed but the point of union is indicated if suitable derivatives are used as starting materials. A yield of 45% was reported for the actual formation of the disaccharide linkage in the case of the 3-linked compound, which is a higher yield than those obtained by methods previously discussed. The oligosaccharides with linkages attached to carbons two and three of one unit are quite unusual. c. Koenigs-Know Reaction.-In contrast to the two previous methods discussed, the formation of the oligosaccharide linkage in the KoenigsKnorr reactions6 is quite obviously not the simple elimination of water between two monosaccharide units. In this reaction an hydrogen halide is eliminated between a glycosyl halide and an hydroxyl group. The first glycosyl halide, tetraacetyl-a-D-glucopyranosyl chloride, was prepared in crystalline form by Colley in 18706' by the action of acetyl chloride on D-glucose. Michae168 was able t o prepare phenolic glucosides by interaction of this compound with the potassium salts of the phenols. Then Koenigs and Knorrs6prepared the more useful tetraacetyl-a-D-glucopyranosyl bromide by the action of acetyl bromide on D-glucose. They found that if a solution of the bromide in methanol was allowed to stand for some time, methyl p-n-glucopyranoside was formed, the first case of the synthesis of an alkyl glycoside using the acylglycosyl halides. Koenigs and Knorr also found that dry, powdered silver carbonate, or hot, dry pyridine or a concentrated aqueous solution of silver nitrate were all three useful as condensing agents when tetraacetyl-a-D-glucopyranosyl bromide was dissolved in absolute methanol. The general reaction may be illustrated as follows:

( I /Ipo\

CH~OAC

H

2

:Ac AcO \I-I/IBr

' k

H

>I

H + 2 R O H +AgzCOs-t

I

OAc

CH~OAC

I

H

6AC

where R indicates the alcohol residue. (56) W.Koenigs and E. Knorr, Sitzungsber. Bays. Akad. Wiss., SO, 103 (1900); Ber., 54, 957 (1901). (57)A. Colley, Ann. chim. phys., [4]21, 363 (1870). (58) A. Michael, Am. Chem. J., 1, 305 (1879).

42


The acetylglycosyl bromides have been the most popular of the acylglycosyl halides for use in the Keonigs-Knorr reaction. I n most cases they are sufficiently stable to be fairly easily prepared; yet they are sufficiently reactive to give good results. The iodide, which is very active but difficult to prepare, also has been as well as the chloride, which is less active than either but nevertheless can be used successfully. The fluorides are quite inactive although one has been used successfully.6ea Although the acylglycosyl halides used so far for oligosaccharide synthesis have contained the acetyl group as the acyl component, the benzoates appear to offer advantages and have been used for the preparation of simple glycosides.EO The halogen of the glycosyl halides is of the a-halogenoether typeE‘ *~~ and has a much higher reactivity than the usual alkyl h a l i d e ~ . 6 ~This halogen atom may be replaced by a large number of groups but here we are concerned mainly with the replacement by alcoholic hydroxyl groups and in some cases by orthoacid groups. The glycosyl halides usually have the alpha‘ configuration, as determined by the isorotation rules of Hudsona4and by the formation or nonformation of orthoesters.66 An outstanding exception to this general rule is L-arabinose where the beta configuration is the stable form.66 In a few cases the isomer of the opposite configuration is known, for example, tetraacetyl-a-D-glucopyranosyl bromide can be converted into the corresponding chloride with the beta configuration.E7*68 While a tetraacetyl-a-D-glucopyranosyl halide is formed by the action of hydrogen bromide or hydrogen chloride on pentaacetyl-8-D-glucopyranose, it has been shown by Brig16Sa that fusion of the pentaacetate with phosphorus pentachloride yields 2-tri(59) B. Helferich and R. Gootr, Ber., 62, 2791 (1929). (69s) Violet E. Sharp and M. Stacey, J . Chem. SOC.,285 (1951). (60) R. K. Ness, H. G. Fletcher, Jr., and C. S. Hudson, J . Am. Chem. SOC.,72, 2200 (1950). (61) C. D. Hurd and R. P. Holysr, J . Am. Chem. SOC.,72, 2005 (1950). (62) W. W. Pigman and R. M. Goepp, Jr., “Chemistry of the Carbohydrates”; Academic Press Inc., New York, p. 160 (1948). (63) L. F. Fieser and Mary Fieser, “Organic Chemistry”; D. C. Heath and Company, Boston, 1st ed., p. 154 (1944). (64) C. S. Hudson, J . Am. Chem. SOC.,46, 462 (1924). (65) E.Pacsu, Advances in Carbohydrate Chem., 1, 118 (1945). (66) This and other apparent anomalies shown by arabinose may be explained by

the fact that the spatial arrangement of the groups about the pyranose ring of 8-1.arabinose is the same a8 for a-D-galactose. Cf.C. 8. Hudson and F. P. Phelps, J . Am. Chem. Soc., 46, 2591 (1924) and ref. 62, p. 102. (67) C. D. Hurd and R. P. Holysz, J . Am. Chem. SOC.,72, 1732 (1950). (68) H. H. Schlubach, Ber., SO, 840 (1926); H. H. Schlubach and R. Gilbert, Ber., 69, 2292 (1930).

THE BYNTHESIS OF OLIGOSACCHARIDES

43

chloroacetyl-3,4,6-triacetyl-~-~-glucopyranosyl chloride, from which 3,4,6triacetyl-@-D-glucopyranosylchloride may be obtained. Both of these chlorides are stable substances, in strong contrast with Schlubach’sss tetraacetyl-0-D-glucopyranosyl chloride, which changes with great ease to the more stable a-form. Thus, Hickinbottomb3 has shown that Brigl’s two acyl-P-n-glucopyranosyl chlorides are sufficiently stable to be used satisfactorily as reagents, and he attributes the stability to the presence of an hydroxyl group or a trichloroacetoxy group on carbon 2. I Normally, when an acetylglycosyl halide reacts with a free hydroxyl group in the presence of silver salts, a Walden inversion occurs.69 Thus, since most of the halides belong to the alpha series, the linkage formed in the normal Koenigs-Knorr reaction usually possesses the beta configuration. Again an outstanding exception is arabinose, in which case it has been proven that the linkage formed belongs to the alpha s e r i e ~ . ~ ~ , ~ ’ Even when the Zemplh m o d i f i ~ a t i o n ~is* used, . ~ ~ by means of which the opposite configuration is obtained, there are indications that a Walden inversion occurs followed by a second inversion catalyzed by the mercuric bromide present.’* A mechanism based on the general theory of ~*~~ displacement reaction^'^ has been suggested by I ~ b e l l . ~According to this mechanism, the ion or molecule replacing the halogen must approach the carbon atom from the opposite side from that occupied by the halogen. This is illustrated below: H ROH

#‘I

H

\ C-Br / 7 Rol,/-lBrHAOAc

I

+H+

HhOAc

0

I I This mechanism also serves to explain why orthoester derivatives are often formed when the acetyl group on carbon 2 is trans to the halogen on carbon atom Then the carbonyl of the acetyl group is in position to take part in the replacement of the halogen:

I

(69) C. S. Hudson and F. P. Phelps, J . Am. Chem. Soc., 46,2591 (1924). (70) E.L.Jackson and C. S. Hudson, J . Am. Chem. Soc., 69, 994 (1937). (71) M. L. Wolfrom in “Organic Chemistry,” Henry Gilman, editor, vol. 11, 2nd ed., John Wiley and Sons, Inc., New York, p. 1570 (1943). (72) G. ZemplBn, Ber., 62, 990 (1929). (73) G. Zemplh and 2. S. Nagy, Ber., 63, 368 (1930). (74) B.Lindberg, Arlciv Kemi, Mineral Geol., Ser. B, 18, No. 9, 1 (1944). (75) L. P. Hammett, “Physical Organic Chemistry,” McGraw-Hill Book Co., Inc., New York. Chapters V and VI (1940). (76) H. S. Isbell, Ann. Rev. Biochem., 9,65 (1940). (77) Harriet L. Frush and H. s. Isbell, J . Research Natl. Bur. Standards, 27, 413 (1941). (78) See E. Pacsu, Advances in Carbohydrate Chem., 1, 77 (1945).

44

W. L. EVANB, D. D. REYNOLDS AND E. A. TALLEP

P

H C-Br

H+’

I I

A new asymmetric center is introduced at the carbon marked* above and two orthoester derivatives may be i~olated.’~The normal type of linkage is formed at the same time as the orthoester typelg and very likely compounds having both the alpha and beta linkages are present in the reaction mixture. For example, the alpha glycoside and an orthoester were isolated in one case80and both the alpha and the beta glycosides and one orthoester form were isolated in another case.81 In the case, however, of the glycosyl halides having the halogen cis with respect to the acetyl group on carbon 2, Isbell and FrushS2 suggest that only the normal Walden inversion takes place in the presence of silver salts. The normal product of the Koenigs-Knorr reaction has in most examples the beta glycosidic linkage which results from a Walden inversion. Although the structure of the alcohol component does not seem to affect the configuration of the linkage formed, the structure of this component is very important. As Koenigs and Knorr used the reaction, it was confined entirely to the preparation of glycosides and not to the preparation of oligosaccharides. At that time suitable alcohol components did not exist for the latter preparations. I n order to obtain an oligosaccharide of definite structure, one must have a derivative in which all the hydroxyl groups but one are blocked by some group or groups which may be removed later without destroying the linkage formed. Otherwise one obtains a mixture from which it is difficult or impossible to isolate definite chemical individuals. Thus the development of suitable derivatives is a very important phase in the achievement of the goal of the organic chemist, the unequivocal synthesis of the compound with which he is working. Most of the natural sugars which have been synthesized were produced soon after suitable derivatives were discovered. (79) E. A. Talley, D. D. Reynolds and W. L. Evans, J . Am. Chem. SOC.,66,575 (1943). (80) P.A. Levene and M. L. Wolfrom, J . Biol. Chem., 78, 525 (1928). (81) H.S. Isbell, J . Am. Chem. SOC.,62, 5298 (1930). (82) H. S. Isbell and Harriet L. Frush, J . Research Natl. Bur. Standards, 45, 161 (1949).


45

The first useful intermediate was prepared by Fischer and D e l b r U ~ k , ~ ~ who treated tetraacetylglucosyl bromide with moist ethereal silver The second carbonate to give 2,3,4,6-tetraacetyl-~-~-g~ucopyranose. type of derivative, developed by Helferich and his coworkers,16bwas the first to give impetus t o the synthesis of oligosaccharides. This type of derivative involved the use of trityl chloride and gives a derivative where all the hydroxyl groups except the primary ones are blocked by an acyl group, usually acetyl. The acetyl groups are readily removed by catalytic saponification which was first applied to sugars by Fischer and Bergmanna4 and later improved by Zemp16n.86~8s~87~aa Freudenberg and his coworkersassintroduced the use of isopropylidene blocking groups, a method which has found wide use in the galactose series. The isopropylidene blocking groups are stable in alkaline solution but are removed by traces of acid, which attack the oligosaccharide linkage more slowly.8g A number of other derivatives have been used but since in most cases they are specialized compounds which have been used only a few times, they will not be discussed individually but will be listed in Table VI. Only the first two methods mentioned above for the preparation of suitably blocked derivatives, are general in scope. The Koenigs-Knorr reaction is normally carried out in a solvent which will dissolve both the acylglycosyl halide and the derivative carrying the hydroxyl group. For oligosaccharide synthesis the solvent should be inert to both reactants, readily obtainable in an anhydrous condition and low-boiling in order that the solvent may be removed easily after the reaction. The solvents most generally used have been chloroform, benzene, carbon tetrachloride, ether, dioxane and xylene. For the synthesis of the simple glycosides, an excess of the alcohol often has been used as the solvent. The acylglycosyl halide, the alcoholic compound and a solvent have been used in every case where the Koenigs-Knorr reaction has been carried out. Koenigs and Knorrbeand Ness, Fletcher and H ~ d s o n ~ ~ ~ ~ (83) E. Fischer and K. Delbruck, Ber., 42, 2776 (1909). (84) E. Fischer and M. Bergmann, Ber., 62, 829 (1919). (85) G. Zemplh, Ber., 69, 1254 (1926). (86) G. Zemplh, A. Gerecs and I. HadAcsy, Ber., 69, 1827 (1936). (87) G . Braun, Org. Syn. Coll. Vol. 11, 1st ed., 122 (1943). (88) For other deacetylation methods see W. A. Mitchell, J . Am. Chem. SOC., 63, 3534 (1941) (barium methylate method) and W. A. Bonner and W. L. Koehler, ibid., 70, 314 (1948) (potassium alkoxide method). (88a) K. Freudenberg, A. Not! and E. Knopf, Ber., 60, 238 (1927). (89) K. Freudenberg, W. Diirr and H. v. Hochstetter, Ber., 61, 1735 (1928). (90) These workers obtained the unusual a-glycoside when they used the tetrabenzoyl-a-D-mannopyranosyl bromide as the acylglycosyl halide without an acidacceptor.

46

W. L. EVANS, L1. D. REYNOLDS AND E. A. TALLEY

have carried out the reaction for the preparation of simple glycosides without the use of a condensing agent but these cases are exceptions to the general rule. Normally, however, a condensing agent is used which will combine with the hydrogen halide as rapidly as it is formed or pull off the halide ion so that the alcohol component can enter on the opposite face. As mentioned above (page 41), silver carbonate, pyridine and silver nitrate were used by Koenigs and Knorr. Silver oxide and silver carbonate have been the most popular condensing agents, with mercuric salts ranking next. Silver nitrate in combination with pyridinegl has been used and has been found to give the highest yields of a-glycosides from 8-acetylglycosyl halides.92 (The latter compounds tend to rearrange to the alpha forms before they react. Ordinarily the majority of the product is the one normally obtained from the alpha halide.) A Walden inversion is indicated when any of the above condensing agents are used. Using quinoline as the condensing agent, however, Helferich and BredereckB3were able t o isolate a small yield of melibiose (6-[a-D-ga~actopyranosyl]-~-g~ucose) octaacetate from tetraacetyl-a-Dgalactopyranosyl bromide and 1,2,3,4,-tetraacetyl-~-~-glucopyranose. Silver oxide gave the compound with the beta linkage.g4*g6Later ~ S ~ that ~ - ~if ~an acetylglycosyl halide is Zemplh and C O W O ~ ~ ~showed allowed t o react with an hydroxyl compound in the presence of mercuric acetate, both the a and p isomers are formed. Also an equivalent or a very slight excess of the hydroxyl compound tended t o give the beta isomer.s7 Later work by Lindberg74 indicated that HHgBr3 is a catalyst for the conversion of the beta linkage to the alpha when only a small amount of the hydroxyl compound is present. In contrast to the procedures with silver salts, the syntheses with mercuric salts were carried out at elevated temperatures, in bensene under reflux. In one caae, mercuric acetate was reported t o give better yields of the compound with the p-linkage than silver oxide, but under the conditions reported to give the ~u-linkage,~~ the product was amorphous.100 Of the examples given above, pyridine and quinoline may serve both as condensing agents and as the solvent. (91)H. H.Schlubach and G. A. Schrater, Ber., 61, 1216 (1928). (92) W.J. Hickinbottom, J . Chem. Soc., 1338 (1930). (93) B. Helferich and H. Bredereck, A m . , 466, 166 (1928). (94) B. Helferich and H. Rauoh, Ber., 69, 2655 (1926). (95)B. Helferich and G. Sparmberg, Ber., 66, 806 (1933). (96) G. Zempl4n and A. Gerecs, Bet., 68, 2720 (1930). (97) G.Zemplbn, Z. Bruckner and A. Gerecs, Ber., 64, 744 (1931). (98) G. Zempl4n and A. Gerecs, Ber., 64, 1545 (1931). (99) G. Zempl4n and Z. Bruckner, Ber., 64, 1852 (1931). (100)P..Casparis and P. BBchert, Pharm. A d a Helv., 22, 134 (1947).


47

Recently a studylo’ has been made of the preparation of glucosides using some of the more readily obtainable catalysts or condensing agents such as zinc oxide, cadmium oxide, mercuric oxide, zinc acetate, mercuric cyanide and mercuric bromide. The yield of glucoside was affected not only by the type of condensing agent but by its amount, the time of contact and the solvent. Another factor affecting the efficiency of the Koenigs-Knorr reaction is the presence or absence of moisture in the reaction mixture. Water is an ROH-type compound where R is hydrogen. It may react with the halide more rapidly than the preferred ROH compound to give a third ROH compound (where the halogen has been exchanged for OH) which will then react with more of the halide. The amount of product lost in these side reactions may be cut down by keeping the active water content of the reaction mixture at a minimum. Desiccants may he added, which will combine with any water present as fast as it is formed. Anhydrous sodium sulfate and anhydrous copper sulfate were the first Up to this desiccants used.80*g1Later, calcium chloride was time, yields had varied from 0.25%g3to 25%lo3of theory. The introduction of the calcium chloride as an internal desiccant resulted in a 59 % yield of 6-(~-gentiobiosyl)-~-glucopyranose hendecaacetate.lo2 Then Kreider and Evans104.10s introduced finely divided calcium sulfate hemihydrate (“Drierite ")lea as the internal desiccant. They prepared the acetylated 8-dihydroxyacetone derivatives of D-glucose, cellobiose and gentiobiose in yields of 46, 52 and 59%, respectively. Reynolds and Evanslo7were able to increase the yield of P-gentiobiose octaacetate from 23%’08 to 74% by using “Drierite” with iodine as a catalyst. The properties of “Drierite” make it an ideal internal desiccant for use a t normal or moderately elevated temperatures since it is inert to nearly all materials except water and it is insoluble in all the usual solvents. It is a very intensive desiccant, ranking next to phosphorus pentoxide. One may be certain of its desiccating power since it may be regenerated easily by heating two to three hours at 230-250” before use. It will take up only about 6% of its weight of water, however, and if it is dehydrated completely it is very slow to re-hydrate.lo6 (101) B. Helferich and K. F. Wedemeyer, Ann., 663, 139 (1949). (102) B. Helferich and R. Gootz, Ber., 64, 109 (1931). (103) B. Helferich and W. Schtifer, Ann., 460, 229 (1926). (104)L. C. Kreider and W. L. Evans, J . Am. Chem. SOC.,67, 229 (1935). (105)L. C. Kreider and W. L. Evans, J . Am. Chern. SOC.,68, 797, 1661 (1936). (106) W. A. Hammond and J. R. Withrow, Znd. Eng. Chern., 26, 653,1112 (1933). (107)D.D.Reynolds and W. L. Evans, J . Am. Chem. Soc., 60, 2559 (1938). (108) B.Helferioh and W. Klein, Ann., 460,219 (1926).

48

W. L. EVANS, D. D. REYNOLDS

AND E. A. TALLEY

Recently anhydrous magnesium perchlorate has been used successfully6gaas an internal desiccant; however, caution is indicated because of the explosion hazard.loSa The use of an entraining agent also has been suggested for the removal of water from the reaction mi~ture.~Og~~lO For this method, either the reaction must be run under vacuum or at elevated temperatures. It should be very effective for use with the Zemplh procedure which uses mercuric salts with benzene under reflux (page 46) but so far the method has had only limited use. Helferich, Bohm and Winklerl have reported that the use of iodine catalyzed the Koenigs-Knorr reaction, which was exceedingly slow when calcium chloride was used as an internal desiccant. This catalyst has . ~ work ~ , of ~ ~ ~ - ~ since been used by a number of other ~ ~ r k e r ~ The Talley, Reynolds and Evans7gon the synthesis of the orthoester type of oligosaccharides, indicated that the presence of iodine favored the formation of a normal biosidic linkage, whereas the absence of iodine favored the formation of an orthoester linkage. The examples of the Koenigs-Knorr reaction are too numerous to discuss in detail. The compounds which have been prepared by this reaction will be listed in table VII and only a few will be discussed at this point. The first oligosaccharide prepared by the Koenigs-Knorr synthesis was P,P-trehalose as the octaacetate.16 This was obtained in 1% yield as a by-product during the preparation of 2,3,4,6-tetraacetyl-~-~-g~ucopyranose by the action of moist ethereal silver carbonate on tetraacetyl-aD-glucopyranosyl bromide. Later, starting with 2,3,4,6-tetraacetyl-PD-glucopyranose and the tetraacetylglucopyranosyl bromide, a 10.5% yield of the crystalline P,P-trehalose (P-D-glucopyranosyl P-D-glucopyranoside) octaacetate was isolated when silver oxide, “ Drierite ” and iodine were used in the reaction mi~ture.1’~This yield probably can be raised, since before use the “Drierite” was heated to 500” for three hours, which probably converted it to the less active form. The first natural disaccharide to be synthesized was gentiobiose, by (108a) See M. J. Stross and G . B. Zimmerman, Ind. Eng. Chem., News Ed., 17, 70 (1939); M. P. Bellis, Hezagon AZph ChiSigma, 40,13 (1949). (109) Soc. pour l’ind. chim. a Blle, British Pat. 584,062 (1947); Chem. Abstracts, 41, 3120h (1947). (110) K. Miescher and C. Meystre, U. S. Pat. 2,479,761 (1949). (111) H. H. Schlubach and W. Schetelig, Z. physiol. Chem., 213, 83 (1932). (112) C. W. Klingensmith and W. L. Evans, J . Am. Chem. SOC.,61, 3012 (1939). (113) C. M. McClosky, R. E. Pyle and G. H. Coleman, J . Am. Chem. SOC., 66, 349 (1944). (114) H. A. Lardy, J . Am. Chem. SOC.,66, 518 (1947).

THE SYNTHESIS OF OLIOOSACCHARIDES

49

Helferich and his coworkers.16b Reynolds and Evanslo7 were able to increase the yield to the point where it became a practical method for obtaining the sugar (see page 47). A solution of tetraacetyl-a-Dglucopyranosyl bromide in pure chloroform was slowly added to a previously stirred mixture of pure chloroform, 1,2,3,4-tetraacetyl-p-~glucopyranose, "Drierite," silver oxide and iodine and the resulting mixture was stirred for twenty-four hours. Yields of as high as 74% of p-gentiobiose (6-[p-~-glucopyranosyl]-p-~-glucopyranose) octaacetate were obtained. Using amorphous 1,2,3,4-tetraacetyl-a-~-glucopyranose, they obtained a 50% yield of the corresponding a-octaacetate. This was a better yield than that (42%) obtained later by Lardy,'I4 who isolated and used the crystalline intermediate, the a-tetraacetate. Freudenberg and his coworkers' 16 synthesized crystalline methyl heptamethyl-0-cellobioside by the action of tetramethyl-a-D-glucoin the pyranosyl chloride on methyl 2,3,6-trimethyl-p-~-glucopyranoside presence of silver carbonate and chloroform. The corresponding methylated cellotrioside was synthesized in a similar fashion a short time later.lJ6 These were a check on the structure of cellobiose and cellulose but did not lead to the synthesis of the free sugars since the methyl groups are not easily removed. A much more elegant synthesis of cellobiose was carried out later by Hudson and his coworkers2S(see page 57). Zemplkn and his coworkers have been able to show evidence in a number of cases that a small excess of the alcohol component with mercuric acetate as the condensing agent, led t o an increase in the ratio of formation of the a-linkage compared to the formation of the 8-linkage. But in only two cases were they able to isolate and obtain reasonably pure oligosaccharide derivatives where the a-linkage had been formed. They ran out of material before they were able t,o complete the recrystallization of methyl decaacetyl-[6-(a-cellobiosyl)-~-~-glucopyranoside]~~ all the way to constant properties. They were not able t o crystallize at their methyl heptaacety~-[6-(a-~-g~ucopyranosyl)-~-~-glucopyranos~de] They converted it to the benzoyl derivative which still did not crystallize. They finally resorted to methylation and then were able to fractionally distill the resulting compound. They state that the compounds with the a-linkage are more difficult to crystallize than the corresponding compounds with the p-linkage.99 It is very difficult t o isolate and purify the tetrasaccharides and higher units. So far no one has synthesized an oligosaccharide with five mono(115) K. Freudenberg,C. C. Andersen, Y. Go, K. Friedrich and N. K. Richtmyer, Ber., 63, 1961 (1930). (116) K.Freudenberg and W. Nagai, Ann., 494, 63 (1932).

50


saccharide components. Helferich and his coworkers117tried to prepare an acetylglycosyl halide form of a tetrasaccharide and were not able to purify it sufficiently to give an individual compound. A change of one group at the end of a chain of four hexose units does not change the solubility in various solvents sufficiently to separate and purify the resulting compound. The acetate of the tetrasaccharide, B-cellobiosylgentiobiose, was isolated in 80% yield but the final purified material amounted to only 15%.”’ The Koenigs-Knorr reaction has been very fruitful in that a large number of oligosaccharides have been prepared by it and with the later procedures the yields are good. However, very few compounds have been prepared with the formation of the alpha linkage although agents have been proposed which give a large proportion of this linkage. But in all cases where the alpha linkage has been obtained, the yields have been low, partly because the materials are difficult to purify, probably due to the presence of the other isomer. The other main deficiency of the reaction is that no general method has been reported by which one can prepare suitably blocked derivatives with the alcoholic hydroxyl at positions other than the primary positions or at the position occupied by the potential carbonyl. In spite of these two deficiencies, the KoenigsKnorr reaction has served for the synthesis of a number of naturally occurring oligosaccharides as well as a number of synthetic sugars for further investigation and a few derivatives where the sugar group serves to make the compound more water-soluble. It has a very important place in the development of carbohydrate chemistry. d. Addition to Compounds of Ethylene Oxide Type.-In 1922, Brig1118 showed that methyl alcohol would add to 3,4,6-triacetyl-1,2-anhydroD-glucopyranose (“Brigl’s anhydride ”) to give the corresponding methyl @-D-glucoside:

To obtain the ethylene oxide type compound, P-D-glucose pentaacetate was treated with an excess of phosphorus pentachloride t o give 2-trichloroacetyl-3,4,6-triacetyl-~-~-glucopyranosyl ~hloride.6~ The ~ ~ ~tri~ chloroacetyl group was removed by treatment with a dry ethereal solution of ammonia at 0”. From the product the anhydride may be obtained by (117) B. Helferich and H. Bredereck with W. Schafer and K. Bauerlein, Ann., 486, 174 (1928).

(118) P.Brigl, 2. physiol. Chem., 122, 245 (1922).


51

the action of dry ammonia in benzene. HickinbottomllO has shown that a number of primary and secondary alcohols give the corresponding P-glucopyranosides with this anhydride but he found that phenol gave the a-glucopyranoside. In one instancelZ0the anhydride has been used to prepare an oligosaccharide. A mixture of the 1,2-anhydro-3,4,6-triacetyl-~-glucopyranose and 2,3,4,6-tetraacetyl-~-~-g~ucopyranose was heated in dry benzene and gave a 11% yield of “neotrehalose” heptaacetate, which was assigned the trehalose structure with the a,@-configuration. At its present stage of development, the method does not shed much light on the structure of the resulting compounds; in fact the structure of the “neotrehalose” may not be assigned correctly. The fact that the anhydride itself is difficult to prepare has hindered general synthetic use of the reaction. lZ1 e. Alkali Salt Elimination.-The first successful synthesis122 of glycosides was carried out by Michael123when he split out potassium chloride between tetraacetylglucosyl chloride and the potassium salts of phenols. Until recently this general method had been applied successfully only to the formation of phenolic glycosides. Fischer and Armstrong28attempted to apply the technique to the synthesis of disaccharides without much success. Recently, Gilbert, Smith and Stacey4 obtained up to SO% of the theoretical yield when they split out sodium bromide in the synthesis of gentiobiose (6-(@-D-glucopyranosy~)-D-glucose). Sodium was first disand then tetrasolved in molten 1,2,3,4-tetraacetyl-~-~-glucopyranose acetyl-a-D-glucopyranosyl bromide was added to the melt. Sodium bromide separated with little or no discoloration if very pure reagents were used, but considerable decomposition took place with impure material. Only a portion of the gentiobiose octaacetate was crystallized out directly; the remainder was separated from the sirup by chromatographic adsorption. The synthesis of octaacetyl cellobiose (4-(/3-~-glucopyranosy1)-D-glucose) was found to proceed in the same way, using 1,2,3,6-tetraacetyl-P-~-glucopyranose as a starting material. The yields were considerably lower, however, only about 40% total. These workers thought that the low yield was due to the formation of both the alpha and the beta linkage. The same workers4 used a similar technique to synthesize the first true ether type of oligosaccharide. The 3-sodium derivative of 1,2: 5-6, (119) W.J. Hickinbottom, J . Chem. SOC.,3140 (1928). (120) W.N. Haworth and W. J. Hickinbottom, J . Chem. SOC.,2847 (1931). (121) E. Hardegger and J. de Pascual, Helv. Chim. Acta, 31, 281 (1948). (122) Ref. 62,p. 188. (123) A. Michael, Am. Chem. J., 1, 307 (1879); 6, 171 (1884);6, 336 (1885); Compt. rend., 89,355 (1879).

W. L. EVANS, D. D. REYNOLDS A N D E. A. TALLEP

52

diisopropylidene-D-glucofuranose was prepared by the action of sodium in liquid ammonia. The product was heated in a sealed tube with a benzene solution of 1,2 :3,4-diisopropylidene-6- tosyl-D-galactopyranose, which split out sodium p-toluenesulfonate to give amorphous 6-(1,2 :3,4diisopropylidene-D-galactopyranose) 3-( 1,2 :5,6-diisopropylidene-~-glucofuranose) ether. The product was purified by fractional distillation and showed the stability t o be expected of a true ether linkage. The linkage was stable t o boiling 1 % hydrochloric acid. Sharp and S t a ~ e y ~ were ~ " not successful in applying the alkali saIt elimination technique t o the synthesis of maltose and of lactose but were successful in the case of disaccharides of trehalose type. 2. Alteration of the Oligosaccharide Linkage

The more obvious way to prepare a new oligosaccharide is t o synthesize it from monosaccharides or simpler oligosaccharides by the formation of a new linkage between the two units. This method has been illustrated by the reactions already discussed. A second method is t o change the configuration of a linkage in existence in one oligosaccharide t o form another; for example, if one could change the beta linkage between the two D-glucose units of cellobiose into an alpha linkage, one would form maltose. The linkage in glycosides is an acetal linkage of the same type as found in one class of oligosaccharides (see page 28). Pacsu found that either stannic or titanium tetrachloride126*126 would transform the beta linkages of glycosides into the alpha linkage. This transformation has been studied further by Lindberg, using hydrogen bromide and mercuric bromide in benzene,?* boron trifluoride in ~hloroform'~7 and concentrated sulfuric acid in acetic anhydridelZ8as catalysts. As a result of his work, Lindberg has suggested a mechanismlZ8for the transformation which may be illustrated as follows:

I+ I---

Two facts are pointed out by Lindberg which indicate that the glycosidic (124) (125) (126) (127) (128)

E. Pacsu, Ber., 61, 137 (1928). E. Pacsu, Ber., 61, 1508 (1928). E. Pacsu, J . Am. Chem. SOC.,62, 2563, 2568, 2571 (1930). B. Lindberg, Acta Chem. Scad., 2, 426 (1948). B. Lindberg, Acta Chem. Scund., S, 1153 (1949).


53

linkage is not completely broken. First, the yields of these transformations are usually good and one finds it difficult to see how this would be so if the alkoxyl groups ever became completely free in the solution. Second, he carried out a transformation on a mixture of isopropyl p-D-glucopyranoside tetraacetate and ethyl P-cellobioside heptaacetate, using titanium tetrachloride as the catalyst. Only isopropyl a-D-glucopyranoside tetraacetate and ethyl a-cellobioside heptaacetate could be isolated and these were obtained as crystalline materials in yields of 66 and 75 %, respectively, indicating that little or no interchange of glycoside groups took place. He found that the rate of transformation increased in the series : methyl, primary alkyl, secondary alkyl and tertiary alkyl ; which he correlated with the tendency of the groups t o repel electrons.128 In the next paper of the series,128aLindberg stated that in the disaccharides, gentiobiose and cellobiose, there are one and two oxygen atoms respectively, oh the carbon atoms in the @-positionto the glycosidic linkage, which will attract electrons and thus lower the reactivity. Investigation of a group of disaccharide models, a series of acetylated glucosides of halogen and oxygen substituted alcohols, gave resuIts in agreement with the hypothesis that with one substituent on the p-carbon atom of the aglucon group (the gentiobiose type), transglycosidation is more rapid than with substituents on two P-carbon atoms (the cellobiose the beta linkage of an type). The next step then was taken in oligosaccharide, gentiobiose, was transformed into the alpha linkage t o form a new oligosaccharide, isomaltose (6-[a-D-ghCOpyranOSyl]-D-glUcose).12Ya No transglycosidation was observed in the case of cellobiose. The transformation was carried out by treating gentiobiose octaacetate (either a- or @-) with a large excess of titanium tetrachloride in absolute chloroform. The resulting mixture of isomaltosyl and gentiobiosyl chloride heptaacetates was treated with mercuric acetate in acetic acid. After removal of part of the gentiobiose octaacetate present by crystallization, Lindberg was able to isolate @-isomaltoseoctaacetate identical with that obtained by Wolfrom and coworkers130 from dextran. It was obtained in 46% yield, the first total synthesis of isomaltose and one of the few syntheses of a disaccharide with an alpha linkage. 3 . Alteration of a Monosaccharide Unit

Next will be discussed the methods by which the structure of a monosaccharide unit of an oligosaccharide has been altered in some way (128a) B. Lindberg, Acta Chem. Scand., 3, 1350 (1949). (129) B. Lindberg, Nature, 164,706 (1949) and Acta Chem. Scand., 3, 1355 (1949). (129a) The name “brachiose” has been suggested for this sugar. See Edna M. Montgomery, F. B. Weakley and G. E. Hilbert, J . A m . Chem. SOC.,71, 1682 (1949). (130) M. L. Wolfrom, L. W. Georges and I. L. Miller, J . Am. Chem. Soc., 71, 125 (1949).

54


in order to obtain a new oligosaccharide. These methods may be grouped under two general headings: first, those changes in which there is a rearrangement in space of the groups around one or more of the asymmetric centers of the monosaccharide and second, those cases where the carbon chain is shortened, resulting in the degradation of a monosaccharide unit. I n theory at least, the carbon skeleton could be lengthened, as has been done in the case of monosaccharides; while no one so far has applied this method to produce a new oligosaccharide; an initial step in such a synthesis has been made as was mentioned earlier (see page 35). In all the methods except one discussed below the configuration at only one carbon atom of one monosaccharide unit was changed. By the use of aluminum chloride, however, the configuration was reversed at both carbon atoms two and three of one monosaccharide unit. a. The Lobry de Bruyn and Van Ekenstein Rearrangement.-Rearrangements of monosaccharides date from the report of the action of alkalies on carbohydrates by Lobry de Bruyn131in 1895. I n the same year, he and van E k e n ~ t e i n reported '~~ that D-glucose could be converted into D-fructose and n-mannose by the action of calcium hydroxide in solution. Similar results were obtained when D-fructose or D-mannose were used as the starting material and a number of bases were found to catalyze the interconversion. The following equilibria of the carbonyl forms will illustrate the reaction: HC=O

HCOH OH-

HAOH I

Aidose

H+

HC=O H+

O !(H I

I

+HOCH OH-

I I

Aldose

H+JrOH-

H HboH

b=O I Khtose

The intermediate is thought to be an enediol formed by a simple hydrogen ~ h i f t . l 3 ~The reaction was applied to disaccharides by Montgomery and Hudsonla4when they treated lactose with a weak solution of calcium hydroxide and isolated a crystalline ketose, 4-(P-~-galactopyranosyl)D-fructose, which they named lactulose. Since these workers oxidized (131) C. A. Lobry de Bruyn, Rec. trav. chim., 14, 156 (1895). (132) C.A. Lobry de Bruyn and W. Alberda van Ekenstein, Rec. trav. chim.,14, 201 (1895)and Ber., 28, 3078 (1895). (133) RI. L. Wolfrom with W. L. Lewis, J . Am. Chem. Soc., 60,837 (1928). (134)Edna M. Montgomery and C. S. Hudson, J . Am. Chem. Soc., 62,2101 (1930)

55


the aldoses to acids in order to simplify the isolation of the ketose, they did not isolate the epimer of lactose which would be expected to be present in the reaction mixture. b. The Bergmann-Schotte Rearrangement.-The Bergmann-Schotte reaction136provides another method for converting a sugar to its epimer. The chemical steps may be illustrated by the preparation of D-mannose from D-glucose. Glucose (I) is first acetylated (11) and then converted t o tetraacetyl-a-D-glucopyranosyl bromide (111) after which it is reduced by the action of zinc and acetic acid in the presence of a catalytic amount of chloroplatinic acid t o yield glucal triacetate (IV). The glucal triacetate is deacetylated to yield glucal (V) which in turn is oxidized by perbenzoic acid in water to yield a postulated intermediate anhydride (VI) which forms mannose (VII) by the addition of water. This may be illustrated by the following equations: CHzOH

/I-

O\

H / H OH HO \

I\

CHzOAc

H

I/

>I

OH A c t 0

/Ipo\ \-I/ H

H

Fc

NaOAc

OH

H

H

>I

HoAO

OAc

I1

I CHzOAc

H

OAc HBr

CHzOAc

OAc

‘H

H

I11

IV r

CHZOH

CHzOH

VI

V

CHzOH

H

H

VII (135) M. Bergmann and H. Schotte, Ber., 64, 440, 1564 (1921).

1

56


When the oxidation is carried out in methanol instead of water, the corresponding methyl a-D-mannopyranoside is formed. Levene and coworker^^^^^^^^ found that in the transformation of a glycal to an aldose, a directive influence is exercised by the position of the hydroxyl on carbon atom 3. Thus in the case of D-glucal, D-galaCtal and D-arabinal, the hydroxyl adds to carbon 2 on the same side of the carbon chain as the hydroxyl on carbon 3 although in the case of D-arabinal the hydroxyls are on the opposite side from those of D-glucal and D-galactal. In all three cases, hydroxyls 2 and 3 of the preponderating sugars produced, are in the cis position. They also made a study of the effects produced by various substituents in the glucal molecule. They found that when 3-methylglucal and triacetylglucal are acted upon by perbenzoic acid, the reaction proceeds abnormally and yields only glucose derivatives. In general, the form with the hydroxyls on carbon 2 and 3 on the same side of the ring predominates if the glycal itself is oxidized. If a glycal substituted on carbon 3 is oxidized, the predominating form obtained is the one where the hydroxyls on carbons 2 and 3 are on the opposite sides of the ring. Levene and T i p ~ o n ' ~emphasize ' the fact that both epimers are formed in this reaction but usually one predominates to such an extent that from a practical point of view the other epimer may be disregarded. The same effect was observed later by Dauben and Evans.1s8 The rearrangement has been applied to the more common disaccharides in the period since Bergmann and his coworkers prepared the epimers of c e l l o b i ~ s eand ~ ~ ~1act0se.l~~Others have used lactose, 141 malt0sel4~and gentiobio~e'~~ as the starting materials for the corresponding mannose derivatives. A good example of how the rearrangement may be used to check structure is the constitutional synthesis of lactose and (136) P. A. Levene and A. L. Raymond, J . Biol. Chem., 88, 513 (1930). (137) P. A. Levene and R. S. Tipson, J . Biol. Chem., 93, 631 (1931). (138) H. J. Dauben, Jr., and W. L. Evans, J . Am. Chem. SOC.,60, 886 (1938). (139) M. Bergmann and H. Schotte, Ber., 64, 1564 (1921). See also W. N. Haworth, E. L. Hirst, H. R. L. Streight, H. A. Thomas and J. I. Webb, J . Chem. SOC., 2636 (1930). (140) M. Bergmann, Maria Kobel, H. Schotte, E. Rennert and S. Ludewig, Ann., 434, 79 (1923). See also A. J. Watters and C. S. Hudson, J . Am. Chem. SOC., 62, 3472 (1930). (141) W. N. Haworth, E. L. Hirst, Millicent M. T. Plant and R. J. W. Reynolds, J. Chem. SOC.,2644 (1930). (142) W. N. Haworth, E. L. Hirst and R. J. W. Reynolds, J . Chem. Soc., 302 (1934).


57

cellobiose by Hudson and his fellow w o r k e r ~ . ~ ~ * ~The ~ 3 , ~steps * 4 for cellobiose are as follows : Tetraacetyl-a-D-ghcopyranosyl bromide was coupled by the Koenigs-Knorr reaction with 1,6-anhydro-2,3-isopropyhdene-P-D-mannopyranose at carbon atom 4 (which carried the only free hydroxyl group). The p-linkage is formed under the conditions used, so the product was 4-(2‘,3’,4’,6’-tetraacetyl-p-~-glucopyranosy1)1,6-anhydro-2,3-isopropylidene-/3-~-mannopyranose. This was acetylated and then treated with an acetolysis solution with concurrent acetylation. The 1,6 anhydro ring was readily ruptured under these conditions to give acetyl groups at the 1 and 6 positions; thus the product was 4-(/3-~-glucopyranosyl)-~-mannoseoctaacetate, which is the octaacetate of epicellobiose. This was converted t o cellobiose by the Bergmann-Schotte reaction. The cellobial acetate was oxidized instead of the free cellobial so that the predominating form would have the hydroxyls on carbons 2 and 3 in the trans position. The synthesis of lactose was carried out in a similar manner using the galactosyl bromide instead of the glucosyl bromide as the starting material. This was the first synthesis of lactose showing positively the points of attachment and configuration of the union of the two hexoses involved. The yields by the Bergmann-Schotte rearrangement are good, when one considers the number of steps involved. c. The Aluminum Chloride Rearrangement.-The origin of the aluminum chloride rearrangement is an example of how careful ’observations often lead t o new and unexpected knowledge. Hudson and K U ~ Z ’ ~ ~ obtained one gram of a new crystalline substance from one preparation of heptaacetyllactosyl chloride by the method of Skraup and Kremann.146 The method consists of boiling a chloroform solution of a sugar acetate, in this case lactose octaacetate, with phosphorus pentachloride and a small amount of anhydrous aluminum chloride as catalyst. The first thought was that the new substance was a new chloro derivative of lactose octaacetate, but further examination14’ showed it to be the heptaacetyl chloride of a new disaccharide which they named neolactose. At first it was thought that neolactose might be identical with Bergsince epimerizations at mann’s 4-(~-~-galactopyranosyl)-~-mannose~~~ carbon 2 are often encountered in carbohydrate reactions. However, (143) (1941). (144) (1941). (145) (146) (147)

A. E. Knauf, R. M. Hann and C. S. Hudson, J . Am. Chem. SOC.,63, 1447

W. T. Haskins, R. M. Hann and C. S. Hudson, J . A m . Chem. SOC.,63, 1724 C. S. Hudson and A. Kunz, J. Am. Chem. SOC.,47, 2052 (1925). Z. H. Skraup and R. Kremann, Monatsh., 22, 375 (1901). A. Kune and C. S. Hudson, J . Am. Chem. SOC.,48, 1978, 2435 (1926).

58


the structure of neolactose was proven to be 4-(P-~-galactopyranosyl)-~altrose. Thus the D-glucose portion of the molecule was converted to D-altrose. Both carbon atoms 2 and 3 of the glucose structure were reversed in their configuration, an unusual stereochemical change. A further of the conditions required for the rearrangement showed that aluminum chloride in the absence of phosphorus pentachloride would chlorinate the lactose octaacetate and give good yields of the heptaacetylneolactosyl chloride. Apparently the reaction involved an adsorption of lactose octaacetate at the surface of the insoluble aluminum chloride since the acetate was largely removed from the chloroform solution by the solid aluminum chloride and finely divided aluminum chloride was more reactive than coarse lumps. Heptaacetyllactosyl chloride was probably formed first and then transformed into the isomeric neolactose compound since normal yields were obtained when the heptaacetyllactosyl chloride was substituted for the octaacetate. Richtmyer and Hudson148were able to obtain yields up to 45% from lactose octaacetate by using a mixture of aluminum chloride and phosphorus pentachloride. The over-all isomerization may be illustrated as follows:

GaO

/I

H

I< gAc

I

H \-

CHzOAc

p^" H>i 0

c1 AlCls GaO

pcld

I
O c-c=o I H~CI-COOCH~

IV

TABLE I11 Physical Properties of Trialkyl Aconitates Trialkyl Aconitate

M. P.

Trimeth y P Triethylgga Tri-n-propyl99

Liquid Liquid Liquid

Tri-act .-amy199

Liquid

Tri-2-ethylhexylg'J Trilaurylgg Tristearyl'J'J

Liquid 10" 55.5O

I

B.P. 160' at 20 mm. 172' at 18 mm. 157"-162" a t 2 mm. 193-197" at 3 mm. -

Refractive Index at 26' -

1.4521 1.4540 1.4600 1.4578

Early investigators had reported the preparation of aconityl chloride in low yields by the use of phosphorus oxychloride and phosphorus pentachloride. loo~lol Froschl and Maier,Io2however, tried unsuccessfully to repeat this work and reported that the use of thionyl chloride was also without success. (99) E. R. Meincke, U. S. Pat. 2,475,629 (July 12, 1949). (99a) C. K. Ingold, J. H. Oliver and Jocelyn F. Thorpe, J . Chem. Soc., 126, 2128-36 (1924). (100) Klimenko and Buchstab, J. Russ. Phys.-Chem. SOC.,22, 99 (1880) (Beilstein, 11,852). (101) A. Michael and G. Tissot, J . prakt. Chem., NF [2], 62, 33143 (1895). (102) N. Froschl and A. Maier, Monatsh., 69, 274 (1932).

ACONITIC ACID I N THE MANUFACTURE O F SUGAR

247

The decarboxylation of aconitic acid to itaconic acid (V) and to citraconic acid (VI) proceeds easily and when carried out under controlled XrCOOH II HC-COOH

V

VI

conditions leads primarily to itaconic acid. Early workers had found that heating aconitic acid above its melting point or in aqueous solutions under pressure led to the formation of itaconic a ~ i d . ~ JAmbler ~ ~ J ~ ~ and coworkers,82-'06J06 after finding that a small amount of an inorganic aconitate catalyzed the decomposition of aconitic acid in aqueous solution to itaconic acid, utilized the crude calcium magnesium aconitates obtained from molasses as the starting materials. Enough sulfuric acid was added t o the alkaline earth aconitates to convert a portion of them to the free acid while a portion remained as the aconitates t o catalyze the decomposition. Tricarballylic acid, 1,2,3-propanetricarboxylic acid, is produced by the reduction of aconitic acid by catalytic method^,^^^-^^' electrolyti~ally,1~~-1~4 or by sodium amalgam.60s116 Sulfotricarballylic acid (VII), its salts, and its esters have become of interest recently due to their

M03s-t-c00R HoQ-fCooH H&-COOH

H2C-COOR

Hz -COOR

Ha -COOH VII

VIII

(103)L. Pebal, Ann., 98, 67-98 (1856). (104) T. Swarts, Jahresber. Fortschritte Chem., 579 (1873);Bull. acad. roy. Belg. 121,36, 7 (1873). (105) J . A. Ambler and A. L. Curl, U.S. Pat. 2,448,506(Sept. 7, 1948). (106) E.J. Roberts, J. A. Ambler and A. L. Curl, U. S. Pat. 2,448,831 (Sept. 7, 1948). (107) S. Fokin, J . Russ. Phys.-Chem. SOC.,40,316 (Chem. Zen&., 1908, ZZ, 1996). (108) S. Fokin, Z . Angew. Chem., 22, 1492-1502 (1909). (109) J. Boeseken, B. Van Der Weide and C. P. Mom, Rec. trau. chim., 36,26&87 (1916). (110) B. B. Allen, B. W. Wyatt and H. R. Henae, J . Am. Chem. SOC.,61,843-46 (1939). (111) R. Malachowski, Bull. intern. acad. polon. sci., 1919A, 265-73. (112) C. Marie, Compt. rend., 136, 1331-32 (1903). (113) U. Pomilio, 2.Elektrochem., 21, 444-48 (1915). (114) V. V. Levchenko, J . Gen. Chem. (U.S.S.R.), 18, 1237-44 (1948). (115) H. Wichelhaus, Ann., 132, 61-66 (1864).

248

ROBERT ELLSWORTH MILLER AND SIDNEY M. CANTOR

surface active p r o p e r t i e ~ . ~ Salts ~ ~ ~of~ this ~ J ~acid ~ are usually prepared by treating aconitic acid in neutral or slightly acidic solutions with sodium bisulfite. The sulfotricarballylic acid may be liberated by treatment with mineral acids and is easily esterified by conventional methods t o yield salts of trialkyl sulfotricarballylates (VIII). A series of sulfotricarballylic acid derivatives of potential use for the resolution of crude oil field emulsions of the water-in-oil type and as detergents has been described by Ericks and M e i n ~ k e . The ~ ~ preparation of these derivatives, salts of monoalkyl sulfotricarballylates and of dialkyl sulfotricarballylates, is illustrated by the following series of reactions.

(c-c=o 1

HC-COOR

HA-COOH

H2A-cOOH

HC-C=O

>O

(!-GOOH

I1

- HnO --+

I ?

b

-HsO

H&-COOR

b

H O a S -C=O

Ht -GOOH

XI1

-

&-COORr Hzc! -COOH

X

1

HO&d-COOH

L = O

HC-COOR

R'OH

HzC-C=O

IX

HzC-COOR

HC-COOR

XI

1

R'OH

HzC-COOR

HOaS-

A

-GOOR'

b

Hz -GOOH HpC-C=O XI11

XIV

Numerous other uses of aconitic acid or its derivatives have been described in the patent literat~re.~~s-l42 Many of these relate to their (116) National Oil Products Go., Brit. Pat. 551,246 (Feb. 15, 1943). (117) P. Nawiasky and G. E. Sprenger, U. S. Pat. 2,315,375(Mar. 30, 1943). (118) N. Oelwerke and G. van der Lane, Brit. Pat. 530,916 (Dec. 24, 1940). (119)T.Curten, Ger. Pat. 722,356 (May 21, 1942). (120) T.Habu, Jap. Pat. 93,028(Sept. 29,1931)(Chem. Abstracts, 26,4488 (1932)); ibid., 110,730 (May 13, 1935) (Chem. Abstracts, 30, 2283 (1936)). (121) T.Habu and S. Ogura, Jap. Pat. 111,256 (June 21, 1935) (Chem. Abstracts, SO, 2284 (1936));ibid., 111,259 (June 21, 1935) (Chem. Abstracts, 30, 2284 (1936)). (122) E.F. Isard, U. S. Pat. 1,993,552(Mar. 5, 1935). (123) H. Kraikalla and W. Wolff, U. S. Pat. 2,039,243(Apr. 28, 1936). (124) H.M. Kvalnes, U. S. Pat. 2,091,241(Aug. 24, 1937). (125) C.N. Anderson, U. S. Pat. 2,118,033(May 24, 1938). (126) E. T. Clocker, U. S. Pat. 2,188,883 (Jan. 30, 1940); 2,188,884(Jan. 30, 1940);2,188,885(Jan. 30, 1940);2,188,886(Jan. 30, 1940);2,188,888(Jan. 30, 1940); 2,188,889 (Jan. 30, 1940);2,188,890(Jan. 30, 1940);2,275,843(Mar. 10, 1942). (127) M. W. Perrin, E. W. Fawcett, J. G. Paton and E. G. Williams, U. S. Pat. 2,200,429(May 14, 1940).

ACONITIC ACID I N T H E MANUFACTURE O F SUGAR

249

incorporation in the preparation of various polymers such as copolymers of alkyl aconitates and vinyl chloride,13’ high molecular weight polyesters prepared from mixtures of ethylene glycol, isopropylene glycol, sebacic acid and aconitic and as plasticizers in the preparation of stabilized vinylidene chloride ~ompositions.13~ (128) H. S. Rothrock, U. S. Pat. 2,221,662 (Nov. 12, 1940); 2,221,663 (Nov. 12, 1940); 2,321,942 (June 15, 1943). (129) A. Hill, U. S. Pat. 2,230,351 (Feb. 4, 1941). (130) G. F. D’Alelio, U. S. Pat. 2,260,005 (Oct. 21, 1941); 2,288,315 (June 30, 1942); 2,308,494 (Jan. 19, 1943); 2,308,495 (Jan. 19, 1943); 2,319,798 (May 25, 1943); 2,319,799 (May 25, 1943); 2,323,706 (July 6, 1943); 2,232,898 (Oct. 26, 1943); 2,337,873 (Dec. 28, 1943); 2,337,874 (Dec. 28, 1943); 2,340,109 (Jan. 25, 1944). (131) A. W. Hanson and W. C. Goggins, U. S. Pat. 2,273,262 (Feb. 17, 1942). (132) M. C. Agens, U. S. Pat. 2,319,576 (May 18, 1943). (133) C. M. Blair, Jr., U. S. Pat. 2,375,516 (May 8, 1945); 2,384,595 (Sept. 11, 1945). (134) F. J. Kaszuba, U. S. Pat. 2,380,896 (July 31, 1945). (135) M. C. Agens and B. W. Nordlander, U. S. Pat. 2,404,204 (July 16, 1946). (136) E. L. Kropa, U. S. Pat. 2,409,633 (Oct. 22, 1946); 2,443,741 (June 22, 1948). (137) F. W. Cox, U. S. Pat. 2,419,122 (Apr. 15, 1947). (138) C. J. F r o ~ c h U. , S. Pat. 2,423,093 (July 1, 1947). (139) D. E. Adelson and H. F. Gray, Jr., U. S. Pat. 2,426,913 (Sept. 2, 1947). (140) T. W. Evans and D. E. Adelson, U. S. Pat. 2,435,429 (Feb. 3, 1948). (141) C. Struyk and S. C. Dollman, U. S. Pat. 2,523,160 (Sept. 19, 1950); 2,523, 161 (Sept. 19, 1950). (142) P. 0. Tawney, U.S. Pat. 2,553,430 (May 15, 1951); 2,553,431 (May 15, 1951).


FRIEDEL-CRAFTS AND GRIGNARD PROCESSES IN THE CARBOHYDRATE SERIES BY WILLIAMA. BONNER Department of Chemistry, Stanford University, California

CONTENTS I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Processes Catalyzed by Aluminum Chloride.. . . . . . . . . . . . . . . . . . . . . . . . . . . ...................... 1. Chlorination of the Acylal Function. . 2. Inversions within the Sugar Mole 3. Catalytic Glycosylations of Arom 111. Applications of the Grignard Reaction.. . . . . . . . . . . . . . . . . . . . . . 1. Formation of Molecular Addition 2. Carbonyl Addition Reactions. . . . . . . . . . . . . . . . . . .......... a. With Acetylated Glyconolactones, . . . . . . . . . . . . . . . . . . . . . . . . . . . b. With Substituted Glyconic Acids and Related Compounds.. . . . . c. With Isopropylideneglyconic Aldehydes. . . . . . . . . . . . . . . . . . . . . . . 3. Metathetical Reactions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . a. With Glucose Polymers. . . . . . . . . . . . . . . . . . . . . . . . . . . . . b. With Polyacetylglycosyl Halides. . . . . . . . . . . . . . . . . . c. With Methylated Glycoses.. . . . . . . . . . . . . . . . . . . . . . . 4. The Use of Other Organometallic Compounds.. .................... IV. Addendum on the Anomeric Configuration of 8-D-Glycopyranosylbeneenes. V. Physical Properties of Products from Friedel-Crafts and Grignard Reactions

252 252

262 262 264 269 274

279 282 284

I. INTRODUCTION Classically, carbohydrate chemistry has been primarily concerned with the isolation, purification, and detailed characterization of the large class of organic substances loosely designated as carbohydrates. I n the course of past work so motivated, innumerable reactions of the carbohydrates were discovered, reactions which proved of utmost importance in achieving these goals. These reactions, naturally enough, had their counterparts in other fields of organic chemistry, since the functional groups contained in the carbohydrates were also to be found in simpler organic substances. Reactions such as oxidation, reduction, acylation, methylation, acetonation, and the like immediately suggest themselves as illustrative of this category. While such reactions are general organic processes of a very common sort, their use in the carbohydrate series has frequently been of such a specific nature that the broader chemical relationships of carbohydrates with other organic substances has been 25 1

252

WILLIAM A . BONNER

underemphasized, and carbohydrate chemistry has, to a certain extent at least, become a specialized and forbidding field. The structural complexity of the carbohydrates, their variety of reactions, and the frequently laborious nature of experimental work in this field have combined, it would seem, to make this situation historically inevitable. Only sporadically in the past, but recently more frequently, has carbohydrate research appeared t o be motivated by the attempt to visualize carbohydrate compounds as general rather than specific organic substances, and to attempt the extension of other organic type-reactions to them. Such a viewpoint is important, since the abundance of natural carbohydrate precursors makes the products of such reactions frequently worth considering as starting materials for further synthetic work. Historically, the time is propitious for such a motivating attitude in carbohydrate research, since improved methods of structure proof in this field, as well as a better general understanding of the mechanisms of organic reactions, have immeasurably simplified the tasks of interpreting the courses of such reactions and characterizing the products resulting from them. In this chapter two such extensions of carbohydrate chemistry into broader organic fields shall be examined, namely, the applications of the Friedel-Crafts and Grignard reactions to carbohydrate starting materials. While these reactions are extremely general, their use in the carbohydrate series has been rather limited, and attempts will be made, where possible, to point out gaps in our present knowledge and suggest further lines of investigation.

11. PROCESSES CATALYZED BY ALUMINUM CHLORIDE 1. Chlorination of the Acylal Function

In view of the tremendous variety of organic substances which react in one way or another under the catalytic influence of anhydrous aluminum chloride,’ the limited application of this catalyst to the sugar series is surprising. The first mention of the action of aqueous aluminum chloride on sugars was made in 1899 by Kahlenberg, Davis, and Fowler12 who studied the rates of inversion of sucrose in aqueous solution in the presence of various inorganic salts, including aluminum chloride. When the metals were arranged in a series according to the decreasing ability of their salts of the same acid radical to invert sucrose, the order simulated (1) C. A. Thomas, “Anhydrous Aluminum Chloride in Organic Chemistry,” Reinhold Publishing Corp., New York (1941). (2) L. Kahlenberg, D. J. Davis and R. E. Fowler, J . Am. Chem. SOC.,21, 1 (1899).

FRIEDEL-CRAFTS A N D GRIGNARD PROCESSES

253

that of the electromotive series. Aluminum salts, however, formed a notable exception. I n spite of the high position of aluminum in the electromotive series, its salts inverted sucrose more rapidly than the salts of any other metal studied, and aluminum chloride showed greater catalytic activity than did aluminum sulfate. The first reports of the use of anhydrous aluminum chloride as a reagent in carbohydrate chemistry were those of von Arlt3 and Skraup and Kremann4 in 1901, who showed th at the anomeric D-glucose pentaacetates as well as D-galactose pentaacetate yiqlded the corresponding tetraacetylglycosyl chlorides "when their chloroform solutions were heated with a mixture of aluminum chloride and phosphorus pentachloride. This reaction, involving replacement of the acylal function6g6 of the compound by chlorine, anticipated Pacsu's production7 of these glycosyl chlorides from the acetylated aldoses b y action of titanium tetrachloride on chloroform solutions of the latter. The higher yields and greater convenience of the titanium tetrachloride technique have generally favored its use in synthetic work, but several further instances of the use of aluminum chloride and phosphorus pentachloride have been reported. Thus, Hudson and Johnson8 in 1916 prepared a tetraacetylgalactosyl chloride different from that of Skraup and Kremann4 by action of these reagents on tetraacetyl-P-D-galactofuranosyl acetate, and Brauns employed them for the production of comparable derivatives of fructoseg and mannose.'" I n 1927 Helferich and Bredereck" prepared 6-chloro-6-desoxy-2,3,4-triacetyl-a-~-glucosyl chloride by action of aluminum chloride and phosphorus pentachloride on 6-chloro-6-desoxy2,3,4-triacetyl-~-~-glucosyl acetate in chloroform, and even as late as 1936 Freudenberg and Soff l 2 prepared tetraacetylglucosyl chloride with these same reagents, using acetyl chloride as solvent. I n all of these processes, it is not clear whether the aluminum chloride, the phosphorus pentachloride, or both are the primary chlorinating agents. While phosphorus pentachloride alone in chloroform has been reporteds t o produce tetraacetyl-a-D-fructosyl chloride from p-D-fructose pentaacetate, its action on P-D-glucose pentaacetate in the absence of (3) F. von Ark, Monatsh., 22, 144 (1901). (4) H. Skraup and R. Kremann, Monatsh., 22, 375 (1901). (5) C. D. Hurd and S. M. Cantor, J . A m . Chem. Soc., 60, 2678 (1938). (6) C. D. Hurd and F. 0. Green, J . A m . Chem. Soc., 63, 2201 (1941). (7) E. Pacsu, Ber., 61, 1508 (1928). (8) C . S. Hudson and J. M. Johnson, J . A m . Chem. Soc., 38, 1226 (1916). (9) D. H. Brauns, J . A m . Chem. Soc., 42, 1846 (1920). (10) D. H. Brauns, J . A m . Chem. Soc., 44, 401 (1922). (11) B. Helferich and H. Bredereck, Ber., 60, 1995 (1927). (12) K. Freudenberg and K. Soff,Ber., 69, 1245 (1936).

254

WILLIAM A. BONNER

solvent is knowg'a to form 2-trichloroacetyl-3,4,6-triacetyl-/3-~-glucosyl chloride. That aluminum chloride alone is capable of chlorinating the number one position of an acetylated aldose, however, has been shownI4 by preparation of tetraacetylglucosyl chloride in fair yield on refluxing 50 g. of anhydrous aluminum chloride with 29 g. of 8-D-glucose pentaacetate in 500 ml. of dry chloroform. 2. Inversions within the Sugar Molecule

A new and unexpected observation was recorded in 1926 by Kunz and Hudson,16 who found that anhydrous'aluminum chloride not only functioned as a chlorinating agent, but also served as a catalyst for the inversion of certain of the asymmetric centers within the sugar molecule. Thus, when octaacetyllactose was refluxed with twice its weight of aluminum chloride in dry chloroform, two derivatives were obtained. The first was the anticipated heptaacetyllactosyl chloride, (I), and the second was named heptaacetylneolactosyl chloride. From the latter, neolactose was obtained as a dextrorotatory sirup on deacetylation.16 Oxidation of the reducing function of neolactose, followed by hydrolysis of the disaccharide linkage, produced D-galactose and D-altronic acid. Furthermore, direct hydrolysis of neolactose produced D-galactose and a sirup, which yielded D-altrosazone with phenylhydrazine, and D-tale mucic acid when oxidized with nitric acid. From these data Kunz and Hudson deduced the structure of neolactose as 4-p-~-galactopyranosylD-altrose, (11). Comparison of the stereochemical arrangements of I and I1 shows that aluminum chloride caused inversion of the configurations of the second and third carbon atoms in the glucose portion of the

(13) P.Brigl, 2. physiol. Chem., 118, 1 (1921);W.J. Hickinbottom, J . Chem. Soc., 1676 (1929). (14) W.A. Bonner, Ph.D. Dissertation, p. 274, Northwestern Univ. (1944). (15) A. Kunz and C, S. Hudson, J . Am. Chem. SOC.,48, 1978 (1926). (16) A. Kunz and C. S. Hudson, J . Am. Chem. SOC.,48,2435 (1926).

FRIEDEL-CRAFTS AND GRIGNARD PROCEBSES

255

lactose molecule. Later Richtmyer and Hudson," employing phosphorus pentachloride in conjunction with aluminum chloride, developed a method for producing heptaacetylneolactosyl chloride in forty-five percent yield. By acid hydrolysis of the neolactose obtained on deacetylation, followed by removal of the D-galactose by fermentation, D-altrose was readily recovered by isolation and purification through its dibenzyl mercaptal. The procedure has recently been abbreviated and adapted to a large scale, whereby 18 g. of D-altrose may be obtained from 1 kg. of lactose hydrate.I8 Lactose is not the only disaccharide which has been so isomerized. also reported the isolation of two products, heptaacetylcellobiosyl chloride and heptaacetylceltrobiosyl chloride, by action of aluminum chloride on a chloroform solution of cellobiose octaacetate. By the previously employed techniques of oxidation and degradation, Richtmyer and Hudson*O were able to prove that celtrobiose was 4-p-~-glucopyranosyl-D-altrose, the second and third carbon atoms in the reducing portion of the cellobiose molecule having, as before, isomerized to the altrose configuration. The generality of this interesting isomerization has not been further extended, and it is not known whether it is specific for disaccharides with a reducing moiety of the glucose configuration, or whether other disaccharides or even monosaccharides might also be employed. Similarly, while aluminum chloride alone engenders the isomerization, the addition of phosphorus pentachloride has been found in both instances to improve the process. It has never been observed whether the latter reagent alone will cause the isomerization, or if other metal halides might also be efficacious. No explanation has been proffered as t o the mechanism of this reaction, or as to why only the second and third centers of asymmetry should be involved. A propos, it is interesting to note14 that the action of aluminum chloride on P-D-glucose pentaacetate gives rise not only to tetraacetyl-a-D-glucosyl chloride, but also t o a sirup of lower specific rotation (100"). The possibility that this product is of the altrose type has been suggested, but never tested. 3. Catalytic Glycosylations of Aromatic Hydrocarbons

In 1945 Hurd and Bonner2' utilized the catalytic action of aluminum chloride in a new connection by successfully alkylating aromatic hydro(17) (18) (19) (20) (21)

N. K. Richtmyer and C. S . Hudson, J . Am. Chem. SOC.,67, 1716 (1935). R. C. Hockett and L. B. Chandler, J . Am. Chem. SOC.,66, 627 (1946). C. S. Hudson, J . Am. Chem. Soc., 48,2002 (1926). N. K. Richtmyer and C. S . Hudson, J . Am. Chem. Soc., 68, 2534 (1936). C. D. Hurd and W. A. Bonner, J. Am. Chem. Sac., 67, 1664 (1945).

256

WILLIAM A. BONNER

carbons with tetraacetyl-a-wglucosyl chloride (111). Neglecting possible side reactions, they were interested in extending the well-known Friedel-Crafts hydrocarbon synthesis to the glycosyl halides : CI

Ar

When either I11 or @-D-glucosepentaacetate was allowed to react with benzene in the presence of small amounts of aluminum chloride, the starting material was recovered, accompanied by traces of a product bearing a strong aromatic odor. These observations suggested that the reaction of the ester functions of these sugar derivatives with benzene was occurring prior to, or a t least simultaneously with, Reaction (1). A scheme such as (2) was postulated as occurring at each of the ester functions: CHsCOCl

AlCh

CHaCOCeH6 CsHs *hHOCOCHa ---\ I Ha0 I *CHOAlCls 'AHOH AICIap

I

(2)

I

If Reaction (2) occurred at each acetyl group of 111 before Reaction (1) proceeded, then eight moles of aluminum chloride would be required, plus an additional amount to promote Reaction (1). Acetophenone should be isolable from the benzene layer, and the carbohydrate product, having undergone deacetylation, would be found in the water layer. Actually, Reaction (1) was realized in the presence of only five moles of catalyst, showing that Reactions (1) and (2) occur simultaneously. When I11 was refluxed for seven hours with five moles of aluminum chloride in a large excess of benzene and the reaction mixture then decomposed with water, the anticipated benzophenone was isolated, along with considerable tar, from the benzene layer. The water layer was neutralized, filtered free of alumina, and taken t o dryness. On acetylating the residue, (tetraacetyl-@-D-glucopyranosy1)benzene (IV) resulted in twenty-seven percent yield. The structure of IV was supported by its oxidation to benzoic acid and its lack of reducing properties. The pyranose ring, the @-designation,and the glucose structure of IV, all implicit in its name, were established subsequently (See pages 277 and ,282). An attempt was made to increase the yield of 13Vby employing the theoretically required eight moles of catalyst. Instead of IV, m. p.

FRIEDEL-CRAFTS AND GRIGNARD PROCESSES

257

156.5", however, a second acetate of m. p. 95" was isolated. This could be deacetylated to give a hydrate, m. p. 157.5") which depressed the melting point of IV. The lack of reducing properties in the hydrate and the acetate, as well as their interconvertibility and the oxidation of both to benzophenone, suggested that the two substances were 1,ldiphenyl-1-desoxy-D-glucitolhydrate (V), and its pentaacetate. V and IV were produced in a ratio of 1:5 when five moles of catalyst were employed, though with eight moles no IV resulted. CsHs-CH

C6Hb-CH-CaH

s

HAOH

A

HO H

&HzOAc

IV

AHzOH.HzO

V

The isolation of V along with I V provided evidence that IV possessed the proposed pyranose structure, as an intermediate with the general structure of IV was considered as the precursor of V. The latter was then postulated as arising by catalytic fission of the oxygen bridge in its precursor, followed by alkylation. Such an hypothesis agreed with the observations of Smith and Natelson, 2 2 who found that polymethylene oxide rings were cleaved with alkylation when benzene solutions of these substances were treated with aluminum chloride. Furthermore, V could be produced from IV on heating a benzene solution of the latter with aluminum chl0ride.~3 Thus, if a structure related t o IV is the precursor of V, then IV must possess its parent ring size, any opening of the ring of I V producing V. This deduction has been confirmed and the ring size of compounds like IV established experimentally by the where two moles of periodate oxidation of ~-~-xylopyranosylbenzene,~~ periodate were consumed and one mole of formic acid produced. Toluene reacted with I11 and aluminum chloride much as did benzene, except that yields were lower and tar formation more extensive. From the organic layer methyl p-tolyl ketone was isolated, while acetylation of the product from the aqueous layer led to 1,l-di-p-tolyl-1-desoxyD-glucitol hydrate (VI). p-P-D-Glucopyranosykoluene, structurally J. Am. Chem. Soc., 63, 3476 (1931). (23) C. D. Hurd and W. A. Bonner, J. Am. Chem. Soc., 67, 1977 (1945). (24) W. A. Bonner and C. D. Hurd, Paper presented before the Division of Sugar Chemistry, 110th Meeting of the American Chemical Society, Chicago, 1946. Cf. also Reference (68). (22) R. A. Smith and S. Natelson,

258

WILLIAM A. BONNER

related t o IV, could not be isolated from the crude reaction mixture, but its presence therein was demonstrated by the isolation of terephthalic acid on oxidation. CH~---~H---CH~-

-

HCOH HOAH

A

H OH HAOH AH20H.H,0 VI

Attempts to employ naphthalene as the aromatic component led to no identifiable carbohydrate product, although methyl 1-naphthyl ketone was obtained by acylation of the naphthalene with the ester functions of 111. The generic term glycosylation has been proposed21 for reactions of the above sort whereby a glycosyl radical is directly attached to a hydrocarbon through a carbon to carbon linkage. Compounds of the types IV and V constituted hitherto unreported classes of carbohydrate derivatives, although compounds closely related to V have been known for over forty years (See page 262). The possible importance of compounds of these classes arises from the ease with which a non-ionic, water-soluble side chain of high molecular weight may be attached to an insoluble hydrocarbon radical through a stable carbon to carbon bond. Since p-D-glucose pentaacetate had been shown to produce tetraacetylglucosyl chloride in the presence of aluminum chloride,I4 an attempt was made25to employ the pentaacetate directly for the catalytic glucosylation of benzene. Such a scheme assumes that the acetylated aldose would undergo initial chlorination a t the acylal function, and the intermediate chloride would then react with the aromatic hydrocarbon in the previously observed manner. Such a series of reactions was found to occur. When p-D-glucose pentaacetate was refluxed in benzene with six moles of aluminum chloride the previously isolated products, IV and the acetate of V, were obtained, though in lower yield and with greater tar formation. The greater availability of the pentaacetate, however, initiated experiments designed to determine optimum conditions for its use in catalytic glucosylations. In this study a series of reactions employing a fixed quantity of b-D-glucose pentaacetate was conducted under standardized conditions, the quantity of catalyst being the only (25) C. D. Hurd and W. A. Bonner, J . Am. Chem. Soc., 67, 1759 (1945).

259


variable. The results of these experiments, based on 40 g. of starting material, are presented graphically in Figure 1. Curves 2 and 3 of Figure 1, representing products of greatest interest, are at a maximum when the theoretical ten moles of catalyst is employed. Amounts of catalyst in excess of the theory increased only the yield of acetophenone. Deficiencies of catalyst generally gave lower yields of everything but tar. The effect of the quantity of catalyst on the ratio of acetophenone to tar is interesting, and was explained in terms of the type of reaction favored at the acetyl groupings under the influence of varying amounts of catalyst. It is knownz6 that esters may react

0.50

0.25

0.75

1.00

1.25

I

0

FRACTION OF THEORETICAL QUANTITY OF CATALYST

FIG.1. Product Yields as a Function of Catalyst Quantity in the Glucosylation of Benzene with B-D-Glucose Pentaacetate. 1. Acetophenone. 2. Crude Acetylated Product. 3. 1,l-Diphenyl-1-desoxy-Dglucitol Hydrate (V). 4. Tar.

catalytically with aromatics in two ways, giving acylation, alkylation, or both, depending on conditions:

c:

* HOCOCHa I 'LHOCOCHa

I

I + CaHe AlClr *CHOH + CeHsCOCHs

(3)

+ CsHa AlClt

(4)

--+

-*

I

bHCsH:

I

+ CH&OOH

Reaction (3), one of acylation, explains the formation of acetophenone and a stereochemically intact carbohydrate product. Reaction (4), (26) Reference 1, page 673 ff.

260

WILLIAM A . BONNER

involving alkylation, would lead t o mixtures of high molecular weight hydrocarbons of varying composition. Furthermore, since the asymmetric centers are disturbed in (4),inversion or racemization would be expected. It was suggested that reactions such as (4)were responsible for the tar formation during catalytic glycosylations. This hypothesis was supported by the continuous boiling range of the tars, their varying optical activity, and their ready oxidation t o high yields of benzoic acid. I n extending the catalytic glycosylation of benzene t o other sugars, 1,l-diphenyl-1-desoxy-D-galactitoland (by inference from oxidation experiments) 8-D-galactopyranosylbenzene were obtained from p-Dgalactose pentaacetate, while 8-D-xylose tetraacetate gave (triacetyl8-D-xylopyranosyl) benzene and 1,l-diphenyl-1-desoxy-D-xylitol. Other hexoses and pentoses thus followed the same general reaction pattern studied in detail for glucose. The isolation of V by catalytic glucosylation of benzene with IV, used t o establish the probability that intermediates related t o IV were the precursors of V, suggestedz3the possibility that reactions of this type might be employed for the synthesis of mixed 1,l-diaryl-1-desoxyglycitols, products having different aromatic groups on the number one carbon. This possibility was realized in practice. When IV reacted with toluene and aluminum chloride, a-l-p-tolylp-1-phenyl-1-desoxy-D-glucitolhydrate (VII), was formed. Similarly, when the acetate of p-p-D-glucopyranosyltoluene was employed with benzene as solvent, a-1 -phenyl-p-1-p-tolyl- 1-desoxy-D-glucitol hydrate (VIII), resulted. In the same way a-1-phenyl-p-1-p-tolyl-1-desoxy-D-

A

HO H I

t:

HO H I

xylitol was obtained by the glycosylation of benzene with p-(triacetylp-D-xylopyranosyl) tohen;. The structures of these products were supported by their oxidation to p-benzoylbenzoic acid. The belief that VII and VIII constituted a n anomeric pair is implicit in their names, and substantiated by their differing physical properties and the fact that they showed a marked mixed melting point depression

FRIEDEL-CRAFTS AND GRIONARD PROCESSES

261

with each other. Despite the nomenclature, however, nothing is known about the stereochemical arrangements of the two aryl groups in VII and VIII, and their names were based on the names of their monoaryl progenitors.

111. APPLICATIONSOF

THE

GRIGNARD REACTION

1. Formation of Molecular Addition Compounds

The earliest attempt to react Grignard reagents with carbohydrate ~ These investigators substances is that of Paal and H O r n ~ t e i nin~ 1906. studied the action of phenylmagnesium bromide on tetraacetyl-a-Dglucosyl bromide and p-D-glucose pentaacetate, but isolated only methyldiphenylcarbinol from either reaction. This, they pointed out, was to be expected from action of the Grignard reagent on the acetyl groupings in these glucose derivatives. Markedly different results were reported early in 1912 by Fischer and Hess12*who studied the action of methylmagnesium iodide on a number of glucose derivatives, reporting only the isolation of more or less stable adducts. Thus, when a mole of tetraacetyl-a-D-glucosyl bromide in ether was mixed with 2.03 moles of methylmagnesium iodide, a white, amorphous solid precipitated. The analysis of this substance corresponded to Cl4HlgO9Br*2CH,MgI,an adduct of two moles of the Grignard reagent to one of the glucose derivative. When the adduct was cautiously acidified, tetraacetyl-a-D-glucosyl bromide was recovered in good yield. On heating the adduct with methanol, then treating with barium hydroxide, methyl p-D-glucoside resulted. Similarly, D-fructose pentaacetate, tetraacetyl-D-glucose, and methyl tetraacetyl-a-D-glucoside gave precipitates with methylmagnesium iodide, all analyzing as adducts containing two moles of Grignard reagent. Precisely similar results were obtained in a broader study conducted eighteen years later by Froschl, Zellner and Zak.2g For example, tetraacetyl-wfructosyl chloride and fifteen moles of ethylmagnesium iodide in which reverted to ether at 0" gave the adduct C14H1909C1~2C2H~Mg11 tJheoriginal fructosyl chloride on acidification. Similar addition products were reported from ethylmagnesium iodide and tetraacetyl-D-fructose, D-fructose pentaacetate, heptaacetyllactosyl bromide, and lactose octaacetate. All of these adducts regenerated unchanged starting material when acidified. It is noteworthy that no mention of methyldialkylcarbinols was made in either of these studies. (27) C. Paal and F. Hornstein, Ber., 39, 1361 (1906). (28) E. Fischer and K. Hess, Ber., 46, 912 (1912). (29) N. Froschl, J. Zellner and H. Zak, Monatsh., 66, 25 (1930).

262

WILLIAM A. BONNER

A recent, thorough study by Jeremias and MacKenzieao has failed completely to substantiate the two reports of adduct formation, and has confirmed the original claim that a tertiary alcohol is formed. These authors studied the action of methyl-, butyl-, and phenylmagnesium halides on fl-D-glUCOSe pentaacetate at mole ratios of 2: 1 and 10 : 1, and at temperatures of 0-5" and 25-350. I n each experiment they observed only the formation of a tertiary alcohol and glucose. No evidence of stable complex formation was noted, and the only reaction found was the normal one of Grignard reagents with esters. Since the experimental conditions of the latter investigators bridged those of the earlier workers, these opposing claims are puzzling and have yet t o be rationalized. 2. Carbonyl Addition Reactions a. With Acetylated Glycono1actones.-Having failed to isolate a carbohydrate product on reacting phenylmagnesium bromide with tetraacetylglucosyl bromide or acetate, Paal and HornsteinZ7next turned their attention t o the utilization of acetylated glyconolactones. Two years before, Houben had shown31 that lactones reacted with Grignard reagents to produce tertiary alcohols, and Paal and Hornstein proposed t o extend this observation to the sugar series, realizing from their previous experiments that an excess of Grignard reagent would be required to allow for full reaction at the acetyl groups. Thus a minimum of ten moles of Grignard reagent would be required per mole of tetraacetyl-Dgluconolactone, eight for the acetyl groups and two for the lactone function. When twelve moles of phenylmagnesium bromide acted on tetraacetylD-gluconolactone in a mixture of ether and benzene, 1,l-C-diphenyl-Dglucitol (IX), could be isolated in ten to twelve percent yield. In

(30) C. G. Jeremias and C. A. MacKenzie, J . Am. Chem. Soc., 70, 3920 (1948). (31) J. Houben, Ber., 87, 489 (1904).


263

addition, methyldiphenylcarbinol resulted from reaction a t the acetyl groups. These investigators argued32for retention of the parent glucose configuration in IX on the basis that steric rearrangements would not be expected under their (‘mild” conditions, an argument hardly persuasive today. As will be shown later, however, there seems little reason to doubt the correctness of their assumption. Following the original paper, Paal extended the reaction by varying both the glyconolactone and the Grignard reagent. Thus, tetraacetylD-galactonolactone and phenylmagnesium bromide gaveg3in thirty percent yield 1,l-C-diphenyl-D-galactitol,while triacetyl-carabonolactone with phenylmagnesium and p-tolylmagnesium bromides yieldedg4 1,1-C-diphenyl-L-arabitol (X) , and 1,1-C-di-p-tolyl-L-arabitol, respectively. The structures of these products were further substantiated at this point by degradative studies. Thus, on oxidation X gave benzophenone and an aliphatic product which appeared to be meso-tartaric acid. On benzoylating X a tetrabenzoate was formed, the tertiary hydroxyl group at the first carbon remaining unaffected. On heating X with mineral acid an anhydro-1,l-C-diphenyl-L-arabitol was isolated, for which structure XI was proposed. By careful permanganate oxida-

tion this was oxidizable to what was presumably the anhydrotrihydroxy acid (XII), eliminating the possibility of a 1,8anhydro bridge. XI1 is the hemiacetal form of an a-keto acid. Since atom 4 in XI, which was believed to be oxidized, is an ether function, and since atoms 2 and 3 have secondary alcohol groupings, one would expect stability a t atom 4 and oxidation to a ketone at positions 2 or 3. Of these alternatives, atom 2 seems preferred, since oxidation a t atom 3 would yield a p-keto acid which would decarboxylate spontaneously. Structure XI1 has never been established by rigorous proof. Modern tools, especially periodate oxidation, should make this a fairly simple problem. (32) C. Paal and F. Hornstein, Ber., 39, 2823 (1906). (33) C. Paal and E. Wiedenkoff, Ber., 39, 2827 (1906). (34) C. Paal and M. Kinscher, Ber., 44, 3543 (1911).

264

WILLIAM A. BONNER

Several years later Paa136 reported the action of p-tolylmagnesium bromide on tetraacetyl-D-gluconolactone and of phenyl-, p-tolyl-, and benzylmagnesium halides on tetraacetyl-D-galactonolactone. A series of products structurally related to IX and X was obtained. One of these products, l,l-C-diphenyl-D-galactitol, was also found to form an anhydro derivative for which a 1,4-bridge was again proposed, but no further structure proof was offered. b. With Substituted Glgconic Acids and Related Compounds.-Early in the studies with acetylated glyconolactones Paal and Zahn reporteds0 an extension of the Grignard reaction to a carbohydrate ester. When methyl D,L-glycerate was suspended in a mixture of ether and benzene and treated with two moles of phenylmagnesium bromide, hydrolysis of the reaction mixture produced 1 ,1-C-diphenyl-D,L-glyceritol (XIII), in OH C6H,--L6HI AHOH bH,OH XI11

forty-two percent yield. This was the first demonstration that an ester in the carbohydrate series reacted in the ordinary fashion, a fact to be anticipated from the lactone studies. It is interesting in this case to note that the free hydroxyl groups in methyl glycerate apparently failed to react appreciably as an alcohol with the Grignard reagent, presumably due to the use of the methyl glycerate in suspension. Twenty-three years later Ohle and coworkers initiated37sa8a series of extensive studies on the reactions of Grignard reagents with a variety of less common carboxylated structures in the sugar series. Their motives9* for embarking on these studies are varied and interesting. They were concerned first with studying the effects of aromatic ring systems on the relative stability of tautomeric sugar modifications, in gaining insight into the factors which caused osazone formation to stop after the introduction of the second phenylhydrazine residue, and lastly in determining if and under what conditions the carbohydrate side chains might undergo intramolecular condensations with the aromatic portions of their products to produce more complex ring systems. While these general objectives were hardly realized, the papers of Ohle and his (35) (36) (37) (38)

C. Paal, Ber., 49, 1583 (1916). C. Paal and K. Zahn, Ber., 40, 1819 (1907). H. Ohle and 0. Hecht, Ann., 481, 233 (1930) H. Ohle and Ingrid Blell, Ann., 493, 1 (1931)

265

FRIEDEL-CRAFTS A N D ORIONARD PROCESSES

students constitute an interesting series of original synthetic studies in the carbohydrate field, and will be discussed from this point of view. acid (XIV), When 1,2 :3,4-diisopropylidene-l-~-arabinosecarboxylic reacted with four moles of methylmagnesium iodide two products were obtained37 in a ratio of seven to one, 1-C-methyl-2,3 :4,5-diisopropylidene-D-glucosone (XV), and 1,l-C-dimethyl-2,3 :4,5-diisopropylidene-8-D-fructose (XVI). The further reaction of methylmagnesium COOH

CHsCO

1

Oc! Me2C’

\

OA

Ot:

OCH

HLO

HLO

\ HCO &HzO--

&HzO-

XIV

XV

iodide with XV produced XVI, as did also the action of this Grignard reagent on the methyl ester of XIV. Acid hydrolysis of XVI produced 1,l-C-dimethyl-2,3-isopropylidene-~-~-fructopyranose (XVII), and 1,lC-dimethyl-D-fructofuranose (XVIII). On treatment of XVIII with acetone and copper sulfate, 1,l-C-dimethyl-4,6-isopropylidene-~-fructose (XIX), and l,l-C-dimethyl-1,2-anhydro-4,6-isopropyliden~~-fructose (XX) resulted. The absence of an acetone residue on carbon atoms OH

I

CHJ-C-CHJ

OH CHa-A-CHs

OH CHa-

CHa-C-CHa

A

-CHJ

CMer

XVII

XVIII

XIX

xx

2 and 3 in XIX and XX was indicated by their reducing properties, but the experimental evidence offered in support of the furanose ring

266

WILLIAM A. BONNER

structure in XVIII, XIX, and XX is not too decisive. XVI also resulted on treatment of XVII with acetone. Compounds XV and XVI were separable by fractional distillation, and could be distilled without decomposition a t atmospheric pressure. The tertiary hydroxyl group of XVI failed to react with acetic anhydride, benzoyl chloride, p-toluenesulfonyl chloride, or methyl iodide and silver oxide, behavior reminiscent of the tertiary hydroxyl in compounds such as IX. Similarly, this hydroxyl could not be converted to a chloride, although it did react with sodium in dry ether. By the action of other Grignard reagents on XIV or its methyl ester it was possible to synthesizea7ethyl, propyl, butyl, isopropyl, and isobutyl derivatives related to XV and XVI. A more extensive investigation of compounds of the type XV appeared later.a8 When six moles of phenylmagnesium bromide acted on XIV two products, 1-C-phenyl-2,3:4,5-diisopropylidene-~-glucosone(XXI), and 1,I-C-diphenyl-2,3 :4,5-diisopropylidene-~-fructose (XXII), were formed. If the methyl ester of XIV was used, XXII was formed almost exclusively. Again, XXI and XXII were separable by fractional distillation. When XXI was hydrolyzed, a reducing 1-c-phenyl-D-ghcosone (XXIII), resulted. That XXIII was in all probability cyclic was shown by its mutarotation in pyridine. The authors present no evidence as to the ring size in XXIII, or as to the position of ring attachment. The deactivating effect of the phenyl group on an adjacent OH I CsHs-CO

I I

CoHr-

OA Me&’

or

\OCH HA0

\

,CMe2

HCO A H 2 0 XXI

1.

HH b O oH q

H 0>Me2

H O AH20XXII

XXIII

carbonyl, however, would suggest that the carbonyl group a t carbon 2 would be the one involved in the pyranose or furanose ring system in XXIII. When XXIII was treated with acetone, a single acetone group entered to form an isopropylidene derivative which was reducing. This fixed the structure as XXIV-a or XXIV-b. XXIII also gave a tetraacetitte on acetylation, for which the authors propose alternative acetylated st,ructures derived from XXIII. The fact that this tetraacetate gave

267


:"

HA0 \

1

H O AH20

'CMe2 CH20/

03)

(a )

XXIV

no hemiacetal bromide or chloride under the usual conditions, however, also suggested the possibility of an acyclic modification, but experimental criteria for deciding this point were not offered. The partial hydrolysis of XXI was not realized. Similar investigations were conducted on XXII. Its partial hydrolysis produced two products, l,l-C-diphenyl-2,3-isopropylidene-~-fructofuranose (XXV), and 1, l-C-diphenyl-2,3-isopropylidene-~-fructopyranose (XXVI). Both XXV and XXVI were non-reducing, establishing the involvement of the reducing carbon atom with an acetone residue. OH CaHs-h-c~Hs I

OH CsHs-

8" I

-CsHs

Me2C'"]-' 0 H I

HCOH HbO-

AHzOH

&H201

xxv

XXVII

On hydrolysis, both gave 1,1-C-diphenyl-D-fructose(XXVII), whose ring size was not established but was believed t o be 5-membered. XXVI regenerated XXII on reaction with acetone, but XXV was unaffected by treatment with acetone and copper sulfate, suggesting its furanose structure. The presence of the furanose structure in XXV on removal of a single isopropylidene residue from XXII is noteworthy, and the authors suggest that during the hydrolysis of XXII into XXVI hydrolytic fission of the pyranose ring also occurred, followed by ring closure to the fourth carbon. When an attempt was made to acetonate XXVII, no

268

WILLIAM A. BONNER

isopropylidene derivative was formed, but rather a reducing anhydride, for which the alternative structures XXVIII were proposed. The failure to observe a normal reaction of XXVII with acetone was looked OH

A

C E H ~ - -CEH~

OH GHbCH2-

A-CHZCEH~ I

Od

CMez

HCO XXVIII

kH20XXIX

upon as evidence for its furanose structure, although this argument is somewhat weakened by their isolation, on partial hydrolysis of XXII, of a product to which structure XXV was assigned. When benaylmagnesium chloride reacted with XIV, 1,l-C-dibenzyl2,3 :4,5-diisopropylidene-~-fructose(XXIX), was obtained,a8 but a product analogous to XV was not observed. XXIX was similarly subjected to partial hydrolysis, and the structures of the hydrolytic products were deduced by similar reasoning. The rather complex nature of the hydrolysis products in the above studies suggests the desirability that the structures proposed by Ohle be examined more extensively by modern methods. An extension of the Grignard reaction to the glycuronic acid type of structure was made by Ohle and Dambergissg in 1930. When 1,2:3,4diisopropylidenegalacturonic acid was placed in a Soxhlet thimble and gradually extracted into a solution containing four moles of methylmagnesium iodide, two products resulted. The first, 6-C-acetyl 1,2 : 3,4-diisopropylidene-~-gaZacto-aldopentose(XXX), corresponded to XV of the earlier study, while the second, 6,6-C-dimethyl-l,2: 3,4-diisopropylidene-D-galactose (XXXI), corresponded to XVI. The action of methylmagnesium iodide' on XXX produced additional XXXI. The hydrolysis of XXXI produced 6,6-C-dimethyl-~-galactose,a reducing sirup whieh gave a crystalline osazone. Ethyl analogs of X X X and XXXI were prepared also. (39) H. Ohle and C. Dambergis, Ann., 481, 265 (1930).

FRIEDEL-CRAFTS

269

I

I 1

\

1

HCO

/CMez

HCO I ObH Me&/

A N D GRIGNARD PROCESSES

\ ,CMez

HCO ObH

‘OCH

I

HCOCHa-

A

0 AH

xxx

XXXI

In 1941 Gakhokidae40 realized a different type of Grignard synthesis on a carbohydrate acid derivative. Methyl ~-erythro-3,4,5-trimethoxy2-oxovalerate (XXXII), was treated with one mole of methylmagnesium iodide t o produce methyl 2-methyl-2-hydroxy-~-erythro-3,4,5-trimethoxyvalerate (XXXIII). The configuration of the second carbon atom in COOCHs I

60 CHaOAH I CHaOqH hHzOCHa

XXXII

COOCHs I

CHsbOH

c:

CHiO H I CHaOqH ~HzOCHI

XXXIII

XXXIII is not known. When the free acid corresponding t o XXXIII was reduced with phosphorus and hydrogen iodide, a-methyl-y-valerolactone was isolated, substantiating st,ructure XXXIII. It is interesting to note that the single mole of Grignard reagent reacted a t the carbonyl function of X X X I I rather than a t the ester function, a fact observed4* in the action of Grignard reagents on other a-keto esters. c. With Isopropylideneglyconic Aldehydes.-The first reaction of the aldehyde function of an aldose with a Grignard reagent was conducted by Gatzi and R e i c h ~ t e i nin ~ ~ 1938. Treatment of 2,3:4,5-diisopro(40) A. M. Gakhokidze, J . Gen. Chem. ( U S S R ) , 11, 109 (1941); Chem. Abstracts, 36, 5464. (41) A. McKeneie, J . Chem. Soc., 86, 1249 (1904); 89, 365 (1906); A. McKenzie and H. Wren, ibid., 89, 688 (1906); A. McKenzie and H. A. Miiller, ibid., 96, 544 (1909); A. McKeneie and P. D. Ritchie, Biochem. Z., 231, 412 (1931); 237, 1 (1931); 260, 376 (1932). (42) K. G&td and T. Reichstein, Helv. Chim. A d a , 21, 914 (1938).

270

WILLIAM A. BONNER

pylidene-D-arabonaldehyde diethyl mercaptal with mercuric chloride and cadmium carbonate gave 2,3 :4,5-diisopropylidene-~-arabonaldehyde (XXXIV). When this was treated with methylmagnesium iodide, a mixture of two diastereoisomeric compounds resulted, namely, 1,2 :3,4diisopropylidene-6-desoxy-~-gulitol(XXXV), and 1,2:3,4-diisopropyllidene-D-rhamnitol (XXXVI). On separation and hydrolysis, XXXVI

r3

CHs CHO

HCloH

OClH Me&-

OAH Me2C-/

/ I

H

I

!

HCO

MezC- /

I

HAO’

\

U

1

HCO I

\ ,CMez

CHzO XXXIV

HO H

\ \ /CMeZ

CHzO

xxxv

OAH

I

HAO/

1

HA0

\

\ ,CMez

CHzO XXVI

produced D-rhamnitol and XXXV 6-desoxy-~-gulitol. Seven years later English and Crisw0ld4~conducted similar reactions with 2,3 :4,5-diisopropylidene-~-arabonaldehyde,varying the Grignard component to include phenyl-, 1-naphthyl-, and cyclohexylmagnesium halides. The mixtures of diastereoisomeric 1-C-substituted ~-arabino2,3 :4,5-diisopropylidenepentanepentols of general formula XXXVII were subjected to repeated crystallization to constant melting point and R AHOH HA0 I \CMe2

XL-

1

O h

Me&/

\OCH2

XXXVII

rotation, except for the substance where R was 1-naphthyl, when the product was a sirup. Yields were sixteen, twenty, and seventy-two percent, respectively, for R as cyclohexyl, phenyl, and 1-naphthyl. All three products formed crystalline substances on hydrolysis, but in general only the least soluble disastereoisomer was isolated. These (43) J. E. English, Jr., and P. H. Griswold, Jr., J . Am. Chem. Soc., 67,2039 (1945).


27 1

same investigator^^^ also treated cyclohexylmagnesium chloride with 2,3 :4,5-diisopropylidene-~-arabonaldehyde, obtained in turn by the periodate oxidation of 1,2 :3,4-diisopropylidene-~-mannitol. The resulting product was enantiomorphic with that previously obtained in the L-series. The authors also present a concrete proof of the locations of the isopropylidene residues in XXXV, XXXVI, and XXXVII, a point previously undecided. The question of the stereochemical configuration of the newly produced center of asymmetry a t the first carbon atom in compounds such as XXXVII has recently been a n s ~ e r e d 4by~ degradative studies. When XXXIV reacted with phenylmagnesium bromide, crystalline 1-C-phenyl2,3 :4,5-diisopropylidene-~-gluco-pentitol(XXXVIII), enantiomorphic with the sample of English and G r i ~ w o l d ,was ~ ~ obtained. By acid hydrolysis of sirup from the mother liquors producing XXXVIII, the diastereoisomeric 1-C-phenyl-D-manno-pentitol (XXXIX), resulted. Hydrolysis of XXXVIII produced 1-C-phenyl-D-gluco-pentito1 (XL) . Catalytic hydrogenation of XL led t o 1-C-cyclohexyl-D-gluco-pentito1 (XLI), which was identical with a sample prepared by hydrolysis of the l-C-cyclohexyl-2,3:4,5-diisopropylidene-~-gluco-pentitol (XLII), resulting from reaction of XXXIV with cyclohexylmagnesium bromide. These reactions established the stereochemical similarity of the least soluble diastereoisomer obtained in the phenyl and cyclohexyl series. The assignment of the gluco-configuration to XXXVIII and the C6Hs I

H~OH Me&-----/

OLH

I

HbO’ I

I

HbO

\

\

,CMez

CHzO XXXVIII

XXXIX

manno-configuration t o XXXIX was based on the following degradative experiments. Methylation of the free hydroxyl group in XXXVIII produced 1-C-phenyl-1-methyl-2,3 :4,5-diisopropylidene-~-gluco-pentitol (XLIV) , which on acid hydrolysis yielded 1-C-phenyl-1-methyl-D-glucopentitol (XLVI). Periodate oxidation of XLVI led t o L-( +)-1-methoxy(44) J. E. English, Jr., and P. H. Griswold, Jr., J . Am. Chem. Soc., 70,1390 (1948). (46) W. A. Bonner, J . Am. Chem. SOC.,73, 3126 (1951).

BXNNOB 'V WVI'ITIM

FRIEDEL-CRAFTS A N D GRIGNARD PROCESSES

(FTOrn

page 67.9)

273

(From page 67.9)

1

1

CsHr HAOMe Me&- /

ObH

I

I

/

Me& /

OAH

I

I / I

HCO'

HCO

HCO

HCO

I

I

CHzO

/

XLV

HAOH HbOH AHzOH XLVII

I

NaIOc

CeHs

I

MeOCH AH0 1. Esterifioation

2. Methylation 3. Hydrolysis

XLVIII

1 Agio

XLIX

I AszO

6OOH

I

MeOCH I

Configurations of the l-C-Substituted-D-pentitols.

HCOMe I

D-(

-)-Man,&

I

Acid

1. Esterifioatioii 2. Methylation 3. Hydrolysis

274

WILLIAM A. BONNER

phenylacetaldehyde (XLVIII) , with destruction of all asymmetric centers except the one whose configuration was in question. Silver oxide oxidation of the aldehyde XLVIII gave O-methyl+-( +)-mandelic acid (L), showing identical physical properties and an identical infrared absorption spectrum with an authentic sample of L prepared synthetically from L-( +)-mandelic acid. Since the stereochemical configurations of the mandelic acids are kn0wn,4~and since the first center of asymmetry of XXXVIII was shown configurationally related to L-(+)-mandelic acid, it followed that XXXVIII must possess the gluco-configuration. Compound XXXIX was shown to have the manno-configuration by similar degradative reactions. Although l-C-phenyl-2,3 :4,5-diisopropylidene-D-manno-pentito1 (XLIII), could not be isolated crystalline from the mother liquors of XXXVIII, methylation of the sirupy product from the mother liquors, followed by hydrolysis of the resulting impure sirupy l-C-phenyl-l-methyl-2,3 :4,5-diisopropylidene-~-munnopentitol. (XLV), produced crystalline 1-C-phenyl-l-methyl-D-mannopentitol (XLVII). Periodate oxidation of XLVII, followed by oxidation of resulting aldehyde XLIX yielded 0-methyl+-( - )-mandelic acid (LI), identical in all respects with a sample prepared synthetically. A flow-sheet summarizing the degradative and synthetic steps establishing the configurations of these l-C-substituted-D-pentitolsis given in Fig. 2. From considerations of the specific rotations of pure XXXVIII, XXXIX, and XL, and of the crude Grignard reaction product consisting of a mixture of XXXVIII and XLIII, it was found that the reaction of phenylmagnesium bromide with XXXIV gives a mixture containing sixty-five percent XXXVIII and thirty-five percent XLIII. An interesting point arose in connection with the periodate oxidations of XLVI and XLVII. On examination of the rotations of the crude aldehydes, XLVIII and XLIX, as well as the rotations of the crude acids, L and LI, obtained on subsequent oxidation, it was concluded that the periodate oxidations of XLVI and XLVII had been attended by slight racemization, and that the extent of racemization was determined by the configuration of the l-C-phenyl-D-pentito1 undergoing oxidation. This is the first report of racemization attending periodate oxidation in the carbohydrate series, 3. Metathetical Reactions a. With Glucose Polymers.-In 1922 Costa4’ attempted to determine the number of free hydroxyl groups in the D-glucose units of cellulose by reaction with ethylmagnesium bromide. Cellulose was heated a t (46) K. Freudenberg, F. Brauns, and H. Siegel,Ber., 66,193 (1923); K. Freudenberg and L. Markert, ibid., 68,1753 (1925); K. Mislow, J . Am. Ghem. Soc., 78,3954 (1951). (47) D. Costa, Gum. chim. ital., 62, 11, 362 (1922).

FRIEDEL-CRAFTS

275

A N D GRIGNARD PROCESSES

100" for twenty-four hours with an excess of the Grignard reagent, causing the liberation of ethane and forming what was thought to be a bromomagnesium derivative of cellulose, (CeH90sMgBr.EtzO),. On treatment of this with water, cellulose was regenerated. From these results, Costa erroneously concluded that the monomer unit of cellulose had one free hydroxyl group rather than three. Similar results were later obtained48on rice starch. Doubt as t o the validity of Costa's claims was cast several years later by Niethammer,49 who failed to obtain any reaction at all when methylmagnesium iodide acted upon carefully dried cellulose. If the cellulose was very slightly moist, however, small amounts of methane were evolved. In view of this, it is probable that Costa's results are explainable in terms of insufficiently dried samples. b. With Polyacetylglycosyl Halides.-It will be recalled that the studies of PaalZ7in 1906 and Emil Fischer28in 1912 dealing with the reaction of Grignard reagents with tetraacetyl-a-D-glucosyl bromide led to no discovery of metathesis involving the hemiacetal bromide. Instead, Fischer reported an addition product and Paal found formation of tertiary alcohols by reaction of the Grignard reagent with the acetate groups. This general problem was reopened by Hurd and Bonner, following their studies21*26 on the catalytic glycosylation of aromatic hydrocarbons (page 255), since it became necessary to prove the stereochemical configurations of their products. Thus, while the glucosylation of benzene with tetraacetyl-a-~-glucosyl chloride (111), led to what was thought to be (tetraacetyl-0-D-glucopyranosy1)benzene (IV), and the acetate of 1 ,l-C-diphenyl-l-desoxy-D-glucitol (V) , no experimental proof of the presence of the retention of the glucose configuration was offered. Indeed, in view of the observations of Hudson and coworkers1s-20regarding aluminum chloride catalyzed isomerizations, it seemed quite likely that some other configuration might actually be present in IV and V. In order to answer this question, a synthesis of I V was sought wherein the possibility of intramolecular inversions was absent. The metathetical reaction of the chlorine atom of I11 with phenylmagnesium bromide seemed well suited for such a synthesis, The basis for assuming that I11 should react metathetically with a Grignard reagent was that it is a hemiacetal chloride, and the simple chlorides of this type, namely, the a-chloro ethers, are known to react in the manner of Equation (5). This type of. reaction has been used60 for the synthesis of a-substituted ethers, and also constitutes one of the (48) D. Costa, Gazz. chim. ital., 64, 207 (1924). (49) H. Niethammer, Cellulosechemie, 10, 205 (1929). (50) J. Houbeii and K. Fuhrer, Ber., 40, 4990 (1907); R. Paul, Bull. 151 2, 311 (1935); W. A. Bonner, J . Am. Chem. SOC.,69, 183 (1947).

SOC.

chim.,

276

WILLIAM A . BONNER

7' + R'MgX-i k"' +

RCH

O 'R

RC

MgXCl

(5)

O 'R

steps of the Swallen-BoordS1synthesis of olefins. Thus, despite earlier f a i l ~ r e s ~ ~to- ~observe 9 a reaction of this type with hemiacetal halides of the carbohydrate series, there was every reason t o believe that the reaction should go as desired under proper conditions. It seemed reasonable to assume that the cause of the earlier failures was that the Grignard reagent reacted preferentially at the acetyl groups rather than at the hemiacetal halide, and that an insufficient amount of Grignard reagent had previously been employed. Thus, nine moles of Grignard would be required for complete reaction with 111. Earlier workers, it appeared, had either used too little Grignard reagent to permit a reaction such as ( 5 ) , or, in experiments where an excess of Grignard was employed, had attempted the reaction at too low a temperature. When twelve moles of phenylmagnesium bromide was treatedS2with tetraacetyl-a-D-glucosyl chloride in ether, a gummy solid precipitated. The mixture was refluxed four hours, cooled, and cautiously decomposed with water. From the ether layer was isolated a quantitative yield of methyldiphenylcarbinol, formed by reaction of the acetyl functions. The water layer was evaporated to dryness and the residue acetylated. On pouring the acetylation mixture into water, a white solid formed. When recrystallized, this proved to contain the same (tetraacetyl-P-D-glucopyranosyl) benzene (IV) , which had been obtained from the catalytic glucosylation of benzene using aluminum chloride. On evaporation of the mother liquors which produced IV, a sirup was recovered, weighing about one-fourth as much as the crystalline IV. Since this sirup had a positive rotation and oxidized to benzoic acid, it was believed to be (tetraacetyl-a-D-glucopyranosyl) benzene, the anomer of IV. The nomenclature of these products was based on their specific rotationlS3 not on their actual stereochemical configurations at the anomeric center. Practically the same ratio of these two products was found starting with phenylmagnesium bromide and tetraacetyl-P-Dglucosyl chloride.64 The isolation from the Grignard glucosylation of benzene of a product identical with that obtained by the Friedel-Crafts method made it apparent that no intramolecular isomerizations or inversions accompanied the latter process, and that products such as IV and V indeed (51)L. C. Swallen and C. E. Boord, J . Am. Chem. Soc., 62, 651 (1930). (62) C. D.Hurd and W. A. Bonner, J . Am. Chem. Soc., 87, 1972 (1945). (53) C.5. Hudson, J . Am. Chem. SOC.,31, 66 (1909). (64) C. D.Hurd and R. P. Holysz, J . Am. Chem. SOC.,72, 1732 (1950).


277

possessed the configuration of their parent aldose. Basing their argument on an analogy with the spontaneous decomposition of hemiacetals, Hurd and Bonner maintained62 that the Grignard adduct to the ester function of the acetylated sugar must decompose according to LII rather than LIII. Such a scheme leaves intact the bond between oxygen and

1411

LIII

the asymmetric center, (C*), and thus would not permit inversion or racemization at this position. The isolation of glucose on reaction of Grignard reagents with /3-D-glucose pentaacetateao provides experimental proof of this point. Having realized Reaction (5) with tetraacetylglucosyl chloride, extensions were made to other sugars and other Grignard reagents. Representatives were prepared of a series of products having the general structure R-GIAc, where R was phenyl, p-tolyl, 1-naphthyl, butyl, isopropyl, and benzyl, and where GlAc was the acetylated glycopyranosyl radical derived from D-glucose, D-xylose, and lactose. Crude products were obtained in yields of sixty to eighty-six percent, along with nearly quantitative yields of methyldiaryl- or methyldialkylcarbinols. The crude products were usually separable into crystalline, low-rotating /3-anomers and high-rotating sirups believed then to be the a-anomers. More recently Hurd and HolyszS4 obtained similar results in extending the Grignard glycosylation to the use of phenyl-, 2-thienyl-, and 5-bromo24hienylmagnesium halides with appropriate derivatives of maltose, gentiobiose, and D-mannose. Both of the (tetraacetyl-wmannopyranosyl)benzene anomers were obtained crystalline. Acetylenebis(magnesium bromide) and tetraacetyl-a-D-glucosyl bromide gave only intractable tars. In general, however, the high yields, greater generality, and ease of conducting the Grignard glycosylation have made it far preferable t o catalytic glycosylation for the synthesis of compounds of the type R-GlAc. The high-rotating, sirupy by-products accompanying the production of IV by the action of phenylmagnesium bromide on tetraacetylglucosyl bromide have recently been investigated by Bonner and CraigS6 and found to be mixtures of IV and the anomeric (tetraacetyl-a-D-glucopyranosy1)benzene. The latter compound was isolable in the free state by deacetylation of the sirupy by-product, and has been characterized in the free, acetylated, and methylated conditions. Hudson’s rules of (55) W. A. Bonner and J. M. Craig, J . Am. Chem. Soc., 72, 3480 (1950).

278

WILLIAM A . BONNER

isorotation have been extended66to the anomeric pairs of fieelseacetylated, and methylated D-glucopyranosylbenzenes, and found to be applicable with about normal validity. Since it appeared initially as though the reaction of Grignard reagents with polyacetylglycosyl halides proceeded a t the ester groupings before Reaction ( 5 ) occurred, an attempt was made6’ t o establish this point experimentally. On adding a 1.5 mole deficiency of phenylmagnesium bromide to tetraacetylglucosyl chloride, then completing the reaction by subsequent addition of p-tolylmagnesium bromide, and finally studying the ratio of glucosylbenzene t o glucosyltoluene produced, it was possible to calculate roughly that during addition of the first eighty-three percent of the total Grignard reagent, the quantity of Grignard consumed a t the ester functions was ten times that consumed metathetically. Thus, addition a t the ester groupings was definitely the preferred course in the early stages of the reaction. Initial efforts have been made68to apply typical substitution reactions to the aromatic ring of IV. While nitration of IV with mixtures of nitric and sulfuric acids appeared to cause degradation and led to no identifiable product, nitration with cupric nitrate produced a twentyfive percent yield of p-(tetraacetyl-p-D-glucopyranosy1)nitrobenzene (LIV). The structure of LIV was supported by its oxidation to p-nitrobenzoic acid. Bromination of IV in the absence of solvent produced l-(tetraacetyl-~-~-glucopyranosyl)-3,4-dibromobenzene (LV), and what appeared to be an inseparable mixture of LV and p-(tetraacetyl-P-Dglucopyranosy1)bromobenzene (LVI). The structures of LV and LVI were again indicated by the oxidation of these substances t o the corresponding substituted benzoic acid. The nitro derivative (LIV), is of special interest because of the potentially useful synthetic variations applicable to the aromatic nitro group. Br

\

Br-=-lc7 H OAc

1:

H 0AHzOAc

LIV

LV

LVI

(56) W. A. Bonner and W. L. Koehler, J . Am. Chem. Soc., 70, 316 (1948). (57) W.A. Bonner, J . Am. Chem. Soc., 68, 1711 (1946). (58) J. M.Craig and W. A. Bonner, J . Am. Chem. Soc., 72, 4808 (1950).

FRIEDEL-CRAFTS

AND GRIGNARD PROCESSES

279

c. With Methylated G1ycoses.-The synthesis of glycosylated hydrocarbons via the Grignard reaction was based on the structural analogy that the glycosyl halides and the a-halo ethers were both hemiacetal halides. A less frequently employed reaction of Grignard reagents is that wherein one of the alkoxyl groups of an acetal is replaced by the organic radical of a Grignard reagent: /OR RCH

\

OR

+ R’MgX-

/R‘ RCH

\

+ Mg(0R)X

(6)

OR

This type of reaction has been used by SpiithK9and Tschitschibabin6O for the synthesis of a-substituted ethers. Since the fully methylated aldoses have a cyclic acetal structure, Bonner and Craige1 attempted to extend Reaction (6) t o the carbohydrate series. When pentamethyl-D-glucose, prepared with methyl sulfate and alkali,g2was caused to react with phenylmagnesium bromide by heating in toluene, butyl ether, or in the absence of solvent, a sirupy mixture resulted which was fractionally distilled. The lower-boiling fractions contained considerable unreacted pentamethylglucose, as shown by their reducing properties after acid hydrolysis. The higher-boiling fractions appeared to consist of mixtures of anomeric (tetramethyl-D-glycosy1)benzenes, since they underwent oxidation to benzoic acid and showed no reducing properties after heating with mineral acid. From the reaction in which toluene was solvent, a small quantity of crystalline material was isolated. This was different than either of the anomeric (tetramethyl-D-glucopyranosyl)benzenes,KKyet had properties of a (tetramethylglycosyl) benzene. It was suggested that this product was derived from some other sugar formed by occurrence of the Lobry de Bruyn transformation63 during original methylation of the glucose in the presence of alkali. 4. The Use of Other Organometallic Compounds

The first attempts t o employ organometallic compounds other than Grignard reagents for the glycosylation of hydrocarbons have been those of Hurd and Holysz. These investigators studied the reactions of a (59) E. Spilth, Monatsh., 36, 319 (1914);Ber., 47, 766 (1914). (60)A. E. Tschitschibabin and S. A. Jelgasin, Ber., 47, 49, 1843 (1914). (61) W.A. Bonner and J. M. Craig, J . Am. Chem. SOC.(In press). (62) E. S. West and R. F. Holden, Organic Syntheses, Vol. XX, p. 97. John Wiley and Sons, New York (1940). (63) C. A. Lobry de Bruyn and W. Alberda van Ekenstein, Rec. trau. chim., 14, 203 (1896);16,92 (1896);16, 257, 262, 274, 282 (1897);18, 147 (1899).

280

WILLIAM A. BONNER

number of organolithium, organos~dium,~' and organocadmiums6 compounds with various acetylated glycosyl halides and, in the cadmium series, observed an interesting variation of the glycosylation reaction. When nine moles of phenyllithium in ether acted upon tetraacetylglucosyl chloride, the reaction mixture being subsequently decomposed with water, four products resulted. From the ether layer a quantitative yield of methyldiphenylcarbinol was recovered. Acetylation of the residue from the water layer, followed by fractional crystallization led to two crystalline substances and a residual sirup. The first crystalline product was (tetraacetyl-P-D-glucopyranosyl) benzene (IV). The second m. p. 142-143", [aID24- 2.3" (chloroform), appeared to be isomeric with IV. It oxidized to benzoic acid and deacetylated to give a sirup which consumed two moles of periodate with liberation of one mole of formic acid. While these properties are to be expected for a structure related to IV, this substance differed from both of the anomeric (tetraacetyl-Dglucopyranosyl)benzenes, nor did it appear to be a mixture of them. Its exact constitution is not yet known. Both phenyllithium and butyllithium reacted with tetraacetylglucosyl bromide to yield products identical with those previously obtained with the corresponding Grignard reagents. Benzyllithium or lithium acetylide with tetraacetylglucosyl bromide resulted in intractable sirups or tars. Sodium acetylide and phenylsodium likewise led to no crystalline product. The lesser tendency of organocadmium compounds to add to carbonyl groupsa6 and their known metathetical reaction6' with a-halo ethers suggested t o Hurd and HolyszG6 the desirability of employing such reagents for glycosylations, since the necessities of using an excess of organometallic compound and of reacetylating the initial reaction product might thereby be obviated. When tetraacetylglucosyl bromide and one mole of diphenylcadmium were refluxed in toluene, (tetraacetyl-@-D-glucopyranosyl)benzene (IV), was isolable in twenty-three percent .yield by chromatographing the crude product on alumina. In addition t o IV, an unstable sirupy product was formed. Essentially similar results were obtained with tetraacetylmannosyl bromide, (tetraacetyl-a-D-mannopyranosyl) benzene resulting in twenty-nine percent yield. With aliphatic cadmium compounds, however, unexpected results were noted. Dibutylcadmium reacted with tetraacetylglucosyl bromide t o give a fifty-seven percent yield of an acetal-like compound, 1,2-(1(64) (65) (66) (67)

C. D. Hurd and R. P. Holysz, J. Am. Chem. SOC.,79, 1735 (1950). C. D. Hurd and R. P. Holysz, J. Am. Chem. SOC.,73,2005 (1950). J. Cason and F. S. Prout, J. Am. Chem. SOC.,00, 46 (1944). R. K. Summerbell and L. N. Bauer, J . Am. Chem. Soc., 68, 759 (1036).

FRIEDEL-CRAFTS

281

AND GRIGNARD PROCESSES

methylpentylidene)-3,4,6-triacetyl-~-glucose(LVII), while dibenzylcadmium led to a thirty percent yield of 1,2-(l-benzylethylidene)3,4,6-triacetyl-~-glucose(LVIII). The structures of LVII and LVIII

1.A =bcH2cEH6

H O

HO H

HbOH HA0 bHIOH

LIX

were supported by evidence of the following sort. LVIII reacted with the quantity of alkali required for three acetyl groups, giving an alkalistable, non-reducing deacetylated product (LIX), which could be reacetylated to LVIII. LIX consumed one mole of periodate, producing thereby no formic acid. On hydrolysis with acid, LIX yielded benzyl methyl ketone and D-glucose, the former identified as the p-nitrophenylhydrazone and the latter as the 0-pentaacetate. Similar criteria supported the structure of LVII. Though the first carbon atoms in LVII and LVIII are asymmetric, only one of the two possible stereoisomers was obtained in each case. It was suggested that the substantial quantities of sirup accompanying the production of these crystalline substances may have contained the other isomer. The authors propose a plausible ionic mechanism for the reaction of organocadmium compounds with tetraacetylglucosyl bromide, leading alternatively to compounds of types IV or LVII. It was reasoned that a carbonium ion was formed at carbon 1 by attack of the cadmium reagent at the bromide function:

I

CHBr &HOCOCH8

1-

I

CH+

RzCd

1

CHOCOCH3

+ RCdBr + R-

(7)

In the case where R is phenyl, R- is acquired by the carbonium carbon, giving IV. When R is benzyl or butyl, an attack by the carbonyl oxygen of the acetate group in position 2 is preferred, and the carbonium character is transferred to the carbonyl carbon. The new carbonium ion is attacked by R-, leading t o LVII or LVIII:

282

WILLIAM A. BONNER

I

I

1

I

I

The isolation of IV by action of one mole of diphenylcadmium on tetraacetylglucosyl bromide provides further evidence that IV actually possesses the parent glucose configuration, and that no inversions occurred during any of the previously discussed catalytic or organometallic glycosylations. In the diphenylcadmium reaction the original ester linkages of tetraacetylglucosyl bromide remain undisturbed, and no question arises as to the stereochemical course of the deacetylation process. Furthermore, hydrolyds of LVII and LVIII produced D-glucose, thus substantiating the earlier results of Jeremias and MacKenzie.So

IV. ADDENDUM ON THE ANOMERIC CONFIGURATION OF P-D-GLYCOPYRANOSYLBENZENES As pointed out on page 276, the nomenclature of tetraacetyl-P-Dglucopyranosylbenzene (IV), its anomer,s6 and related compounds was based on their specific rotations in accordance with Hudson’s convent i o n ~ ,and ~ ~ not on the actual stereochemical configurations of the phenyl group about the anomeric centers. Thus, for example, it has not been known if the rotationally designated P-D-xylopyranosylbenzene (LX), actually possesses the configurational trans P-structure (LXI), or cis a-structure (LXII).

This problem has recently received attention, and it has been .shown that P-D-xylopyranosylbenzene indeed has the 1,2-trans structure LXI.68 The structure proof rests on the fact that the configuration of the anomeric center in LX can be correlated with that of L-(+)-mandelic acid46 (68) W. A. Bonner and C . D. Hurd, J . Am. Chem. Soc., 78,4290 (1951).

283


(LXIII). Only LXI would permit this relationship, in that the anomeric configuration of LXII would be related to D-( -)-mandelic acid. Periodate oxidation of the ring in LXI led to sirupy D-Zphenyldiglycolaldehyde (LXIV), which in turn was oxidized with silver oxide to sirupy D-2-phenyldiglycolic acid (LXV). The latter was converted through its ester (LXVI), to crystalline D-( +)-2-phenyldiglycolamide (LXVII), m. p. 172-1725', [c~]"D 102.2" (ethanol). O--CH2CH=O LXI -+ CJI-A-H AH=O

LXIV

A

d

b

AH2

AHa

AH*

LOOH

AOOEt LXVI

LXV

CIONR, LXVII

COOH

HO-LH

IH-

AaHs

AH LXIII

AH LXVIII

Independent synthesis of the crystalline amide LXVII established its +)-mandeli0 acid. identity and its configurational relationship to I,-( The latter acid was converted to ethyl L-(+)-mandelate (LXVIII), and the ether linkage introduced by reaction with ethyl bromoacetate in the presence of silver carbonate, under conditions such that Walden inversion was impossible. The resulting ethyl D-( )-2-phenyldiglycolate (LXVI), was subjected t o ammonolysis, giving a crystalline product, m. p. 174174.5", [Cx]'*D 106.2'. This showed no mixed melting point depression and an identical infrared absorption spectrum with the sample of LXVII obtained from p-D-xylopyranosylbenzene. The enantiomorphic L-( -)-2phenyldiglycolamide was also prepared by identical synthetic steps from D-( -)-mandelic acid. The isolation of LXVII on degradation of 8-D-xylopyranosylbenzene clearly showed that the rotationally designated 8-anomer actually possessed the /3-configuration (trans). Since anomeric designations based on optical rotation generally accord with designations based on actual configuration, it seems probable that the other rotationally designated 8-anomers in the glycosylaromatic hydrocarbon series also possess the &configuration, and that the question of anomeric structure in this series has been answered.

+

t3 00

V. PHYSICAL PROPERTIES OF PRODUCTS FROM FRIEDEL-CRAFFEI AND GRIGNARD REACTIONS Produd,

Empirical Formula

M.P.,

-

C."

T." Solvent

Reference

-

~

1-(Tetraacetyl-a-mglucopyranosy1)butane &mXylopyranosylbenzene (Triacetyl+D-xylopyranosyl) benzene a-mGlucopyranosylbenzene &mGlucopyranosylbenzenemethanolate (Tetraacetyl-a-D-glucopyranosy1)benzene (Tetraacetyl-&D-glucopyranosyl)benzene (IV)

109-109.5 149.5-150 169.5 186.5-187 Sirup 70-71 156.5

77.2 -14.4 -57.7 90.5 18.3 95.1 -18.6

20 25 25 26 23 23 25

CHClt Hz0 CHClr MeOH HzO CHCls CHClt

(Tetrapropionyl-&D-glucopyranosyl)benzene (Tetrabenzoyl-@-D-glucopyranosyl)benzene (Tetramethyl-a-mglucopyranosyl)benzene (Tetramethyl-&~-glucopyranosyl)benzene (x,x,x-Trimethyl-&D-glucopyranosyl)benzene

69.5 184.5-185.5 sirup sirup

-14.1 -22.9 93.2 18.0

25 25 24 19

CHCls CHCla CHCL CHCla

106-107 139.5-140 107-108 180-180.5 217 197.5-198 181.5-182.5

36.3 53.6 25.6 -18.8 -7.5 61.5 22.6

24 26 27 26 20 25 25

CHCla CHCls CHClt CHClo CHClr CHClr MeOH

165-165.5

-40.3

28 CHClr

58

164.5-165 126 138.5

-29.0 -60.2 -42.8

30 CHClt 20 CHClr 20 CHCla

58 52 52

hydrate (Tetraacetyl-a-n-mannopyranosy1)benzene (Tetraacetyl-&D-manpyranosyl)benzene (Heptaacetyl-&gentiobiosyl)benzene (Heptaacetyl-&lactosyl)benzene (Heptaacetyl-pmaltosyl) benzene ppw Glucopyranosylnitrobenzene p (Tetraacetyl-&D-glucopyranosy1)nitrobenzene (LIV) 1-(Tetraacetyl-&~-glucopyranosyl)-3,4-dibromobenzene (LV) p(Triacety1-&mxylopyranosyl)toluene p (Tetraacetyl-&D-glucopyranosy1)toluene

*

Specijk Rotation

52,64 24 25, 52 55 56 55 21, 25, 52, 54,64,65 56 56 c 55 m 55 0

$ k

55 54,64,65 54

54 52 54 58

2 2

m

1-(Tetraacetyl-Bwglucopyranosy1)naphthalene 2- (Tetraacetyl-&pglucopyranosyl)thiophene

2-(Tetraacetyl-&~-glucopyranosyl)-5-bro~othiophene 1,2:3,4Diisopropylidene-6-desoxy-~gulitol (XXXV) 1,2: 3,4Diisopropylidene-~-rhamnitol(XXXVI) 1-C-Cyclohexyl-D-ghco-pentitol (=I) 1-C-Cyclohexyl-cglum-pentitol 1-C-Cyclohexyl-2,3 :4,5-d&~propylidene-~-gZuwpentitol (XLII) 1-C-Cyclohexyl-2,3:4,5-diisopropylidene-~gZucopentitol I-C-Cyclohexyl-2,3 :4,5diisopropylidene-~,cglumpentitol 1-C-Cyclo hexy~-1,2,3,~tetraacetyl-5-trityl-~-g~ucopentitol l-C-Cyclohexyl-1,2,3,4tetr~cetyl-~trityl-~-gZumpentitol 1-C-Phenyl-D-glum-pentitol(XL) 1-C-Phenyl-cglucc-pentitol 1-C-Phenyl-2,3:4,5-&isopropylidene-~-glucopentitol (XXXVIII) l-C-Phenyl-Z,3 :4,5-diisopropylidene-1gZu~opentitol 1-C-Phenyl-1-methyl-Dgluco-pentitol(XLVI) 1-C-Phenyl-1-methyl-2,3 :4,5diisopropylidene-~glum-pentitol (XLIV) 1-CPhenyl-D-manno-pentitol(XXXIX) 1-C-Phenyl-1-methyl-wmunwpentitol(XLVII) 1-C(1-Naphthyl)-cgZuco (or manno)-pentitol

186.5-187 123-124

1.3 20 -13.8 24

CHClo CHCla

52 54

135-136

-19.1

28

CHCli

54

sirup 66.5-67 148 148

3.0 1.o -15.0 15.0

19 19 24 25

27.2

25

Pyridine 44,45

25

Pyridine 43

75-76 75-76 90

-27.4 0.0

c

42 42 Pyridine 43, 44, 45 Pyridine 43, 44 MeOH

MeOH

-

44

15.0

25

Pyridine 44

-15.0 30.5 -37.7

25 25 25

Pyridine 43

53.2

22

Pyridine 45

79-80 172.5-173

-53.0 39.2

25 23

Pyridine 43 Pyridine 45

Sirup 172.5-173 142-144 187

75.6 -44.8 -49.9 70.2

26 25 25 25

Pyridine Pyridine Pyridine Pyridine

134 134 138-138.5 137 79-80.5

-

Pyridine 45 Pyridine 43

45 45 45 43

V. PHYSICAL PROPERTIES OF PRODUCTS FROM FRIEDEL-CRAFTS AND GRIGNARD REACTIONS(Continued) Empirical Formula

Product ~

~~

M . P., C."

a

Specific Rotation

T.a

Reference Solvent

-

~

1-C( l-Naphthyl)-2,3 :4,5diisopropylidene-~-gZuco (or manno)-pentitol 1,l-CDibenzyl-carabitol l,l-CDibenzyl-~-galactitol 1,l-CDibenzyl-wglucitol l,l-C-Diphenyl-D,bglyceritol(XIII) 1,l-CDiphenyl-barabitol (X) l,l-CDiphenyl-2,3,4,5-t.etrabenzoyl-carabitol l,l-CDiphenyl-1,4-anhydro-carabitol(XI) 1,1-CDiphenyl-wgalactitol hydrate 1,l-CDiphenyl-wgalactitolpentaacetate hydrate 1,l-CDiphenyl-wgalactitolx,x-dibeneoate 1 l-CDiphenyl-1,4anhydro-wgalactitol 1,l-CDiphenyl-D-glucitol (IX) 1,l-C-Di-ptolyl-carabitol 1,l-C-Di-ptolyl-wgalactitol 1,l-C-Di-ptolyl-wglucitol 1,l-Diphenyl-1-demxy-wxylitol 1,l-Diphenyl- l-desoxy-wgalactitol 1,l-Diphenyl-l-desoxy-wglucitolhydrate (V) 1,1-Diphenyl-l-desoxy-wglucitolpentaacetate 1,l-Di-ptolyl-l-desoxy-wglucitolhydrate (VI) a-1-Phenyl-&l-p-toly 1-1-desoxy-wxylitol u-l-Phenyl-&1-p-tolyl-l-desoxy-wglucitolhydrate (VIII)

t9 00

sirup 156-157 182-184 146-147 157-158 171 181-182 172-174 157-160 151 172-173 108-111 157-160 186-187 194-196 169.5-170 167-168 174 157.5-158 95-95.5 158.5-160.5 163.5-164 151.5-153.5

-

19 Hz0 1.5 20 EtOH 0.0 0.0 85.6 20 Hz0 0.0 8 MezCO -114.8 72.9 20 HzO 14.6 20 EtOH 64.7 18 EtOH 20 HtO -82.1 71.3 25 H2O 71.6 18 EtOH 49.5 20 EtOH 97.2 20 EtOH 73.2 20 Dioxane 28.6 27 Me&O 47.4 25 Dioxane 28.0 25 CHClr

31.5

-

55.8

-

-

25

Dioxane

43 34 35 35 36 34

34

34 33 35 35 35 27, 32

34

35 35 23, 25 25 21, 23, 25 21, 23, 26 21 23

23

zE 4 W

0

1:

3

9

a-l-p-Tolyl-&l-phenyl-l-desoxy-wglucitolhydrate (VII) 1-CMethyl-wglucosone 1-C-Methyl-2,3 :4,5-diisopropylidene-wglucosone

(XV)

-

6GAcetyl-l,2 :3,4diisopropylidene-~-gd&aldopentose (XXX) 6C-Propionyl-l,2 :3,4diisopropylidene-~-guZu&~aldopentose 1-C-Phenyl-wglucosone (XXIII) 1-C-Phenyl-D-glucosone x-phenylhydrazone 1-C-Phenyl-wglucoaone tetraacetate 1-C-Phenyl-4,5 (or 5,6)-isopropylidene-wglucosone (XXIV) 1-C-Phenyl-2,3 :4,5-diisopropylidene-wglucosone

1,l-C-Dimethyl-D-fructfuranose(XVIII) 1,l-C-Dimethyl-wfructse phenylhydrazone l,l-C-Dimethyl-2,3-isopropylidene-j3-~-fructopyranose (XVII) l,l-C-Dimethyl-4,6-isopropylidene-wfructose (XIX) 1,l-CDimethyl-2,3 :4,5-diisopropylidene-kDfructose (XVI) l,l-CDimethyl-1,2-anhydro-4,6-~propylidene-~fructose (XX) 6,6CDmethyl-~-galectose 6,6-C-Dimethyl-wgalactosazone 6,6-GDimethyl-1,2 :3,4-diisopropylidene-w galactose (XXXI) 1,l-C-Diethyl-2,3-isopropylidene-~-fructopyranose

167-170 sirup

58.8 -22.5

25 Dioxane 23 37 18 H i 0

sirup

-40.6

17 CHClj

37

sirup

-128.5

20

CHCls

39

Sirup 134.5 154.5 128.5

-120.7 -17.7 -253.0 95.7

20

CHClj 18 HzO 18 EtOH 18

39 38

38

169

-93.4

18 CHCls

134 163 150 (d.)

-24.8 -14.3

18 CHCls 18 HIO

-

-

38

38

19.5

18 EtOH

sirup

13.3

18 CHCls

37

18 CHCli

37

18 CHClr

-

37 39 39

18 CHCla 18 EtOH

39

139-140 sirup 215 81-82 128

-22.9 -8.9

-

-62.3 28.1

-

-

L4tl m

x

5!1 1

-

164

88

J

-

37

;d"

8 2!u, M

u,

N

00 l

V. PHYSICAL PROPERTIES OF PRODUCTS FROM FRIEDEGCRAFTS AND GRIGNARD REACTIONS(Continued) Product

M . P.,

Empirical Formula

Specifi Rotation Reference

T.

Solvent

-

l,l-C-Diethyl-2,3-isopropylidene-x-benmyl-~f ruetopyranose 1,l-C-Diethyl-2,3 :4,5diisopropylidene-~-fructt3e 6,6-C-Diethyl-1,2 :3,4-diisopropylidene-~-galactse l,l-C-Dipropyl-2,3-isopropylidene-~-fructopyranose l,l-C-Dipropyl-2,3: 4,5-diie~propylidene-~fructose l,l-C-Diisopropyl-2,3 :4,5diisopropylidene-~fructose 1,l-C-Dibutyl-2,3 :4,5-diisopropylidene-~-fructose l,l-C-Diisobutyl-2,3 :4,5diisopropylidene-~fructose 1,l-C-Dibeneyl-D-fructose l,l-C-Dibeneyl-~-fructse tetraacetate l,l-CDibenzyl-2,3-k.opropylidene-~-fructopyranose l,l-CDibenzyl-4,5-isopropylidene-wfructose l,l-C-Dibenryl-2,3 :4,5diisopropylidene-~-fructose (XXIX) 1,l-C-Diphenyl-D-fructose(XXVII) hydrate 1,l-CDiphenyl-x,x-anhydro-D-fructose(XXVIII) 1,l-CDiphenyl-D-fructosetetraacetate 1,l-C-Diphenyl-2,3-isopropylidene-~-fructopyranose (XXW l,l-C-Diphenyl-2,3-isopropylidene-~-fruc~furanose (XXV)

128 83-84 87-88 105-106 83

20.5 -19.0 -59.3 23.4 -16.6

20 20 18 20

CHClr CHClr EtOH CHCla

37 37 39 37 37

81-82 64-65

-19.2 -14.1

18 CHCl, 18 CHCls

37 37

125-126.5 149 94 127-127.5 107

-15.3 5.3 23.6 32.9 7.3

20 18 18 18 18

CHCla MetCO MezCO CHCla MetCO

37 38 38 38 38

121.5-122

-49.3 55.3 -+ 42.3 77.7 3.2

18 18 18 18

CHCla MerCO Me&O CHCl,

38 38 38 38

81

149.5 143

18 CHCli

104

-149.6

18 MetCO

38

174

-99.3

18 MetCO

38

E5 M

00

V. PHYSICAL PROPERTIES OF PRODUCTS FROM FRIEDEL-CRAITS AND GRIGNARD REACTIONS(Continued) ____

Product

Empirial Formula

M . P.,

Specijic Rotation Reference

C."

T." Solvent

1 Y

18 CHCls

m

194.5

-193.5

sirup

-21.4

18

-

40

sirup

-10.5

18

-

40

38

201.7 17 EtOH 37.7 22 MeOH

34 65

103

24.7 22 CHCla

65

78-79

29.4 22 CHCla

65

111-1 17 Sirup

m $+

1,l-C-Diphenyl-2,3 :4,&diisopropylidene-~-fructOse (XXII) 2-Methyl-2-hydroxy-cerythro-3,4,5-trimethoxyvaleric acid Methyl Zmethyl-2-hydroxy-~-e~ythro-3,4,5trimethoxyvalerate (XXXIII) 5,5-Diphenyl-2,5-anhydo-2,3,4trihydroxy~aleric acid (XII) 1,2-(1-Methy1pentylidene)-D-glucose I,%( l-Methylpentylidene)-3,4,6-triacetyl-~-glucose

2

k-

2

U

0

E4,

?s 20 d

mu, u, M

m


THE NITROMETHANE AND 2-NITROETHANOL SYNTHESES BY JOHNC. SOWDEN Washington University, Saint Louis, Missouri

CONTENTS

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Some Reactions of Nitroparaffins.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

291 293 1. The Condensation of Nitroparaffins with Aldehydes.. . . . . . . . . . . . . . 293 2. Action of Acids on Salts of aci-Nitroparaffins.. . . . . . . . . . . . . . . . . . . . . 295 3. The Reduction of Nitroparaffins and Nitroalcohols.. . . . . . . . . . . . . . . . 296 4. The Preparation of Nitroolefins from Acetylated Nitroalcohols. . . . . . . 296 111. Early Attempts to Condense Nitromethane with Aldose Sugars 1. The Experiments of Pictet and Barbier.. . . . . . . . . . . . . . . . 2. Degradation of Sugar Cyanohydrins by Alkali in the Presence of Nitromethane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297 IV. Carbohydrate C-Nitroalcohols. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 1. Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 299 a. From Benzylidene-Substituted Aldoses . . . . . . . . . . . . . . . . . . . . . . . 299 b. From Unsubstituted Aldoses.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 2. Conversion to Aldose Sugars by the Nef React,ion... . . . . . . . . . . . . . . . 307 V. C-Nitrodesoxy Sugars and C-Nitrodesoxy Inositols . . . . . . . . . . . . . . . . . . 310 VI. The Acetylated Carbohydrate C-Nitroolefins, . . . . . . . . . . . . . . . . . . . . . . . 313 1. Preparation. . . . . . . . .... ........... 313 a. From Carbohydrate C-Nitroalcohols . . . . . . . . . . . . . . . . . . . . . . . . 313 314 b. From Aldose Sugars.. . . . . . . . . . . . . . . . . . . . . . . . 315 2. The 2-Desoxy Aldose Synthesis.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . VII. The 2-Nitroethanol Synthesis of Higher-Ca.rbon Ketoses. . . . . . . . . . . . . . . . 316

I. INTRODUCTION The classical Kiliani-Fischer cyanohydrin method' of lengthening the carbon chain of the aldose sugars was instrumental, in the hands of Emil Fischer, in solving the fascinating problem of the configurational relationships among the various reducing sugars. Concurrently, the synthesis supplied an experimental basis for the Van't Hoff-Le Be1 theory of the tetrahedral carbon atom, a result of prime significance to the entire field of organic chemistry. Although the theoretical implications that were derived by application of the cyanohydrin synthesis in the sugar series somewhat overshadow its importance as a practical synthetic method, nevertheless it remains one of the most useful means of pro(1) C.

s. Hudson, Advances i n carbohydrate Chem., 1, 1 (1945). 291

292

JOHN C. SOWDEN

gressing from readily available sugars to rarer members of the carbohydrate family. Indeed, until recently, the cyanohydrin synthesis comprised the only general method for the preparation of higher-carbon aldose sugars. The individual reactions that constitute the KilianiFischer synthesis proceed in good yields. The addition of hydrocyanic acid t o an aldose sugar is practically quantitative2 while the reduction of aldonic lactones to aldose sugars by means of sodium amalgam can be controlled to give excellent yields.a Nevertheless, certain higher-carbon aldoses are practically inaccessible by this method because of the asymmetric nature of the addition of hydrocyanic acid to the asymmetric aldoses. The ratio in which the two epimeric cyanohydrins are produced in the addition reaction is governed mainly by the configuration of the reacting aldose and the epimeric preference shown may vary from negligible (ribose and HCN)4 to nearly quantitative (mannose and HCN).6 Usually, the preparation of a higher-carbon aldose from an available lower-carbon sugar by means of consecutive cyanohydrin syntheses is practicable only when the successive intermediate cyanohydrins comprise the preferred epimers in the individual hydrocyanic acid additions. Higher-carbon ketose sugars are not available via the cyanohydrin synthesis. However, they may be prepared from lower-carbon aldose sugars by the diazomethane method of Gatzi and ReichstehB This general method, as improved and extended by Wolfrom and coworker^,^ entails the reaction sequence: aldose -+ acetylated aldonic acid -+ acetylated aldonyl halide + acetylated diazodesoxyketose --j acetylated ketose + ketose. The individual reactions comprising this synthesis proceed in satisfactory yields. However, the relatively large number of consecutive reactions that are involved makes the method somewhat tedious and results in a low over-all yield. Supplementary synthetic methods for preparing higher-carbon aldose and ketose sugars from the more accessible lower-carbon sugars are obviously desirable. The present review describes the recent development of two such methods based on the application to sugar (2) W. Militser, Arch. Biochem., 21, 143 (1949). (3) N. Sperber, H.E. Zaugg and W. M. Sandstrom, J. Am. Chem. Soc., 69, 915 (1947). (4) P. A. Levene and W. A. Jacobs, Ber., 43, 3141 (1910);F. P. Phelps and F. J. Bates, J. Am. Chem. Soc., 66, 1250 (1934);Marguerite Steiger and T. Reichstein, Helv. Chim. Acta, 19, 184 (1936). (5) E.Fischer and J. Hirschberger, Ber., 22,365 (1899);G . Peirce, J . Biol. Chem., 23, 327 (1915). (6) K. Gatsi and T. Reichstein, Helu. Chim. Acta, 21, 186 (1938). (7) M. L. Wolfrom, S. W. Waisbrot and R. L. Brown, J . Am. Chem. Soc., 64,2329 (1942),et seq. I

NITROMETHANE AND %NITROETHANOL SYNTHESES

293

synthesis of certain well-known reactions of the nitroparaffins. The nitromethane synthesis, like the cyanohydrin synthesis, results in the addition of one carbon atom to an aldose carbon chain with the production of the two next higher epimeric aldose sugars. The 2-nitroethanol synthesis adds two carbon atoms to an aldose carbon chain with the production of two ketose sugars epimeric a t carbon 3.

11. SOMEREACTIONS OF NITROPARAFFINS During the past two decades the nitroparaffins have evolved from their prior status as relatively rare substances to their present position of increasing importance in the roster of large-scale commercial organic chemicals. This striking development stems from the observation by Hass, Hodge and Vanderbilts at Purdue University that the nitroparaffins can be produced economically by the direct nitration of paraffin hydrocarbons in the vapor phase. Even before nitroparaffins were available in other than small laboratory amounts, however, many of their important chemical reactions had been studied thoroughly in smallscale experiments. The nitroparaffins for these studies were prepared principally by the Victor Meyer reactiong of alkyl halides with silver nitrite. The early interest in the aliphatic nitro compounds undoubtedly arose in large measure from their relationship to the nitroaromatics that achieved such eminence in organic chemical industry during the last half of the nineteenth century. Excellent comprehensive reviews1° of the chemistry of the nitroparaffins are available elsewhere and it is intended to discuss here only those reactions of aliphatic nitro compounds which have found application in the chemistry of the carbohydrates. 1. The Condensation of Nitroparafins with Aldehydes

When a primary or secondary nitroparaffin is allowed to react with an aldehyde in the presence of a basic catalyst, the product is a nitroalcohol. RCHO

+ R'CHZNOI+ R.CHOH.CHR'.NOz; RCHO + RX'.CHN02 + R.CHOH*CRz'.N02

This condensation reaction, discovered by L. Henry" in 1895, has (8) H. B. Ham, E. B. Hodge and B. M. Vanderbilt, Znd. Eng. Chem., 28, 339 (1936). (9)V. Meyer and 0. Stliber, Be?-.,6, 203 (1872);V. Meyer, Ann., 171, 23 (1874). (10) H.B. Hass and Elizabeth F. Riley, Chem. Rev., 32, 373 (1943);H. B. Ham, Znd. Eng. Chem., 36, 1146 (1943). (11) L. Henry, Compt. rend., 120, 1265 (1895).

294

JOHN C. SOWDEN

been employed to prepare a large variety of nitroalcoholsla and is one of the most fruitful reactions of the nitroparaffins. The condensation of nitromethane with formaldehyde is not typical of the general reaction since more than one molecule of formaldehyde tends to condense with one molecule of nitromethane even in the presence of a large excess of the latter. When equimolar quantities of formaldehyde and nitromethane are allowed to react the following approximate percentages of the three possible condensation products are obtained :la CHzO

+ CHpNOz

+

CHzOHCHzNOa 9 percent

+ (CHzOH)*GHNOz + (CHzOH)a.CNOz 13 percent

78 percent

Even when a five-molar excess of nitromethane is employed the yield of 2-nitroethanol by this reaction is only about 40 percent. With homologs of either nitromethane or formaldehyde the tendency for more than one molecule of aldehyde to condense with one molecule of nitroparaffin decreases sharply with increasing molecular weight or complexity of either component. Many different basic catalysts have been used to promote the condensation reaction. However, the necessary conditions for a successful reaction of this type are invariably mild since several competing reactions occur. The aldehyde component may undergo intermolecular aldol condensation or, in the case of formaldehyde or aromatic aldehydes, intermolecular dismutation in the presence of strong alkali. The reducing sugars, of course, are subject to more complex reactions of isomerization and fragmentation in the presence of bases. Nitroparaffins, and particularly nitromethane, are sensitive to the action of alkalis. Nitromethane forms successively methazonic" and nitroacetic" acid while its higher homologs yield trialkylisoxazoles. 2 CHPNO~ + CH.CH=N02Na

II

NOH sodium methazonate

+ 2 HzO; CH.CH=N02Na + Na00C.CH=N02Na II

NOH

disodium nitroacetate

x""d

3 CHaCHyNOz + C H 8 . C =C*CH*

NI' trimethylisoxazole

B. M. Vanderbilt and H. B. Hass, Znd. Eng. Chem., 32, 34 (1940). I. M. Gorski and S. P. Makarov, Ber., 67, 996 (1934). P. Friese, Ber., 9, 394 (1876); M. T. Lecco, ibid., 9, 705 (1876). W. Steinkopf, Ber., 42, 3925 (1909). W. R. Dunstan and T. S. Dymond, J . Chem. SOC.,69, 410 (1891); W. R. Dunstan and E. Goulding, ibid., 77, 1262 (1900); S. B. Lippincott, J . Am. Chem. Soc., (12) (13) (14) (15) (16)

62, 2604 (1940).

295

NITROMETHANE AND %NITROETHANOL SYNTHESES

Finally, the aldehyde-nitroparaffin condensation, like the aldehydehydrocyanic acid condensation, tends to be reversed by strong alkali. Thus, both the reactants and the product of this reaction may be destroyed by a too strenuous application of the promoting catalyst. 2. Action of Acids on Salts of aci-Nitroparaflns

The primary and secondary nitroparaffins are typical pseudo acids, forming metallic salts when treated with bases.

+

R.CHZNOZ NaOH

-+

+

RCH=NO2Na HzO; R2CHNOz

+ NaOH

-+

R2.C=NOzNa

+ H20

Acidification of these nitronic acid salts may lead to a variety of products depending upon the nature and strength of the acid employed. Weak acids, such as acetic or carbonic acids, simply regenerate the nitroparaffin. Warm, concentrated mineral acids hydrolyze the salts of primary aci-nitroparaffins to produce fatty acids and salts of hydroxylamine. This is in reality a reaction of the nitronic acids and occurs when the primary nitroparaffins themselves are warmed with concentrated mineral acid. l7 R.CH=NOzH

+ H&O4 + Hz0

ReCOOH

+ NHaOH.HSO4

Under appropriately controlled conditions the intermediate hydroxamic acids are produced in about 50 percent yield.18 R-CH=NO1H

His01

R.COH=NOH

__*

R.CO.NHOH

Cold, dilute mineral acids decompose the nitronic acid salts of primary and secondary ni troparaffins to yield aldehydes and ketones respectively (Nef reaction). l9 2 R.CH=NOZNa 2 RzC=NOzNa

+ 2 HzSOa + 2 HzSOl

-+ --f

+ +

+

+ +

2 R-CHO 2 NaHSO4 NzO H10 2 RzCO 2 NaHS0.f NzO HzO

Satisfactory conditions for the preparation of either end-product, i.e. fatty acid or aldehyde from the salt of a primary aci-nitroparaffin, do not overlap appreciably since the requisite reactions may be performed individually with yields of 85-90 percent. A combination of the aldehyde-nitroparaffin condensation reaction, (17) V. Meyer and C. Wurster, Ber., 6, 1168 (1873). (18) E. Bamberger and E. Riist, Ber., 36, 45 (1902); S. B. Lippincott and H. B. Ham, Znd. Eng. Chem., 31, 119 (1939). (19) J. U. Nef, Ann., 280, 263 (1894).

296

JOHN C. SOWDEN

discussed in section 1, and the Nef reaction constitutes the essential steps of the nitromethane and 2-nitroethanol syntheses in the sugar series. 3. The Reduction of Nitroparafins and Nitroalcohols

The reduction of nitroparaffins t o amines has been realized with a great variety of reducing agents. Under reducing conditions somewhat milder than those required to produce the amines, the intermediate alkyl hydroxylamines and oximes are produced.2o RCHzNOt -+ RCH=NOH

-+

RCHzNHOH -+ RCHaNHz

The reduction of nitroalcohols t o aminoalcohols is complicated to some extent by the instability of the nitroalcohols in the presence of bases due to the reversal of the aldehyde-nitroparaffin condensation reaction. This reduction can be carried out smoothly, however, with Raney nickel and hydrogen.21 Thus the interesting sugar aminoalcohols are readily available from the corresponding sugar nitroalcohols.

4. The Preparation of NitrooleJins from Acetylated Nitroalcohols The nitroalcohols are esterified by the usual acylating agents in the presence of acidic catalysts. With the nitroglycols of the sugar series, acetic anhydride containing a trace of sulfuric acid gives rapid and complete acetylation. Basic acetylation catalysts, such as pyridine or sodium acetate, are not satisfactory, presumably due to interaction with the nitro group. It was observed in 1928 by Schmidt and Rutz22that a-acetoxy nitroparaffins are especially sensitive to mild alkali due to their tendency to lose the elements of acetic acid. Thus, nitroolefins result when solutions of such esters in ether or bensene are refluxed with sodium bicarbonate. R-

xcocH' H-

AHNO2 -+ RCH=CHN02

+ CH&OOH

The acetylated nitroolefins of the sugar series, available in high yield from the corresponding acetylated nitroalcohols by this reaction, almost invariably crystallize with great ease. (20) Cf. H. B. Hass and Elizabeth F. Riley, Chem. Rev., 82,373 (1943) for numerous references on reduction of nitroparailins. (21) K. Johnson and E. F. Degering, J . Am. Chem. Soc., 61, 3194 (1939); B. M. Vanderbilt and H. B. Ham, Znd. Eng. Chem., 82, 34 (1940). (22) E. Schmidt and G . Rutz, Ber., 61, 2142 (1928).

NITROMETHANE AND

%NITROETHANOL

SYNTHESES

297

111. EARLY ATTEMPTS TO CONDENSE NITROMETHANE WITH ALDOSE SUGARS 1 . The Experiments of Pictet and Barbier

I n 1921 Pictet and BarbieP recorded an attempt to produce highercarbon sugar alcohols from aldose sugars by means of the reaction sequence : RCHO

+ CHsNOz

--t

R*CHOH*CHINOZ + R.CHOH*CHzNHz+ R.CHOH.CH20H

The aldehydes studied were glycolaldehyde, D,L-glyceraldehyde, Larabinose and D-glucose. The glycolaldehyde and D,L-glyceraldehyde employed were of doubtful purity, having been prepared by the oxidation of ethylene glycol and glycerol, respectively, with hydrogen peroxide in the presence of ferrous ion.24 Experimentally, the aldehydes were heated in dilute aqueous potassium bicarbonate solution with an equimolar amount of nitromethane until the odor of the nitroparaffin had disappeared. Aluminum amalgam then was added to the reaction mixture in order to reduce any nitro compounds present t o the corresponding amines. The latter were precipitated with mercuric chloride and, after decomposition of the mercurichlorides with hydrogen sulfide, the resulting amine hydrochlorides were treated with nitrous acid. Glycerol, identified as the crystalline tribenzoate, was obtained in very low yield from glycolaldehyde by the above reactions. No product could be identified from either D,L-glyceraldehyde or L-arabinose. From D-glucose, a very small yield of an optically-inactive, crystalline material was obtained. The identification of this substance by Pictet and Barbier as "D-gluco-a-heptite " is questionable since they record for their product a melting point (134-135') several degrees higher than that '(127-128') observed elsewhere for D-gluco-D-gulo-heptito1.26 It must be concluded that these experiments did. not demonstrate unequivocally that a nitromethane-aldose sugar condensation had been achieved, 2. Degradation of Sugar Cyanohydrins by Alkali i n the Presence of

Nitromethane

The condensation of ethyl glyoxylate with aldose sugars in the presence of sodium cyanide was reported by Helferich and Peters in (23) A. Pictet and A. Barbier, H e b . Chim. Acta, 4, 924 (1921). (24) H. J. H. Fenton and H. Jackson, J . %hem. SOC.,71, 1 (1899). (25) E. Fischer, Ann., 270, 64 (1892).

298

JOHN C. SOWDEN

1937.28 This reaction, similar in nature to the benzoin condensation, led to analogs of ascorbic acid. It was observed that the reaction proceeded especially Gel1 when a methyl alcoholic solution containing an acetylated sugar cyanohydrin and ethyl glyoxylate was treated with alkali.

Tetraacetyl-Dxylonic Nitrile

The authors state, in part, “Whether the different reactions-saponification or trans-esterification of the acetyl groups, splitting out of alcohol to form the lactone, the condensation itself-occur ‘simultaneously’ or ‘successively’ and in which ‘sequence,’ is not further investigated; indeed, for the practical application, it is unimportant. The essential feature is that all the reactions can proceed quite smoothly in the same medium.” Reaction conditions similar to those employed by Helferich and Peters, with the exception that ethyl glyoxylate was replaced by nitromethane, were applied by Sowden to tetraacetyl-L-arabonic nitrile, pentaacetyl-D-gluconic nitrile and D-gluconic nitrile. I n all these instances, however, the nitrogen-containing reaction products were noncrystalline. Moreover, further treatment of the sirupy reaction products by acetylation or propionylation followed by distillation, benzoylation, acetonation, tritylation, bromination or reduction also failed t o produce crystalline derivatives. These preliminary experiments had little practical importance but are of some interest chronologically since the first crystalline carbohydrate C-nitroalcohol, 1-nitro-1-desoxy-D-mannitol, was obtained eventually by the degradation of a substituted sugar cyanohydrin with alkali in the presence of nitr~methane.~?I n order to change the solubility characteristics of the expected sugar nitroalcohol and in the hope of endowing it with a greater tendency toward crystallization, a sugar cyanohydrin containing the alkali-stable benzylidene acetal moiety was synthesized from 4,6-benzylidene-~-glucose.~~ (26) B. Helferich and 0. Peters, Ber., 70, 465 (1937). (27)J. C.Sowden and H. 0. L. Fischer, J . Am. Chem. Soc., 66, 1312 (1944). (28)L. Zervas, Ber., 64, 2289 (1931).

%NITROETHANOL

NITROMETHANE AND

CHO

HC=NOH

HboH

HbOH

b

-

HO H

HObH

NHaOH

HA0

I

\\

HCOH

299

SYNTHESES

CHCsHa

Ha 0// 4,6-BenzylideneD-glucose

AcObH AczO, NaOAc

HA0

-A

b

b

H OAC \\ CHCeHi

H OH \\ CHCsHa

I

H&O

I

//

//

HzCO 4,6-Benzylidene-2,3,5triacetyl-D-gluconic Nitrile

HzCO

When lthis nitrile, 4,6-benzylidene-2,3,5-triacetyl-~-glucon~c nitrile, was treated with sodium methoxide in methanol solution in the presence of nitromethane, there was obtained readily from the reaction mixture crystalline 4,6-bensylidene-l-nitro-l-desoxy-~-mannitol.Hydrolysis of the benzylidene acetal with dilute sulfuric acid then gave the crystalline 1-nitro-1-desoxy-D-mannit 01. CN

CHzNOz

HhAc AcdH HA0

b

A

H OAC \\ CHCaHs Hz 0//

CHaNOz

HobH HobH CHiNOn, CHsONa

HbO

i

HobH

-

HobH

&SO4

H OH \\ C H C ~ H B

A

Ha 0//

HboH HbOH HAOH

1-Nitro-1-desoxyD-mannitol

The above method of producing a carbohydrate C-nitroalcohol is now of only minor interest since subsequent experiments have shown that substituted aldoses with a free reducing group as well as the unsubstituted aldose sugars will undergo the aldehyde-nitroparaffin condensation reaction. 20 IV. CARBOHYDRATE C-NITROALCOHOLS 1. Preparation C-nitroa. From Benzylidene-Substituted A1doses.-Carbohydrate alcohols have been prepared from several bensylidene-substituted aldoses in which the carbonyl hemiacetal function is unsubstituted. In these condensations the reaction mixture containing methanol, sodium (29) J. C. Sowden and H. 0. L. Fischer, U. S. Pat. 2,480,785(1949).

300

JOHN C. SOWDEN

methoxide, benzylidene sugar and nitromethane remains homogeneous throughout and the resulting benzylidenenitroalcohols can be recovered from the acidified reaction mixture in yields of from 20 to 65 percent, depending on the benzylidene sugar employed. The presence of a benzylidene acetal moiety elsewhere in the molecule seems to enhance the reactivity of the carbonyl hemiacetal function of the sugars. Thus, the 4,6-benzylidene-~-glucose isolated by Zervas2* readily forms a crystalline sodium salt when treated with sodium hydroxide. That this salt formation occurs on the hemiacetal hydroxyl is confirmed by the production in high yield of l-ben~oyl-4~6-benzylideneP-D-glucose when sodium 4,6-benzylidene-~-glucose is treated with benzoyl chloride in chloroform. I n the benzylidene sugar-nitromethane condensation, this enhanced reactivity of the sugar carbonyl group may be largely responsible for the success of the reaction in a homogeneous medium. The condensation in the presence of alkali is a reversible reaction and the position of the equilibrium between sugar derivative and nitromethane on the one hand and sugar nitroalcohol derivative on the other should be governed by the carbonyl reactivity of the former and the stability of the latter in the presence of alkali. d,~-BenzyEidene-~-Erythrose.-The condensation of this benzylidene sugar with nitromethaneSoconstitutes the most satisfactory example of the reaction to date both with regard to yield of products and to the absence of marked epimeric preference in the formation of the two CH2NO2 I

CHzNOz I

H~OH\CHC~H~

b/

Hs 0 4,B-Benzylidenesorbitol

2,4-Benz lidenewery tLose

(30)J. C. Sowden, J. Am. Chem. Soc., 73, 808 (1950).

H~OH

H A H 1-Nitro-1-desoxy-D-ribitol

NITROMETHANE AND Z-NITROETHANOL SYNTHESES

301

benzylidenenitroalcohols. The sirupy benzylidene sugar itself was prepared by the cleavage with sodium metaperiodate of 4,6-benzylidenesorbitol, obtained in turn by catalytic hydrogenation of 4,6-benzylidene&glucose. The separation of the epimeric benzylidenenitroalcohols was facilitated in this instance by a remarkable difference in their solubilities in chloroform or anhydrous ether, benzylidenenitrodesoxyribitol being readily soluble in the cold solvents whereas the benzylidenenitrodesoxyarabitol is virtually insoluble. Hydrolysis of the benzylidene acetals with dilute sulfuric acid produced the unsubstituted sugar nitroalcohols. The configurations of the latter were proved by converting them via the Nef reaction (see page 307) t o the corresponding known aldose sugars. The following experimental details, and those appearing subsequently, are included t o describe typical examples of the preparation and reactions of the carbohydrate C-nitroalcohols. Experimental Details.a'.J'-A solution of 12.8 g. of 4,6-benzylidene-~-glucose,m. p. 185-186', in 150 cc. of 95% ethanol was shaken with hydrogen in the presence of 1.5 g. of platinum oxide (Adams catalyst) at room temperature and a n initial pressure of 50 pounds per square inch. The reduction was complete in eighteen hours with the absorption of approximately one mole-equivalent of hydrogen. Concentration of the filtered solution yielded 10.5 g. (82 %) of 4,6-benzylidenesorbitol, m. p. 131-134". Recrystallization from ethanol by the addition of ether yielded the pure compound, m. p. 132-133'. Thirty grams of 4,6-bcnzylidenesorbitol was treated with a solution containing 48 g. of sodium metaperiodate and 9 g. of sodium bicarbonate in 600 cc. of water. After standing two hours a t room temperature, the solution was concentrated to dryness a t reduced pressure. The residue was extracted several times with warm ethyl acetate and, after washing with water, the extract was concentrated a t reduced pressure. The resulting sirupy erythrose derivative was dissolved in a mixture of 250 cc. of absolute methanol with 75 cc. of nitromethane, and 6 g. of sodium in 300 cc. of absolute methanol were added. After standing ten hours a t room temperature, the solution was treated with 16.5 cc. of glacial acetic acid and concentrated to a small volume at reduced pressure. Water was added and the concentration repeated. The resulting partly crystalline residue was taken u p with ether and water and the ether layer was separated and washed with a small volume of cold water. After drying and concentrating at reduced pressure, the ether solution yielded a crystalline mass. The crystals were extracted with chloroform at room temperature, leaving a residue of 7.0 g. of nearly pure 3,5-benzylidene-l-nitro-l-desoxy-~-arabitol, m. p. 138-142". Concentration of the chloroform extract to dryness followed by extraction of the residue with anhydrous ether yielded as a residue a n additional 1.7 g. of this material. Recrystallization from water yielded the pure isomer, m. p. 145-146". Concentration of the ether extract to dryness gave 10.6 g. of crystalline material which on recrystallization from ether and petroleum ether gave pure 3,5-benzylideneI-nitro-1-desoxy-D-ribitol, m. p. 106-107'. The yield of crystalline benzylidenenitroalcohols was 19.3 g. (64%). (31) J. C. Sowden, J . Am. Chem. SOC.,71, 1897 (1949).

302

JOHN C. SOWDEN

Five grams of 3,5-benaylidene-l-nitro-l-desoxy-~-arabitol was heated for one hour at 65-70' (stirring) with a solution containing 40 cc. of water, 10 cc. of ethanol and 0.15 cc. of sulfuric acid. After removal of the resulting benaaldehyde by distillation in vacuo and of the sulfuric acid by ion-exchange, concentration of the solution to dryness gave a crystalline residue. Recrystallisation from absolute ethanol yielded 2.85 g. (85%) of 1-nitro-1-desoxy-D-arabitol,m. p. 147-148". Hydrolysis of 3,5-benaylidene-l-nitro-l-desoxy-~-ribitolas described for the arabitol derivative gave amorphous 1-nitro-1-desoxy-D-ribitolin 90% yield. Acetylation then gave the crystalline tetraacetate in 85% yield, m. p. after recrystallisation from absolute ethanol, 64-65'.

Since many nitrogen-containing organic compounds are explosive, some mention is appropriate here of possible hazards in working with nitromethane. Occasionally, some evidence of decomposition, in the form of mild evolution of heat and gases, has been observed by the author in concentrated, acidified aldose-nitromethane reaction residues from which the bulk of the nitroalcohols had been separated. Such residues usually have been either discarded a t once or stored a t -20" when further crystallization was anticipated. Generally, it may be stated that the aldose-nitromethane condensation reaction does not involve serious explosion hazards. Quite another matter, however, is the handling of the dry sodium salt of mi-nitromethane. This salt crystallizes with one molecule of ethanol of crystallization, the latter being gradually lost on standing, and, superficially, this salt would appear to be a convenient form in which to handle the reagent. The ethanol-free salt is, however, an extremely sensitive and violent explosive. The substance detonates with great force when ~ a r m e d ' ~orJ ~brought into contact with a small amount of ~ a t e r . ' ~ J *The corresponding potassium salt is even more unstable, exploding when attempts are made t o dry it.38 Thus, if it is found necessary a t any time to employ the dry alkali salts of aci-nitromethane, they should be approached with a degree of caution commensurate with their violent nature. d,4-Benzylidene-~-Xylose.-This benzylidene pentose was obtained from 2,4-benzylidenesorbitol by cleavage with lead tetraacetate according ~ with nitromethanes6 to the procedure of v. V a r g h t ~ ~Condensation under conditions similar to those described above for 2,CbenzylideneD-erythrose gave crystalline 2,4-benzylidene-6-nitro-6-desoxysorbitol (3,5-benzylidene-l-nitro-l-desoxy-~-gulitol) in 50 percent yield. (32) V. Meyer, Ber., 27, 1600 (1894). (33) N. Zelinsky, Ber., 27, 3407 (1894). (34) L.von Vargha, Ber., 68, 18, 1377 (1935). (35) J. C. Sowden and H. 0. L. Fischer, J . Am. Chem. Soc., 67, 1713 (1945).

NITROMETHANE AND

CHiOH HbO

\

%NITROETHANOL

CHaOH HA0

303

SYNTHESES

CHiOH

CHIOH

c:'

HA0

A\

HAoH

HAO'

HbO'

HbOH

HAOH

HAOH

c:

HOLH CHCsHs-+ HO H CHCsH6+ HO H CHCsH6-t HO H HbO' HLOH

AH0

AH20H 2,4-Benzylidenesorbitol

AHzNO~ 2,4-BenzylideneGxylose

AH2N0, 0-Nitro-6desoxysorbitol

The isolation of the concomitant epimeric 3,5-benzylidene-1-nitro-1desoxy-L-iditol from this reaction has not been realized as yet. The configuration of 6-nitro-6-desoxysorbitol followed from its conversion via the Nef reaction t o sirupy L-gulose and the oxidation of this sugar t o the known crystalline L-gulonic y-lactone.as From the sirupy sugar there was prepared also a crystalline calcium chloride-a-L-gulose compound similar in every respect except direction of mutarotation and sign of equilibrium rotation t o that reported by Isbell for D-gulose and calcium ~hloride.~' Q,G-Benzylidene-~-GIucose.-The condensation of benzaldehyde with D-glucose in the presence of zinc chloride leads to a mixture of 4,6-bensylidene-D-glucopyranose2* (m. p. 188') and non-reducing 1,2-benzylidene~-glucofuranose~~ (m. p. 176-177'). Preparations of lower melting point, such as that of Brigl and Grtinera8 (m. p. 172'), probably consist of a mixture of the two isomers. For condensation with nitromethane, preparations of 4,6-bensylidene-~-glucose melting above 180" are satisfactory. The condensation with nitromethane4"leads to crystalline 5,7-benzylidene-1-nitro-1-desoxy-D-gluco-D-gulo-heptitol in a yield of 20 percent. In addition there is obtained in low yield (3-5 percent) a crystalline 2,6-anhydro-5,7-benzylidene-l-nitro-l-desoxyheptitol.The position of the anhydro ring in the latter compound was established by the following evidence : The benzylideneanhydronitroalcoholconsumed one molecularequivalent of lead tetraacetate. Its crystalline diacetate, in benzene solution, was inert to the action of sodium bicarbonate, indicating the absence of the -CHOAcCH2N02 grouping (Schmidt and Ruts reaction, see page 313). Hydrolysis of the benzylidene acetal function gave a (36) E. Fischer and 0. Piloty, Ber., 24, 521 (1891); H. Thierfelder, 2. physiol. Chem., 16, 71 (1891). (37) H. S. Isbell, Bur. Standards J . Research, 6 , 741 (1930). (38) J. C. Sowden and Dorothy J. Kuenne, in press. (39) P. Brigl and H. Griiner, Ber., 66, 1430 (1932). (40) J. C. Sowden and H. 0. L. Fischer, J . Am. Chem. SOC.,68, 1611 (1946).

304

JOHN C. SOWDEN

crystalline anhydronitroalcohol that consumed two molecular-equivalents of sodium metaperiodate to produce one molecular-equivalent of formic acid but no formaldehyde. The tetraacetate of the anhydronitroalcohol, in benzene solution, also was inert to the action of sodium bicarbonate. The 2,6-position for the anhydro ring is in accord with these observations.

:t:

HobH HA0

/

/

1

CHzNOz

CHzN02

H HbOH boH

-+

H b >\cHc,,,

b/’

Hz 0 4,B-Beneylidene-aD-glucopyranose

HoAH H L

I \\

HCOH CHCaHs

A/

Hz 0 5,7-Benz lidene-lnitro-l-dksoxy-Dghco-n-gub-heptitol

and

Hk:Ti HOAH

b / I >
, 73 (230), 75 (88a, 230),79 (230),80 (230), 81 Knorr, E.,41,45 Knowles, H.I., 218 Kobel, Maria, 56,57,74 (140) Kohler, F.,102 Kohler, Leonore, 102 Koehler, W. L., 45,278, 284 (56) Koenigs, W.,41, 45 K6thnig, M.,138, 142, 148, 173, 174 Kolthoff, I. M.,235 Koshland, D.E.,Jr., 309 Kossel, A., 136 Kosterlitz, H.W.,13 Krebs, H.A,, 239,245 Kreider, L. C., 47,66 (105),70 (105),79 (105) Kremann, R., 57, 253 Krizkalla, H.,248 Kropa, E.L., 249 KroPBk, A., 90, 101 (31b),103 Krotkov, G.,309 Kruyff, J. J., 177 Kuenne, Dorothy J., 303 Kuhn, L. P.,142 Kuhn, R., 102, 139, 141 (39),161, 163, 188, lBp, 200 (30) Kunz, A.,57, 58,66 (145),73 (147),254, 275 (15,16) Kvalanes, H.M.,248

L Ladenburg, A., 180 La Forge, F. B., 161 La Lande, W.A., Jr., 220 LaUement, A,, 190

41 5

Lamb, R. A., 13, 16 (16),17 (16),20 (16) Lampen, J. O.,310 Lardy, H.A., 48, 49, 67 (114),77 (114) Lauer, K.,236 Laufer, L.,138 Leavenworth, C. S.,239 Lee, J., 138,139 (28),149 (29),151 (29), 161, 162, 163 (28,141, 142) Leete, J. F., 37, 68 (224),69 Leger, F.,106 Leitch, Grace C.,24 (43), 25 (43), 92, 98 (38) Leonard, F., 138, 149 (29),151 (29),161 Lespagnol, A., 190 Levallois, A., 117 Levchenko, V. V.,247 Levene, P. A., 13,22, 23 (lo),44, 47, 56, 67 (211),69, 135, 136, 137, 141 (2), 143 (2),145 (3),146, 147, 148 (56), 151 (56), 155, 156, 157, 158, 159, 161, 164, 168, 170, 172 (51,88), 292, 315 Levi, I., 37 Levine, A. S.,87 Lewy, G.A.,202 (53),203 Lewis, W.L., 54, 91,94 Lieser, Th., 117, 118 (32) Lifson, N.,309 Liggett, R.W.,238,241 Lindberg, B.,43, 46, 52, 53, 77 (129) Linderos, F.,232 Link, K. P.,143, 145 (53), 180, 182, 183, 184 (16,20), 185, 186, 187, 188, 189, 190, 191, 193, 194 (22),195, 198 (16, 22, 41,45), 199 (16,20, 22, 26, 36), 200 (16,20), 202 (22,28) Linstead, R. P., 74 (234),81 Lippincott, S. B.,294, 295 Lippmann, E. O.,von, 232,235 (21) Livingston, L. G.,309 Ljubitsch, N.,118 Loach, J. V., 24 (44a), 25 (44a),61 Lobry de Bruyn, C. A., 32, 64, 93,279 Lock, M.V., 145, 146, 148, 173, 174 Lohmar, R.,183, 186, 187, 188, 189, 190, 191, 194 (22), 198 (22), 199 (22), 202 (22,28) Long, C. W., 24 (44a),25 (44a),61 Lorber, J., 13, 19, 20 (33) Lorber, V., 309

416

AUTHOR INDEX FOR VOLUME VI

LouguKme, W.,235 Lowy, B. A., 165 Luckett, Sybil, 21, 23 (36) Ludewig, S., 56, 57, 74 (140) Ludtke, M., 121, 122 Ltihrs, E., 35 Lythgoe, B., 136, 148, 149 (96), 151 (96), 160 (4), 161 (107), 162, 163, 164, 165 (114), 166

M McCalip, M. A., 233, 234 (34), 235 (34), 236 McCleery, W. L., 233 McClenahan, W. S., 115, 116 (25) McClosky, C. M., 48, 71 (226), 75 (113), 81 McCreath, D., 14, 15 (20), 16 (20), 19, 23 (20) MacDonald, N. S., 62, 72 (168) McDowell, H. D., 79 (238), 80 (238), 81 McGlashan, J., 233, 235 (39) McIntire, F. C., 120 McKenrie, A., 269 MacKenrie, C. A., 262, 277 (30), 282 McLean, A. C., 148, 149, 151 (95, loo), 165 (100) McNicoll, D., 25 (48) Maehly, A. C., 14, 15 (18) Maier, A., 246 Maillard, L. C., 86, 98 (15) Maker, S. M., 236 Makarov, S. P., 294, 317 Malachowski, R., 235, 245, 246, 247 Malachta, S., 90 Marie, C., 247 Marini-Bettblo, G. B., 103, 105 (73) Market, L., 274, 282 (46) Marrian, G. F., 202 (54), 203 Martin, A. J. P., 144 Mashevitskaya, S. G., 87 Maslowski, M., 235, 245 (49) Mason, R. I., 193 Mamro, E. J., 309 Mathers, D. S., 67 (213), 69 Maurer, K., 40 Maxwell, W., 233 Meade, George P., 221 Medes, G. J., 309

Mehltretter, C. W., 13, 21 (124, 23 (1’W Meier, F., 90 Meigen, W., 102 Meincke, E. R., 245, 246, 248 (98) Meisenheimer, J., 315 Merck, E., 145 Merrill, Alice T., 181,201 (18,52), 203 Messmer, E., 118, 119 (45), 120 (43) Metcalf, E. A., 92, 103 (42) Meyer, G. M., 13, 22, 23 (10) Meyer, K. H., 117 Meyer, V., 293, 295, 302, 309 (9) Meystre, C., 48, 66, 80 (195) Michael, A., 41, 51, 245, 246 Micheel, F., 12, 13 (4), 115 Michelson, A. M., 156, 170 (127), 172 (127) Middendorp, J. A., 88, 98 (20), 99 (20), 100 (20), 101 (20), 102 (20), 103 (20) Miescher, K., 48, 66, 80 (195) Militrer, W., 292 Miller, I. L., 32, 53, 77 (130) Miller, J. G., 198 (44), 202 Miller, R. E., 241 Minsalts, J., 158 Miolati, A., 237 Mitchell, W. A., 45 Miti, K., 233 Modrow, Irmgard, 67 (202), 68, 75 (202) Mom, C. P., 247 Montgomery, Edna M., 12, 32, 54, 73 (134) Montgomery, R., 86, 94 (12), 97 Moog, L., 12, 25 (47), 33, 34 (16) Moore, S., 180, 182, 183, 184 (16, 20), 185, 186, 188, 189, 190, 191, 194 (22), 195, 198 (16, 22, 41), 199 (16, 20, 22), 200 (16, 20), 202 (22, 28) Mom, T. P., 144 Mori, T., 156, 315 Morrell, R. S., 59 Mottern, M. H., 232 Miiller, A., 12 Mliller, H. A., 269 Mukherjee, S., 174 Mulder, G. J., 84 Muller, R. H., 184 Munro, J., 15, 16 (24) Myrbiick, K., 178

417

AUTHOR INDEX FOR V O L U M E V I

N

P

Nagai, W., 49 Nagy, Z . S., 43 Natelson, S., 257 Naujoks, E., 105 Nawiasky, P., 248 Neale, S. M., 118 Nef, J. U., 93, 295, 302 (19) Neher, H. T., 91 Nelson, E. K., 232, 233, 235 Ness, R. K., 42, 45, 151, 152, 154 (111), 155, 159 Netsch, R., 241 Neukom, H., 110 Neumiiller, G., 178 Newbold, G. T., 149, 151 (loo), 165 (100) Newth, F. H., 88, 100 (22), 101 (22), 103, 104 Newton, Eleanor B., 137 Neymann, H. von, 88, 100 (25), 101 (25), 102 (25) Nichols, 9. H., Jr., 79 (238), 80 (238), 81 Nicholson, V. S., 88, 91 (21), 102 (21), 103 (21) Nickerson, M. H., 191 Niethammer, H., 275 NoB, A., 45, 67 (88a), 75 (88a) Nordlander, B. W., 249 Norman, L. W., 233 Nuttall, W. H., 99, 100 (60)

Paal, C., 261, 262,263,264,275,276 (27), 286 (27, 32, 33, 34, 35, 36), 289 (34) Pacsu, E., 14, 16 (224, 17 (22a), 20 (22a), 23, 42, 43, 52, 67 (200, 203), 68, 70 (65), 75 (200), 95, 108, 117, 144, 159, 253 Paine, H. S., 239, 240, 243 (72) Parnas, J. K., 173 Parsons, H. B., 233 Partridge, S. M., 99, 144, 145 de Pascual, J., 40, 51 Pasternack, R., 149, 163 Paton, J. G., 248 Patterson, T. L., 218 Peat, S., 11, 61, 121, 122, 174 Pebal, L., 247 Peel, Elizabeth W., 148, 167 (93) Peniston, Q. P., 142 Percival, E. G. V., 15, 16 (24), 18,20 (29), 22, 23 (34) Perrin, M. W., 248 Peters, O., 298 Peterson, W. H., 120, 121 Pfeiffer, P., 110 Phelps, F. P., 42, 43, 137, 142 Phelps, I. I p . See 8-DD-Galactopyranose, 1,2-isopropylidene-, Galactopyranose, l,Ganhydro-. 13, 22 D-Galactose, 88, 254 -, 6-trityl-, 12 methyl ethers of, 11-25 a-D-Galactopyranoside, methyl, 114, 116 a-D-Galactose, 6-(&cellobiosyl)-, dihyp-D-Galactopyranoside, methyl, 114, 116 drate, 79 a-D-Galactopyranoside, methyl 3-ben- D-Galactose, 1,2 :3,4-diisopropylidenezoyl-4,6-benzylidene-, 14 6,6-C-diethyl-, 288 -, methyl 4,6-benzylidene-, 13, 15 -, 1,2 :3,4-diisopropylidene-6,6-Cp-n-Galactopyranoside, methyl 4,6-bendimethyl-, 287 zylidene-, 13, 15 -, 2,3-dimethyl-, 13, 16, 20 3-carbethoxy derivative, 15 anilide, 20 -, methyl 4,6-benzylidene-3-methyl-, 15 methyl a-D-pyranoside, 20 a-D-Galactopyranoside, methyl 4,B-benmethyl p-D-pyranoside, 20 zylidene-2-tosyl-, 14, 15 8-D-Galactose, 2,4-dimethyl-, 17, 20 p-D-Galactopyranoside, methyl 4,Gbenanilide, 20 zylidene-2-tosyl-, 15 methyl a-D-pyranoside, 20 -, methyl 2,3-dibenzyl-, 13, 19 methyl p-D-pyranoside, 20 -, methyl 2,6-dimethyl-, 114 monohydrate, 20 -, methyl 2,6-dimethyl-3,4-isopropyli- -,‘ 2,6-dimethyl-, 13, 17, 20 dene-, 114 anilide, 20 -, methyl, 2,6-dinitrate, 13, 18 methyl 8-D-pyranoside, 20 *D-Galactopyranoside, methyl 3,4-isomonohydrate, 20 propylidene-, 17, 114 D-Galactose, 3,4-dimethyl-, 13, 18, 20 8-D-Galactopyranoside, methyl 3,4-isomethyl p-D-pyranoside, 20 propylidene-, 17, 114 a-D-Galactose, 4,Gdimethyl-, 13, 19, 20 D-Galactopyranoside (a and p ) , methyl methyl 8-D-pyranoside, 20 3,4-isopropylidene-, 13 phenylosazone, 19, 20 8-D-Galactopyranoside, methyl 3,4-iso- D-Galactose, 6,6-C-dimethyl-, 268, 287 propylidene-, 6-nitrate, 14, 15 phenylosazone, 287 a-D-Galactopyranoside, methyl 3,4-iso- -, 6,6-C-dimethyl-1,2 :3,4:-diisopropylipropylidene-6-tosyl-, 14 dene-, 268 6-D-Galactopyranoside, methyl, 6 4 8-D-Galactose, 6- (p-D-galactopyranosyl)-, trate, 12 73

430

SUBJECT INDEX, VOLUME VI

&Galactose, 2-(~-galactosyl)-, 40 FGentiobiose, 12-(&gentiobiosyl)-, p-D-Galactose, &(&.mglucopyranosyl)-, tetradecaacetate, 80 75 -, 1%(8-&mannopyranosyl)-, hendecaa--Galactose, 6(8-D-mannofuranosyl)-, acetate, 80 79 8-Gentiobioside, methyl, 77 p-D-Galactose, %methyl-, 15, 16 heptaacetate, 77 anilide, 16 heptabensoate, 77 methyl pyranoaides, and 8, 16 -, methyl 12-(p-cellobiosyl)-, tridecaa-D-Galactose, 3-methyl-, 15, 16 acetate, 80 methyl Fpyranoside, 16 a-Gentiobiosyl bromide, heptaacetyl-, 66 phenylosasone, 16 a-Gentiobiosyl chloride, heptaacetyl-, 77 D-Glucal, 55 &D-Galactose, 4(?)-methyl-, 14, 16 phenylosasone, 15-17 n-Glucaric acid, 90 KH salt, 86, 90 a-D-Galactose, &methyl-, 14-16 phenylosasone, 18 -, dibensimidaaole from, 202 D-Galactose, 2,3,4,&tetramethyl-, 6, 12, dihydrochloride tetrahydrate, 202 17,25 dipicrate trihydrate, 202 anilide, 25 “Glucinic acid,” 84 methyl a-D-pyranoside, 25 ~-Glucitol,4,&benaylidene-, 141, 300 methyl 8-mpyranoside, 25 -, l-deaoxy-1,l-diphenyl, hydrate, 275, a-pyranose form, 25 286 -, 2,3,5,6tetramethyl-, 12, 25 pentaacetate, 286 a-D-Galactose, 2,3,4trimethyl-, mono- -, I-desoxy-1,l-di-p-tolyl-,hydrate, 257, hydrate, 12, 23 280 anilide, 23 LGlucitol, I-desoxy-1-nitro-, 306-308 D-Galactose, 2,3,5trimethyl-, 13, 23 D-Glucitol, 6desoxy-&nitro-, 308, 313 -, 2,3,&trimethyl-, 23 -, 1-desoxy-(a-l-phenyl)-(&l-ptolyl)-, hydrate, 260, 286 a-D-Galactose, 2,4,&trimethyl-, 23 anilide, 23 -, 1-desoxy-@-l-phenyl)-(a-l-p-tolyl)-, hydrate, 260,287 hemihydrate, 23 methyl a-D-pyranoside, 23 -, 1,l-C-dibenryl-, 286 methyl 8-D-pyranoside, 23 -, 1,l-Gdiphenyl-, 262, 286 D-Galactose, 3,4,6trimethyl-, 13, 23 -, 1,l-C-di-ptolyl-, 286 D-Galactose dibenzyl mercaptal, diiso- a-D-Glucofuranose, 3-acetyl-6-bromo-6propylidene-, 14 desoxy-1 ,%ieopropylidene-&(tetraD-Galactose phenylosaaone, from 2acetyl-fl-n-glucopyranosyl)-, 76 methyl-D-galactose, 15 -, 3-acetyl-6-desoxy-l,2-isopropylidenemGalactoside, mgalactosyl, 73 S-(tetraacetyl-@-D-glucopyranosyl)-, octaacetate, 73 77 “4-Galactosido-mannose,” 8 fl-D-Glucofuranose, l,&anhydro-, 13 DGalacturonic acid, 90 a-D-Glucofuranose, 3,&anhydro-&(&.~-, 1,2:3,4-diisopropylidene-, 268 gluoopyranosyl)-1,2-isopropyliGentianose, 35 dene-, 77 Gentiobiose, 7, 32, 33, 37, 48, 53, 77 -, 6,&anhydro-l,Zisopropylidene-, 67 a-octaacetate, 77 D-Glucofuranose, 1,sbenzylidene-, 303 p-octaacetate, 77 a-D-Glucofuranose, 3,5-benaylidene-B synthesis of, 51 (&D-glucopyranosyl)-1,2-isopro-, 12-(8-cellobiosyl)-, 50 pylidene-, 77 tetradecaacetate, 80 tetraacetate, 77


-, 3,5-benzylidene-l,2-isopropylidene-, -,

431

6-(@-gentiobiosyl)-,hendecaacetate, 67 ' 80 -, 5,bbenzylidene-1,2-isopropylidene-, -, 2-(j3-~-glucopyranosyl)-,octaacetate, 67 40, 76 D-Glucofuranose, bdesoxy-l,2-isoproD-Glucopyranose, 6-(a-~-glucopyranopylidene-, 67 sy1)- (Isomaltose), b-octsacetate, 77 -, bdesoxy-1,2-isopropylidene-&nitro-, octamethylated derivative, 77 311 &D-Glucopyranose, b@maltosyl)-, hena-D-Glucofurano8e, 6-desoxy-1,2-isoprodecaacetate, 80 pylidene-5- (tetraacetyl-&~-gluco-, 6-(,9-~-mannopyranosyl)-, octaacepyranosy1)-, 77 tate, 79 -, 1,2:5,bdiisopropylidene-, 67 -, 6-(&crharnnopyranosyl)-, heptaD-Glucofuranose, 2,3,Strimethyl-, 13 acetate, 71 n-Gluco-n-gulo-heptitol, 297 a-D-Glucopyranose, 1,2,3,4-tetraacetyl-, -, 5,7-benzylidene-l-desoxy-l-nitro-, 67 303 fl-D-Glucopyranose, 1,2,3,4-tetraacetyl-, D-Gluco-D-gulo-heptonic acid, ~-(B-D67 galactopyranosy1)-, 35 -, 1,2,3,6tetraacetyl-, 68 D-Glucoheptulose, synthesis of, 317 -, 1,3,4,6-tetraacetyl-, 68 D-Gluconic acid, 89, 90, 95 a-D-Glucopyranose, 2,3,4,6-tetraacetyl-, Sketo-, 89 68 bphosphate, 137 fl-D-Glucopyranose, 2,3,4,6tetraaoetyl-, -, 2,3,4,btetramethyl, Q-lactone,6 40, 68 -, 2,3,5,btetramethyl-, 7 -, b(fl-D-xylopyranosyl)-, heptaacetate, y-lactone, 6 71 n-Gluconic y-lactone, tetraacetyl-, 262, a-D-Glucopyranoside, methyl, 88, 116, 264 127 D-Gluconic nitrile, 4,6-beneylidene-2,3,68-D-Glucopyranoside, methyl, 41, 116, triacetyl-, 299 127 fi-D-Glucopyranose, 1,banhydro-, 112, a-D-Glucopyranoside,methyl 4,6benzyli129 dene-, 67, 125 -, l,banhydro-3-methyl-, 129 8-D-Glucopyranoside, methyl 4,bben-, &(a-L-arabinopyranosy1)-,heptazylidene-, 125 acetate, 71 a-D-Glucopyranoside, methyl 4,GbenD-Glucopyranose, 4,6-benrylidene-, 67, sylidene-2-(tetraacetyl-&~-glucopyranosy1)-, 76 303 a-D-Glucopyranoee, 4,bbenrylidene-3fl-D-Glucopyranoside, methyl &(a-cello(a-~-glucopyranosyl)-1,2-isopropylibiosy1)-, decaacetate, 79 dene-, 76 -, methyl 6-(p-cellobiosyl)-, decaacetetraacetate, 76 tate, 79 -, 4,bbenzylidene-1,2-iopropylidene-, a-D-Glucopyranoside, methyl bdesoxy-, 130 67 pn-Glucopyranose, 6-(fl-cellobiosy1)-, fl-D-Glucopyranoside, methyl bdesoxy-, 130 hendecaacetate, 79 a-D-Glucopyranoside, methyl 2,3-di-, 4-(&~-galact~pyranosyl)-, octamethyl-, 125 acetate, 73 -, &(a-D-galactopyranosy1)-, octaace- &D-Glucopyranoside, methyl 2,3-ditate, 73 methyl-, 125 -, b(fl-D-galactopyrsnosyl)-, octaace- crD-Glucopyranoside,methyl 2,4-ditate, 73 methyl-, 125

432

-,

SUBJECT INDEX, VOLUME V1

methyl 2,fMimethyl-, 125 8-D-Glucopyranoside,methyl 4,6-dimethyl-. 125 -, methyi 4,6ethylidene-, 125 a-D-Glucopyranoside, methyl 2- (&Dglucopyranosy1)-, 76 j?-D-Gluoopyranoside, 8-D-glucopyranosyl- (Isotrehalose), 75 < octaacetate, 75 (?)-D-Glucopyranoside, a (?)-D-glucopyranosyl-, (Neotrehalose), 75 heptaacetate, 75 monohydrate, 75 octaacetate, 75 8-D-Glucopyranoside, methyl heptamethyl-4-(j3-D-glucopyranosyl)-, 76 -, methyl 2-methyl-, 117, 125 -, methyl 3-methyl-, 117, 125 -, methyl Pmethyl-, 117, 119, 124 -, methyl &methyl-, 117, 127 a-D-Glucopyranoside, phenyl, 127 8+Glucopyranoside, phenyl, 127 -, phenyl 3-methyl-, 125 -, methyl 6-(B-L-rhamnopyranosyl)-, hexaacetate, 71 -, methyl 2,3,4-triacetyl-, 67 a-D-Glucopyranoside, methyl 2,3,4-tribenzoyl-, 67 8-D-Glucopyranoside, methyl 2,3,6-trimethyl-, 67 D-Glucopyranoside polysaccharides, cuprammonium complexes, 116 a-D-Glucopyranosyl bromide, 6-(B-cellobiosy1)-, decaacetate, 66 -, 6-(@-gentiobiosy1)-,decaacetate , 66 -, 2-(@-~-glucopyranosyl)-,heptaacetate, 76 -, 6-(B-lactosyl)-, decaacetate, 66 -, 6-(~-~-mannopyranosyl)-, heptaacetate, 66 -, tetraacetyl-, 41, 66 a-D-Glucopyranosyl chloride, B-(B-cellobiosy1)-, decaacetate, 79 -, 6-chloro-6-desoxy-2,3,4-triacetyl-,253 -, 6-(~-~-glucopyranosyl)-,heptaacetate, 77 -, 6-(@+rhamnopyranosyl)-, hexaacetate, 71 -, 6-(~-D-XylOpyranO~yl)-,hexaacetate, 71

-,

tetraacetyl-, 41, 42, 253 2,3,4-trkcetyl-. 68 j3-kGlucopyranosy1 chloride, 3,4,6-triacetyl-, 40 -, 3,4,6-triacetyl-, 68 -, 3,4,6-triacetyl-2-trichloroacetyl-,254 8-D-Glucopyranosylfluoride,tetraacetyl-, 66 a-D-Glucopyranosyl halides, tetrabenzoyl-, 42 a-D-Glucopyranosyl iodide, tetraacetyl-,

'-,

42

&D-Glucopyranosyldihydroxyacetone , pentaacetyl-, 70 3+~-GlucopyranosylgIyceraldehydedibenzylcycloacetal, tetraacetyl-, 70 D-Glucosaccharic acid, See D-Glucaric acid. D-Glucosamine, stereochemistry of, 8 D-Glucosan B < 1,6 >. See 6-DGlucopyranose, lJ6-anhydro-. PGlucose, 88, 305, 309 1,Zenediol, 93 labeled with 0 4 a t 1, 309 three types of labeled, 309 L-Glucose, 307, 308 n-Glucose, IJ2-anhydro-, 86 a-D-Glucose, 6-(a-1rarabinopyranosyl)-, (Vicianose), 71 6-D-Glucose, l-benzoyl-4,6-benzylidene, 300 D-Glucose, l,Z(1-benzy1ethylidene)3,4,6-triacetyl-, 281, 289 -, 4,6-benzylidene-, 299, 301 sodium salt, 300 a-D-Gh.wose, 6-(/3-~ellobiosyl)-,80 D-G1ucose, Zdesoxy-. See ~-arabo-2Desoxyhexose. -, &desoxy-hitro-, 311 nitrodesoxyinositols from, 311 ~D-G1ucose,4- (B-D-galactopyranosyl)-, monohydrate, (Lactose), 73 -, 6-(B-D-galactopyranosyl)-, (Allolactoee), 73 B-octaacetate, 73 -, 2-(/3-~-glucopyranoeyl)-,76 D-Glucose, 3-(D-glucopyranosyl)-, 40 -, 3-(a(?)-~-glucopyranosyl)-,76 poohacetate, 76

433


p-D-Glucose, 4-(fl-~-ghcopyranosyl)-,(8Cellobiose), 76 P-octaacetate, 76 D-Glucose, 6-(8-D-glucopyranosyI)-, (Geptiobiose), 77 oroctaacetate, 77 D-octaacetate, 78 a-D-GIucose, 6-(&1actosyl)-, 80 0-hendecaacetate, 80 D-Glucose, 1,2-(l-methylpentylidene)-, 289 3,4,6-triacetate, 281, 289 -, 2,3,4,6-tetramethyl-, 6-8, 36, 92 -, 2,3,6trimethyl-, 6 a-D-Glucose, 6-(&~-xylopyranosyl)-, (aPrimeverose), 71 1,2-Glucoseen, tetramethyl-, 92, 94 a-Glucosidase, 36, 37 8-Glucosidase, 32, 36 ‘~4-Glucosido-mannose,”8 D-Glucosone, 1-C-methyl-, 287 -, l-C-methyl-2,3 :4,bdiisopropylidene-, 287 -, 1-C-phenyl-, 266, 287 x-phenylhydrazone, 287 tetraacetate, 287 -, 1-Gphenyl- 2,3 :4,5-diisopropylidene-, 265, 266, 287 -, l-C-phenyl-4,5(or 5,6)-isopropylidene-, 287 ~-D-G~UCOSYI chloride, tetraacetyl-, 276 D-Glucuronic lactone, 90 Glutaric acid, m’bo-trihydroxy-, 136, 145 Glyceraldehydedibenzylcycloacetal,67 D,L-Glyceritol, 1,l-C-diphenyl-, 264, 286 Glycerol tribenzoate, 297 Glycine, 86 Glycogen, 8, 37 specific rotation, 119 Glycosylations of aromatic hydrocarborn, 255-261 Glyoxylic acid, ethyl ester, 297 Grignard process in carbohydraterseries, 251-289 ’ Guanine, 137 cuprous salt, 138 Guanosine, 137, 138, 146, 165 synthesis of, 165 -, 6acetyl-, 172 -, &acetyl-2,3-benzylidene-, 170

-, -, -,

2,%benzylidene-, 170 2,3-benzylidene-5-trityl-,172 2,3-isopropylidene-, 170 L-Gulitol, 3,5-benzylidene-l-desoxy-lnitro-, 302 -, 6desoxy-, 270 -, 6-desoxy-l,2 :3,4-diisopropylidene-, 270,285 L-Gulonic ylactone, 303 crD-Gulopyranoside, methyl, 130 L-Gulose, 303, 308 a-L-Gulose-calcium chloride compound, 303

H Haworth, Walter Norman, obituary, 1-9 Helinus ovatus, 232 Heptitol, 2,6-anhydro-5,7-benzylidene-ldesoxy-1-nitro-, 303, 304 D-arabo-Hexitol, 1,2-didesoxy-l-nitro-, tetraacetate, 316 Hexosans, in cuprammonium, 129 HHgBr,, as catalyst, 46 Hydrofuramide, 101 “Hydrol,” 32 Hydroxyapatite, as adsorbent, 219, 220, 223 5-Hydroxymethylfurfural. See 2-Furaldehyde, bhydroxymethyl-. 5-Hydroxymethylfuroic acid. See 2Furoic acid, 5-hydroxymethyl-.

I L-Idofuranose, diisopropylidene-6desoxy-6-nitro-, 311 cr-D-Idopyranoside, methyl, 130 -, methyl 4,6-benrylidene-, 130 p-D-Idopyranoside, methyl 4,6-benzylidene-, 130 cr-D-Idopyranoside, methyl 2-methyl-, 130 D-D-Idopyranoside, methyl %methyl-, 130 D-Idosan @, 3-methyl-, 129 d d o s e , 6-desoxy-6-nitro-, 311 nitrodesoxyinositola from, 311 Inosine, 155 &phosphate, 170 -, 2,%isopropylidene-, 170

434


Inosinic acid, 155 Inositols, nitrodesoxy-, isomeric, 312 Insecticides, trialkyl saonitates as, 246 “Instability factors’’ of aldopentoses and aldohexoses, 124 Inulin, 9, 88 Iodine, as catalyst, 48 Ion exchangers, in sugar refining, 208,230 Isoguanine, combination with D-ribose, 137 Isomaltose, 31 octaacetate, 53 Isopropyl alcohol, 125 Isopropylidene derivatives, 113, 114 Isorotation rules, 108, 277, 282, 283 Isosucrose, 34,74 Isotrehalose, 39, 75 Isoxazole, trimethyl-, 294 Itaconic acid, 247

K bKeto-D-gluconic acid, 89 Kiliani-Fischer synthesis, 292 Koenigs-Knorr reaction, synthesis oligosaccharides by, 41-50 mechanism of, 43

Of

L Lactal. 8 Lactic acid, proportions of D- and Lisomers in, 195, 196 Lactose, 7, 24, 34, 61, 64, 73, 88, 140 -, octamethyl-, 6 a-Iarctosyl bromide, heptaacetyl-, 66 a-lactosyl chloride, heptaacetyl-, 254 Lactulose, 54, 73 Lead tetraacetate oxidation, 115, 116, 302, 303, 311 Leucomstoc, 9 Leuwnoatoc dextranicum polysaccharide, 121 Levulinic acid, 84, 85, 106 from 0 4 labeled glucose, 106 Levulinic aldehyde, o-hydroxy-, 99 -, 5-methoxy-, dimethylacetal, 106 Lichenin, specific rotation of, 119 a-WLyxopyranoside, methyl, 130 8-n-Lyxopyranoside, methyl, 130 n-Lyxose, 32, 60,136

M Maillard reaction, 86 Maleic. acid and anhydride, 108 Maltobionic acid, 7 methylated methyl ester, 7 Maltose, 7, 35, 37, 61 Maltoside, maltosyl, tetradecaacetate, 80 a-Maltosyl bromide, hepacetyl-, 66 IrMandelic acid, 282, 283 n-Mandelic acid, 0-methyl-, 274 IrMandelic acid, 0-methyl-, 274 Mannans, 9,121 n-Mannaric acid, dibenzimidazole from, 202 &hydrochloride, 202 dipicrate, 202 hexaacetyl derivative, 202 D-Mannitol, 95 -, 4,&benzylidene-l-desoxy-l-nitro-, 299 -, 1-desoxy-1-nitro-, 298, 299 pentaacetate, 313 IrMannitol, 1-desoxy-1-nitro-, 306 D-Mannitol, 1,2 :3,4-diisopropylidene-, 271 D-Mannofuranose, 2,3 :5,6diisopropylidene-, 68 D-Mannofuranoside, 2,3 :5,tbdiisopropylidene-D-mannofuranosyl 2’,3’ :5‘,6’-diisopropylidene-,79 a-D-Mannofuranosy1 chloride, 2,3 :5,6diisopropylidene-, 66 n-Manno-D-gala-heptitol,l-desoxy-lnitro-, 307 hexaacetate, 313 D-Manno-D-tala-heptitol, l-desoxy-lnitro-, 307 D-Mannoheptulose, synthesis of, 317 8-D-Mannopyranose, l,&anhydro-, 114, 129 -, 1,6-anhydro-4-benzyl-, 114, 129 -, 1,6-anhydro4benzyl-2,3-isopropylidene-, 114 -, l,&anhydr0-2,3-diacetyl-P. (tetraacetyl-8-Wgalactopyranosyl)-, 74 -, l,&anhydro-2,3-diacetyl4(tetraacetyl-8-D-glucopyosyl)-, 78 -, l,&anhydro-2,3-isopropylidene-, 34, 57, 68, 114


-,

1,6-anhydr0-2,bisopropylidene-4(tetraacetyl-&D-gluopyranosy1)-,78 -, 1,6anhydro-4-methyl-, 129 -, 1,6-annhydro-4-(tetraacetyl-p-D-glucopyranosy1)-, 78 a-D-Mannopyranose, 4- (8-n-galactopyranosy1)-, (a-Epilactose), 74 a-octaacetate, 74 fl-D-Mannopyranose, 4-(BD-galactopyranosy1)-, (8-Epilactose), 74 -, B-(fl-gentiobiosyl)-, hendecaacetate, 80

435

Methaeonic acid, 294 Methyl qcglycerate, 264 Methyl 1-naphthyl ketone, 258 Methyl ptolyl ketone, 257 Methyldiphenylcarbinol, 263, 276, 280 SMethylfurfural. See 2-FuraldehydeJ 6methyl-. Molisch test, 98 Mucic acid. See Galactaric acid. Mutarotation, of D-ribose, 142 of L-ribose, 142 of n-ribose anilides, 162 of 5-trityl-~-ribose, 142 Mycobacterium tuberculosis polysaccharides. 9

a-D-Mannopyranose, 6-(&~-glucopyranosy1)-, (a-Epigentiobiose), 78 a-octaacetate, 78 p-n-Mannopyranose, @-r+mannopyranosyb, octaacetate, 79 N -, 1,2,3,4-tetraacetyl-, 68 a-D-Mannopyranoside, methyl, 114, 116, Naphthalene, l-(tetraacetyl-fl-D-gluco130 pyranosy1)-, 285 fl-D-Mannopyranoside, methyl, 130 Nef reaction, 295, 301,303, 307-310, 312 a-D-Mannopyranoside, methyl 4 4 % ~ - Neolactose, 57, 73, 254 glucopyranosy1)-, 78 a-Neolactosyl chloride, heptaacetyl-, 254 -, methyl 2,3-i-isopropylidene-, 114 Neotrehalose, 75 -, methyl Cmethyl-, 130 heptaaoetate, 75 a-D-Mannopyranosyl bromide, 4-(j3-~monohydrate, 75 glucopyranosy1)-, heptaacetate, 66 octaacetate, 75 -, tetraacetyl-, 66 Nicotinamide, 166 a-D-Mannopyranosyl fluoride, 3,bdiaceNitroacetic acid, 294 tyl-4-(tetraacetyl-8-D-glucopyranoNitroalcohols, reduction to aminoalco~yl)-,78 hob, 296 D-Mannosaccharic acid. See D-ManNitrobenzene, p-(8-D-glucopyranosy1)-, naric acid. n-Mannosan @. See 19-DMsnnopyrsnose, 1,banhydro-. &Mannose, 55, 306-307 labeled with 0 4 , 309 cMannose, 308 phenylhydrazone, 308 &D-Mannose, 4-(a-D-glucopyranosy1)-, (Epimaltose), 78 octaacetate, 78 a-D-Mannose, 4-(&D-glucopyranosyl)-, (Epicellobiose), 78 cr-octaacetate, 78 Melibiose, 7, 24, 46 p-octaacetate, 73 Mercaptals. See Thioacetals of the respective sugar; for example, DRibose, dibenzyl thioacetal.

284

tetraacetate, 278, 284 2-Nitroethanol, syntheses with, 291-318 precautions in syntheses, 317 I-Nitroheptene-1, D-gluco-pentaacetoxy-, 314 -, D-manno-pentaacetoxy-, 313 1-Nitrohexene-1, D-urabo-tetraacetoxy-, 313, 316 -, D-xylo-tetraacetoxy-, 314 -, Irxylo-tetraacetoxy-, 313 Nitromethane, condensation with aldehydes, 293 aci-Nitromethane, explosive hazard of sodium salt, 302 Nitromethane syntheses, 291-318 NitroiSlefins, 296

436

SUBJECT INDEX, VOLUME M

C-Nitroolefins, acetylated carbohydrate, 296, 313-318 Nitroparafis, 293-296 aci-Nitroparaffins, 295 1-Nitropentene-1, D-erythro-triacetoxy-, 313,315

D-gluccr-Pentitol, 1-methyl-1-C-phenyl-, 271, 285 D-manno-Pentitol, 1-methyl-1-C-phenyl-, 274, 285 Icgluco (or manno)-Pentitol, 1-C-(1naphthy1)-, 285 D-gluco-Pentitol, 1-C-phenyl-, 271, 285 0 cgluoo-Pentitol, 1-C-phenyl-, 285 D-manno-Pentitol, 1-C-phenyl-, 271, 285 Oligosaccharides, 27-81 Periodate oxidation, 148, 150, 158, 162, enzymatic syntheses of, 36-39 165,168,170,172-174,188,189, 191, ether type, 31 257,271,274,280,281,283,301,304 linkage types, 28 Phenylacetaldehyde, el-methoxy-, 271, syntheses of, 27-81 274 the term, 28 Phytomonas tumefaciens polysaccharide, Optical rotation in cuprammonium solu120 tions, measurement of, 132 Polysaccharides, bacterial, 9 Orthoacetate, deztro, 3,4,6-triacetyl-~- a-Primeverose, 71 mannopyranose 1,2,6-(tetraacetyl-p- 1,2,3-Propanetricarboxylicacid. See D-glucopyranose), 79 Tricarballylic acid. lev0 isomer, 79 1,2,3-l?ropenecarboxylicacid. See Orthoester formation, mechanism of, 43 Aconitic acid, 8-0xa-3-azabicyclo[3,2, lloctane, 104 Paeudomonas saccharophilia, 34, 38 Oxygen atoms, distance between, 111, Pyranose, origin of term, 8 112 Pyridine, m condensing agent, 46 Pyruvic acid, 97

P

D-gluco-Pentitol, 1-C-cyclohexyl-, 271, 285 L-gluco-Pentitol, 1-C-cyclohexyl-, 285 D-gluco-Pentitol, 1-C-cyclohexyl-2,3 :4,5diisopropylidene-, 271, 285 L-gluco-Pentitol, l-C-cyclohexyl-2,3 :4,5 diisopropylidene-, 285 D,r.-gluco-Pentitol, l-C-cyclohexyl-2,3 : 4,5-diisopropylidenel 286 D-gluco-Pentitol, l-C-cyclohexyl-1,2,3,4tetraacetyl-5-trityl-, 285 egluco-Pentitol, 1-C-cyclohexyl-1,2,3,4tetraacetyl-5-trityl-, 285 D-gluco-Pentitol, 2,3 :4,6diisopropylidene-1-methyl-1-Gphenyl-, 271, 285 L-gluco (or manno)Bentitol, 2,3:4,6 diisopropylidene-1-C-( I-naphthy1)-, 286 D-gluco-Pentitol, 2,3 :4,5-diisopropylidene-1-C-phensl-, 271. 285 L-gluco-Pentiti, a,i :4,bdiisopropylidene-1-C-phenyl-, 285

Q &-Enzyme, discovery of, 9 Quinoline, as condensing agent, 46 Quinoxaline, 2- (D-arabo-tetrahydroxybutyl)-, 178, 187 Quinoxalines, from aldoses, 176-180

R Raffinose, 7, 35, 37 Rearrangement, the AlCls, 57 -, the Bergmann-Schotte, 55 -, the HF, 58 -, the Lobry de Bruyn, 64 -, the pyridine, 59 “Revertose,” 36 Reynold’s number, 212 D-Rhamnitol, 270 -1,2 :3,4-diisopropylidene1 270, 285 8-cRhamnopyranose, 3,4-dibenzoyl-, methvl-1.2-orthobenzoate.155 a-eRhamiopyranoside, methyl, 116, 130


a-cRhamnopyranosy1 bromide, triacetyl-, 66 -, tribenzoyl-, 155 LRhamnose, 89 Ribaric acid, 2,3,4-trimethyl-, 146 a-Ribazole, 168 SRibazole, 168 Ribitol, 145 Ribitol, 1,5-anhydro-, 150 -, 1,5-anhydro-2,3,4-tribenzoyl-,150 D-Ribitol, 3,5-benzylidene-1-desoxy-1nitro-, 141 . -, 1-desoxy-1-nitro-, 141, 300, 305 Ribitol, 2,4-dimethyl-, 157 D-Ribitol, 2,5-dimethyl-, 158 -, &methyl-, 172 -, 2,3,4,5-tetraacetyI-, 149 Ribitylaminobenzene, acetate, 164 Ribitylaminobenzenes, 149 D-Ribofuranose, 2,bisopropylidene-, 168 -, tetraacetate, 147, 148 -, 1,2,3-triacetyl-, 147, 148 -, 1,2,3-triacetyl-5-trityl-,148 D-Ribofuranoside, aniline, 162 -, miline 2,3,5-trimethyl-, 163 -’ dihydronicotinamide, 167 -, methyl, 146 -, methyl 5-benzyl-2,3-isopropylidene-, 147 -, methyl 2,3-isopropylidene-, 147, 157, 168, 169 SRibofuranosides, arylamine triacetyl-, 149 Ribonic acid, the term, 135 D-Ribonic acid, beneimidazole from, 137, 143 -, cadmium salt, 136, 139 LRibonic acid, cadmium salt, 136 D-Ribonic lactone, 2,3,5-trimethyl-, 159 DRibonyl chloride, tetraacetyl-, 149 D-Ribopyranose tetraacetate, 151 p-D-Ribopyranose, tetraacetate, 143, 148, 162 -, tetrabenzoate, 150, 151, 152, 153 D-Ribopyranose, 2,3,4-tribenzoyl-, 151 -, 2,3,4-trimethyl-, 158 D-Ribopyranoside, aniline, 162 triacetate, 162 -, 3,4dimethylaniline, complex with sodium sulfate, 163

437

0-n-Ribopyranoside, ethyl, 159 -, methyl, 130, 158, 159 -, methyl tribenzoyl-, 152, 153, 155 Ribopyranosides, methyl 2,3-anhydro-, 174 8-D-Ribopyranosyl bromide, triacetyl-, , 151, 164, 166 a-D-Ribopyranosyl bromide, tribenzoyl-, 150, 152, 153 8-D-Ribopyranosyl bromide, tribeneoyl-, 150, 151, 153, 159 8-D-Ribopyranosyl chloride, triacetyl-, 151 a-D-Ribopyranosyl chloride, tribeneoyl-, 153 p-D-Ribopyranosyl chloride, tribenzoyl-, 153 Ribose, chemistry of, 135-174 esters of, 148-151, 155-158 ethers of, 146-148 phosphoric esters of, 155-158 D-Ribose, 135-174, 314 benzylphenylhydrazone, 136 bromine water oxidation, 142 pbromophenylhydrazone, 138-141 condensation with ammonia, 160 condensation with aniline, 161, 162 condensation with 3,4-dimethylaniline, 163 condensation with 2-nitro-4,5-dimethylaniline, 161 diphenylmethane-dimethyldihydrazone, 136 labeled with W4, 141 mutarotation, 142 orthoesters, 159 phenylosaeone, 136 polarographic behavior, 142 L-Ribose, 135 physical properties, 141 mutarotation, 142 D,cRibose, 141 D-Ribose, anhydro-isopropylidene-, 172 isomer, 172 -, 5-benzoyl-, 170 -, 5-benzoyl-2,3,4-triacetyl-,166 -, 5-benzyl-, 147, 148, 170 triacetate, 147 -, 2-desoxy-. See ~-erythro-2-Desoxypentose.

438

SUBJECT INDEX, VOLUME V I

-, -, -, -, -,

dibenryl thioacetal, 143 diethyl thioacetal tetraacetate, 149 diisobutyl thioacetal, 143 dimeric anhydride, 173, 174 2,bdimethyl-, 146 -, dimethyl thioacetal, 143 -, di-n-propyl thioacetal, 143 -, ethylene thioacetal, 143 -, 2,3-isopropylidene-, 146 -, &methyl-, 146, 168 -, Smethyl-, p-bromophenylosasone, 156 D-Ribose 1-phosphate, 155 D-Ribose 2-phosphate, 155 D-Ribose Bphosphate, 157 &Ribose &phosphate, 137, 155-157, 170 D-Ribose, 2,3,4-trimethyl-, 146 -, 2,3,&trimethyl-, 146, 163, 168 a-D-Ribose, 5-trityl-, 148, 167 mutarotation, 142 triacetate, 148 aldehydo-D-Ribose tetraacetate, 149, 164 D-Riboside, methyl 2,3-isopropylidene-5methyl-, 146 D-Ribosides, arylamine, 138 -, of purines and pyrimidines, 164 Ribosimine, 161 u-D-Ribosyl bromide, triacetyl-, 66 a-tRibosyl bromide, triacetyl-, 66 Ring shapes, in glycopyranosides, 122 Robinobiose derivative, 71 Ruff degradation, 59 Rutinose heptaacetate, 71 S

D-saccharic acid. See o-Glucaric acid. Samevieria eeglancia, 232 Schardinger dextrins, specific rotations of, 119 diamylose, 119 hexaamylose, 119 tetraamylose, 119 Schmidt and Rutr reaction, 303,313,314 Sedoheptuloae, 140 Seliwanoff test, 98 Sorbitol. See also D-Glucitol. D-Sorbitol, 2,&anhydro-, 112 a-chrbofuranoside, a-Dglucopyrano~yl-,38, 78

csorbose, 8, 37, 38 Starch, 8, 37, 88 -, soluble, specific rotation, 119 Sucrose, 7, 33-35, 37, 74, 85,88 hydrolysis, 252 labeled with Cl4, 38 octaacetate, 74 refining, 205-230 -, octamethyl-, 6 Sugar carbonates, 7 Sulfotricarballylic acid, 247 derivatives, 248 Surface-active properties, 231, 244, 247, 248 “Sweetening-off ” operation, in sugar refining, 213 “Synthad,” a synthetic granular adsorbent, 209-211, 216-218, 221, 222, 225-230

T meso-Tartaric acid, 263 D( -)-Tartaric acid, preparation, 194, 195 Tartaric acid, racemic, resolution of, 195 tTartaric acid. See tThrearic acid. Terephthalic acid, 258 Theophylline, 7-B-~-ribofuranosyl-,165 triacetate, 164 Thiol-D-ribonate, ethyl tetraacetyl-, 149 Thiophene, 6-bromo-2-(tetraacetyl-B-~glucopyranosy1)-, 285 -, 2-(tetraacetyl-~-~-glucopyranosyl)-, 285 GThrearic acid, dibensimidazole from, 202 dihydrochloride dihydrate, 202 Toluene, p-(@-r+glucopyranosyl)-,257 tetraacetate, 260, 284 -, glycosylation of, 257 -, p-(triacetyl-o-D-xylopyranosyl)-, 280,284 Trehalose, 37 the three types, 39, 40 Tricarballylic acid, 247 Trimethylisoxasole, 294

U Uracil, 4-ethoxy-l-(triacetyl-~-ribopyranosy1)-, 104


-,

1-D-ribopyranosyl-, 164 Uric acid, combination with mribose, 137 Uridine, 164 -, 2,34sopropylidene-, 170

439

D-Xylitol, 1-desoxy-1,l-diphenyl-, 260, 286 -, 1-desoxy-(a-1-pheny1)-(fl-l-p-tolyl)-, 260, 286 o-Xylofuranose, 5-aldo-1,2-isopropyliV dene-, 311 &D-Xyloketofuranoside, a-mglucopyraValeric acid, 2,5-anhydro-5,5-diphenylnosyl-, 38, 73 2,3,4trihydroxy-, 289 heptaacetate, 73 -, %hydroxy-2-methyl-(~-erythro-3,4,5- D-Xyloketose, 37 trimethoxy)-, 289 cu-D-Xylopyranoside, methyl, 116, 130 methyl ester, 289 8-D-Xylopyranoside, methyl, 130 y-Valerolactone, a-methyl-, 269 a-D-Xylopyranosyl bromide, triacetyl-, Van't Hoff-LeBel theory, 291 66 Vicianose, 71 a-L-Xylopyranosyl bromide, triacetyl-, Vitamin Bz,137 66 135, 149, 160, 161 Vitamin BIZ, fl-D-Xylopyranosyldihydroxyacetone, Vitamin C (Ascorbic acid), synthesis of, 8 tetraacetyl-, 70 fl+Xylo pyranosyldihydroxyacetone, W tetraacetyl-, 70 D-Xylose, 88, 136, 314 Wohl-Zemplh degradation, 60 labeled with C14,310 cXylose, 2,4-beneylidene-, 302 A L-Xylosone, 8 Xanthylic acid, 157 Xanthosine, 149 Y synthesis of, 165 Xylan, 9, 122 Yeast nucleic acid, 137


ADVANCES IN CARBOHYDRATE CHEMISTRY Volume 1 C. S. HUDSON,The Fischer Cyanohydrin Synthesis and the Configurations of Higher-carbon Sugars and Alcohols. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 NELSONK. RICHTMYER, The Altrose Group of Substances PACSU, Carbohydrate Orthoesters . . . . . . . . . . . . . . EUQENE ALBERTL. RAYMOND, Thio- and Seleno-Sugars.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 ROBERTC. ELDERFIELD, The Carbohydrate Components of the Cardiac Gly147 cosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C. JELLEFF CARRand JOHN C. KRANTZ, JR.,Metabolism of the Sugar Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 and Their Derivativ R. STUART TIPSON,The istry of the Nucleic Acids.. . . . . . . . . . . . . . . . . . . . . 193 THOMAS JOHN SCHOCH, The Fractionation of Starch.. 247 ROYL. WHISTLER, Preparation and Properties of Star . . . . . . . . . . . . . . . 279 CHARLES R. FORDYCE, Cellulose Esters of Organic Aci 309 ERNESTANDERSONand LILA SANDS, A Discussion o Research on Plant Polyuronides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 329

Volume 2 C. S. HUDSON, Meleeitose and Turanose.. . . . . . . . . . . . . ......... 1 STANLEY PEAT,The Chemistry of Anhydro Sugars. . . . . F. SMITH,Analogs of Ascorbic Acid.. ...................................... 79 R. LESPIEAU,Synthesis of Hexitols and Pentitols from Unsaturated Polyhydric 107 Alcohols . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HARRYJ. DEUEL,JR. and MARQARET G. MOREHOUSE, The Interrelation of Carbohydrate and Fat Metabolism. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 119 M. STACEY, The Chemistry of Mucopolysaccharides and Mucoproteins. . . . . . . . . 161 TAYLOR H. EVANS and HAROLD HIBBERT,Bacterial Polysaccharides. . . . . . . . . . . 203 E. L. HIRSTand J. I(. N. JONES, The Chemistry of Pectic Materials.. . . . . . . . . . 235 EMMA J. MCDONALD, The Polyfructosans and Difructose Anhydrides . . . . 253 JOSEPH F. HASKINS, Cellulose Ethers of Industrial Significance. . . . . . . . . . . . . . . . 279

Volume 3 C. S. HUDSON, Historical Aspects of Emil Fischer’s Fundamental ‘Conventions for Writing Stereo-Formulas in a Plane. . . . . . . . . . . E. G. V. PERCIVAL, The Structure and Reactivity of the Derivatives of the Sugars.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . HEWITTG. FLETCHER, JR.,The Chemistry and Configuration of the Cyclitols. . BURCKHARDT HELFERICH, Trityl Ethers of Carbohydrates. . . . . . . . . . . . . . . . . . . . LOUISSATTLER,Glutose and the Unfermentable Reducing Substances in Cane Molasses.. ... ... ..... ..... JOHN W. GREEN,The Halogen Oxidation of Simple Carbohydrates, Excluding the Action of Periodic Acid.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441

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23 45 79

129

442

ADVANCES IN CARBOHYDRATE CHEMISTRY

COMPTON, The Molecular Constitution of Cellulose.. . . . . . . . . . . . . . . . . . . . SAMUEL GURIN,Isotopic Tracers in the Study of Carbohydrate Metaboliim. . . . KARLMYRB~~CK, Products of the Enzymic Degradation of Starch and Glycogen M. STACEY and P. W. KENT,The Polysacoharides of Mycobacterium tuberculosis R. U. LEMIEWand M. L. WOLFROM, The Chemistry of Streptomycin.. . . . . . . .

JACK

185 229 252 311 337

Volume 4

IRVING LEVI and CLIFFORDB. PURVES, The Structure and Configuration of Sucrose (Alpha-D-GlucopyranosylBeta-D-Fructofuranoside) . .. . . , , . . . . . . . . . . . . . .. .. . H. G. BRAYand M. STACEY, Blood Group Polysaccharides.. C. S. HUDSON, Apiose and the Glycosides of the Parsley Plant.. . . . . . . . . . . . . . . CARLNEWERQ,Biochemical Reductions at the Expense of Sugars.. . . . . . . . . . VENANCIO DEULOFEU, The Acylated Nitriles of Aldonio Acids and Their Degradation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ELWINE. HARRIS,Wood Saccharification ................ J. B~ESEKEN, The Use of Boric Acid for t the Configuration of Carbohydrates. . . ., ....................... ROLLAND LOHMAR and R. Derivatives.. . . . , , , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . J. K. N. JONES and F. SMITH,Plant Gums and Mucilages.. . . . . . . . . . L. F. WIQGINS,The Utilization of Sucrose.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

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1 37 57 75 119 153 189 211 293

Volume 6 HEWITTG. FLETCHER, JR.and NELSON K. RICHTMYER, Applications in the Carbohydrate Field of Reductive Desulfurization by Raney Nickel.. . . . . . . . . . W. Z. HASSIDand M. DOUDOROFF, Enzymatic Synthesis of Sucrose and Other Disaccharides. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ALFRED GOTTSCHALK, Principles Underlying Enzyme Specificity in the Domain of Carbohydrates.. ..... . . . . . . . . . . . . , . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Z. I. KERTESZ and R. J. MCCOLLOCH, Enzymes Acting on Pectic Substances. . . R. F. Nickerson, The Relative Crystallinity of Celluloses.. . . . . . . . . . . . . . . . . . . . G. R. DEANand J. B. GOTTFRIED, The Commercial Production of Crystalline Dextrose ..... . . . .. . . . . . , . . . . , . . . . . . . . . . . , . . . . , . . . . . . .. . . . . . . . . . . . . . E. J. BOURNE and STANLEY PEAT,The Methyl Ethers of D-G~UCOW. .. . . ... .. . L. F. WIGQINS,Anhydrides of the Pentitols and Hexitols.. . . . . . . . . . . . . . . . . . . . MARYL. CALDWELL and MILDREDADAMS,Action of Certain Alpha Amylases ROYL. WHISTLER, Xylan.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I

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29 49 79 103 127 145 191 229 269

Advances in Carbohydrate Chemistry, Volume 6

Advances in Carbohydrate Chemistry, Volume 6

ADVANCES IN CARBOHYDRATE CHEMISTRY