Advances in Carbohydrate Chemistry, Volume 6

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

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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

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

v

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

vii

Obituary of Walter Norman Haworth

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

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

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11 12 . 12 . 13 . 14 14 16

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The Synthesis of Oligosaccharides

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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. . . . . . . . .

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

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The Formation of Furan Compounds from Hexoses

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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

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83 84

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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

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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. . . . . . . . . . . , . . . . . . . . . . . . .

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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

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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

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

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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

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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

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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

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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

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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.

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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-

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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

WALTER NORMAN HAWORTH

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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

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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

WALTER NORMAN HAWORTH

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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

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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

WALTER NORMAN HAWORTH

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

This Page Intentionally Left Blank

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).

THE METHYL ETHERS O F D-GALACTOSE

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).

THE METHYL ETHERS O F D-GALACTOSE

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

THE METHYL ETHERS OF D-GALACTOSE

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

THE METHYL ETHERS OF D-GALACTOSE

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).

This Page Intentionally Left Blank

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

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

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).

THE SYNTHESIS O F OLIGOSACCHARIDES

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

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

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

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

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

THE SYNTHESIS OF OLIQOSACCHARIDES

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

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

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

THE SYNTHESIS O F OLIGOSACCHARIDES

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

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

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).

THE SYNTHESIS OF OLIGOSACCHARIDES

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).

THE SYNTHESIS OF OLIGOSACCHARIDES

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

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

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).

THE SYNTHESIS O F OLIGOSACCHARIDES

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).

THE SYNTHESIS OF OLIGOSACCHARIDES

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

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

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 SYNTHESIS OF OLIGOSACCHARIDES

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

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

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).

THE SYNTHESIS OF OLIQOSACCHARIDES

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

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

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<

/I

OAc

:: I

.H \

A\]i

H

c1

.kc

0

CHzOAc

where Ga indicates the galactosyl residue. The chlorine atom may be removed by shaking the heptaacetylneolactosyl chloride with silver carbonate in aqueous acetone to give the heptaacetate, which on deacetylation gives the free sugar. Cellobiose behaved in a similar fashion, - ~ - atrose. l * 49,1 giving celtrobiose, 4- (/3-~-glucopyranosyl) d. The Hydrogen Fluoride Rearrangement.-Another unexpected result was obtained by Braunslsl during his study of the preparation of acetylglycosyl fluorides when he discovered a method for converting 4-(P-Dglucopyranosy1)-D-glucose (cellobiose) into its epimeric form, 4-(P-Dglucopyranosy1)-D-mannose (epicellobiose). As a result of a prolonged treatment of the cellobiose octaacetate with anhydrous hydrogen fluoride at room temperature, the acetyl group on carbon 2 was removed and the resulting hydroxyl group was epimerized. The hexaacetyl-[4-(@-~(148) N.K.Richtmyer and C. S. Hudson, J . Am. Chem. Soc., 87, 1716 (1935). (149) C. S. Hudson, J . Am. Chem. SOC.,48, 2002 (1926). (150) N. K.Richtmyer and C. S. Hudson, J . Am. Chem. SOC.,68, 2534 (1936). (151) D.H. Brauns, J . Am. Chem. Soe., 48, 2776 (1926).

THE SYNTHESIS O F OLIGOSACCHARIDES

59

glucopyranosyl)-~-mannosyl]fluoride (hexaacetylepicellobiosyl fluoride) which was thus formed can be converted directly to the epicellobiose octaacetate, from which the free sugar may be obtained by deacetylation. e. The Pyridine Rearrangement.-The pyridine rearrangement may be thought of as a modification of the Lobry de Bruyn-Van Ekenstein rearrangement, with the pyridine acting as a mild alkali. It was first used to transform glyceraldehyde into dihydroxyacetone by simply boiling the former in the dry pyridine.'b2 The conversion was as high as 49 %, as measured by means of derivatives. This method was applied to oligosaccharides by Arnold and Evans.15s They refluxed 3-(tetraacetyl-P-D-glucopyranosy1)-glyceraldehydein pyridine and then acetylated the product. They isolated 8-9 % of the p-nitrophenylhydrazone of P-D-glucopyranosyl-dihydroxyacetonepentaacetate. Of the rearrangements discussed, the first two are quite general in scope. Not enough results have been reported to indicate whether this is true of the other methods or not. In all cases, except possibly the Bergmann-Schotte, one of the important problems t o overcome is the separation of the desired product from the by-products and a portion of the starting material that are present in the final reaction mixture. I n each case, the rearrangement is an equilibrium reaction although in a few cases the reaction goes practically to completion. f. The Ru$ Degradation.-There are many examples where the carbon chain of an oligosaccharide has been shortened by one carbon atom at a time. The Ruff degradation was developed from the observation of FentonIb4that tartaric acid was oxidized by hydrogen peroxide in the presence of ferrous salts. Ferric salts were not effective. Cross, Bevan and Smith'56 applied the reagent t o carbohydrates in an attempt to elucidate the mechanism for €he oxidation of carbohydrates in living organisms. ' Hydrogen peroxide alone had little effect but ferrous salts in traces caused the reaction t o proceed. Derivatives of osones were isolated from the mixture.156 A short time later found that calcium D-gluconate could be oxidized with hydrogen peroxide in the presence of basic ferric acetate as catalyst. D-Arabinose was isolated as its oxime, showing that a sugar with one less carbon atom was formed by the cleavage of the carbon-carbon bond. Later, the sugar was (152) (153) (154) (1896). (155) (156) (157)

H . 0. L. Fischer, C. Taube and E. Baer, Ber., 60, 479 (1927). H. W. Arnold and W. L. Evans, J. Am. Chem. SOC.,68, 1890 (1936). H. J. H. Fenton, Proc. Chem. Soc., 9, 113 (1893); J . Chem. SOC.,69, 546

C. F. Cross, E. J. Bevan and C. Smith, J . Chem. SOC.,73, 463 (1898). R. S. Morrell and J. M. Crofts, J . Chem. SOC.,83, 1284 (1903). 0. Ruff, Ber., 31, 1573 (1898); 34, 1362 (1901).

60

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

obtained in relatively pure form in 34-40% yieldlSs by this reaction. However, only 17 % of D-lyxose was obtained from calcium D-galactonate under the same conditions. Quite recently the method has been improved through the removal of ionized material from the reaction products by ion-absorbing resins, and D-lyxose was preparedlSs8in a yield equal to that obtained for D-arabinose, namely, about 46 %. The reaction was applied to disaccharides (see also page 64) by Ruff and Ollendorffll when they oxidized lactobionic acid to give 3-(p-~galactopyranosy1)-D-arabinose (see page 32). It was isolated as the phenylbenzylhydrazone, from which the free sugar was regenerated by treatment with formaldehyde. development of another g. The Wohl-Zemplh Degradation.-The degradation procedure, essentially the reverse of the cyanohydrin synthesis, was begun by W ~ h l .As ~ first ~ ~ carried out, D-glucose was converted to the oxime by treatment with hydroxylamine, and the oxime was converted on acetylation a t elevated temperatures with acetic anhydride and fused sodium acetate to the pentaacetyl-D-glucononitrile. The cyanide group of the nitrile could be removed by strong alkali, silver nitrate or ammoniacal silver nitrate t o yield the pentose, D-arabinose. The preferred methodlBOwas by the use of ammoniacal silver nitrate, which gives the diacetamide of the pentose as an intermediate. The acetamide is hydrolyzed by a strong acid such as sulfuric. The series of reactions may be illustrated as follows:

H-g=oc! H-

HO-

-OH-

I

H-C=NOH H-

HnNOH

-H

HO-

L L

-OH

AciO

NaOAc

-H

-HO-

b'-H 1

Diacetamide

-0Ac

b-H

Nilrile

H-C(NHCOCHa)* , Ag( NHI)i 0 H

L

H-

AcO-

Oxime I

D-GIucose

CN

H-C=O HOH Ha504

I D- A r a h o s e

Considerably later, Zemplbn continued the development of the method. He161sought to check by degradation the structure of cellobiose wh ch had been suggested not long before by Haworth and cowork(158) R. C. Hockett and C. S. Hudson, J . Am. Chem. SOC.,66, 1632 (1934). (158a) H. G.Fletcher, Jr., H. W. Diehl and C. S. Hudson, J . Am. Chem. Soc., 72, 4546 (1950). (169) A. Wohl, Ber., 26, 730 (1893). (160) A. Wohl, Ber., S2, 3666 (1899). (161) G. Zemplh, Ber., 69, 1254 (1926).

THE SYNTHESIS O F OLIOOSACCHARIDES

61

ers.lB2 The method of Ruff had a number of side reactions which made the isolation of the final product difficult. The hydrolysis step with strong acid in Wohl's procedure would also hydrolyze the linkage between the two units of the disaccharide. Zemplh found that catalytic amounts of sodium alcoholates would saponify the nitrile group as well as the acetyl groups (see page 45). The resulting cyanide group was removed from the reaction mixture by precjpitation with silver acetate in acetic acid. Since the acetates are usually more easily crystallized than the free sugars, the latter were usually acetylated before they were isolated from the reaction mixture. ZemplBn'61 degraded cellobiose and isolated which, when three heptaacetates of 3-(~-~-glucopyranosyl)-~-arabinose saponified by sodium methylate, yielded the same 3-(/3-~-glucopyranosyl)D-arabinose. The octaacetylcellobioseantioxime also was isolated during the preparation. Only one form of the oxime, the syn, is dehydrated to the nitrile, a factor which cuts the yield somewhat. However, 50% of the theoretical amount of the cellobionic nitrile was obtained and this gave 80 yo of the theoretical amount of the 3-(/3-~-glucopyranosyl)D-arabinose. The latter compound was treated again by the WohlZemplBn procedure to give the 2-(~-~-g~ucopyranosyl)-~-erythrose. The latter compound could not be converted into an osazone although it would form a hydrazone. On this basis, Zemplh assumed that the structure proposed by Haworth was correct, since, if the hydroxyl group on carbon 2 of the erythrose section was blocked by the glycosidic union, it could not form an osazone. Negative evidence of this type may lead to wrong conclusions, however, especially if not based on crystalline materials. For example, ZemplBn16S attempted to degrade syrupy melibiose in the same manner. He was not able to isolate the 5 - ( a - ~ galactopyranosy1)-D-arabinoseformed nor its osazone, although hydrolysis gave a mixture of arabinose and glucose. On this basis, Zempldn assumed that the union in melibiose was in the 3 position of the original D-glucose unit. Later, it was shown that the union was actually in the 6 position.ls4 Zemplen also degraded lactosel66 and maltose166in the same manner as cellobiose. He repeated the work of Ruff and Ollendorff" and obtained the same compound from calcium lactohionate by oxidation as he obtained from lactose by his method. He reported, however, that the isolation was much more difficult from the lact,obionate. (162) W. Charlton, W. N. Haworth and S. Peat, J . Chem. Soc., 129,89 (1926): E. L. Hirst, ibid., 129, 350 (1926). (163) G. Zemplbn, Ber., 60, 923 (1927). (164) W. N. Haworth, J. V. Loach and C. W. Long, J . Chem. Soc., 3146 (1927). (165) G. Zemplbn, Ber., 69, 2402 (1926); 60, 1309 (1927). (166) G. Zemplbn, Ber., 60, 1555 (1927).

62

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

In a similar manner, GakhokidzeKO converted 2-(P-~-glucopyranosyl)D-glucose into a 8-D-glucopyranosyl D-arabinoside heptaacetate, lB7and (page 40) in two steps into similarly his 3-(~-glucopyranosyl)-~-glucose the corresponding D-glucopyranosyl D-erythroside.61 MacDonald and Evans16*have obtained an unusual pentose derivative by degrading gentiobiose by the Zemplh procedure to give ~-(P-Dglucopyranosy1)-D-arabinofuranose. This rather unusual straight-chain disaccharide theoretically should contain within its structure a furanoid ring in the pentose section of its molecule and a pyranoid ring in its hexose portion. Most of the known oligosaccharides having less than twelve carbon atoms, have the hexose portion of their molecules as sidechain derivatives. h. The Degradation by Oxidation of Glyca1s.-The glycals contain a double bond which may be cleaved by suitable oxidation methods t o give an aldehyde group a t the carbon atom which was next to the double bond in the original glycal. Thus a new monosaccharide unit would be formed which would contain a smaller number of carbon atoms than the original glycal unit. During their study of the properties of D-glucal, Fischer, Bergmann and SchottelBgtreated the compound with ozone in order to determine the position of the double bond. The main product was D-arabonic acid acetate when the triacetyl-D-glucal was ozonized in glacial acetic acid. Small amounts of D-arabinose were isolated as the hydrazone. In connection with an attempt to prepare aldehydo sugars, the ozonization of triacetylglucal was repeated by Hurd and Fi1a~hione.l~~ They had hoped to obtain a 2,3,5-triacetyl-4-formyl-aldehydo-~-arabinose but not only was the formate group removed but an acetate radical as well during the process of heating with water to hydrolyze the ozonide. Evidence was found that both formic and acetic acids were present in the final reaction mixture as well as a mixture of di- and triacetylarabinose. In their work on diacetyl-L-arabinal, Felton and Freudenbergl'l were in a pure state. not able to obtain the expected 2,3-diacetyl-~-erythrose From the product of the ozonization of the unesterified L-arabinal, however, they did prepare a sirup which gave positive tests for the presence of the dimethylacetal of 4-formyl-aldehydo-~-erythrose. The (167) This wasyreported as anzoctaacetatezbut the structural formula given and the analysis agreed for the heptaacetate. (168) N. S. MacDonald and W. L. Evans, J . Am. Chem. SOC.,64, 2731 (1942). (169) E. Fischer, M. Bergmann and H. Schotte, Ber., 63, 509 (1920). (170) C. D. Hurd and E. M. Filachione, J . Am. Chem. SOC.,61, 1156 (1939). (171) G. E. Felton and W. Freudenberg, J . Am. Chem. SOC.,67, 1637 (1935).

63

THE SYNTHESIS OF OLIGOSACCHARIDES

reactions involved in the usual ozonization may be illustrated as follows:172 CHzOAc

CHZOAC

-+

Ac

I

H

r

/\H

H

Triacetylglucal

1

YHO

IHi;-;!-HJ AcOCH

I

HCO*c

0

-+

H/i-og I\

AcO

\I

OAc

i0/O

-+H10.

Zn

- HaOr

H H Ozonide

Diacetyl-D-arabinose, HCOOH, and Triacetyl-D-arabinose

u-Arabinose triacetate forrnate

I n order to prevent the oxidation of the aldehyde groups to the acids, it is necessary to use some means t o remove the hydrogen peroxide formed during the hydrolysis of the ozonide. Hurd and Filachione170 carried out the hydrolysis in pyruvic acid. Other w ~ r k e r have ~ ~ ~ ~ - ~ ~ used zinc dust in this step, and hydrogenation with platinum as a catalyst177 has been mentioned in connection with hydrocarbons. The reaction was applied to the oligosaccharide series by Gakhokidze. He converted heptaacetyllactosyl bromide into 3-(/3-~-galactopyranosyl)n-arabinose with an overall yield of 33% of theory.17a The hexaacetyllactal was ozonized in glacial acetic acid and treated with zinc dust to give 70% of 3-(/3-D-galactopyranosy1)-~-arabinosehexaacetate, which was saponified to give 87 % of 3-(/3-~-galactopyranosyl)-~-arabinose. In the same way, cellobiose was converted into 3-(/3-~-glucopyranosyl)~ - a r a b i n o s e , maltose ~~~,~~ into ~ 3-(a-~-glucopyranosy~)-~-arabinose~~~~~~~ and 3-(a?-~-glucopyranosyl)-~-glucoseinto 2-(a?-~-glucopyranosyl)-~a r a b i n ~ s e '(isolated ~~ as the calcium salt of the acid). (172) For a general discussion of ozonolysis see A. L. Henne and P. Hill, J. A m . Chem. Soc., 68, 752 (1943). (173) A. M.Gakhokidze, J. Gen. Chem. ( U . S. S. R . ) , 16, 1907 (1946). (174) A. M.Gakhokidze, J. Gen. Chem. ( U . S . S. R.),16, 1914 (1946). (175) A. M.Gakhokidze, J . Gen. Chem. ( U . S. S. R.),18, 60 (1948). (176) A. M.Gakhokidze, Zhur. Obschchd Khim. (J.Gen. Chem.), 19,2082(1949). (177) Ref. 63, p. 67. (178) The [a]'', value for the intermediate hexaacety~-[3-(~-~-glucopyranosyl)u-arabinose] is given as 54.0' in Chem. Abstracts, 41,6209~(1948),instead of the value -554.0' in the paper. (179) According to an unsupported statement in connection with this work,*76 2-desoxy-maltose was converted into hexaacetyl-2-desoxy-cellobiose.

64

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

In connection with some studies on the structures of disaccharides, Gakhokidze has reported the oxidation of several glycals with alkaline permanganate. The oxidation gave the corresponding acid with one less carbon atom, which waa treated by essentially the Ruff degradation (page 59) to give finally a sugar with two carbons less than the starting material. The reactions were first used to check on the structure18oof the 3-(~-glucosyl)-~-glucose, which he had synthesized previously (see page 40). The octaacetate was converted in 78% yield into the acetylglycosyl halide, which gave 80 % of the hexaacetyl glycal. Saponification gave 79 % of the glycal itself, 3-(~-glucopyranosyl)-~-glucal.The glycal was dissolved in water and after the addition of a solution of potassium hydroxide, was treated with potassium permanganate until discoloration of the solution stopped. The acid was precipitated as the lead salt, which, after filtering and washing, was decomposed by hydrogen sulfide. The acid was then converted into the calcium salt by boiling with calcium carbonate. The amorphous calcium salt of 2-(~-glucopyranosyl)-~arabonate was obtained in 68% yield. After methylation, followed by hydrolysis, the calcium 3,4,5-trimethyl-~-arabonate was oxidized by hydrogen peroxide in the presence of ferric acetate. The D-erythrose derivative was isolated as the calcium salt after oxidation with bromine water. This product showed that the union in the original compound was connected to the 3 position of the D-glucose which underwent degradation. The reactions were first used to prepare an actual oligosaccharide when malta1181was oxidized with potassium permanganate in the same way to give 60% of theory of calcium 3-(c~-~-glucopyranosyl)D-arabonate. This product was boiled in water with barium carbonate and ferric sulfate and, after filtration and cooling, was treated with 30% hydrogen peroxide to give 79 % of 2-(c~-~-glucopyranosyl)-~-erythrose. LactoselS2and cellobiose"J3 were treated in essentially the same manner to give the corresponding erythrose derivatives. The reactions may be illustrated as follows: COOH

CHzOH

-

CaCOa

\ *GO \//

I

H H

AH

\H 'H

CHIOH

Glycal * G = glucosyl or galactosyl residue (180) (181) (182) (183)

A. A. A. A.

M. M. M. M.

Gakhokidze, Gakhokidze, Gakhokidze, Gakhokidee,

(Acid)

Zhur. Obshchd Khim. Zhur. ObshcheZ Khim. Zhur. 06shcheZ Khim. Zhur. Obshchd Khim.

( J . Gen. Chem.), 19, 2100 (1949). ( J . Gen. Chem.), 20, 116 (1950). ( J . Gen. Chem.), 20, 120 (1950). ( J . Gen. Chem.), 20, 289 (1950).

T H E SYNTHESIS O F OLIGOSACCHARIDES

65

CHO

-

HAOG

Fef++

HAOH

Ha01

hHeOH Erythrose derivative

IV. CONCLUSION The more useful reactions for the synthesis of oligosaccharides have been those which led to definite products and the most valuable has been the Koenigs-Knorr. Its value would be increased however if the alpha linkage were easier to obtain and if intermediates which had their active centers at other positions than the glycosyl and primary carbon atoms were more easily and generally obtainable. Rearrangements, especially the Bergmann-Schotte, have proved useful but here again the reactions are limited by the availability of the starting materials. The degradations by the Wohl-ZempltSn procedure and by oxidation are generally applicable but have not been used to a large extent, probably because few of the compounds produced exist in nature. One great difficulty in carrying out all the types of synthesis, in common with most organic chemical reactions, is that they do not go to completion and give only one definite chemical individual. I n most cases in the past, workers have depended upon crystallization to isolate and purify the product wanted. Other substances present, unused reactants and by-products, interfere with this process. Also in the case of new compounds one does not have seed crystals available to be used as nuclei. Later workers have used chromatographic methods184quite successfully for isolating the products. One has a much better chance of obtaining seed crystals from the purified material than directly from the reaction product. Once seed are obtained, crystallization methods may be used to isolate larger quantities of material. In order to extend the usefulness of this review to workers in the field, lists are given of the glycosyl halides and alcohol compounds which have been used for the synthesis of oligosaccharides, as well as the products obtained. The yields given are usually those of the first material isolated while the properties are those of the purified sample. (184) For a review of methods as applied to carbohydrates see W. W. Binkley and M. L. Wolfrom, I ‘ Chromatography of Sugars and Related Substances,” Sugar Research Foundation, Inc. (New York), Scienti3c Reports Ser., No. 10,33pp., August (1948). For more general reviews, see “Chromatographic Analysis,” Discussions of the Faraday Society, No. 7, 336 pp. (1949) and “Partition Chromatography,” R. T. Williams and R. L. M. Synge, editors, Biochemical Society Symposia, No. 3, Cambridge University Press, Cambridge, 103 pp. (1950).

V. TABLEOF GLYCOSYL HALIDES

aa

Q,

Substance Triacetyl-8-D-arabinopyranosylbromide Triacetyl-8-L-arabinopyranosylbromide Triacetyl-a-L-rhamnopyranosylbromide Triacetyl-a-D-ribosyl bromide Triacetyl-a-L-ribosyl bromide Triacetyl-a-D-xylopyranosylbromide Triacetyl-a-L-xylopyranosyl bromide Tetraacetyl-a-D-gdactopyranosyl bromide Tetraacetyl-a-D-glucopyranosylbromide Tetraacetyl-8-D-glucopyranosyl fluoride 2,3:5,6iisopropylidenea-~-manoofuranosyl chloride Tetraacetyl-a-D-mannopyranosylbromide Heptaacetyl-a-cellobiosyl bromide Heptaacetyl-a-gentiobiosyl bromide Heptaacetyl-a-lactosyl bromide Heptaacetyl-a-maltosyl bromide ~eptaace~y~-[~(&~-g~ucopyranosy~)-a-~-mannopyranosy~] bromide ~eptaacety~-[6(~-~-ma~opyranosy~)-a-~-g~ucopyranosy~] bromide Decaacetyl-[6(~-cellobiosyl)-a-~~lucopyranosyl] bromide ~caacetyl-[6(&gentiobiosy~)-a-~-glucopyranosy~] bromide Decaacetyl-[6-(&~actosyl)-a-~-g~ucopyranosy~] bromide

Melting point, "C.

139 138-139 71-72 94.5-95.5 94.5-95.5 101-102 102 84-85 88-89 86 119 @.p. 0.1) 62 182 144 145 (d.), 144 112-113 168-169 172.0-172.5 209, 205 (d.) 193-194 138-142

in CHCll (e 5)

[a]~20--2~

-283.4" +287.1, +283.6 -169 (c, 12 in CtH9Clr) -223.9 +224.8 +211.9 -211.6 +217 (+242 in CsHe) +197.8 +21 (t, 18") +85.7 +131.6 +94.5, +95.8 +lo1 .l +108.7, +107.4 +180.1 +78.0 +151.5 (t, 30') +63.8, 69.91 +63.3. (t, 17')

-

References

185 185, 186 187 112 112 188, 189 105 25 188 59a 190 191 151, 174 192 145, 173 175, 193 25 79 98, 117 194 195

(185) M. Gehrke and F. X. Aichner, Ber., 60,918 (1927). (186)D.H.Brauns, J. Am. Chem. SOC.,46, 1484 (1924). (187)E. Fischer, M. Bergmann and A. &be, Ber., 63, 2362 (1920). (188) D.H. Brauns, J. Am. Chem. SOC.,47, 1280 (1925). (189) C. S. Hudson and J. M. Johnson, J . Am. Chem. SOC.,37, 2748 (1915). (190)I(. Freudenberg and A. Wolf, Ber., 60,232 (1927). (191) D. H. Brauns, Bur. Standasds J. Research, 7 , 573 (1931). (192) D.H. Brauns, J. Am. Chem. Soe., 49,3170 (1927). (193) D.H. Brauns, J. Am. Chem. SOC.,61, 1820 (1929). (194) B. Helferich and R. Gootz, Ber., 64, 109 (1931). (195) K. Miescher and C. Meystre, Helu. Chim. A h , 26, 224 (1943).

r

r M

<

*

-5

U

P 4

3p p

5 m

'P

? 2

VI. TABLEOF COMPOUNDS OF ALCOHOLIC TYPE Substance Dihydroxyaeetonemonoacetate Glyceraldehydedibenzylcycloacetal 2,3:4,5-Dibenzylidene-~-fructopyranose 2,3:4,5-Dikopropylidene-~-fructopyranose

3,4,5,6-Tetraacetyl-keto-~-fructose 1,2:3,4Diisopropylidene-a-~-galactopyranose 2,3,4-Triacetyl-a-~-galactopyranosylchloride 1 2:5,6-Diisopropylidene-oc-~-glucofuranose

80-82 (b.p. 0.3) 109-110 160 96-97 112 131-139 (b.p. 0 . 5 ) 132 110-111

1,2-Isopropylidene-5,6anhydro-a-~-glucofuranose 133.5 1,2-Isopropylidene-3,5-benzylidene-a-~-glucofuranose 149 4,6-Benzylidene-~-glucose 188 1,2-Isopropylidene-4,6-benzy~dene-~i-~-gluco152-153 pyranose 1,2-Isopropylidene-5,6-ben~ylidene-a-~-glucofuranose 146-148 1,2-1sopropylidene-6-desoxy-wglucofuranose 95 Methyl 4,6-benzylidene-cu-~~glucopyranoside 164-165 Methyl 2,3,4triacetyl-~~-glucopyranoside 134.Ck134.5 Methyl 2,3,4-tribenzoyl-~~-glucopyranoside 143 Methyl 2,3,6-trimethyl-&~-glucopyranoside 59-60 1,2,3,4-Tetraacetyl-a-~-glucopyranose 102-103 1,2,3,4Tetracetyl-j3-~-gIucopyranose

128-129

' C

<5.

Rotation solvent"

Melting point, "C.

-

References

-22.9" -33.0 (t, 30") +51.0 -60.9 +207.8 - 18.3( t , 19")

CHC13 HzO CHCl3 CzHzCL CHCL 0 H2

196 197 198,199 200,201 198,202,203 88a, 204 205 206

-26.5

HzO

207,208

+23.4 - 4 . 0 (final)

CHCla MeOH

209 51,210

+25.8

CHCIs

51

+21.8 -26.3 +117.5 -19.1 +131.4 (t, 17") -47.5 +119 ( t , 26")

CHCla CHCls CHCls CHCla CsHiN CHCla CHCls CHCla Hz0

211 212 213,214 215,216 217,218 115,219 114 23,100

VI. TABLEOF COMPOUNDS OF ALCOHOLIC TYPE(Continued) Melting point,

Substance

solvent

1,2,3,6-Tetraacetyl-p-~-glucopyranose 1,3,4,6-Tetraacetyl-~~-glucopyanose 2,3,4,6-Tetraacetyl-or-~glucopyranose 2,3,4,6-Tetraacetyl-p-~-glucopyranose 2,3,4Triacetyl-a-~-glucopyranosylchloride 3,4,6-Triacetyl-p-~-glucopyranosyl chloride 1,6-Anhydro-2,3-isopropyiidene-~-mamopyranose 2,3 :5,6-Diisopropylidene-~-mamofwanose

1,2,3,4Tetraacetyl-p-~-mmnopyranose

[a]D20--28

134 138 112.5-113, 99-1W 137.5-138 124-125 158 (d.) 161-162

I

:::.5-136.5

-30.2

+189.2 (t, 19") +24.6 (t, 15')

Hz0 CHCl3 CHCls CHCls EtOAc

220 50 51, 221 22 1 98 50, 222

-58.8 +38.4 (t, 14") ---* -5.6 (1hr)+ + 1 . 1 -22.5

HzO Acetone H20 CHClj

24 223

-

+134.8 +14.8 (t, 18')

~~

b

References-

Dimorphous.

(196) H. 0. L. Fischer, E. Baer and L. Feldmann, Ber., 63, 1732 (1930). (197) H. 0. L. Fischer and E. Baer, Ber., 66, 337 (1932). (198) P. Brigl and R. Schinle, Ber., 66, 325 (1933). (199) P. Brigl and 0. Widmaier, Ber., 69, 1219 (1936). (200) E. Pacsu, E. J. Wilson, Jr., andL. Graf, J. Am. Chem. SOC.,61,2675 (1939). (201) See M. L. Wolfrom, W. L. Shilling and W. W. Binkley, J . Am. Chem. SOC., 72, 4544 (1950). (202) B. Helferich and H. Bredereck with Irmgard Modrow, Ann., 466,177 (1928). (203) E. Pacsu and F. V. Rich, J. Am. Chem. SOC.,64, 1697 (1932) and 66, 3018 (1933). (204) K. Freudenberg and R. M. &on, Ber., 66, 2119 (1923). (205) G. Zemplhn, A. Gerecs and H. Flesch, Ber., 71, 774 (1938). (206) E. Fischer and Charlotte Rund, Ber., 49, 93 (1916).

224,225

(207) H. Ohle and L. v. Vargha, Ber., 62, 2435 (1929). (208) K. Freudenberg, H. Toepffer and S. H. Zaheer, Ber., 63, 1966 (1930). (209) P. Brigl and H. Griiner, Ber., 66, 1428 (1932). (210) L. Zervas, Ber., 64, 2289 (1931). (211) P. A. Levene and A. L. Raymond, Ber., 66,384 (1933). (212) K. Freudenberg, H. Eich, Claudia Knoevenagel and W. Westphal, Ber., 71, 441 (1940). (213) D. S. Mathers and G. J. Robertson, J. Chena. SOC.,696 (1933). (214) K. Freudenberg, H. Toepffer and C. C. Andersen, Ber., 61, 1750 (1928). (215) J. W. H. Oldham, J. Chem. Soc., 127, 2840 (1925). (216) G. Zemplb and Z. CsiirGs, Ber., 62, 993 (1929). (217) B. Helferich, W. Klein and W. Schiifer, Ann., 447, 19 (1926). (218) B. Helferich and Johanna Becker, Ann., 440, 1 (1924). (219) J. W. H. Oldham, J. Am. Chem. Soc., 66, 1360 (1934). (220) B. Helferich and W. Klein, Ann. 466, 173 (1927). (221) A. Georg, Helu. Chim. Ada, 16, 924 (1932). (222) P. Brigl, 2.physiol. Chem., 116, 1 (1921). (223) J. C. Irvine and A. F. Skinner, J. Chem. SOC.,1089 (1926). (224) B. Helferich and J. F. Leete, Ber., 62, 1549 (1929). (225) D. D. Reynolds and W. L. Evans, J. Am. Chem. SOC.,62, 66 (1940).

0 4

VII. TABLEOF Substance Tetraacetyl-a-D-arabinopyranosyldihydroxyacetone Tetraacetyl-cr-carabinopyranosyldihydroxyacetone Tetraacetyl-a-Dbarabinopyranosyldihy . droxyacetone Triacet yl-3-a-carabinopyranosylgly ceraldehydedibenzylcycloaeetal 3,4Diacetyl-~-ribopyranose1,2-(3'-aeetoxyacetonyl) orthoacetate 3,4Diacetyl-~-ribopyranose1,2-(3'-acetoxyacetonyl) orthoacetate 3,4Diacetyl-~~-ribopyranose 1,2-(3'-acetoxyacetonyl) orthoacetate Tetraacety 1-&wxylopyranosyldihydroxyacetone Tetraacet yl-,f?-cxylopyranosyldihydroxyacetone Pentaacet yl-8-D-glucopyranosyldihy droxyacetone Tetraacetyl-3-&~-glucopyranosylglyceraldehydedibenzylcycloacetal %(&D-Galactopyranosyl)-D-erythrose Hexaacetyl-[2- (@-galactopyranosyl)-~erythrose] 2- (a-wGlucopyranosy1)-werythrose

I

OLIGOSACCHARIDEG

Rotation solvent

Melting point, "C.

YieW %

'

References

102

+9.04"

CHCla

32

105

102

-9.07

CHCla

33

105

116

+o.o

CHC13

142-143

+4.2

CHC13

7

153

97-98

-11.6

CHCls

20

65, 112

97-98

+11.8

CHCL

20

65, 112

124.5-125.0

kO.0

CHCI,

117

-60.3

CHCI,

33

105

117

+60.2

CHC13

20

105

103

-25.2 (t, 18")

CHC13

46

105, 153

172-173 154-155

-19.9 +22.5 (final?)

CHC13 H2 0

50 60

153 165, 182

138-140 141

+87.5 (final?)

-

-

-

-

H2

0

79

105

112

182 181

Hexaacetyl-[%(a-D-ghcopyranosyl)-Derythrose]

2-(p-D-Glucopyranosyl)-D-erythrose

I 127 149-150

Hexaacetyl-[%(&D-ghcopyranosyl)-Derythrose] 128-131 Hexaacetyl- (a?-~-glucopyranosy1 D-erythroside) 148 Heptaacetyl-[B-(a-L-arabinopyranosyl)-,3-~glucopyranose] 158-159 6-(a-~-Arabinopyranosyl)-a-~-glucose (Vicianose) 210 (d.)

Hexaacetyl-[6-(8-L-rhamnopyranosy1)-a-~galact~pyranosyl]chloride 166.5-167.5 Methyl hexaacetyl-[6-(8-crhamnopyranosyl)-L3-~-galactopyranoside] (Robinobiose derivative) 161.5-162.5 Hexaacetyl-[6-(&~-rhamnopyranosyl)-~-~glucopyranosyl] chloride 150.&151 Heptaacetyl-[&(@-crhamnopyranosyl)-j3-Dglucopyranose] (Rutinose heptaacetate) 16&169 Methyl hexaacetyl-[6-(8-~rharnnopyranosyl)-&D-glucopyranoside] 139.5-140 Heptaacetyl-16-(/h-xylopyranosyl)-&Dglucopyranose] 2 16-217 6-(p-D-Xylopyranosyl)-a-D-glucose(aPrimeverose) 208 Hexaacetyl-[6-(,?-D-xylopyranosyl)-a-Dglucopyranosyl] chloride 19Ck192 3- (Tetraacety~-~-~-galactopyranosyl)-2,4diacety1-D-arabinose 154

$36.8 (final?)

H20

f9.4

-

181 183

-

-

183

-

-

51

CHCla

+56.6(10min.) (t, 140)

+

+40.5

58

34

93, 226

-

HzO

e

3

93

%z

205

E

m

+67.6

CHCL

-39.21 (t, lio)

CHC1,

31

205

f65.88

CHCl3

60

227

0 0 rn

-29.66

CHCl,

69

227

d d

-45.91

CHCla

-

-26.2

CHCl,

22, 57

226, 228

HzO

40

228

f70.8

CHClj

50

229

-80.8

EtOH

70

173

15

0

+23.8+

-3.4

(.

227

r

0

E Y

+X z! ti Fi.

2

VII. TABLEOF OLIGOSACCHARIDES (Continued) Substance

Melting point, "C.

3- (B-D-Galactopyranosyl)-Ct-warabinose 166-168 (d.) Heptaacetyl-pwglucopyranosyl D-arabinoside] 168-180 a-D-Glucopyranosyl &L-araboketofuranoside Heptaacetyl-[2-(wglucopyranosy1)-earabinose] 139 2-(Tetraacetyl-a?-~-glucopyranosyl)diacetyl-warabinose 142 3-(a-D-Glucopyranosyl)-~rabinopyranose dihydrah 3-(Tetra,acetyl-~t-~-glucopyranosyl)-2,Pdiacetyl-D-arabmose 153 172 3-(a-D-Glucopyranosy1)-warabinose (A) Heptaacetyl-[3-(&wglucopyranosyl)-w 196 arabinose] (B) Eeptaacetyl-[3-(~wglucopyranosyl)-D157-161 arabinoze] (C) Heptaacetyl-[3- (fi-wglucopyranosyl)-Darabinose] 105.5-106.0 3- (Tetraacetyl-&~-glucopyranosyl)-2,4159 diacetyl-D-arabinopyranose 161 b(&D-Glucopyranosyl)-Darabinose (A) Heptaacetyl-[&(B-D-glucopyranosyl)-w arabinofuranose] 161-162 (B)Heptaacetyl-[5-(~-~-glucopyranosyl)-w !32-133 arabinofuranose]

[(I]DZ0-"

-50.3-

-63.1 (t, 19")

-21.5 (t, 19")

-

-

Rotation solvent

Yieldc %

References

HzO

11, 165, 173

CHC18 -

50 42

-

51

f25.8

CHCl,

176

+156 (final?)

H2Q

43

-42, f16.5 (final?)

CHCls Hz0

175 166, 175

-16.95 (t, 16")

CHC1.q

161

-50.25 (t, 16")

CHCla

161

4-12.0(t, 16")

CHCli

161

-54.0 -90.4

-

174 161, 174

-14.4

CHCla

168

t23.1

CHClr

168

a-D-Glucopyranosyl &r+xyloketofuranoside 156-157 Heptaacetyl-[a-D-glucopyranosyl 8-Dxyloketofuranoside] 180-181 Heptaacetyl-[C (SD-galactopyranosyl)-a-Daltrosyl] chloride 182 (d.) Octaacetyl-[P (,%+galactopyranosyl)-a-Daltropyranose] 178 Octaacetyl-[4-(Swgalactopyranosyl)-~Daltropyranose] 148 4-(Tetraacetyl-&wgalactopyranosyl)-2,3,6triacetyl-pwal tropyranose 135-136 4-(&wGalactopyranosyl)-waltrose (Neolactose) 190 (d.) P(&DGalactopyranosyl)-a-Dfructose (Lactulose) 158 6-(Tetraacetyl-&~-galactopyranosyl)-l,2:3, 4-diisopropylidene-a-D-galactopyranose 101-102 6-(&~-Galactopyranosyl)-&~-galactose Octaacetyl-[D-galactosyl ~-gahctoside] 82-83,85 DGalactosyl n-galactoside 110 (d.) Octaacetyl-[4- (B-D-galactopyranosyl)-p-Dglucopyranose] 8SYO 4-(fl-wGalactopyrsnosyl)-n-D-glucosemonohydrate (Lactose) 202 (d.) Octaaeetyl-[6-(n-D-galactopyranosyl)-j3-~glucopyranose] (Melibiose) 172-173, 1 7 i Octaacetyl-[6-(fl-&galactopyranosyl)-p-Dglucopyranose] 166 6-(8-~-Galactopyranosy1)-a-~-glucose (Allolactose) 174-176 (d.) ~~

c

~

~

HzO

+22

CHCG

59

40

+71.2

CHCls

33-45

147, 148

f53.4

CHCln

147

-7.1

CHClz

147

+10.0+

+21.0

+35.5 (final) -23.8(2 &.)

+ -51.5

€190

E

-4.5

+52.7

+97.2, +102.5

Overall yield.

230 230 49,59a 59a

CHCls

58

25

H20

27, 8d

25

CHCl,

0.0 +54.2(5 min.) + +30.7

10-15

18,50 -

+

d

e

CHCL

8') -44.7 (t, 1 +23.2+ +34.1 (t, 17") +51.7, +58 56

+81+

40

HzO

~~

As first isolated from the previously isolated derivative.

-

+43

93, 231 70

HzO

94,95 95

0

E: 0

f

d 0

X P

EU 2!

VII. TABLE OF OLIGOSACCHARIDES (Continued) Substance

Melting point, "C.

6-(1,2:3,4Diisopropylidene-~~-~-galactose) 3-(1,2:5,6-diisopropylidenea-~-g1ucose) ether 220 (b.p. 0.2 mm) 1,6-Anhydro-2,3-diacetyl-4-(tetraacetyl-p-~galactopyranosy1)-wmannopyranose 193-194 Octaacetyl-[P (&D-galactopyranosyl)-a-~mannopyranose] 96-97 4(p-D-Galactopyranosyl)-a-D-mannose (a-Epilactose) 150-160 (hydrate) P(&D-Galactopyranosyl)-&wmannose (&Epilactose) 195-196 Heptaacetyl-[4- (&wglucopyranosyl)-a+altropyranosyl] chloride 141-142 Octaacetyl-[C(&D-glucopyranosyl)-a-Daltropyranose] 129-130, 112b Octaacetyl-[4 (&wglucopyranosyl)-p-Daltropyranose] 103-105, 113-114b 4-(&wGlucopyranosyl)-waltrose monohydrate (Celtrobiose) 133-148 Octaacetyl-(a-wglucopyranosyl B-wfructofuranoside) 69-70, 89* a-D-Glucopyranosyl 8-D-fructofuranoside (Sucrose) 183-184 Octaacetyl-[p-D-glucopyranosyl a-Do-fructofuranoside] (?) 131-132 p-D-Glucopyranosyl a-D-fructofuranoside (?) (Isosucrose) 194 (d.)

[(I]D20--25

Rotation solvent

Yield. %

References

-74 (t, 18")

CHCla

4

-62.7

CHC13

25

+41.2

CHCla

25

+38+

+27

HzO

232

+17+

+27

HzO

25, 140

+64.2

CHCla

149, 150

+48.0

CHCl,

150

-13.0

CHClo

150

+13.6

H2 0

150

+60

CHCla

26, 234

+66.5

HzO

26, 234

+20.4 (t, 27')

CHCla

21, 233

+34.2

Hz0

233

Octaacetyl-[1-@-wglucopyranosy1)-wfructose] 129 l-(Tetraacetyl-~-~-glucopyranosyl)-2,3 :4,sdibenzylideneD-fructpyranose 143-144 1-(~-wGlucopyranosyl)-2,3:4,5dibenzylidene-D-fructopyranose 166-176 1-(Tetraacetyl-,9-~-glucopyranosyl)-2,3 :4,sdiisopropylidene-D-fructopyranose 162-163 1-(p-~-Glucopyranosyl)-2,3 :4,5-&isopropyfidene-D-fructopyranose 174-175 1-(8-D-Glucopyranosyl)-D-kebfructose dihydrate 132-135 1,2:3,4-Diisopropylidene-6-(tetraacetyl-8-Dglucopyranosy1)-a-Dgalactopyranose 141 1,2:3,4-Diisopropylidene-6-(p-~-glucopyranosy1)-a-D-galactopyranose 84-88 6-(p-~-Ghcopyranosyl)-~-wgalactose cryst. Octaacetyl-[a (?)-wglucopyranosyl p( ?)-Dglucopyranoside] 68-70,120 a(?)-wGlucopyranosy1 @(?)-D-glucopyranoside (Neotrehalose) 85,80 (Tetraacetyl-~-glucopyranosyl)-3,4,6-triacetyl-D-ghcopyranoside 155-156 Octaacetyl-[a(?)-wglucopyranosyl @(?)-D140-141 glucopyranoside]

a(?)-D-Glucopyranosyl p(?)-wghcopyranoside monohydrate Octaacetyl- (8-wglucopyranosyl p-D-glucopyranoside) 8-D-Glucopyranosyl p-D-glucopyranoside (Is0trehalose) b

Dimorphous.

-

+14.1

199,202,235

-41.5

20

199

-40.5

86

199

-32.9

60

200

-45.6

90

200

-59.2

90

199,200

b X

2

B

-52.6

-

88a

z

-67.5 +1.6(10min.)+

-

88a

rn

-

+13.9

+68.1, +67

15,40

+67.1,+70

-

+78

11

{ 1:

-

about 145

+95

-

180.5-181.5

-18.4

130-135

-41.5 ft. 17")

As first isolated from the previously isolated derivative.

10.5 -

230 49,59a

i2

0 csl 0

E

ta

49,59a

E

120

X

120 120 15,111, 113 15. 111

d d

*

5

2!

VII. TABLEOF OLIGOSACCHARIDES (Continued) Rotation

Substance Methyl Z(tetraacety1-p-D-glucopyranosy1)4,6-benrylidene-a-~-glucopyranoside 232 Methyl Z(&D-glucopyranosyl)-a-D-glucopyranoside 252 (d.) Heptascetyl-I2-(j3-D-glucopyrsnosyl)-a-P glucopyranosyl] bromide 194 (d.) Octaacetyl-[%(&D-glucopyranosyl)-p-Dglucopyranose] 192 Octaacetyl-[2-(8-Dglucopyranosyl)-Dglucopyranose] 189 2- (&D-Glucopyranosyl)-a-D-glucose 180 (hydrate) 1,2-Isopropylidene-4,6-benzylidene-3(tetraacetyl-a (?)-wglucopyranosy1)-a-D-glucopyranose 142 1,ZIsopropylidene4,6enzyliden&-(a ( ?)-D glucopyranosy1)-a-sglucopyranose 190-192 3-(a(?)-D-Glucopyranosy1)-D-glucose 162 Octaacetyl-I3-a( ?)-D-glucopyranosyl-&Dglucose] 149 Methyl heptamethyl-[4-(p-D-glucopyranosyl)-p-~-glucopyranoside] 86 Octaacetyl-L4-(@-wglucopyranosyl)-p-Dglucopyranose] 221 4(&D-Glucopyranosyl)-p-D-ghcose (Cellobiose) 225-226 1,%Isopropylidene-3cety1-5-(tetraacetyl@-D-glucopyranosyl)-6-bromo-6-desoxy-crDglucofuranose 169

Yieldc %

solvent

-

+47

References

214, 236

+62.1 (t, 18")

-

214, 236

+95.6

-

236

-32.5

78

-

-40.5 (t, 18") +34.5+ +19.9

a

r

3P "5

236

U

50 50,236

5

U

3

z 0 +30.4

45

51

+39.2 (t, 18") +84.8 (final?) ( *, 18")

89 55

51 51

8') +41.3 (1, 1

83

r U m 9

3

M

-

- 15.5srs (t, 18")

-59.75 (t, 18")

51 115

40

4

35

4, 25

35

208

9

*r c3

I? M

cc

1,ZIsopropylidene-3,6-anhydro-5-(p-~-

glucopyranosy1)a-D-glucofuranose

130

1,2-hpropylidene-3-acetyl-5- (tetraacetyl&~-glucopyranosyl)-6-desoxy-~-~-glucof uranose 128 1,2-Isopropylidene-5-(tetraacetyl-j3-Dglucopyranosyl)-6-desoxy-a-D-gluco141 furanose Octamethyl-[6-(a-mglucopyranosy1)-p-D130-135 (b.p. 0.04 glucose] Octaacetyl-[6-(a-~-glucopyranosyl)-p-~143-144 glucopyranose] (isomaltose) 1,2-Isopropylidene-3,5-benzylidene-6-(tetraacetyl-p-pglucopyranosy1)-a-D-glucofuranose 166 1,2-Isopropylidene-3,5-benzylidene-6(@-Dglucopyranosy1)-a-D-glucof uranose 219 6-(~D-Glucopyranosyl)-D-glucose(Gentiobiose) Methyl heptaacetyl-[6-(p-~-glucopyranosyl)j3-~-glucopyranoside] 32 Methyl heptabenzoyl-[6-(p-~-glucopyranosy1)-&D-glucopyanoside] 203 Methyl 6- (&D-glucopyranosy1)-p-wgluco120 pyranoside Heptaacetyl-[6-(p-D-glucopyranosyl)-cr-nglueopyranosyl] chloride 136.5-137 Octaacetyl-[6-(,rh-glucopyranosyl)-cr-D glucopyranose] 191-192

As first isolated from the previously isolated derivative.

f20.16

HIO

-46

CHCIi

-

212

-11.0

CHC13

-

212

e

$95.1 {+93.1

EtOH He0

-

99

B

+96.9

CHCL

208

80

m cc

%

46

129, 130

e

3:

m

m

s -20.7

CHCl,

-13.9

CsHaN -

-

30

199

0

r

0

91

199

80

199

E: D

i -

h -16.99

CHCL

f2.0

CHCh

-

99

t61.8

H20

-

218

+82.83 (t, 18")

CHClt

46

98

+51.6 (t, 30")

CHCla

50

107, 114

Overall yield.

23

99

0

m*

i? tr

2!

VII. TABLEOF OLIGOSACCHARIDES (Continued) ~

Rotation solvent

Substance Octaacetyl-16-(8-D-glUCOpyranOSyl)-B-Dglucopyranose] 4-(a-D-Glucopyranosyl)-B-wmannose(epimaltose) Oetaacetyl-[4- (a-~-gIucopyranosyI)-cu-~ mannopyranose] 1,6-Anhydro-2,3-isopropylidene-4(tetraacetyl-@-wglucop yranosy1)-D-mannose 1,6-Anhydro-4-(tetra.acetyl-~-~-glucopyranosy1)-wmannose 1,6-hhydro-2,3-diacetyl-4-(tetraacetyl-B-~glucopyranosy1)-wmannose Octaacetyl-14- (&D-glucopyranosyl)-a-Dmannopyranose] 4-(B-D-Glucopyranosyl)-a-D-mannose hydrate (Epicellobiose) 3,6-Diacetyl-4- (tetraaeetyl-8-D-glucopyranosy1)-cu-D-mannopyranosyl fluoride Methyl 4(,9-~-glucopyranosyl)-~~mannoside 4(j3-wGlucopyranosyl)-a-mmannose Octaacetyl-[6-(j3-D-g-glucopyranosyl)-a-w mannopyranose] 6- (&wGlucopyranosyl)-a-wmannose (a-Epigentiobiose) a-DGlucopyranosyl a-csorbofuranoside

196

-5.35 (t, 18")

215-216 (d.)

+97+

157

+115 ( t , 17")

Yieldc %

References

23, 74, 80 4, 23, 107

3 r 2b

60, 48d

142

+117 ( t , 17")

80

142

p

176

-50.0

32

144

P

192-193

-68.9

91

144

131-132

-69.8

93-96

144

199-200

f36.5

90

139, 144

135-136

+11.8+

94

139, 144

145

+20.8

-

151

227-228 175-176

+46 (t, 17") +20+ +12.5 ( t , 18")

90

237 135, 237

114, 142-143*

+26.0

45.5

138, 225

167.5-168.0 178-180

-5.09+33

68, 23d -

138 39

2

.-a

Z

f5.8

0

r

2!

* 3

m

+

* I4

-11.06

:: *

M

1,2:3,PDikopropylidene-6- (2', 3' ,5',6 'diisopropylidene-p-D-mannof uranosyl)-cu205-210 (b.p. 1) D-galactopyranose 6- (p-~-Mannofuranosyl)-cY-Dgrtlactose :ryst. Deztro 3,4,6-triacetyl-~-mannopyranose 1,2,6'- (tetraacetyl-&D-glucopyranose) orthoacetate 168-169 Levo 3,4,6-triacetyl-~-mannopyranose 1,2,6'-(tetraacetyl-~-~-glucopyranose) orthoacetate 174.0-174.5 Octaacetyl-[6-(p-r+mannopyranosyl)-p-~glucopyranose] 30-95 (amorph.) Oetaacetyl-[j3-D-mannopyranosyl p-Dmannopyranose] 152- 153 2,3 :5,6-Diisopropylidene~-mannofuranosyl 2',3' :5',6'-d%opropylidene-~-rnanno180-181 furanoside Octaacetyl-[p-cellobiosyldihydroxyacetone] 169 Octaacetyl-[p-gentiobiosyldihydroxyacetone] 172 1,2:3,4-Diisopropylidene-6-(heptaacetyl-~cellobiosyl)-cr-D-galactopyranose 227 6- (&cellobiosyl)-a-Pgalactose dihydrate

CzHzCL H20

+17.1 ( t , 30")

CHCla

-

230 230

79

23

e

s:

-27.6 (t, 32")

CHC18

-

+38.9 (t, 19")

CHClz

-

f19.6

CHC13

39

79

+84 (t, 18") -27.1 -25.9

CzHzClr CHCI, CHC13

52.5 59

230 105 105

-4:. 1 (t, 18") +22.9(10 min) + +9.25 (t, 19")

CzHzClr HzO

32 43

230 230

235

+26.2

CHCla

-

97

248-249

-23.53

CHC13

-

97

223-224 (d.)

+48.37 ( t , 18')

CHCla

28.6

98

246.5

-10.9

CHCL

45, 25

103, 238

-

Methyl decaacetyl-[6-(cr-ce~lobiosyl)-&~glucopyranoside] Methyl decaacetyl-16-(@cellobiosyl)-@Dglucopyranoside]

-44.6 ( t , 18") +144+ +134

79 79

M

Decaacetyl-[6-(/3-cellobiosyl)-a-~-g~ucopyranosyl] chloride Hendecaacetyl-[6-(~-cellobiosyl)-~-~glucopyranose] b

Dimorphous.

c

As 6rst isolated from the previously isolated derivative.

Overall yield.

-a

CD

VII. TABLEOF OLIGOSACCHARIDES (Continued) Substance

1

Melting point "C.

I

247-252 (d.) 6-(&Cellobiosyl)-a-~-glucose Hendecaacetyl-[6-(&gentiobiosyl)-@D221 glucopyranose] Hendecaacetyl-[6-(@gentiobiosyl)-@D122-123 mannopyranose] 6-(@-Lactosyl)-l,2: 3,4-diisopropylidene-a-~galactopyranose hydrate 117 Hendecaacetyl-[6-(&lactosyl)-@~-glucopyranose] 198 257 (d.) 6(~Lactosyl)-a-~-glucose Hendecaacetyl-[6-(&maltosyl)-pD-gluco242.2-242.7 pyranose] Hendecaacetyl-[l%(&D-mamopyranosyl)-p118-119 gentiobiose] Hendecaacetyl-[l%(&D-rnanoopyranosyl)-,9epigentiobiose] (6'-,9-~-mannopyranosyl6-@wglucopyranosyl-&D-mttnnopyranoopyranose) 1112-113 Methyl tridecaacetyl-[l2-(p-cellobiosyl)-~236-237 gentiobioside] Tetradecaacetyl-[12-@-cellobiosyl)-& 239-240 gentiobiose] Tetradecaacetyl-[l%(@gentiobiosyl)-p207-209 gentiobiose] 105 Tetradecaacetylmaltosylmaltoside ~

0

Rotation solvent

YieldC %

I

3

Hz0

95

103

-8.0

CHCl,

25, 59

102, 103

M -4 P

-21.02

CHCla

73.4

225

m

-39.8 ( t , 18")

H20

29

230

-2.53 f34.7-t

CHCla Hz0

25, 42 95

+42.5

CHCla

60

238

+20.2

CHCL

58

239

4-15.0-

+8.4

$22.6

+11.2 -16.35 -19.6

(t, 19")

( t , 15")

-11.1 +105.4 d

Overall yield.

r Z

U U

CHCh

46

CHCla

76-

CHCla CHCla CHCls

103, 195 103

239

9

5

2

sz +-

1:

el M

*

240

I3

80-t 15'

117

M

16

102 49

8'

-

~

As first isolated from the previously isolated derivative.

References

Of finally purified material.

kr 4

(226) C. M. McCloskey and G. H. Coleman, J . Am. Chem. Soc., 66, 1778 (1943). (227)G. Zemplbn and A. Gerecs, Ber., 67, 2049 (1934);66, 1318 (1935). (228) B. Helferich and H. Rauch, Ann., 466, 168 (1927). (229) G. Zemplkn and R. BognAr, Ber., 72, 47 (1939). (230) K.Freudenberg, A. Wolf, E. Knopf and S. H. Zaheer, Ber., 61,1743 (1928). (231) C. S. Hudson and J. $1. Johnson, J . Am. Chem. SOC.,37, 2748 (1915). (232) W.N. Haworth, E. L. Hirst, Millicent M. T. Plant and R. J. W. Reynolds, J . Chem. SOC.,2644 (1930). (233)J. C. Irvine, J. W. H. Oldham and A. F. Skinner, J. Am. Chem. Soc., 61, 1279 (1929). (234) R. P.Linstead, A. Rutenberg, W. G. Dauben and W. L. Evans, J . Am. Chem. Soc., 62,3260 (1940). (235) Ref. 199 reported that their product had practically the same melting point and optical rotation as the substance of ref. 202 but recorded [cx]*~D = -13.91. (236) K. Freudenberg and K.Soff, Ber., 69, 1245 (1936). (237) W. N. Haworth, E. L. Hirst, H. R. L. Streight, H. A. Thomas and J. I. Webb, J . Chem. Soc., 2636 (1930). (238) S. H. Nichols, Jr., W. L. Evans and H. D. McDowell, J. Am. Chem. Soc., 62, 1754 (1940). (239) E. A. Talley and W. L. Evans, J. Am. Chem. Soc., 66, 573 (1943). (240) G. Zemplbn and A. Gerecs, Ber., 64, 2458 (1931).

This Page Intentionally Left Blank

THE FORMATION OF FURAN COMPOUNDS FROM HEXOSES BY F. H. NEWTE Department of Chemistry, University College of North Wales, Bangor, North Wales

CONTENTS I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 83 11. Furan Compounds Derived from Hexoses.. . . . . . . . . . . . . . . . . . . . . . . . . . 84 1. 5-Hydroxymethylfurfural.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84 2. 5-Halogenomethylfurfurals ........................... 87 3. 5-Methylfurfural.. . . . . . . . ........................... 88 111. Furan Derivatives from Hexose Acids.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89 IV. Possible Mechanisms of Formation of Furan Derivatives.. . . . . . . . . . . . . . . . 91 V. 5-Hydroxymethylfurfural.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96 1. Preparation.. ..... . . . . . . . . . . . . . . . . . . . . . 96 2. Physical Properties.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97 3, Color Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 98 4. Chemistry and Transformation Products. . . . . . . . . . . . . . . . . . . . . . a. Reactions of the Hydroxymethyl Group.. . . . . . . . . . . . . . . . . . b. Reactions of the Aldehyde Group. . . . . . . . . . . 101 c. Reactions of the Furan Ring.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 103

I. INTRODUCTION The degradation of carbohydrates by acids has been known for many years and during the later years of the nineteenth century considerable attention was given to this reaction, in which three molecules of water are eliminated from the sugar molecule t o give the furan nucleus. By the end of 1910, nearly all the reactions in which furan compounds are obtained from carbohydrates had been discovered and it was firmly established that these changes are brought about by acidic conditions only. Further interest in the degradation of sugars then waned and contributions to this field of chemistry were concerned mainly with the reactions of the furan compounds themselves. The early workers did not put forward any theory on the possible course of the reaction but in recent years, work has been resumed on the formation of furan compounds and several mechanisms have been proposed to explain the formation of 5-hydroxymethylfurfural (synonym, 5-hydroxymethyl-2-furaldehyde) and furfural (synonym, 2-furaldehyde) from hexoses and pentoses respectively. There is, however, little evidence in support of them. The importance of this aspect of carbohydrate chemistry is very great 83

84

F. H. NEWTH

and there is room for considerable advance in the knowledge of the changes which occur when sugars are degraded by acids. In view of this, it is well to review the information and ideas which a t present exist.

11. FURAN COMPOUNDS DERIVED FROM HEXOSES 1. 6-Hydroxymethylfurfural

It is more than a century since the first acidic degradation of a carbohydrate was studied. In 1840 Mulder’ isolated formic acid and a compound he called “glucinic acid” by the action of sulfuric acid on sucrose. This acid was later purified by Grote and Tollens2 who established its formula and renamed it levulinic acid (I). They showed also that it was obtained, together with formic acid and colored polymeric humins, by the vigorous action of mineral acids on g l u c o ~ e . ~Further CHsCO.CHp.CH2.COOH I

work by numerous investigators led to the conclusion that this degradation was common to the hexoses, levulinic and formic acids being always the final products obtained by strongly acidic treatment. A few years later it was confirmed that the degradation of carbohydrates with acids gave rise also to furfural (11). This had been obtained fifty years earlier by Dobereiner by the action of sulfuric acid and manganese dioxide on sugar but its significance was not realized at the time. Furfural however was obtained only from pentoses, under normal acid conditions. In 1895 Dull,” who was studying inulin and its products of hydrolysis, found that when either fructose or sorbose was treated with an aqueous solution of oxalic acid under pressure, a substance was obtained which had the formula C6H6Os and resembled furfural in its properties. This substance was further investigated by Kiermayer4 who found that fructose and sucrose were the best sources when they were heated with 0.3% aqueous oxalic acid a t 120”. It was however only the fructose portion of the sucrose molecule which was transformed since the glucose moiety was recovered unchanged. Kiermayer prepared several derivatives of C6H603 and from its reactions concluded that its structure was probably P-hydroxy-6-methylfurfural (111). Van Ekenstein and (1) G. J. Mulder, J . prakt. Chem., 21, 229 (1840). (2) A. von Grote and B. Tollens, Ber., 7, 1375 (1874). (3) A. von Grote and B. Tollens, Ann., 206, 226 (1881). (3a) G. Diill, Chem. Zlg., 19, 166, 216 (1895). (4) J. Kiermayer, Chem. Ztg., 19, 1003 (1895).

THE FORMATION OF FURAN COMPOUNDS FROM HEXOSES

HC-

CH

HC

C-CHO

II

II

\o/

HC-C-OH CHa-C I‘

HCA-CHO

0 ‘’

I1

85

HOCH2.C

-CHO

\O/

I11

IV

Blanksma6 continued the investigation of the formation of hydroxymethylfurfural and confirmed Kiermayer’s results that it was formed from hexoses by elimination of three molecules of water on acidic degradation and showed that ketoses reacted more readily than aldoses, a fact which was observed by Kiermayer when sucrose was treated with aqueous oxalic acid. Kiermayer had observed also that levulinic acid was obtained when hydroxymethylfurfural was treated with aqueous oxalic acid under pressure and this received further confirmation by Van Ekenstein and Blanksma.6 It was these authors who first pointed out that the complete degradation of hexoses to levulinic acid took place through the intermediate formation of hydroxymethylfurfural. Further work by Van Ekenstein and Blanksma’ led to a revision of the formulation of hydroxymethylfurfural. It was found that chitose on dehydration gave hydroxymethylfurfural which when oxidized was converted into hydroxymethylpyromucic acid, identical with the compound obtained by Fischer and Andreae from chitonic and chitaric acids.s The nature of chitose (a 2,5-anhydrohexose) was such that Kiermayer’s original formulation of 0-hydroxy-8-methyl-furfural could not obtain and the accepted formulation, w-hydroxymethylfurfural (5-hydroxymethyl-2-furaldehyde (IV)) was assigned t o the compound. Although ketoses are more easily degraded than aldoses to 5-hydroxymethylfurfural, it was shown t o be possible to obtain it from glucose by both Erdmanng and Heuserlo who isolated it from the products of dry distillation of cellulose and by boiling cellulose with hydrochloric acid. The yields from these experiments were very low however and many by-products were obtained. It is probable that the more drastic reaction conditions caused the greater part of the 5-hydroxymethylfurfural to decompose to levulinic and formic acids. There is no doubt that glucose is more resistant to acidic degradation than fructose. This has been confirmed recently by Haworth and Jones” who adopted Kiermayer’s (5) W. Alberda van Ekenstein and J. J. Blanksma, Chem. Weekblad, 6,717 (1909). (6) W. Alberda van Ekenstein and J. J. Blanksma, Chem. Weekblad, 7,387 (1910). (7) (a) J. J. Blanksma, Chem. Weekblad, 6, 1047 (1909) and (b) W. Alberda van Ekenstein and J. J. Blanksma, Ber., 43, 2355 (1910). (8) E. Fischer and E. Andreae, Ber., 36, 2587 (1903). (9) E. Erdmann and C. Schaefer, Ber., 43, 2398 (1910). (10) E. Heuser, Cellulosechemie, 4, 15, 101 (1923). ( 1 1 ) W. N. Haworth and W. G. M. Jones, J . Chem. SOC.,667 (1944).

86

F. H. NEWTH

method for the preparation of 5-hydroxymethylfurfural and performed many experiments to discover the optimum conditions for its formation from sucrose. It was shown with certainty that only the fructose moiety underwent reaction since the glucose was recovered from the reaction mixture in nearly quantitative yield as potassium hydrogen D-ghcosaccharate. Continuing this work on the formation of furan compounds from sucrose, Montgomery and Wiggins12 found that the oxalic acid prescribed by Kiermayer was unnecessary for the formation of 5-hydroxymethylfurfural, which was produced in the absence of any added acid catalyst. Acidity did develop however when sucrose was heated under pressure with water alone and this was ascribed to the formation of acetol which could produce a sufficient hydrogen-ion concentration to catalyze the degradation of the fructose to 5-hydroxymethylfurfural. Treatment of both L-sorbose and D-glucose with water under these conditions also gave 5-hydroxymethylfurfural, although the yield, in the case of the latter sugar, was much lower. Examples of the degradation of anhydro-sugars by heating with water under pressure have also been given13in which the difructose anhydrides, 1,a-anhydroglucose and chitose were converted into 5-hydroxymethylfurfural when their aqueous solutions were heated at temperatures from 100” to 150”. Attention has recently been given to the formation of 5-hydroxymethylfurfural on heating aqueous solutions of glucose following a suggestion made several years before14that furan compounds are responsible for the Maillard reaction.ls This is a “browning” effect which is observed when aqueous solutions of reducing sugars are heated with amino acids and is believed to be operative in food processing. A study of the chemical interactions of sugars with amino compounds has been carried out by Wolfrom and his coworkers16in which it has been demonstrated that 5-hydroxymethylfurfural, in the case of glucose, and furfural in the case of pentoses are important precursors in the formation of brown colors which develop when aqueous solutions of these substances are heated with glycine. It has been found” that aqueous solutions of glucose become highly (12) R.Montgomery and L. F. Wiggins, J . SOC.Chem. Ind. London, 66,31 (1947). (13) C. Tanaka, Mem. CoZZ. Sci., Kyoto Imp. Univ., [A]18, 265 (1930). (14) (a) M.L. Roxas, J . BioZ. Chem., 27, 71 (1916);(b) V. A. Beckley, J . Agri. Sci., 11, 69 (1921). (15)L. C. Maillard, Compt. rend., 164, 66 (1912);Ann. chim., [9],6, 258 (1916). (16) (a) Liebe F. Cavalieri and M. L. Wolfrom, J . Am. Chem. SOC.,68, 2022 (1946);(b) M. L. Wolfrom, Liebe F. Cavalieri and Doris K.Cavalieri, ibid., 69,2411 (1947);(c) M.L.Wolfrom, R. D. Schuetz and Liebe F. Cavalieri, ibid., 70, 514 (1948); (d) M. L. Wolfrom, R. D. Schuetz and Liebe F. Cavalieri, ibid., 71, 3518 (1949). (17) B. L. Scallet and J. H. Gardner, J . Am. Chem. SOC.,67, 1934 (1945).

THE FORMATION OF FURAN COMPOUNDS FROM HEXOSES

87

colored when heated for several hours at loo", which is ascribed to the formation of 5-hydroxymethylfurfural followed by its polymerization to form humin substances. The presence of 15 parts per million of 5-hydroxymethylfurfural after 2.5 hours heating permitted a colorless solution but after 7 hours the solution which contained 170 p.p.m. was highly colored; the color decreasing somewhat when the 5-hydroxymethylfurfural was removed from the solution by extraction. The discoloration of starch hydrolyzates is also ascribed to Ei-hydroxymethylfurfural formed by the destruction of the glucose molecule.ls In addition to acting as a possible color precursor, it has been statedlSa that 5-hydroxymethylfurfural inhibits microbial fermentation. Furfural is also an inhibitor but to a lesser degree. Removal of these substanceslsb formed during acid hydrolysis of carbohydrate mashes by adsorption on carbon, or inactivation by adding corresponding amounts of sodium bisulfite, is essential for smooth fermentation. In this respect observations on the relative preservative and germicidal action of various sugars may very well be due t o the ease with which 5-hydroxymethylfurfural is formed during sterilization of the media rather than to wholly structural or osmotic pressure differences as has been claimed.lsn-d 2. 5-Halogenomethylfurfurals

A degradation similar to that which results in the formation of 5-hydroxymethylfurfural occurs when hexoses are treated with concentrated halogen acids, but instead of the hydroxymethyl compound, 5-chloromethyl- and 5-bromomethylfurfura1 (V) are obtained when the corresponding acids are used. Hydrofluoric and hydriodic acids however fail to give the corresponding halogen derivatives. Fenton and Gostlinglg CH-CH

A

A-CHO

X*CH2

X

=

C1 or Br

'0'

V

noticed an intense purple coloration when carbohydrates were treated with hydrogen bromide in ether and showed that this was due to the formation of 5-bromomethylfurfura1. With ketohexoses the char(18) B. Singh, G. R. Dean and s. M. Cantor, J . A m . Chem. Soc., 70, 517 (1948). (18a) S. G. Mashevitskaya and E. A. Plevako, J . Applied Chem. (U.S.S.R.), 11, 511 (1938). (18b) S. S. Block, U. S. Pat. 2,474,139 (June 21, 1949). (18c) F. J. Erickson and F. W. Fabian, Food Research, 7 , 68 (1942). (18d) L. Tarkow, C. R. Fellers and A. S. Levine, J . Bact., 44, 367 (1942). (19) H. J. H. Fenton and Mildred Gostling, J . Chem. Soc., 73, 554 (1898); 76, 423 (1899); 79, 361 (1901).

88

F. H. NEWTH

acteristic color developed after a few minutes but long standing was necessary before it was given by aldohexoses. They were able to isolate 5-bromomethylfurfura1 from the products of reaction with cellulose, starch, inulin, sucrose and fructose but not from glucose, lactose and galactose or, as would be expected, from xylose. Other workers have since modified the method of preparation,20~21J2 but Hibbert and Hillza showed that cellobiose and methyl a-D-glucopyranoside alsc ?ve 5-bromomethylfurfural and that it could be obtained from glucose, galactose and lactose, although in low yield, in contradiction to Fenton and Gostling. Fenton and coworkersz4also obtained 5-chloromethylfurfural from sucrose, fructose and cellulose by treating the carbohydrate in an inert solvent with hydrogen chloride. They discarded this method however as being tiresome owing to the formation of tarry, humus substances and found that it was more convenient to use aqueous hydrochloric acid containing calcium chloride. This method was adopted also by Fischer and NeymannZ6but with the omission of the calcium chloride. Recently, the optimum conditions have been described for the preparation of 5-chloromethylfurfural from sucrose.ll There is no reason to suppose that the transformations which occur during these degradations are any different from those by which 5-hydroxymethylfurfural is formed. It is indeed probable that this is the initial product, the hydroxyl group of which is then replaced by halogen. Support for this view is found in the facile conversion of 5-hydroxymethylfurfural itself to 5-chloromethyl- or 5-bromomethylfurfural when treated with the appropriate acid. 3. 6-Methylfurfural The 6-deoxyhexoses undergo a degradation similar to the hexoses themselves when treated with acids to give 5-methylfurfural (VI). CHr-

iH-iH

-CHO

'0' VI

Like furfural, it is considerably more stable than 5-hydroxymethylfurfural and is not so likely to polymerize or become degraded during (20)J. A. Middendorp, Rec. trav. chim., S8, 1 (1919). (21) W.N. Haworth, E. L. Hirst and V. S. Nicholson, J . Chem. Soc., 1513 (1927).

(22) F. H. Newth and L. F. Wiggins, J . Chem. Sec., 396 (1947). (23) H. Hibbert and H. S. Hill, J . Am. Chem. SOC.,46, 176 (1923). (24) (a) H. J. H. Fenton and Mildred Gostling, J . Chem. Boc., 79, 807 (1901); (b) H. J. H. Fenton and F. Robinson, J . Chem. SOC.,96, 1334 (1909). (25) E. Fischer and H. von Neymann, Ber., 47,973 (1914).

T H E FORMATION O F FURAN COMPOUNDS FROM HEXOSES

89

the course of its formation. It is therefore possible t o obtain it by the simple procedure of distilling a solution of the sugar (rhamnose) in aqueous mineral acid, when it is obtained in the distillate. The earlier workers obtained only low yields,26but later it was possible to isolate it in quantitative yield by the same method, thus showing a similarity to the formation of furfural from pent~ses.~’

111. FURAN DERIVATIVES FROM HEXOSEACIDS Although gluconic acid does not give 5-hydroxymethylfuroic acid (VII) when subjected to conditions which were effective in producing 5-hydro~ymethylfurfura1,~8 Fischer found that from the products of the reaction of D-galactonic acid with hot pyridine, in addition t o D-talonic acid formed by epimerization, a small amount of 5-hydroxymethylfuroic acid was obtained.29 Chitonic and chitaric acids as the calcium salts were also converted to the acetyl derivative of this furan derivative when heated with sodium acetate and acetic anhydridea8 5-Hydroxymethylfuroic acid has also been obtained, together with simple dibasic organic acids, as a metabolic product of various species of Aspergillus in culture solutions containing D-glucose or sucrose.3o It is interesting to find that neither D-gluconic acid nor 5-hydroxyrnethylfurfural are converted to 5-hydroxymethylfuroic acid when included in the culture medium. In contrast to gluconic acid, 5-ketogluconic acid (VIII) is readily transformed int,o methyl 5-formylfuroate (IX) in almost quantitative

1”

HC. HOCHZ-C

II

-COOH

HOCH~.CO.(CHOH)S.COOH

‘0’

VII

VIII HCOHC-C

CH

II

II

C-COOMe ‘0’

IX (26) (a) E. VotoEek, Ber., SO, 1195 (1897); (b) M. M. Runde, E. W. Scott and J. R. Johnson, J . Am. Chem. SOC.,62, 1284 (1930). (27) Elizabeth E. Hughes and S . F. Acree, J . Res. Nat. Bur. Standards, 28, 293 (1939). (28) J. J. Blanksma, Rec. trav. chim., 29, 403 (1910). (29) E. Fischer, Ber., 27, 1524 (1894). (30) T. Sumiki, Bull. Agr. Chem. SOC.Japan, 6, 10 (1929); 6, 105 (1930); J . Agr. Chem. SOC.Japan, 6, 1153 (1930); 7, 819 (1931).

90

F. H. NEWTH

yield by boiling methanolic hydrogen ~hloride;~' and it would appear that this difference in reactivity between gluconic acid and VIII is related to their structural difference which is similar to that between glucose and fructose; the latter being the more easily convertible to 5-hydroxymethylfurfural. As would be expected by analogy with the foregoing examples, the saccharic acids on treatment with acidic reagents are converted into furan 2,5-dicarboxylic acid (X) (known t o earlier workers as dehydro-

&8"

HC-

HOOC-

-COOH

'0' X

mucic acid). It was first obtained by Tollens and coworkers when potassium hydrogen saccharate was heated under pressure with hydrochloric acids2 and later by heating either galactosaccharic acid (mucic acid) or glucosaccharic acid with concentrated sulfuric Allomucic acid obtained by epimerization of mucic acid was also converted A claim to into the dicarboxylic acid by heating with halogen a ~ i d . 3 ~ have obtained furan 2,&dicarboxylic acid by the destructive distillation of potassium mucate was madea6but the work of Tollens proved this to be incorrect. The best yield (55%) of the diacid was obtained much laterS6when potassium hydrogen saccharate was boiled under reflux with concentrated hydrobromic acid for 63 hours. These conditions however did not give a satisfactory yield with mucic acid which requires the more drastic dehydration with concentrated sulfuric acid. The conditions required for the formation of this furan compound from the saccharic acids are probably the most drastic which have been used in the formation of the furan nucleus from carbohydrates and it is only because of the extreme stability of the product that its isolation is possible here. An interesting biochemical oxidation was observed recently when it was found that the inclusion of either n-glucuronic lactone or D-galacturonic acid in the human diet causes a great increase in the amount of furan 2,5-dicarboxylic acid excreted in the (31) (a) E. VotoEek and S. Malachta, Coll. Czech. Chem. Comm., 6, 241 (1934); (b) E. VotoEek and A. KroSlBk, ibid, 10, 259 (1938). (32) 0. Sohst and B. Tollens, Ann., 246, 1 (1888). (33) B. Tollens and P. A. Yoder, Ber., 34, 3446 (1901). (34) E. Fischer, Ber., 24, 2140 (1891). (35) H. Schmidt and A. Cobensl, Ber., 17, 559 '(1884). (36) I. K. Phelps and W. J. Hale, Am, Chem. J., 26, 445 (1901). (37) B. Flaschentrager, B. Cagianut and F. Meier, Helv. Chim. Acta, 28, 1489 (1945).

THE FORMATION OF FURAN COMPOUNDS FROM HEXOSES

91

IV. POSSIBLE MECHANISMS OF FORMATION OF FURAN DERIVATIVES The sequence of reactions in which three molecules of water are eliminated from a hexose molecule, giving rise to the furan ring, remains unknown. Several mechanisms have been proposed but there is little evidence at present t o support them. In 1944 Haworth and Jonesll suggested a series of dehydration reactions to explain the degradation of fructose t o 5-hydroxymethylfurfural. The first step is the elimination of water from fructofuranose (XI) a t C1 and Czgiving the intermediate XII. Further dehydration occurs t o give XI11 which undergoes a tautomeric change t o XIV and from this 5-hydroxymethylfurfural (IV) is obtained by loss of a third molecule of water. HO.CH-CH.OH

I

HO.CH-CH*OH

]/OH C

HOCHrCH

\o/

\

- HOCH2.CH 1 1 C=CH.OH HOCH2.CI

I

+

CHaOH

XI

4 HOCHr.

\O' XIV

lHoH H.CHO

C=CHOH

\o'

\O/ XI1

HC-

+

HC-CHOH

-+

XI11

HC-CH

II

HOCH2.C

II

C.CHO

O '/ IV

A similar interpretation was given earlier2' t o explain the behavior of tetramethylfructofuranose with acids. This important sugar, encountered in the constitutional studies on sucrose, was found to be unstable, and treatment with dilute hydrochloric acid a t 80" brought about a change in which three methoxyl groups were eliminated as methyl alcohol, giving rise to 5-methoxymethylfurfural (XVI) . This degradation occurred not only with aqueous acid but also when the methylated fructose was warmed with acetic anhydride in the presence of sodium acetate and many of the anomalies which attended the constitutional study of this sugar could be attributed to this behavior. It is clear then that the presence of methoxyl groups in a ketohexose does not impede the degradation t o a furan body and similarly the methoxyl groups do not block furfural formation when methylated pentoses are heated with mineral acids.s8 Although there is no direct comparative evidence it would appear that the presence of methoxyl groups may facilitate the degradation of fructose t o the furan compound since higher temperatures are necessary t o bring about the degradation of fructose itself. It is of (38) (a) H. T. Neher and W. L. Lewis, J . Am. Chem. SOC.,63, 4411 (1931); (b) H. G. Bott and E. L. Hirst, J . Chem. Soc., 2621 (1932).

92

F. H. NEWTH

interest that the trimethyl fructose obtained from methylated melezidoes t o ~ e ,which * ~ may now be designated 1,4,6-trimethylfructofuranose,40 not give any furan compound although the acidic conditions employed in its isolation from hendecamethyl melezitose were very similar to those by which 5-methoxymethylfurfural was obtained from tetramethylfructofuranose. It is possible however that some 5-methoxymethylfurfural was formed but in too low a yield for its isolation. Although the presence of four methoxyl groups in the molecule seems to facilitate the conversion of fructose to methoxymethylfurfural, tetramethylglucose is quite stable towards acidic reagents and no mention has ever been made of its degradation to a furan compound, which is in accordance with observations on the relative stabilities of fructose and glucose. Following a suggestion by Raymond4l that tetramethyl-l,2-glucoseen (XVII) was possibly an intermediate in the epimeric conversion of tetramethylglucose into tetramethyl mannose, Wolfrom and coworker^*^ found that in aqueous acid solution at room temperature, instead of the formation of tetramethylmannose, the tetramethyl-l,2-glucoseen was smoothly converted into 5-methoxymethylfurfural (XVI). A 5 % soluH

C A-OMe

MeO-

H-

c:

-H

A

I

v

0

-0Me

MeOCH2-C

II

II

C-CHO

0 ''

I

H-6

HC--CH

XVI

(!.JHtOMe XVII

tion in 3 N . hydrochloric acid a t 25" showed a sharp decrease in specific rotation from 15" to - 15" in one hour, thereafter rising until the rotation was zero after 10 hours and from the reaction mixture 5-methoxymethylfurfural was isolated. When the reaction was stopped after one hour and the product treated with phenylhydrazine, a crystalline phenylosazone was obtained having m. p. 120.5-121.5' andDI.[ - 9" and for which the analytical figures were in good agreement with the formula C18H1~0N4.0CHa. It formed a crystalline monoacetate and Wolfrom assigned to it the structure XVIII, considering that the intermediate

+

(39) Grace C. Leitch, J . Chem. SOC.,588 (1927). (40) C. 5. Hudson, Advances in Carbohydrate Chem., 2, 30 (1946). (41) A.L. Raymond in Henry Gilman's "Organic Chemistry," John Wiley & Sons, New York (1938), Vol. 11, 1512. (42) M. L. Wolfrom, E. G . Wallace and E. A. Metcalf, J . Am. Chem. SOC.,64, 265 (1942).

T H E FORMATION O F FURAN COMPOUNDS FROM HEXOSES

93

substance in the formation of 5-methoxymethylfurfural is the unsaturated osone XIX. This is the only intermediate which has been isolated in the XH=N.NH.Ph. I

CHO

A0

=N.NH.Ph.

I

t!H

II

II

CH I

CH I

H-C-OH

H-C-OH I

I

CH20Me

CHzOMe

XIX

XVIII

formation of a furan compound from a carbohydrate. Apart from the analytical data, however, no further evidence has been given t o support the formula of either XVIII or XIX, but the reaction is considered in terms of consecutive electronic displacements by I ~ b e 1 1on ~ ~the basis of the intermediate being XIX. Until recently it was thought that the acidic degradation of glucose gave only levulinic acid. As mentioned previously this must have been formed through the intermediate 5-hydroxymethylfurfural, but the conditions for the formation of this furan body, being more drastic than those necessary for fructose, brought about its subsequent degradation to levulinic acid. Haworth and Jones" however suggested that glucose might be made to undergo the degradation to 5-hydroxymethylfurfural if it was first converted into its enolic form (XX) which by loss of water would then give the intermediate XII. HO*CH-CH.OH HOCH2(CHOH)3.CHOH.CH0.+ H O C H 2 . h h=CH.OH d H dH

xx -+

HO.CH-CH*OH HOCH2--bR

A=CH.OH

'0' XI1

Two more molecules of water could then be eliminated exactly as was postulated in the degradation of'fructose. The formation of the enolic form XX as a first stage in the treatment of glucose with alkali was first suggested by Lobry de Bruyn and Van E k e n ~ t e i nand ~ ~ later by Nef,46 (43) H.S. Isbell, J . Res. Nat. Bur. Standards, 32, 45 (1944). (44) Lobry de Bruyn and W. Alberda van Ekenstein, Rec. trav. chirn., 14, 195 (1895). (45) J. U. Nef, Ann., 367, 295 (1907).

94

F. H. NEWTH

and the action of alkali on glucose has been more recently studied by Evans48 and coworkers and by Wolfrom and Lewis.*' Solutions of glucose were treated therefore with alkali under conditions which would ensure the maximum amount of 1,a-enediol formation and subsequent treatment of the neutralized reaction products with dilute aqueous oxalic acid under pressure ah in the case of sucrose led to the isolation of 5-hydroxymethylfurfural as anticipated. It has been mentioned earlier that the presence of acid was found to be unnecessary in bringing about the degradation of fructose or sorbose and, in addition, it was f o ~ n d 1 ~ ,that 1 ~ , glucose ~~ was converted into 5-hydroxymethylfurfural by heating with water alone although the yields were not so great as those obtained when glucose was treated initially with alkali. Further study has shown that 5-hydroxymethylfurfural is produced in small amounts when solutions of glucose at an and the course of the reaction has been observed acid pH are heated16ce17 by measurements of the ultraviolet absorption spectra a t intervals. Wolfrom and coworkersleonoticed that before the characteristic absorption band of 5-hydroxymethylfurfural a t 285 mp reached its maximum intensity, the series of absorption curves showed the initial development of a distinct band a t 228 mp a t a much greater rate in the early stages of the reaction. This later failed t o increase further in intensity whilst the band a t 285 mp increased to its maximum. The absorption band a t 228 mp was interpreted as being due to an intermediate in the reaction and on the basis that a,p-unsaturated aldehydes (R-CH=CH-CHO) show high absorption in the general region of 230 mp48 the following scheme was proposed: The intermediate (XXII), thought t o be responsible for the absorption band a t 228 mp, is formed by loss of water a t Czand CSin glucose reacting in its aldehydoform (XXI). The X X I I could then give rise t o XXIII by cyclic dehydration, from which 5-hydroxymethylfurfural (IV) could result by a final dehydration producing a third double bond in conjugation with the two already present. The alternative route through the intermediates XXIV, XXV and XXVI is based on an analogy with the transformation of tetramethyl-l,2-glucoseen into 5-methoxymethylfurfural in which XXV is the corresponding intermediate unsaturated osone. A similar scheme has been postulated t o explain the conversion of pentoses into furfural.lBd In connection with the interpretations of the data obtained by the measurements of ultraviolet absorption, it should be mentioned (46) W. L. Evans, Rachel H. Edgar and G. P. Hoff, J . Am. Chem. Soc., 48, 2665 (1926). (47) M. L. Wolfrom and W. L. Lewis, J . Am. Chem. Soc., 60,842 (1928). (48) L. K. Evans and A. E. Gillam, J . Chem. Soc., 565 (1943).

THE FORMATION O F FURAN COMPOUNDS FROM HEXOSES

HC=O

HC=O

I

HC=O

HCOH

I

HOCH

I HCOH I HCOH

-H,O

HC CH

AH

d

95

It

-11~0

C-CH=O

__t

T

HbOH

IV -HzO

R

HC=O

b=O

I

HZ

-H~O +

HbOH

-

HAOH

HC=

CH

II

CH HAOH

&H20H

&HzOH

XXIV

xxv

-+ t

I

CH

I/OH C

HOCHz-CH

\o/

\ CH=O

XXVI

that a solution of glucose in 50% sulfuric acid shows an intense absorption band at 284 mp after standing a t room temperature for 69 hours; on making the solution alkaline the absorption band disappears very rapidly and no 5-hydroxymethylfurfural or levulinic acid is obtained from the solution.49 It has been shown by the writer that faintly acid solutions of fructose when heated at 100" show a series of ultraviolet absorption curves similar to those given by glucose under the same conditions. This would suggest that the transformation of fructose and glucose into 5-hydroxymethylfurfural follows the same course. It is indeed improbable that different mechanisms should obtain for different sugars in a transformation which is so general. The disadvantage of the scheme postulated by Wolfrom is that it applies only t o glucose and does not permit an interpretation with respect to fructose. It does not require the existence of glucose as its 1,a-enediol (XX) as suggested by Haworth, but for which there is no evidence of existence in acid solution. There may be some significance in the observation made by Blanksma28 that mannitol and gluconic acid are not transformed into furan compounds since in the former there is no possibility of the formation of an enolic form and in the latter its formation may be difficult. A similar explanation might account for the more difficult degradation of glucose compared with fructose if the 1,2-enediol is not so readily formed from the aldose. Although fructose (49) E. Pacsu and L. A. Hiller, Jr., J . Am. Chem. Soc., 70, 523 (1948).

96

F. H. NEWTH

is represented in Haworth's scheme in the furanose form it could be that the first stage in the degradation of fructose is the formation of the 1,kenediol (XX) rather than the dehydration at C1and C2 in fructofuranose. This would mean that the intermediate XX, although nothing is known about its existence in acid solution, would be common to both fructose and glucose and XI1 could result from a dehydration between the hydroxyl groups at C2 and CI. It should be noticed that XI1 is the enolic form of chitose and weight is added to Haworth's scheme by the facile conversion of chitose itself into 5-hydroxymethylfurfural. It has been reported that chitose shows an absorption band in the ultraviolet at 360 mplS which precludes an interpretation of the absorption band at 228 mp in Wolfrom's experiments as being due to chitose. It is clear that the whole subject needs clarifying and re-examination of many of the reactions in order to adduce comparative evidence for the ease or difficulty with which these transformations occur.

v. 5-HYDROXYMETHYLFTJRFURAL 1. Preparation

The source of 5-hydroxymethylfurfural which has been most commonly employed is sucrose. In the method described by Haworth and Jones, l1 following Kiermayer's condition^,^ a 30 % solution of sucrose in water containing 0.3% oxalic acid was heated at 120-140' under pressure for 2.5 hours. The resulting solution, which was red-brown colored, was filtered from the black humin material always formed in this reaction and the filtrate stirred for one hour with basic lead acetate; this being to neutralize the solution and adsorb impurities. After separ& tion of the inorganic precipitate by centrifuging, the 5-hydroxymethylfurfurd was removed from solution by continuous extraction with ethyl acetate. Evaporation of the solvent from the extract after drying over magnesium sulphate gave a brown syrup which crystallized slowly a t 0". When distilled in a high vacuum 5-hydroxymethylfurfural wm obtained in 27% of the theoretical yield as a pale yellow, mobile liquid, which crystallized completely and immediately a t 0". The writer has found when using this method that it is better to carry out this distillation soon after the isolation of the syrup. On several occasions the distillation of material which had been kept for some time resulted in complete decomposition of the furan compound. The quantity of humin formed in this reaction varies; 10-20 g. being produced from 100 g. of sucrose when heated a t temperatures between 130' and 160". Below 130' the quantity of humin is less but the yield of 5-hydroxy-

THE FORMATION O F F U R A N COMPOUNDS FROM HEXOSES

97

methylfurfural is also low. Above 170" the quantity of humin increases rapidly with increase in temperature. The nature of this substance is unknown beyond its being polymeric. It has been shown recently however that it is formed from 5-hydroxymethylfurfural by the action of dilute acids a t 130°.60 A modified method of preparation of 5-hydroxymethylfurfural given by Montgomery and Wiggins12 dispenses with the oxalic acid which is shown t o be unnecessary for this reaction. By heating a 30% solution of sucrose at 160-170" a yield of 22% of the theoretical was obtained. I n this case the reaction was carried out in the presence of hydrogen as it was found that the yield was decreased and the quantity of humin increased by heating in air instead of hydrogen. A by-product which is encountered in the preparation of 5-hydroxymethylfurfural is 5,5'-diformyldifurfuryl ether (XXVII). It is a crystalHCOHC-C

II

1

CH

H

-CH**O.CH*-

A

C

4

H &-CHO

'0'

'0'

XXVII

line compound, m. p. 112", and was first obtained from 5-hydroxymethylfurfural on distillation or by standing it over concentrated sulfuric acid4 It was later obtained in 8 % of the theoretical yield by heating 5-hydroxymethylfurfural a t 100"; by heating in the presence of pyruvic acid the yield was increased t o 23%.61 The presence of the ether has been demonstrated in the undistilled hydroxymethylfurfural syrups obtained by degradation of carbohydrates with water at 155-165°.62 The best preparative method seems to be continued distillation of 5-hydroxymethylfurfural, when the ether itself distils a t temperatures of about 200" and pressure of 0.01-0.05 mm. and can thus be obtained in moderate yield as a very pure compound. 2. Physical Properties

5-Hydroxymethylfurfural is a low melting compound which can be recrystallized from an ether-light petroleum mixture, forming colorless crystals which on exposure t o air and light become discolored. It is miscible with water in all proportions and dissolves readily in organic solvents. Its physical properties are conveniently summarized in Table I. (50) J. J. Blanksma and G . Egmond, Rec. trav. chim., 66, 309 (1946). (51) T. Iseki, 2.physiol. Chem., 216, 130 (1933). (52) K. Aso, J . Agr. Chem. Soc. Japan, 10, 1201 (1934).

F. H. NEWTH

TABLE I Properties of 6-H ydroxymethylf urfural Melting point Boiling point Density Refractive index Heat of combustion Molecular extinction coefficient

31.5",11-*0~63 35-35.5°,6433.3-33.5" (corr.)lEo 114-116"/1.0 mm.,ao 115-120"/0.5 mm.,68 110" (bath temp. 135-140")/0.02 mm.ll di616, 1.268; d430, 1.2629" 1.556; naOra0 1.552; naga01.563a0;n ~ l 1.562711 ' 665 Kcals/mole.*o X(max.) mp, 283; E, 14.3OOL7;228, 285; 3,620, 16,500180; 230, 284; 3,080, 16,7001*

3. Color Reactions There are a number of well-known tests for carbohydrates which depend on color formation. Thus in the Molisch test the substance is treated with mineral acid in the presence of a-naphthol and a characteristic purple color is formed. I n Seliwanoff's test only ketoses give an immediate red color when warmed with mineral acid and resorcinol, and similarly ketoses give a blue coloration when warmed with sulfuric acid and diphenylamine in the Ihl-Pechmann reaction. I n their work on 5-hydroxymethylfurfural, Van Ekenstein and B l a n k ~ m a ' showed ~ that this compound gave similar colors with the same reagents. For instance, 5-hydroxymethylfurfural treated with hydrochloric acid and resorcinol or phloroglucinol gave red colors ; with a-naphthol, deep violet; with diphenylamine, dark blue; and an orange color with aniline acetate. It was then certain that the formation of colored substances from the carbohydrates themselves could be ascribed to a furan compound which results from the reaction with the mineral acid present. There was a t the time however some confusion of 5-hydroxymethylfurfural with furfural since the latter also gives similar colorations with the corresponding reagents. The subject was investigated by MiddendorpZ0who examined spectroscopically some of the colors and by the position of the absorption bands showed that the coloring matters produced from the hexoses were the same as those from 5-hydroxymethylfurfural, but those obtained from furfural and methylfurfural were different. The latter however agreed with the colors given by pentoses and methylpentoses. It was thus established that the color reactions used in testing for hexoses are t o be attributed to 5-hydroxymethylfurfural and with pentoses, t o furfural. It is unlikely that the colored products are formed from the furan compounds themselves, but under the acidic conditions employed they decompose t o give a substance (53) H. P. Teunissen, Rec. trav. chim., 49, 784 (1930). (54) T. Reichstein, Helu. Chim. Acta, 0, 1066 (1926).

THE FORMATION OF FURAN COMPOUNDS FROM HEXOSES

99

which is capable of forming colored products with the reagents. The Dische reaction for 2-deoxypentoses has been interpreted in this way,55 in which the characteristic blue coloration given with diphenylamine is attributed to the formation of w-hydroxylevulinic aldehyde (XXVIII). HOCH2.CO.CH2.CH2.CHO XXVIII

The recent developments in partition chromatography of sugars on paper have involved the use of some of the reagents mentioned above and their application has been very successful in the spraying of the chromatograms to demonstrate the position of sugars on the paper.S6~67~68 4. Chemistry and Transformation Products

The number of furan compounds with substituents at positions 2 and 5 is great and only those compounds and the reactions by which they are formed have been selected which illustrate the chemical behavior of 5-hydroxymethylfurfural itself and its immediate derivatives. a. Reactions of the Hydroxymethyl Group.-The compound behaves like a normal primary alcohol inasmuch as esters are readily formed. Thus by heating 5-hydroxymethylfurfural with acetic anhydride and sodium acetate, crystalline acetoxymethylfurfural is formed.6g Benzoxymethylfurfural also is obtained by treatment with benzoyl chloride in the presence of alkali.20 Oxidation has been carried out using concentrated nitric acid; there is however simultaneous oxidation of the aldehyde group and furan 2,5-dicarboxylic acid (X) is prod~ced.~.This may be obtained also by oxidation of 5-chloromethylfurfural with chromic or nitric By restraining the oxidation of 5-hydroxymethylfurfural with nitric acid, it has been possible to isolate the partially oxidized compound, furan Z15-dialdehyde (XXIX). Better yields, however, have been obtained from 5-chloromethylfurfural and from the latter compound is obtained also 5-formylfuroic acid (XXX). 6 0 HCOHC-C

II

8"

-CHO

OHC-"8-I:COOH

'0' '0' XXIX xxx (55) R. E. Deriaz, M. Stacey, Ethel G. Teece and L. F. Wiggins, J . Chem. SOC., 1222 (1949). (56) S. M. Partridge, Biochem. J., 42, 238 (1948). (57) W. G . C. Forsyth, Nature, 161, 239 (1948). (58) S. M. Partridge, Nature, 164, 443 (1949). (59) J. Karashima, 2. physiol. Chem., 180, 241 (1929). (60) W. F. Cooper and W. H. Nuttall, J . Chem. Soc., 101, 1074 (1912).

100

F. H. NEWTH

The hydroxyl group is very easily replaced by halogen. Using a solution of hydrogen chloride in ether, Reichstein and Zschokkefllobtained from 5-hydroxymethylfurfural the 5-chloromethylfurfural which had been prepared earlier by Fenton and coworkers in their studies on the degradation of carbohydrates with halogen In the same way 5-bromomethylfurfura1 is easily obtained from 5-hydroxymethylfurfural when it is treated with hydrogen bromide in ether.20s22The ease with which the hydroxyl group is replaced by a halogen atom is not a usual feature of primary alcohols and is here undoubtedly due to an electronic effect of the furan ring. Although they are so easily formed, the halogen compounds are also very reactive and for this reason they are useful intermediates in the formation of derivatives of 5-hydroxymethylfurfural. In boiling water both 5-chloromethyl- and 5-bromomethylfurfura1 are immediately hydrolyzed to the 5-hydroxymethyl compound in quantitative yield.60 They are also hydrolyzed by methanol or ethanol and in the presence of barium carbonate 5-metho~ymethyl-~~ and 5-ethoxymethylfurfural are obtained.20@162 Treatment of the bromo-compound with silver acetate in glacial acetic acid provides 5-acetoxymethylfurfural, and 5-benzoxymethylfurfural is prepared in a similar manner.24s It is interesting to find that when 5-bromomethylfurfura1 is heated with a solution of sodium cyanide in ethanol, it is the 5-ethoxy compound rather than the nitrile which is formedaB2 5-Chloromethylfurfural undergoes a Friedel-Crafts reaction with both benzene and toluene in the presence of aluminum trichloride to give 5-benzylfurfural (XXXI) and 5-p-tolylmethylfurfural (XXXII) ;24b and 5-methylfurfural (VI) can be obtained by reduction of the 5-chloromethyl or 5-bromomethyl compound with stannous chloride2“ or with zinc dust and acetic Both 5-halogenomethylfurfurals undergo a HC-CH

HC-CH

0 - C H z - b

b-CHO

C H S O - C H B

‘O/ XXXI

‘0’

XXXII

E

CH HCA-cH,.cH,-tl

HCOHC-

CH C--CHO II

0 ‘’

‘O/

II

C-CHO

XXXIII (61) T. Reichstein and H. Zschokke, Helv. Chim. A d a , 16, 251 (1932). (62) W. F. Cooper and W. H. Nuttall, J . Chem. SOC.,99, 1193 (1911). (63) T. Reichstein and H. Zschokke, Helv. Chim. A d a , 16, 249 (1932).

THE FORMATION OF FURAN COMPOUNDS FROM HEXOSES

101

reaction of the Wurtz-Fittig type when heated with finely divided silver in benzene to give 2,2’-difurfurylethane-5,5’-dialdehyde(XXXIII).22*248 Finally, in this section, mention can be made of the dehydration which occurs between two molecules of 5-hydroxymethylfurfural when heated, to give the ether XXVII. This also is an unusual behavior for a primary alcohol. b. Reactions of the Aldehyde Group.-In many ways the behavior of furfural and benzaldehyde is analogous. In the presence of alkali, furfural undergoes the Cannizzaro reaction to give furfuryl alcohol and furoic acid. With potassium cyanide, furoin, the analog of benzoin, is formed and hydrofuramide is obtained when furfural is treated with ammonia. The aldehyde group attached to the furan nucleus is behaving very much as an aromatic aldehyde and a similar behavior would be expected with 5-hydroxymethylfurfural. In the presence of alkali, 2,5-dihydroxymethylfuran (XXXIV) and 5-hydroxymethylfuroic acid (VII) are formed2*and the corresponding compounds are obtained from 5-methoxymethylfurfural.~4 HC-

CH

II

HOCHr-

C-CHzOH

‘ 0 ’ XXXIV

5-Hydroxymethylfurfural, however, does not form a hydrofuramide derivative when treated with ammonia and neither does it give the corresponding derivative of furoin; in both cases resinous material is formed.20 On the other hand, 5-methylfurfural does react with ammonia to give a hydramides6 and although no furoin derivative is formed, It 5-formylfuroic acid gives a cyanohydrin with hydrogen cyanide. appears then that the reactions of the aldehyde group, which in furfural are those of an aromatic aldehyde, are modified by the presence of a substituent at position 5 in the furan ring. Bisulphite addition compounds are given by all the 5-substituted furfurals with the exception of 2,5-diformylfuran. 5-Ethoxymethylfurfural forms a diethyl acetaIz6and the diacetates of 5-methylfurfural and 5-acetoxymethylfurfural have been obtained.66 The 5-substituted furfurals all condense with amino compounds to give a series of crystalline hydrazones, phenylhydrazones and substituted phenylhydrazones; and the semicarbazones, oximes and anilides are also well-characterked derivatives. A feature of the 2,4-dinitrophenylhydrazones is that some (64) J. J. Blanksma, Chem. Weekblud, 9, 186 (1912). (65) J. J. Blanksma, Chem. Weekblud, 6, 717 (1909).

102

F. H. NEWTH

have been obtained in two forms, which may be cis and trans isomers.66 Like furfural, which gives two oximes, the syn- and anti-forms of the ~ ~ ~5-methyloximes of 5-hydroxymethylfurfural14 5 - b e n z y l f u r f ~ r a land furfurale7 have been obtained. A condensation occurs between 5-hydroxymethylfurfural and malonic esterz0and in a similar way, two molecules of malonic ester react with furan 2,5-dialdehyde.68 A condensation product, XXXV, has also been obtained with hydant0in.6~ 5-Hydroxymethylfurfural and its acetyl derivative undergo the Perkin reaction with sodium acetate and acetic anhydride giving 5-acetoxymethylfuran 2-acrylic acid (XXXVI).’O Similar products of the same reaction are obtained from 5-methylfurfuraP and 5,5’-diformyl-l,l’-furylmethylether (XXVII).61,72 HC-CH HOCH2-C

NH.CO.NH

II

-CH=C-

I

1 co

‘ 0 ’

xxxv HCCH&O*OCH2-

-CH=CH.COOH

‘ 0 ’ XXXVI

Some mention has been made already of the oxidation of the aldehyde group simultaneously with the primary alcohol group by nitric acid, giving furan 2,5-dicarboxylic acid. Oxidation of the aldehyde group alone is possible with moist silver oxide. With this reagent, 5-hydroxymethylfurfural is smoothly converted into 5-hydroxymethylfuroic acid” and the same product is obtained from 5-acetoxymethylfurfural, the acetyl group of which is removed during the reaction.70 In the same way, 5-methylf~rfural~’s~~ 5-methoxymethyl- and 5-ethoxymethylfurfural give good yields of the corresponding furoic acids.20m26.6S 5-Bromomethylfurfural also is oxidized by silver oxide in water, when hydrolysis of the bromine atom occurs at the same time.19.21 Alkaline permanganate is unsatisfactory for the oxidation of 5-hydroxymethylfurfural, but has H. Bredereck, Ber., 66, 1833 (1932). K. Fromhertz and W. Meigen, Ber., 40, 403 (1907). W. F. Cooper and W. H. Nuttall, J. Chem. Soc., 106,2219 (1914). T. Iseki, 2. physiol. Chem., 216, 127 (1933). J. Karashima, 2. physiol. Chem., 180, 241 (1929). R. Kuhn, F. Kohler and Leonore Kohler, Z . physiol. Chem., 247, 197 (1937). K. Aso, J. Agri. Chem. SOC.Japan, 16, 56 (1939). (73) I. J. Rinkes, Rec. trav. chim., 49, 1118 (1930).

(66) (67) (68) &9) (70) (71) (72)

THE FORMATION

OF FURAN COMPOUNDS FROM HEXOSES

103

been used successfully in the conversion of the 5-methoxy-derivative to furan 2,5-dicarboxylic a ~ i d . ~ ~ * 4 ~ Although furfural is easily reduced to furfuryl alcohol by means of sodium amalgam or by hydrogenation in the presence of a palladium oxide catalyst,74 the reduction of 5-hydroxymethylfurfural to 2,5-dihydroxymethylfuran (XXXIV) does not occur so readily. With sodium amalgam or zinc dust in acetic acid, a resinous product is obtained.20 The formation of XXXIV by hydrogenation in the presence of Raney nickel has been described recently, however, when it was obtained from 5-hydroxymethylfurfural together with the fully reduced d i ~ a r b i n o l . ~ ~ In contrast, the reduction of 5-methylfurfural t o 5-methylfurfuryl alcohol (XXXVII) is achieved easily using copper ~ h r o m i t eor~platinum ~ oxide7?as catalyst. Reduction of the aldehyde group to -CHI has been HC-

I CHs-C

CH

& -CH,OH

‘ 0 ’ XXXVII

successfully carried out in the case of 5-hydroxymethylfurfural by the Wolff -Kischner method of heating the hydrazone with sodium ethoxide to give XXXVIIs3 and in the same way 5-formylfuroic acid has been converted into methylfuroic acid.’* c. Reactions of the Furan Ring.-Considering first the addition reactions of the furan ring, the most important is the addition of hydrogen. Hydrogenation occurs readily at temperatures above 100” and in the presence of Raney nickel, 5-hydroxymethylfurfural is converted into 2,5-dihydroxymethyltetrahydrofuran (XXXVIII) in good yield and 5-hydroxymethyltetrahydrofuran2-carboxylic acid (XXXIX) is obtained from 5-hydroxymethylfuroic acid.’g Similarly, 2,5-dimethylfuran is converted to the tetrahydrofuran derivative using nickel on kieselguhr.80 HzC-CHz HOCH2-cHI

HzC-CHz lH.CHnOH

‘o/ XXXVIII

HOCH2-AH

AH.COOH

‘O/ XXXIX

(74) R. Adams and W. E. Kaufmann, J . Am. Chem. Soc., 46, 3029 (1923). (75) F. H. Newth and L. F. Wiggins, Research, 3, 50 (1950). (76) D. Dinelli and G. €5. Marini-Bettblo, Gazz. chim. ital., 71, 117 (1941). (77) E. W. Scott and J. R. Johnson, J . Am. Chem. SOC.,64,2549 (1932). (78) E. VotoEek and A. KroBlhk, Coll. Czech. Chem. Comm., 11, 47 (1939). (79) W.N.Haworth, W. G . M. Jones and L. F. Wiggins, J . Chem. SOC.,1 (1945). (80)S. Fried and R. D. Kleene, J . Am. Chem. Soc., 63, 2691 (1941).

104

F. H. NEWTH

Hydrogenolysis products accompany the main reaction product to a small extent. Reduction of the furan ring also occurs at normal temperatures with sodium amalgam.81 In furan 2,5-dicarboxylic acid, the most reactive positions are 2 and 5, at which hydrogen first adds with the formation of 2,5-dihydrofuran 2,5-dicarboxylic acid (XL). This undergoes a rearrangement when treated with alkali to the 2,3-dihydrofuran compound, XLI, and this on further treatment with sodium amalgam is reduced to tetrahydrofuran 2,5-dicarboxylic acid (XLII) which has also been obtained by the direct catalytic hydrogenation of furan 2,5dicarboxylic acid.79

"Zi=x"

HOOC-

H

HzC-CH H*COOH

H0OC-L

\O/

XI,

Il-cooH

'd XIAI

H zC-CH HOOC-AH

2

AH.cooti

'O/ XLII

In the tetrahydrofuran compounds there is opportunity for the existence of cis and trans isomers. They have been separatedsl in the case of XL and XLII, the cis-form of which forms an anhydride. Evidence for the existence of the cis-form of 2,5-dishydroxymethyltetrahydrofuran (XXXVIII) is found in the behavior of either its dichloroor di-toluene-p-sulfonyl derivative with methanolic ammonia. From this reaction the dicyclic compound, 8-oxa-3-azabicyclo [3,2,1] octane (XLIII) is obtained which can have been formed only from the cis-form of the dicarbinol.82 An example of the addition of bromine t o the furan @HzC-----CH& I

\

I

NH'

0 XLIII (81) (a) H. B. Hill, Ber., 32, 1221 (1899); (b) H. B. Hill and A. S. Wheeler, Am. Chem. J., 20, 169 (1898). (82) F. H. Newth and L. F. Wiggins, J . Chem. Soc., 155 (1948).

THE FORMATION OF FURAN COMPOUNDS FROM HEXOSES

105

ring has been given in which 5-methylfuroic acid forms a t e t r a b r ~ m i d e ; ~ ~ and Diels-Alder addition of maleic anhydride and acetylene dicarboxylic acid t o 2,5-dimethylfuran has been reported.84 The writer has found that no addition reaction occurs with 5-hydroxymethylfurfural and maleic anhydride. Nuclear substitution in the compounds under discusison is not of great importance since the most reactive positions in the furan ring, 2 and 5, are already substituted. I n certain compounds such as 2,5dimethylfuran and 5-methylfuroic acid, substituents have been introduced at positions 3 and 4 and there are instances of the elimination of one group and its replacement by another.36~73~83~85~86 The most important aspect of the chemistry of the furan ring in 5-hydroxymethylfurfural is its scission under the influence of acidic reagents. In the very earliest work on the acidic degradation of hexoses, levulinic and formic acids were obtained which were shown subsequently to have arisen from the decomposition of 5-hydroxymethylfurfural. This degradation was studied by T e u n i s ~ e n who ~ ~ , measured ~~ its rate and showed it to be a unimolecular reaction. He proposed the scheme represented by XLIV-XLIX for the conversion of 5-hydroxymethyl-

XLIV

XLV HC-CH

HOCH2--&

CHZ-CH~ AH

+ H c o o H -+ Hocrr,-Ao

AH AH XLVI

AH0 +

XLVII CkzCHflIH

-*

CHICOCHZCHZCOOH.

LO

\cH,';"..

XLVIII

XLIX

(83) H. B. Hill and W. L. Jennings, Am. Chem. J., 16, 159 (1893). (84) (a) K. Alder, 0. Diels and E. Naujoks, Ber., 62, 544 (1929); (b) K. Alder and K. H. Backendorf, Ann., 636, 101 (1938). (85) H. Gilman and R. R. Burtner, Rec. truo. chim., 61, 667 (1932). (86) H. Gilman and N. 0. Calloway, J. Am. Chem. SOC.,66, 4197 (1933). (87) H. P. Teunissen, Rec. truv. chim., 60, 1 (1930).

106

F. H. NEWTH

furfural to levulinic acid in dilute acid solution. A similar but less detailed scheme has also been proposed by Pummerer, Guyot and Birkofere8 in which evidence for the existence of XLVII as an intermediate is based on an analogy with furfuryl alcohol, from which the dimethylacetal of 5-methoxylevulinic aldehyde is obtained by very mild acidic treatment and which is further converted t o levulinic acid with mineral acid. It has been shown recently that it is in fact C1 in the glucose molecule which is eventually embodied in the formic acid, when the 5-hydroxymethylfurfural obtained from the glucose is decomposed, by the use of glucose containing isotopic C14 at the reducing group and its subsequent detection in the formic acid 0nly.89 I n contrast to the furan ring, the tetrahydrofuran ring is more stable t o acids and the compounds resemble cyclic ethers. Cleavage is possible and the diacetate of 2,5bishydroxymethyltetrahydrofuran gives 1,2,5,6-tetraacetoxyhexane on acetolysis and treatment with hydrogen bromide in glacial acetic acid gives 2,5-dibromo-1,6-diacetoxyhexane. Tetrahydrof~ran-2~5-dicarboxylic acid, however, is more stable, and more drastic conditions are necessary to bring about the cleavage of its ring.7g Finally, the formation of derivatives of pyridine from 5-hydroxymethylfurfural and related compounds on treatment with ammoniag0 may be considered in this section on the furan ring. 5-Hydroxymethylfurfural itself gives 2-hydroxymethyl-5-hydroxypyridine(XLIV) with ammonia, which is presumably formed by opening of the ring in the intermediate aldehyde-ammonia compound followed by closure t o give the 6-membered ring. CH

/ - --\\

HC

C-OH

XLIV (88) R. Pummerer, Olga Guyot and L. Birkofer, Ber., 68, 480 (1935); (compare F. Leger and H. Hibbert, Canad. J . Res., 16B, 68 (1938)). (89) J. C. Sowden, J . Am. Chem. Soc., 71, 3568 (1949). (90) K. Aso, J . Agri. Chem. SOC.Japan, 16, 249 (1940).

CUPRAMMONIUM-GLY COSIDE COMPLEXES BY RICHARDE. REEVES Southern Regional Research Laboratory. Bure2u of Agricultural and Industrial Chemistry. Agricultural Research Administration. u . Department of Agriculture. New Orleans. Louisiana

.

CONTENTS

I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . I1. The Cuprammonium-Glycol Reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Spatial Requirements for Complexing . . . . . . . . . . . . . . . . IV. Correlations between Reaction with Cuprammonium a ................... of Carbohydrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Reaction with Acetone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 . Glycol Cleavage b y Lead Tetraace ....................... V . Cuprammonium Complexes and the Str f Polysaccharides . . . . . . . . . 1. The D-Glucopyranoside Polysaccharides . . . . . . . . . . . . . . . . . . . . . . . . . a . Cellulose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ............... b . Lichenin, Starch, Glycogen and the Schar c . Laminarin ..................... ..................... d . The Polysaccharide from Phytomo e. The Dextran from Leuconostoc dextranicum . . . . . . . . . . . . . . . . .

.

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

. . . .

.. . .. ..

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

VI Cuprammonium Complexes and the Sh of Pyranoside Rings . . 1 The Significance of Ring Shapes in Glycopyranosides . . . . . . . 2. Factors which Influence Pyranoside Ring Shapes . . . . . . . . . . . . . . . . . . 3. Special Aspects of the Reactions of Glycopyranosides with :uprammonium . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....... a D-Glucopyranosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . b D- and L-Galactopyranoside series . . . . . . . . . . . . . . . . . . . . . . . . . . c Hexosans (1, 5)p( 1,s) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....... d Other Glycosides .............................. ....... VII Appendices . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....... 1. The Preparation of Cupra A . . . . . . . . . . . . . . . . . . . . ....... 2 . The Preparation of Cupra B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Determination of Optical Rotations in Cuprammonium Solutions., . . 4. Conductometric Measurements in Cuprammonium Solutions . . . . . . . .

.

.

. . . .

107

108 109 110 113 113 115 116 118 117 119 120 120 121 121 122 122 122 123 125 125 128 129 130 131 131 131 132 134

108

RICHARD E. REEVES

I. INTRODUCTION Much has been learned about spatial relationships in organic molecules through investigations on those reactions in which two positions are simultaneously engaged in a reaction; an early historical example is the conclusion that the carboxyl groups of maleic acid are in cis position because the acid forms an anhydride whereas the anhydride does not form in the case of fumaric acid, to which the trans position is accordingly assigned. In the field of carbohydrate chemistry knowledge has been gained in this way from studies on the cyclis acetals and ketals; cyclic esters such as orthoesters, borates and carbonates ; glycol cleavage reagents; and the cuprammonium-glycoside complexes. Carbohydrate orthoesters' and borate esters2 have been the subjects of reviews in this publication. This chapter undertakes a review of the complexing reaction between cuprammonium and carbohydrate molecules with special consideration of the spatial relationships that are revealed by this reaction. Knowledge regarding the shapes which sugar molecules take in solution is of importance to an understanding of many of their chemical reactions; shape is probably the determining factor in all cases where a reactant makes even temporary contact with groups attached to more than a single carbon atom. Knowledge regarding shapes is also essential to any attempted correlation of physical properties. For example in the application of the well known rules of isorotation3 the difference in rotation of the a! and @ forms of a sugar or sugar derivative will equal 2A only in those instances where the shapes of the molecules, aside from the first carbon atom, are the same for the two forms.aa Molecular shapes are known to constitute the basis for the specific action of enzymes. Enzymatic reactions with carbohydrates require contact between enzyme and substrate at two or more points.* The contribution of molecular shapes to enzymatic reactions may, however, be greater than the mere determination of specificity. If contact between enzyme and substrate w.ere to occur when the latter possessed an unusual, high-energy molecular shape the shape might provide the energy or drive which causes certain of the reactions to occur.6 (1) E. Pacsu, Advances in Carbohydrate Chem., 1, 78 (1945).

(2) J. Boeseken, Advances in Carbohydrate Chem., 4, 189 (1949). (3) C.S.Hudson, J . Am. Chem. SOC.,S1,66 (1909); Scientific Papers of the Bureau of Standards, No. 533 (1926). (3a) E. Pacsu, J . Am. Chem. SOC.,61,2669 (1939);C.S. Hudson, ibid., 61, 2972 (1939). (4) A. Gottschalk, Nature, 160, 113 (1947);Advances i n Carbohydrate Chem., 6, 49-78 (1950). (5) High-energy molecular shapes are not to be confused with a and 6 isomerism, or pyranose-furanose-aldehxdetransformations.

CUPRAMMONIUM-GLYCOSIDE COMPLEXES

109

11. THECUPRAMMONIUM-GLYCOL REACTION The reactions between cuprammonium and the carbohydrates herein considered are called glycol-complexing reactions since they involve an attachment between cuprammonium and two suitably locating hydroxyl groups. Entirely analogous reactions are exhibited between certain simple glycols and cuprammonium. The relative position of the two hydroxyl groups is the determining factor in whether or not a complexing reaction will occur, and in the extent of such reaction if one does occur. Most of the observed complexes involve hydroxyl groups located on adjacent carbon atoms; however, in a few instances reaction occurs with carbinol groups separated by a carbon atom. And reaction with carbinol groups even more widely separated must be considered whenever the molecule as a whole is able to take a shape which would bring the two hydroxyl groups into close proximity. I n the present state of knowledge it is impossible to describe completely the structure of any cuprammonium-glycol complex. Although the relative position of the two hydroxyl oxygen atoms can be located with considerable accuracy, the nature of their linkage to the central copper atom is unknown as are the number and nature of the other groups attached to the central atom. Cuprammonium is a strong base, while the cuprammonium-glycol complexes are either much less strongly dissociated into cations and hydroxyl groups; or the complexes may even be electro-negative in character, a condition which would apparently require the incorporation of hydroxyl ions into the complex. The reaction between cuprammonium and a glycol appears to occur instantaneously, a fact which might be regarded as a n indication that, initially a t least, the reaction is ionic. The reaction between cuprammonium and a glycol is a reversible, bimolecular association. It is evidenced by spectrophotometric and conductometric phenomena; and, with optically active glycols, is often accompanied by dramatic changes in optical rotation. Methods of following the conductometric and rotational changes are given in appendices to this chapter. The region of most pronounced change in absorption spectra lies in the near ultraviolet, between 300 and 400 mp, and certain glycols also produce a change in the visible region and the near infrared. 6 The composition of cuprammonium varies widely with ammonia concentration' and, probably, with hydroxyl ion concentration as well. (6) R. E. Reeves, J . Am. Chem. SOC.,73, 957 (1951). (7) J. Bjerrum, Kgl. Danske Videnskab. Selskab, Mal.-fys. Medd., 11, 10 (1932);

12, 15 (1934).

110

RICHARD E. REEVES

It appears likely that the composition of cuprammonium-glycol complexes is variable in much the same manner. The spatial demands placed upon the glycol by the oriented valences of the central copper atom may differ slightly with the number and nature of the other complexed groups; therefore it is desirable to work with standard cuprammonium solutions. If not, at least the composition of the cuprammonium and the concentration of glycol should be stated whenever properties of cuprammonium-glycol complexes are reported. I n this chapter the term “ cupra” when employed represents a reactive cuprammonium; two extensively used standard solutions will be designated cupra A and cupra B, respectively. There seems t o be no pronounced tendency for cuprammonium t o combine with more than a single glycol group; even exceedingly great excesses of a highly reactive glycol have failed to show any indication of reaction involving two glycols and a single cuprammonium.6 The whole theory of the molecular dispersity of cellulose in cuprammonium, upon which viscometrically measured molecular weights are based, is dependent upon the premise that cuprammonium combines with only one glycol group. Entirely different results may be obtained when copper and glycol groups are brought together in the presence of alkali metal hydroxides. Under such conditions copper may combine with two glycol^.*^^ Even though ammonia be present, a high concentration of strong alkalies may bring about reaction between copper and two glycol groups; such an occurrence would account for the insolubility of sodiumcupricellulose. 111. SPATIALREQUIREMENTS FOR COMPLEXING Adjacent groups attached t o carbon atoms which form a part of a five-membered planar ring or a six-membered strainless ring must be located, approximately, in one of the positions shown in Figure 1. I n these diagrams the lower of the two linked carbon atoms is presumed t o be nearer the observer. The projection of the angle made by the two valence bonds onto a plane perpendicular t o the carbon-carbon bond is called the projected angle between the groups under consideration. By convention this angle is negative if measured in a clockwise direction from the nearer group; positive if measured counter-clockwise. Irregularities in ring shape may produce small variations in the magnitude of the projected angles; transition from one ring conformation to another would change the angles. However, ring shapes will require (8) H. Deuel and H. Neukom, Mukromot. Chem., 4, 97 (1949). (9) P. Pfeiffer, H. Simons and E. Schmidt, 2. anorg. Chem., 266, 318 (1948).

CUPRAMMONIUM-GLYCOSIDE COMPLEXES

111

the stable position of adjacent groups to be recognizably near one of the angles 0", +60", k 120°, or 180". Even in acyclic substances energy levels tend t o locate adjacent groups at the 60" or 180" angles.

FIG.1.-The

Various Angles between Groups Located on Adjacent Carbon Atoms.

The distances between the centers of oxygen atoms of hydroxyl groups located a t different projected angles are given in Table I. I n calculating these distances tetrahedra1 angIes were employed for the carbon valenczs ; carbon-carbon and carbon-oxygen bond distances of 1.54 and 1.45 A, respectively, were accepted.1° TABLEI The Distances between the Centers of Oxygen Atoms on Adjacent Carbon Atoms'Q Projected Angle Oxygen-Oxygen Distance

B

0" 60" 120" 180"

2.51 2.86 3.45 3.71

The behavior of cuprammonium in the presence of a glycol can be explained as a simple bimolecular association. There are, however, (10) R. E. Reeves, J. Am. Chem. Soc., 71, 2116 (1949).

112

RICHARD E. REEVES

restrictions which apply t o the structure of the glycol. The distance between two hydroxyl oxygen atoms which is most favorable for complexing with cuprammonium lies in the vicinity of 2.51 +%, which is the distance between oxygen atoms of hydroxyls in the 0" angle. Cuprammonium reacts with hydroxyl groups located at distances slightly greater than the optimum, but affinity for the glycol decreases as the distance increases until, at 3.45 A, no detectable amount of reaction occurs. When cuprammonium combines with adjacent hydroxyl groups a new five-membered ring is formed. If the hydroxyls are located in the true cis position (0" projected angle) the copper-containing ring will be symmetrical, considering only the atoms of the new ring. Hydroxyls not in the true cis position yield asymmetric rings upon complexing with cuprammonium, and the new rings exert a large rotational moment the sign of which is determined by the nature of the asymmetry (whether the projected angle between the hydroxyl groups be positive or negative), and the magnitude of which is, a t least roughly, proportional t o the extent of asymmetry. Those projected angles between hydroxyl groups which are capable of forming cuprammonium complexes have been determined by investigating substances in which the location of the adjacent hydroxyls is fixed by ring system, and is known." Table I1 lists the behavior of a number of those substances in cuprammonium. It is apparent that reaction occurred a t projected angles of 0" and 60°, but not at 120" or 180". By referring t o the oxygen-oxygen TABLEI1 The Behavior with Cuprummonium of Adjacent Hydroxyl Groups Located at Different Projected Angles" Substance

Projected Valence Angle

Erythritol anhydride (cis-2,3-dihydroxytetrahydrofurane) Methyl 2,6-anhydro-a-~-altropyranoside Cellulose D-Glucosan (1,4)p(1,6) 2,6Anhydrosorbitol Methyl 4,6-benzylidene-a-~-altropyranoside

0"

0 ' -60' - 120" 120" 180"

+

Behavior with Cupra

Highly reactive Highly reactive Reactive Unreactive Unreactive Unreactive

distances assigned to hydroxyl groups in these various projected angles in Table I the spatial requirements for complexing become apparent. (11)

R.E.Reeves, J . Am. Chem. SOC.,71,212 (1949).

CUPRAMMONIUM-GLYCOSIDE COMPLEXES

113

Complexing has also been observed with hydroxyl groups located in the 1,3 position, but only in the rare instances where the two groups have been located by the shape of the molecule in the position of closest approach. I n this position the distance between such oxygen atoms lies within the range where complexing is possible.

IV. CORRELATIONS BETWEEN REACTION WITH CUPRAMMONIUM AND OTHER REACTIONS OF CARBOHYDRATES Since reaction with cuprammonium provides a measure of the relative position of adjacent hydroxyl groups it is of interest to compare cuprammonium data with existing information on other reactions in which two hydroxyl groups participate.

1. Reaction with Acetone One instance where correlation with cuprammonium data appears possible is the reaction between adjacent cis glycol groups and acetone to form isopropylidene derivatives. Although data on the kinetics and equilibria of isopropylidene formation are too meager to prove that reactivity with acetone parallels reactivity with cuprammonium, isolated observations support such a supposition. Knauf , Hann, and HudsonI2 have noted the ease of formation of the acetone derivatives of D-mannosan, and this is one of the substances most reactive toward cuprammonium.6 Tipsonla has noted that the optically active 2,3-butanediols react with acetone more readily than the meso form, and this is the order in which these substances react with cuprammonium. l 4 Although reaction constants for the acetone and cuprammonium reactions are not available, the literature does contain data on the properties of acetone derivatives of glycosides which may be compared with the properties of the corresponding cuprammonium complexes. Table I11 lists a number of glycosides for which rotational shifts in cuprammonium have been determined and for which optical rotations on the parent glycoside and its acetone compound are available in a single solvent. It is seen that the rotational shifts due to reaction with acetone, although much smaller than those due to cuprammonium complexing, are of opposite sign from those occurring upon the latter reaction. The probability of a correlation in all nine instances without interrelation of the two phenomena is 1/256; hence it is very probable that a common (12) A. E. Knauf, R. M. Hann and C. S. Hudson, J . Am. Chem. SOC.,88, 1447 (1941). (13) R. S. Tipson, J . Am. Chem. SOC.,70, 3610 (1948). (14) R. E. Reeves and J. R. Jung, J . Am. Chem. SOC.,71, 209 (1949).

TABLEI11 Comparison of Shifts i n Optical Rotation Due to Reaction with Acetone and with Cuprammonium Shift i n Molecular Rotation Substance

manno nos an(1,5)8(I,6) 2,3-IsopropylidenePBenzyl-D-mannosan(1,5)@(1,6) 2,3-IsopropylideneMethyl a-D-Mannopyranoside 2,3-IsopropylideneD-Gdactosan( 1,5)8(1,6) 3,4Isopropylidene2-Methyl-~-galactosan(l,5)8( 1,6) 3,F.IsopropylideneMethyl a-D-galactopyranosided 3,4IsopropylideneMethyl 8-D-galactopyranoside 3,4-IsopropylideneMethyl 2,6-dimethyl-8-~-galactopyranoside 3,4-IsopropylideneMethyl a-bfucopyranoside 3,4-Isopropylidene-

Solvent

-127.6" -58.8 -76 -13 +79.2 +24.3 -22 -61.7 -35 -72 +194.8 +168 0 +20.96" -24 -4.5 -197.4 - 166

HzO HzO CHC13 CHClo H2 0 H2 0 H2 0 H2 0 H2 0 HzO H2 0 H2 0 H2 0 HzO CHCI, CHC13 HzO Hz0

Reference

12 12 10 16 17 18 15, 20 15 10 21 17 22 17 15 24 24 17 22

Reference

of Acetone CompounG

i n Cupra Bc

+8,793

- 141,600

10

+15,356

- 136,000

10

-9,679

+175,200

19

Ec1

-8,899

+108,100

lo

u

-9,392

+95,900

10

m

+1,521

-202,700

23

3M

+4,905

- 198,900

23

2!

+4,149

-151,000

23

-1,051

+182,500

23

,. All D line rotations were measured on crystalline derivatives. Molecular rotation of isopropylidene derivative minus molecular rotation of parent substance. Molecular rotation in cupra B minus molecular rotation in water. Optical rotation calculated to the anhydrous basis. Incorrectly given as -21" in ref. 23.

*aw a

CUPRAMMONIUM-GLYCOSIDE COMPLEXES

115

factor is responsible for the isopropylidene and cuprammonium rotational s h i f t ~ . ’ ~ -As ~ ~was mentioned before, the sign of the rotational shift of the latter reaction is believed t o be determined by the sign of the projected angle between the reacting hydroxyl groups.

2. Glycol Cleavage by Lead Tetraacetate The methods of Hockett and coworker^^^^^^ and Reevesz7 allow classification of glycosides and related substances into three distinct categories depending upon rate of consumption of one mol of lead tetraacetate: One group reacts immeasurably rapidly; a second group reacts rapidly, but at a measurable rate; and a third group reacts distinctly more slowly than the second. But since rates of reaction with lead tetraacetate are complicated by the situation that, in many instances, the primary oxidation products react more rapidly than do the original glycosides, an exact assignment of relative reactivities t o the substances within each group has not been attempted from the published data. I n Table I V a number of glycosides and related substances are grouped according t o lead tetraacetate reactivity into one of the three categories, and for each substance is given the specific resistance increment, a n arbitrary measure of cuprammonium reactivity. The data reveal the unmistakable correlation between reaction with lead tetraacetate and cuprammonium. The highly reactive substances are those in which adjacent cis hydroxyls are held in the true cis (0”) position; the group having intermediate reactivities are those with cis hydroxyls on six membered rings, not fixed in the true cis position; the third and least reactive group contains only trans hydroxyl groups. (15) F. Micheel, Ber., 62, 687 (1929). (16) W. T. Haskins, R. M. Hann and C. S. Hudson, J. Am. Chem. Soc., 70, 1290 (1948). (17) F. J. Bates and Associates, “Polarimetry, Saccharimetry and the Sugars,” U.S. Govt. Printing Office, Washington (1942). (18) R. G. Ault, W. N. Haworth and E. L. Hirst, J . Chem. Soc., 517 (1935). (19) R. E. Reeves, J . Am. Chem. Soc., 72, 1499 (1950). (20) R. M. Hann and C. S. Hudson, J . Am. Chem. Soc., 64, 2435 (1942). (21) S. P. James, F. Smith, M. Stacey and L. F. Wiggins, J . Chem. Soc., 625 (1946). (22) 0. Th. Schmidt and E. Wernicke, Ann., 688, 70 (1947). (23) R. E. Reeves, J . Am. Chem. Soc., 71, 1737 (1949). (24) D. J. Bell, J . Chem. Soc., 692 (1945). (25) R. C. Hockett and W. S. McClenahan, J . Am. Chem. Soc., 61, 1667 (1939). (26) R. C. Hockett, M. T. Dienes and H. E. Ramsden, J. Am. Chem. Soc., 66, 1474 (1943). (27) R. E. Reeves, Anal. Chem., 21, 751 (1949).

116

RICHARD 1. REEVES

TABLEI V Cuprammonium Reactivities of Substances Grouped According to Reactivity with Lead Tet~aacetate*~-27 Substance

A Specific resistance

cupra Aa

Reference

-

(Group 1 ; reacts instantly with Pb(0Ac)r) Erythritol anhydride Methyl 2,6-anhydro-a-~-altropyranoside (Group I; reacts rapidly with Pb(OAc),) hlethyl a-D-mannopyranoside Methyl a-D-galactopyranoside hlethyl fl-D-galactopyranoside hle thy1 8-D-arabinopyranoside Methyl or-L-rhamnopyranoside (Group 3: reacts slowly with Pb(0Ac)r) Methyl or-D-glucopyranoside Methyl (3-D-ghcopyranoside Methyl a-D-xylopyranoside

177 240

111 75 90

b

11

100

19 23 23 23 19

50 67 46

28 28 19

!i78

The increase in specific resistance produced by an 0.01 molar solution of suhstance dissolved in cupra A. Calculated from data presented in Figure 2 of ref. 11, employing a cell constant of 0.116;cf. ref. 14.

V. CUPRAMMONIUM COMPLEXES AND THE STRUCTURE OF POLYSACCHARIDES The literature contains numerous observations on the properties of polysaccharides in cuprammonium solutions; the work on cellulose is especially voluminous. Viscometric measurements in cuprammonium solution are regularly employed to determine the size of cellulosic molecules. However, before the spatial requirements for complexing with cuprammonium became known the properties of the complexes of polysaccharides could not be interpreted in terms of the structure of their monosaccharide units. With the present understanding of cuprammonium-glycol complexing, some of the earlier observations will be reexamined. 1. DGlucopyranoside Polysaccharides

It has been shown that reaction with cuprammonium is greatly influenced by the position of a substituent group on the glucopyranoside ring.28.29 This is illustrated for monosaccharides of known structure (28) R. E. Reeves, J. Am. Chem. SOC.,71, 215 (1949). (29) R. E.Reeves, J . Biol. Ghem., 164,49 (1944).

CUPRAMMONIUM-GLYCOSIDE

COMPLEXES

117

by the data in Table V. Substitutions a t positions 2, 3, or 4 produce characteristic effects ; substitution on position 6 is not specific since similar behavior could arise if some rings were substituted a t position 2, others at position 4.

Substance Methyl Methyl Methyl Methyl

Behavior

2-methyl-j3-~-glucopyranoside 3-methyl-P-D-glucopyranoside 4-methyl-~-~-glucopyranoside 6-methyl-~-~-glucopyranoside

Strongly dextrorotatory complex No complex Strongly levorotatory complex Complex of intermediate rotation I

It will be shown that the position of linkage between the glucose units in polysaccharides determines their rotatory behavior in cuprammonium in the same manner that position of substitution does in the monosaccharides. a. Cellulose.-The solvent action of cuprammonium on cellulose has been known for nearly a century;30the strikingly large lev0 optical rotation of the resulting solution was observed by Levallois in 1884.31 Although the problem of the gross structure of cellulose is outside the scope of this review, it is of interest that L i e ~ e has r ~ ~interpreted the behavior of cellulose with cuprammonium in support of a micellar theory of cellulose structure; S t a ~ d i n g e r of , ~ a~ long chain theory; Compton,34 of a particulate theory; Hess136of a theory of secondary valence association between C6HI0O6units; and P ~ C S ofUa, theory ~ ~ of acetal linkages in equidistant open-chain units and the laminated chain structure of cellulose. Considering the fine structure of cellulose, it is known that the majority, if not all, of the glucose units are linked by glycosidic combination into chains; carbon atom 1 of one unit being linked to carbon atom 4 of the adjacent unit. Meyer’s surmise37 that the copper enters into a complex with the hydroxyl groups on carbon atoms 2 and 3 of a single (30) E. Schweizer, J . prakt. Chem., 72, 109 (1857). (31) A. Levallois, Compt. rend., 98, 44, 732 (1884). (32) Th. Lieser, Papier Fabr., 86, Tech. Wiss. Tl., 272 (1938). (33) H. Staudinger, “Die Hochmolekularen Organischen Verbindungen,” Springer, Berlin (1932). (34) J. Compton, Contrib. Boyce Thompson Inst., 10, 57 (1938). (35) K. Hess, “Die Chemie der Zellulose und Ihrer Begleiter,” Akademische Verlagsgesellschaft, Leipeig (1928). See pages 289-321. (36) E. Pacsu in “Progress in the Chemistry of Organic Natural Products,” edited by L. Zechmeister. Springer, Vienna, (1948). (37) K. H. Meyer, “Natural and Synthetic High Polymers,” Interscience Publishers, Inc., New York, (1943). See page 291.

RICHARD E. REEVES

118

glucose unit has received support from the parallel behavior of the substituted monosaccharides.29~38The various detailed structures proposed for the cuprammonium-cellulose complex may be classified as unsupported spec~lations;~~*36~~9 for, as with other cuprammonium-glycol complexes, the number and nature of the groups attached to copper is unknown and probably variable. Hess and cow0rkers~0-~~ have made extensive studies of the levo optical rotation exhibited by solutions of cellulose in cuprammonium. A book by Hess36 reviewing this work contains convincing proof of the similarity of purified celluloses from different sources, the reversibility of the complexing reaction, and the one-to-one ratio between copper and glucose. The cuprammonium solutions employed in this work were not sufficiently strong to drive the complexing reaction to completion, hence specific rotations calculated from Hess' data are somewhat lower than those calculated from the data of Comptona4and others44 where much stronger cuprammonium solutions (or higher copper to glucose ratios) were employed. The latter workers found the specific rotation of purified cotton cellulose to be -1200' (436 mp) in cuprammonium containing 15 g. copper, 240 g. ammonia and 1 g. sucrose per liter. Since the high optical activity of the cuprammonium-cellulose complexes can now be attributed to the formation of asymmetric five-membered rings containing copper and the glycol group of carbon atoms 2 and 3, the magnitude of the optical rotation may be employed to calculate the number of free glycol groups in substituted celluloses which are

Methoxyl Content %

0.0 2.3

13.6 6*5

I I

Observed Rotation in Cupra B (436 m r )

-3.00' -2.65 -2.11 -1.79

Groups per glucose unit

-0CHs none 0.125 0.35 0.735

I

-CHOH-CHOH1 .oo 0.89 0.72 0.63

(38) R. E. Reeves, Science, 99, 148 (1944). (39) S. M. Neale, J . Teztile Znat., 16T,363 (1925). (40) K.Hess and E. Messmer, Kolloid-Z., 96, 260 (1925). (41) K.Hess, W.Weltzien and E. Messmer, Ann. 896, 1 (1923). (42) K.Hess, E. Messmer and N. Ljubitsch, Ann. 444, 315 (1925). (43) E. Messmer, 2. physik. Chem., 126, 369 (1927). (44) R. E. Reeves and H. J. Thompson, Contrib. Boyce Thompson Inst., 11, 55 (1939).

CUPRAMMONIUM-OLYCOSIDE

119

COMPLEXES

soluble in cuprammonium. These calculations have been made (Table VI) employing optical rotation data44 for a series of partially methylated celluloses prepared by the action of diaaomethane on cotton fiber. The optical rotation of uncomplexed cellulose and methyl cellulose is negligibly small in comparison with that of the complex; hence the number of unsubstituted glycols was calculated to be in proportion to the optical rotations in a standard cuprammonium solution. 6. Lichenin, Starch, Glycogen and the Schardinger Dextrins.-Other D-glucopyranoside polysaccharides known to have, predominantly, the 1,4 linkage between glucose units are lichenin, starch and glycogen. Hess and M e s ~ m e rinvestigated ~~ the optical rotation of lichenin in relatively dilute cuprammonium solution, and Reeves29 investigated soluble starch and glycogen in strong cuprammonium. The specific TABLEVII Specific Rotations (436 mp) in Aqueous and CuprammoniumSolutions (Datafrom ref. 8.9 unless otherwise noted) Substance

Specific Specific Rotation in Water Rotation in or Alkali Cuprammonium 0

-36" -20b +375 +366

Water 2N NaOH Water Water

-1O8Ob - 726d

-20'

2 N NaOH 2 N NaOH

-313 -370 -241

+255 +290 +318

Methyl 4-methyl-~-n-glucopyranoside Cellulose Starch (soluble) Glycogen

- 1008 - 1200 -715 -597

Cellulose Lichenin Schardinger dextrinse Diamylose Tetraamylose Hexaamylose

c

-8.3d

0 . 2 N NaOH 0.2N NaOH 0 . 2 N NaOH

These solutions contained 0.03 mole substance, 0.236 mole copper, and 14.1 mole ammonia per liter. Data from ref. 41. cThese solutions contained 0.04 mole substance, 0.10 mole copper, 10.0 mole ammonia and 0.2 mole NaOH per liter. d Data from ref. 45. The rotations of the Schardinger dextrins were calculated from data of ref. 43. According to currently accepted nomenclature tetraamylose is Schardinger's a-dextrin, or cyclohexaamylose; diamylose is an alcohol-containing complex of a-dextrin; hexaamylose is Schardingers 8-dextrin, or cycloheptaamylose. 0

(45) K. Hess and E. Messmer, Ann., 466, 194 (1927).

120

RICHARD E. REEVES

rotations of these substances in aqueous and in cuprammonium solutions are compared in Table VII with those of cellulose and of methyl 4-methyl-~-~-glucopyranoside; all show strong levorotation in cuprammonium, characteristic of reactions involving the 2 and 3 hydroxyls of D-glucopyranosides. M e ~ s m e rinvestigated ~~ the behavior of the Schardinger dextrins in cuprammonium solutions and found that the extent of levorotation was strongly dependent upon the concentration of sodium hydroxide added to the cuprammonium. There is reason to believe that the specific rotation values given for the Schardinger dextrins in Table VII do not represent complete interaction between the 2,3 glycol groups of the dextrins and cuprammonium ; under more strongly alkaline conditions Messmer found a specific rotation of - 1309" for one of the dextrins. Freudenberg and Cramer46have recently reported that the Schardinger dextrins do not show levorotatory shifts in cuprammonium, and partly on this account, have attributed an unreactive conformation t o the pyranoside rings of the dextrins. A private communication from Professor Freudenberg to the author discloses that the measurements referred to were made a t extremely high dextrin concentrations (unfavorable copper-glycol ratios) ; a t lower dextrin concentrations levorotatory shifts were observed although their magnitude was not as great as that of starch. Professor Freudenberg agrees that the behavior of the dextrins in cuprammonium should not be interpreted as supporting an unreactive ring conformation. c. Laminarin.-Laminarin is a D-glucopyranoside polysaccharide which has been shown by Barry47 to be linked through the 1- and 3-positions of the glucose units. By analogy with the corresponding monono complexing would saccharide, methyl 3-methyl-~-~-glucopyranoside, be expected when laminarin is dissolved in cuprammonium. Specific rotations (436 mp) of -29" in water and +34" in cuprammonium have been reportedz9for this substance and the small rotatory shift is interpreted as an indication that complexing occurs only to a very slight extent, if a t all. d. The Polysaccharide from Phytomonas tumefaciem-McIntire, Peterson and Riker48 isolated a D-glucopyranoside polysaccharide from the crown gall organism Phytomonas tumefaciens which showed a strong dextrorotatory shift when dissolved in cuprammonium. Specific rotations (436 mp) of -23" in water and +960" in cuprammonium have been (46) K. Freudenberg and F. Cramer, Ber., 83, 296 (1950). (47) V. C. Barry, Sci. Proc. Roy. Dublin Soe., 22, 59 (1939). (48) F. C. McIntire, W. H. Peterson and A. J. Riker, J . Biol. Chem., 143, 491 (1942).

CUPRAMMONIUM-GLYCOSIDE COMPLEXES

121

reported for this p o l y s a ~ c h a r i d e . ~ 9Under ~ ~ ~ comparable conditions the values for the monosaccharide, methyl 2-methyl-P-~-glucopyranoside, were -69" and +985", r e s p e c t i ~ e l y . ~On ~ the basis of the rotational behavior of this polysaccharide it has been s u g g e ~ t e that d ~ ~the ~ ~glucose ~ units of this new polysaccharide are linked through the 1 and 2 positions; this conclusion has been established by recent work in which the classical methylation procedures were employed.60 e. The Dextran from Leuconostoc dextranicum.-The dextran from Leuconostoc dextranicum has been s h o ~ n to ~ be ~ rcomposed ~ ~ of D-glucopyranose units approximately 90 percent of which are linked through the 1 and 6 positions. The dextran gave specific rotations (436 mp) of ~ +297" and - 128" in water and cuprammonium, r e s p e c t i ~ e l y . ~The 6-linkage leaves both the 2,3 and 3,4 glycol groups free to react with cuprammonium ; hence the behavior of glucopyranosides substituted in this position is not predictable as is the case when one of the other positions is substituted (see page 117). The moderate levorotatory shift of the dextran might be interpreted as an indication of the presence of some 1,4 linkages; on the other hand the substituents might cause the 2,3 glycol to become more reactive than the glycol at the 3,4 positions. 2. Mannans

Hess and coworkersfi3 have isolated mannose-containing polysaccharides from both ivory nuts and from pine wood pulp, and these mannans appeared to have identical properties. Both gave specific rotations of approximately -45" in N sodium hydroxide and + 2 8 5 O in cuprammonium (0.04 mole hexose anhydride, 0.10 mole copper, 10.0 moles ammonia per liter). The exact composition of these polysaccharides is not known; Yundt54 has recently stated that mannan "A" from ivory nuts assayed only 50 percent mannose. The cuprammonium rotation data cannot be interpreted in terms of the fine structure until the composition of the mannans is known with certainty. (49) R. Hodgson, A. J. Riker and W. H. Peterson, J . Biol. Chem., 168, 89 (1945). (50) E. W.Putnam, A. L. Potter, R. Hodgson and W. Z. Hassid, J . Am. Chem. Soc., 72, 5024 (1950). (51) S. Peat, E.Schluchterer and M. Stacey, J . Chem. Soc., 581 (1939). (52) E. C.F.Fairhead, M. J. Hunter and H. Hibbert, Can. J . Res., Series B, 16, 151 (1938). (53) K.Hess and M. Liidtke, Ann. 466,18 (1928). (54) A. P. Yundt, J . Am. Chem. SOC.,71, 757 (1949).

122

RICHARD

E. REEVES

3. Xylans

Hess and Ludtke66 have reported xylan preparations from bamboo and pine wood pulp having specific rotations of -1840” and -1700”, respectively. The solutions contained 0.04 moles pentose anhydride, 0.10 mole cupric hydroxide, 10 moles ammonia and 0.2 mole sodium hydroxide, per liter. These optical rotations suggest that the cuprammonium complex was formed with the glycol group on the second and third carbon atoms of the xylose units. YundtS4has interpreted optical rotation measurements in cuprammonium on xylans from barley straw and birchwood as indicative of complexing a t these positions, hence a 1,4 linkage was attributed to the xylopyranoside units. If these speculations are correct the structures of the above mentioned xylans may all be similar to that of the xylan from espartograss which was investigated by the classical methylation procedures.66

VI. CUPRAMMONIUM COMPLEXES AND

THE

SHAPEOF PYRANOSIDE

RINGS 1. The Significance of Ring Shapes in Glycopyranosides The pyranoside rings of glycosides have a chemical stability not shared by reducing forms of the same sugars. This is evidenced in aqueous solution by the absence of mutarotation and by the drastic conditions required to effect configurational changes on the ring carbon atoms or to alter the position of the ring oxygen linkage. This type of chemical stability does not, however, imply physical stability of ring shapes (conformations).ST The conformational stability of pyranoside rings may vary widely, from the stable glucosides to the unstable altrosides and lyxosides; as yet conformational stability has not been related to chemical stability. This discussion is concerned only with the former; the tendency of pyranoside rings to exist in and react in one or more particular shapes. Changes in ring conformation vastly alter the relative position of groups within the same molecule. In cases involving interaction between or reaction with two functional groups, ring shapes may determine the course of reactions. The formation of certain hexosans, (1,5)/3(1,6), has been explained upon the basis of the conformational behavior of the aldohexose.1° (55) K.Hess and M. Ludtke, Ann. 466, 18 (1928). (56)R. A. S. Bywater, W. N. Haworth, E. L. Hirst and S. Peat, J . Chem. Soc., 1983 (1936). (57) Freudenberg (ref, 46) employs the term “konstellation” in preference to “conformation.”

CUPRAMMONIUM-GLYCOSIDE COMPLEXES

123

2. Factors which InJEuence Pyranoside Ring Shapes

The factors which govern pyranoside ring shapes have recently been reviewed,l9 with this conclusion: Pyranose ring forms assume a chair form in preference to any boat form wherever both are structurally possible. Any substituent (other than hydrogen) oriented perpendicular to the pyranose ring introduces an element of instability into the conformation-especially important is an erected oxygen atom on position 2 when its C-0 valence bisects the two (2-0 FIG. 2.-TheArrangevalences of carbon atom 1 (the A2 condition illus- ment of Carbon-Oxygen trated by Figure 2), or a carbinol group at posi- VakmeS about Carbon tions 5 erected on the same side of the ring with f ~ ~ another erected group (the Hassel and Ottar tional Instabsty (the A2 effect). Condition). Table VIII lists the “instability factors” for the various aldohexopyranosides and aldopentopyranosides (D-series) in the two chair conformations. The Symbols C1 and 1C refer to Figure 3.

2:gE:

b& GI

81

18

89

PB

83

38

FIG.3.-The Eight Pyranose Strainlcss Ring Conformations and the Corresponding Symbols. By convention the heavy lines represent the sides of the three-dimensional figures nearer the observer. The dark circles represent ring oxygen atoms, the numbered circles carbon atoms 1 to 5.

Consideration of these factors as “instability units” allow prediction of preferred ring shapes for the various aldoses. The predicted ring shapes are

a

124

RICHARD E. REEVE8

listed in the last column of the table. In arriving at these conclusions the effect of one ordinary erected group has been weighted as one unit, the A2 conditions as of 2.5 units, the Hassel and Ottar effect as 0.5 unit. ConTABLEVIII The “Instability Factors” for the Various Aldose Pyranosides in the C l and 1C Conformations Instability factorsa c1

a-D-Allose p-D-Allose a-D- Altrose 19-D- Altrose a-D-Galactose p-D-Galactose a-D-Glucose p-D-Glucose r-D-Gulose j3-D-Gulose a-D-Idose 8-D-Idose a-D-Mannose p-D-Mannose a-D-Talose P-D-Talose a+- Arabinose 8-o- Arabinose a-D-Lyxose P-D-Lyxose a-D-Ribose @+-Ribose a-D-Xylose 8-D-Xylose

1,3 3 1,233 A2,3 194 4 1 None 1,3,4 3,4 1,22384 A2,3,4 172 A2 1,2,4 A2,4 1,2,3 A2,3 1,2 A2 1,3 3 1 None

1c

Predicted Normal Conformation

c1 c1 c1,1c C l , 1c

c1 c1 c1

c1

c1,1c

c1 1c C l , 1c c1 c1, 1c c1,1c c1,1c

1c

1C c1,1c c1, l C

c1

c1 C1

c1

a A number in these columns refers to an erected group (other than hydrogen) on the carbon atom bearing that number. A2 refers to the exalted influence of a n erected group on carbon 2 in the particular orientation illustrated in Fig. 2. H refers to the Hassel and Ottar influence when an erected group on carbon 5 occurs on the same side of the ring with another erected group.

formational instability is anticipated (but not necessarily realized under all experimental conditions) when the two forms differ by not more than one instability unit; or when the most stable ring forms contains as many a8 2.5 instability units.

125

CUPRAMMONIUM-GLYCOSIDE COMPLEXES

3. Special Aspects of the Reactions of Glycopyranosides with Cuprammonium a. D-Ghcopyranosides.-By employing a series of substituted derivatives it has been shown that the D-glucopyranosides exist and react in the C1 ring conformation. 28 Cuprammonium reacts with the glycol group a t positions 2,3 or 3,4 of D-ghcopyranosides, but with no other pair of hydroxyl groups. The evidence upon which this conclusion is based is given in Table IX. The first two groups of substances in the table TABLEIX The Behavior of Various D-Glucopyranosides and Secondary Alcohols in Cuprammonium Solution28 Substance

Methyl Methyl Methyl Methyl Methyl

4-methyl-p4,6-dimethyl-p4,6-ethylidene-p4,6-benzylidcne-a4,6-benzylidene-p-

Methyl 3-methyl-pPhenyl 3-methyl-pMethyl 2,3-dimethyl-aMethyl 2,3-dimethyl-/3Methyl 2,4-dimethyl-a-

-2020"

-

- 1990 - 1970 -2160 -2230

52 73 69 82

Lev0 Levo Lev0 Levo

-

16 2 10 14 7

No No No No No

+ + -

-

83 32 20 9 74

-

at at at at

2,3 2,3 2,3 2,3

complcx a t 2,4, 2,6, or 4,6 complex a t 2,4, 2,6, or 4,6 complex a t 4,6 complex a t 4,6 complex at 3,6

Rotational shift equals ([a1438Cupra B -[alas,,water) X (molecular weight/100). in specific resistance of 0.01 molar glucoside or secondary alcohol in Cupra A. Showing increments in specific resistance comparable to those exhibited by the non-complexing glucosides. a

* Increase

show strong evidence of complexing; the substances of the third group do not react with cuprammonium. Among the non-reacting glucosides are those with free hydroxyls a t the 2,4, 2,6, 3,6 and 4,G positions; in fact at all possible positions except 2,3 and 3,4. The fourth group in the table merely shows that simple secondary alcohols produce specific

126

RICHARD E. REEVES

resistance changes as great as those observed with the noncomplexing glucosides. Table I X also shows that the 2,3 glycol forms strongly levorotatory complexes, the 3,4 glycol strongly dextrorotatory complexes. Proceeding on the assumption that the pyranoside ring can be represented, in a first approximation, by a regular skew hexagon with tetrahedral angles between sides, oriented in one of the eight Sachse strainless ring conformations, it is possible by inspection of molecular models to evaluate, approximately, the angle between any pair of adjacent hydroxyl groups. Those angles between the hydroxyl groups of positions 2,3 and 3,4 of D-glucopyranosides have been estimated and are shown in Table X. TABLEX The Angle Between Adjacent Hydroxyl Groups of the D-Glucopyzanose Ring Conformation

2,s Hydroxyls

c1

- 60"

1c B1 1B B2 2B B3 3B

180" -120" - 120" -60" 180" 180" 60"

-

1

S,4 Hydroxyls

+60" 180" +60°

180" +120° +120" 180" +60"

The conformations referred t o in Table X are those illustrated in Figure 3 and the angles are those projected onto a plane perpendicular to the carbon-carbon bond as defined in a preceding section. It is apparent that the hydroxyl pair a t the 2,3 position can assume the complex-forming -60" angle, but not the 0" or the +60" angles, while the hydroxyl pair at position 3,4 can form the +60" angle but not the 0" or -60" angles. This situation is probably responsible for the strikingly different optical behavior of the first two groups of substances listed in Table IX. 'Group I contains D-glucopyranosides substituted t o allow complex formation only at position 2,3 while the second group is substituted to allow reaction only at position 3,4. Strongly levorotatory complexes form at position 2,3 (-60" angle), while complexes of similar dextrorotation form at position 3,4 (+SO0 angle). The glycosides listed in Table XI have hydroxyl groups a t positions 2,3, and 4 unsubstituted (i.e., both 2,3 and 3,4 glycols are free). Complex formation in these substances produces a much smaller shift in optical rotation than it does in those compounds which can react at only one site. The affinities for cuprammonium of the reacting sub-

127

CUPRAMMONIUM-GLYCOSIDE COMPLEXES

stances have been found t o be approximately Since there is no reason t o suspect a marked difference in the amount of cuprammonium complex formed,by the three classes of reacting glucosides under similar conditions, the reason for the relatively low shift in rotation of the glucosides in Table XI must lie in simultaneous formation of dextroand levorotatory complexes (compensating complexes). Only the C1 and 3B conformations would allow the formation of compensating complexes in the glucopyranoside series. TABLE XI The Behavior of Compensating Complexes i n Cuprammonium28 DGlucopyranoside

I

Rotational shift

hfethyl 6-methyl-pMethyl aMethyl 0Phenyl aPhenyl 8-

I

A Specific resistance

I

I

+435" +244 +250 +292 -74

70 50 67 61 85

All the glucopyranosides substituted to restrict complex formation to the 2,3 position showed marked evidence of reaction with cuprammonium. This behavior would be compatible with ring conformations Cl, B2, and 3B except that three of the substances, the 4,B-ethylidene and 4,6-benzylidene compounds, could not exist in either the B2 or 3B conformations for steric reasons because of the spatial requirements of the second ring; hence, these three substances must exist in the C1 conformation. Both of the glucosides substituted to allow complex formation only a t the 3,4 position showed marked evidence of complex formation behavior compatible with ring conformation C1, B1, or 3B. It is noteworthy that a single conformation, C1, is compatible with the properties of all the complex forming D-glucopyranoside derivatives here examined. Furthermore, this is the form which has been assigned t o the D-glucopyranoside units of cellulose6*and sucrose69which have been examined by physical methods in the crystalline state, Cox60 has listed some reasons for believing that glycoside molecules do not readily change from one conformation t o another in solution, or even on passing from the crystalline state to the dissolved state. While it is now certain that the arguments advanced against possible interchange of conforma(58) W. T.Astbury and M. M. Davies, Nature, 164, 84 (1944). (59) C. A. Beevers and W. Cochran, Nature, 167, 872 (1946). (60)E. G. Cox, T. H. Goodwin and A. I. Wagstaff, J . Chem. SOC.,1495-1504 (1935).

128

RICHARD E. REEVES

tion cannot apply with equal validity to all glycosides and all permutations of conformation changes, nevertheless the data in the glucopyranoside series are consistent with a single conformation persisting in the crystalline state and, at ordinary temperatures, in solution. b. D- and L-Galactopyranoside Series.-Employing procedures similar to those described in the preceding section it has been shown that the D-galactopyranosides and L-arabinopyranosides exist and react in the C1 ring conformation, the L-galactopyranosides series (represented by L-fucopyranosides and D-arabinopyranosides) in the 1C conformation. 28 As is the case in the glucoside series it is believed that complexing occurs only at the 2,3 and the 3,4 positions. D-Galactopyranosides form levorotatory complexes at both of these positions whereas the D-glucopyranosides form levorotatory complexes at the. former, but dextrorotatory complexes at the latter. Table XI1 lists the calculated projected angles between the two reactive hydroxyl pairs for the D-galactopyranoside series in all eight Sachse strainless ring conformations. Only the C1 and 3B conformations would be expected to yield levorotatory complexes (-60" angle) at both the 2,3 and 3,4 positions. In ,addition t o apparently valid theoretical arguments favoring the chair form over the boat form, consideration of the behavior of the anhydride, D-galactosan (1,5)p(1,6), led to rejection of the 3B conformation. The considerations have been interpreted as indicating that both the a- and fl-D-galactopyranosides possess the C1 ring conformation, The same conformation was assigned TABLE XI1 Calculated Angle between Adjacent Hydroxyl Goupa for Daalactopyranosides in Each Ring Conformation28 Glycol Conformation B,d

c1 1c B1 1B B2 2B B3 3B

-

60"

180" - 120" - 120" - 60" 180" 180"

-

60"

3,4

-60' +60" -60" +60" 0" 0" +60°

-60"

Anticipated Behavior in Cuprammonium Solution Lev0 Complex Dextro Complex Lev0 Complex Dextro Complex Lev0 Complex. m

Dextro Complex Lev0 Complex

0 The only optically active pyranoside known to possess the 0" angle is methyl 2,6-anhydro-cu-~-altropyranoside.This substance exhibited a very high conductance effect and a low rotational shift (see reference 11).

129

CUPRAMMONIUM-GLYCOSIDE COMPLEXES

to the L-arabinopyranosides, while the D-arabinopyranosides and L-fucosides were regarded as belonging to the L-galactose series, and thus to have the 1C ring ~onformation.~3 c. Hexosans (1,5)0(1,6).-The hexosans of the levoglucosan type offer a particular opportunity for the study of pyranose ring conformations because only two of the eight theoretically possible Sachse strainless ring conformations satisfy the steric requirements of the hexosan rings. Thus, in order to make a definite assignment of ring conformation for substances of this type it is only necessary to choose between two possible ring forms. The two pyranose conformations which, in the D-hexoses, are capable of forming hexosans of the (1,5)p(1,6) type are those designated 1C and 3B in Figure 3. There are apparently valid theoretical arguments favoring the chair form structures over the boat form^.'^*^^ The hexosans offered a possibility of testing these arguments experimentally. The results indicated that for each of ten D-hexosans examined it was the chair form, l C, adopted by the molecule in solution.10 The experimental facts upon which these conformational assignments are based are given in Table XIII. TABLE XI11 Comparison of Observed Behavior in Cuprammonium of Some n-Hexosans (1,5)0( 1,6), with the Behavior Predicted for Two Different Ring Formslo

Substance

Observed Complex

Complex Anticipated for Ring Conformation

1C n-Glucosan 3-Met hylD-Galactosan 2-MethylD-Mannosan 4-Methyl4-Benzyln- Altrosan D-Idosan 3-Methyl-

1,3 1,3 DextroDextroLevoLevo' LevoDextroCompensating No complex

1,3 113 DextroDextroLevoLevoLevoDextroCompensating No complex

3B Compensating

No complex LevoLevoDextroDextroDextroLevo1,3 1,3

D-Glucosan (1,5)0(1,6) and its 3-methyl derivative are believed to form low rotating complexes involving the hydroxyl groups on carbon atoms 2 and 4. Approximate calculations of the 02-04 distance indicates that such complexing might be expected provided the pyranoside (61) 0. Hassel and B. Ottar, Acta Chem. Scand., 1, 929 (1947).

130

RICHARD E. REEVES

ring has the 1C conformation.1° A similar type of complex has also been encountered with methyl 3-methyl-P-~-idopyranoside (see Table XIV). Reeves1@ has attempted to explain the ease of formation of the altrose and idose anhydrides in dilute aqueous a ~ i d s ~ in ~ ,terms 6 ~ of the ring conformation of the parent aldehexose. Thus sugars the 0-form of which can exist in the 1C ring (see Table VIII) form anhydrides; those which do not exist in the 1C ring do not form anhydrides. d. Other G1ycosides.-The types of cuprammonium complexes formed TABLEXIV The Types of Cuprammonium Complexes Formed b y Various Glycoaides and Assignments of Ring Conformation~1~ Ring Conformation Methyl Glycopyranoside

a-D-Mannopyranoside 4-Methyl8-D-kIannopyranoside a-L-Rhamnopyranoside a-D-Mtropyranoside 4,6-Benzylidene8-D-Altropyranoside 4,6-Benzylidenea-D-Gulopyranoside 6-Desoxy-a-~-glucopyranoside 6-Desoxy-p-~-glucopyranoside a-D-Idopyranoside 2-Me t hyl4.6-Benzylidene 3-Methyl-p-~-idopyranoside 4,6-Benzylidene-p-~-idopyranoside a-D-Xylopyranoside 8-D-Xylopyranoside a,p-D-Ribopyranoside p-D-Ribopyranoside a-D-Lyxopyranoside p-D-Lyxopyranoside

Type of Complex

DextroDextroDextroLevoDextro-LevoNo complex Dextro-LevoNo complex DextroCompensating Compensating Compensating LevoDextroL3 DextroCompensating Compensating Compensating Compensating Dextro-LevoDextro-Levo-

from Complex

c1 c1

from “Instability Factors ”

c1 c1

c1 1c

C1,lC

C1,lC Cl C1,lC

C1,lC Clb C1,lC

c1 c1 c1 c1 1c 1c 1c c1 1c

c1 Cl c1

c1 C1,lC C1,lC

1c5

cl b

Cl, 1 c ClC ClC 1c

1c

1c C1,lC C1,lC

c1 c1

c1

c1 C1,lC C1,lC

Assignment based on relationship to L-mannose series. “he 1C conformation is unlikely because of the spatial requirements of the benzylidene ring. c Assignment based on the D-glucose series. 0

(62) N. K. Richtmyer and C. S. Hudson, J . Am. Chem. SOC.,61, 214 (1939). (63) E. Sorkin and T. Reichstein, Helu. Chim. A d a , 28, 1 (1945).

CUPRAMMONIUM-GLYCOSIDE COMPLEXES

13 1

by glycosides other than those mentioned in the preceding sections have been determined in certain instances.lg By making the plausible assumption t ha t boat-form conformations will not occur in significant amounts i t is possible, merely by knowing the types of cuprammonium complex, t o choose between the two chair forms, or t o recognize those instances when both chair conformations are present in solution a t the same time. Table XIV lists twenty-three methyl glycopyranosides, the type of complex formed by each, the conformation assigned as a result of the behavior of cuprammonium, and the conformation which was previously assigned (in Table VIII) from consideration of the ‘ I instability factors.” Inspection of Table XIV shows that, in general, there is excellent agreement between the conformations assigned from the cuprammonium complexes and those assigned upon consideration of the “instability factors.” The only noted instances of disagreement occur with methyl 8-D-mannopyranoside and methyl a-D-gulopyranoside; both of which behaved as though exclusively in the C1 conformation in cuprammonium while consideration of the instability factors had indicated th a t appreciable amounts of both chair forms were to be expected. The two substituted 0-D-idopyranosides are not in disagreement with the predictions since, in their cases, only one of the two chair conformations is capable of reacting with cuprammonium. VII. APPENDICES 1. The Preparation of Cupra A

Cupra A contains 0.01 mole copper, 3 moles ammonia and 10 ml. ethanol per liter. It may be prepared by dissolving a slight excess of cupric hydroxide in ammonia and adjusting the solution, after analysis, to the proper concentration. Alternatively28 it may be obtained by diluting a stock solution containing between 5 and 8 g. of copper per liter prepared by passing a current of air through concentrated A.C.S. ammonium hydroxide in the presence of copper turnings. The ammonia and turnings are contained in a tall glass cylinder which is cooled in an ice-bath during the reaction. This stock solution may be preserved in the refrigerator without added stabilizer for a long time. After analysis for copper and ammonia, portions of the stock solution are diluted to the proper concentrations. When tightly stoppered, cupra A is stable at room temperatures. 2. The Preparation of Cupra B Cupra B contains 15.0 k 0.1 g. copper (0.235 mole), 240 k 5 g. ammonia (14.1 mole), and 1 g. glycerol per liter. It cannot be pre-

132

RICHARD E. REEVES

pared directly from cupric hydroxide and ammonia. A glass cylinder of 2 to 3 liter capacity is fitted with a gas inlet tube and filled nearly to the top with copper turnings. The copper may be cleaned with dilute acid and rinsed with water immediately before use. It is then covered with concentrated ammonium hydroxide, 1 gram of glycerol is added per liter of ammonia, and the cylinder is covered with a loosely fitting stopper. I t is then cooled in an ice-water bath to approximately 10” and a vigorous current of air is passed through a large wash bottle containing concentrated ammonia, and then through the reaction cylinder. The concentration of copper in the solution should be followed by a rapid, approximate colorimetric procedure until it reaches approximately 17 g. copper per liter. At this point the solution is decanted into a tightly stoppered bottle and stored in the refrigerator pending accurate analyses for copper and ammonia. It will usually be necessary to build up the ammonia content by the introduction of ammonia gas at this point, and a second analysis is often required before final adjustment to the desired concentrations can be made. The TAPPIa4methods are satisfactory for analysis of cuprammonium ; alternatively, electrolytic depositions methods may be employed for the coppera6and Kjeldahl techniques for the ammonia.

3. Determination of Optical Rotations in Cuprammonium Solutions Optical rotations in cuprammonium solutions are usually determined with the mercury blue line, (436 mp). Lacking a suitable monochromator, the blue line may be isolated by a combination of commercially available filters. Corningaafilter 3389 may be used in combination with Corning 5113 standard thickness, 5113 one-half standard thickness, or with an interference type filter designed to have maximum transmission at approximately 436 mp, and capable of eliminating the longer mercury wave-lengths. Satisfactory mercury vapor lamps include General Electric 100 watt AH-466 or Hanovia S-lOO.aa Strong cuprammonium is itself an excellent filter for all the mercury lines longer than 436 mp; hence with cupra B only a single filter (Corning 3389 to eliminate the 405 mp line) is required. Use of the single filter with cupra B yields a much greater intensity of blue line light than results from the combination filters. For aqueous solutions, or dilute cuprammonium solutions, the combination filter should be.employed. (64) Testing Methods, Recommended Practipes of TAPPI; T 206m. (65) G. W. Slomin, “Rapid Quantitative Electrolytic Methods of Analysis,” 6th Ed. (1943). E. H. Sargent and Co., Chicago, Ill. (66) The mention of trade products does not imply their endorsement by the U. S. Department of Agriculture over similar products not mentioned.

CUPRAMMONIUM-GLYCOSIDE COMPLEXES

133

Measurements with cuprammonium are conveniently made in specially constructed optical cells. These are horizontal tubes with windows fused onto the ends, and a neck for introduction of liquid. The windows must be essentially parallel, and free from strain detectable in polarized light. The inside length should be 50 mm. rt 0.03 mm. A tube having an inside diameter of 8 mm. will contain less than 3 ml. of solution. The observation cells are centered in the beam of the polarimeter by being mounted in two aluminum rings, the diameter of the rings being 30 mm. A small aluminum or brass cap to fit one end of the tube is required t o eliminate light reflected from the sides of the tube. The mounted tube and cap are shown in Figure 4.

FIQ.4.-A

Convenient Polarimeter Tube Assembly.

Optical cells meeting the above specifications have been made by the American Instrument Co., Silver Spring, Maryland.66 It is necessary to check the zero point of the empty tubes from time to time to make certain that strains have not developed during use. When optical rotations are measured in a saccharimeter instead of a polarimeter it must be recalled that the factor of 0.3462 for converting sugar degrees t o angular degrees applies only to the sodium D line. For the mercury blue line the conversion factor should be taken as 0.6623. The mercury blue line is more difficult to read in a polarimeter th a n the longer visible wave-lengths. The difficulty is greatly magnified by turbidity in the solution or by incomplete exclusion of the mercury lines in the vicinity of 405 mp. The measurements should be made in a darkened room, allowing approximately a minute for the eye to grow accustomed to the darkness. The zero point of the instrument should be taken at the same wave-length. Specific rotations in cuprammonium are based upon the weight of the glycol-containing molecule, not upon the weight of the copper glycol complex. This provision is necessary since the structures and molecular weights of the complexes are unknown. The optical rotations are the result of a reversible reaction, hence they are particularly dependent upon the concentrations of the reactants. The composition of the

134

RICHARD E. REEVES

cuprammonium and the concentration of substance should always be reported, and if possible copper to glycoside ratios should be chosen so that the complexing reaction is driven nearly to completion.

4. Conductometric Measurements in. Cuprammonium Solutions In the investigation of cuprammonium-glycoside complexes means independent of optical activity are required for the recognition of complexes. Such methods are necessary for the study of reaction between cuprammonium and optically inactive glycols, as well as for those substances which, though optically active, form complexes without exhibiting large rotatory changes. Complex-formation is associated with a decrease in conductivity of the cuprammonium solution; the extent of the change under an arbitrary set of conditions has been employed as a measure of reactivity with cuprammonium. The results are usually expressed in terms of the increase in specific resistance resulting from an 0.01 molar glycoside concentration in cupra A. In one instance" conductivity measurements were employed to calculate the constant for the complexing reaction. This would probably be the more satisfactory method of comparing the different glycol groups. Specific resistance increments (A,p.mB.) of 20 ohm, cm-2 may be encountered without the actual occurrence of cuprammonium-glycol complexing; values above 20 are indicative of a significant amount of complexing. Measurements are made with a commercial, 1,000-cycle conductivity bridge employing small dip-type platinized platinum electrodes having a constant of approximately 0.1. The solutions must be thermostatted and kept stoppered except when measurements are in progress. It is often desirable to investigate a range of concentrations spanning the 0.01 molar concentration, and to read the value at the desired concentration from the curve through the experimentally determined points. This graphical method must be applied with caution, however, for in the case of highly reactive substances the theoretical curve for specific resistance versus concentration is S-shaped. In such instances if it is not desired to use a single reading a t 0.01 molar concentration the plot should be made with specific conductivity versus concentration.

THE CHEMISTRY OF RIBOSE BY ROGERW. JEANLOZ AND HEWITTG. FLETCHER, JR. National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Public Health Service, Federal Security Agency, Bethesda, Maryland

Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts

.

CONTENTS I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . ...................... 135 11. Ribose.. ..... .............................................. 136 f D-Ribose.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 2. The Preparation of Ribose.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Physical Properties of Ribose. .. ............................... 141 4. Identification of Ribose.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5. Chemical Properties of Ribose.. . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Ribose Derivatives.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 1. Ethersof Ribose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146 2. Esters of Ribose with Organic Acids.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148 3. Acylohalogenoriboses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151 4. Phosphatesof Ribose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155 5. 0-Ribosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 158 6. N-Ribosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 160 7. Acetals of Ribose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 168 8. Anhydrides of Ribose.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172

I. INTRODUCTION In 1891 Emil Fischer and Oscar Piloty' epimerized L-arabonic acid to a new pentonic acid which, using the consonants of the name of its parent isomer, they called ribonic acid; reduction of the lactone of this acid gave a sirup, the new sugar L-ribose. Some eighteen years later Levene and Jacobs2*8recognized D-ribose as a natural product and today this sugar, a component of the nucleic acids, the coenzymes and vitamin BIZ, ranks in biological importance with D-glucose. While the comparative inaccessibility of D-ribose for many years discouraged extensive research with this sugar, recent chemical and technical advances have made it much more readily available and the various aspects of the chemistry of this substance are rapidly being investigated in a number of (1) E. Fischer and 0. Piloty, Ber., 24, 4214 (1891). (2) P. A. Levene and W. A. Jacobs, Ber., 42, 1198 (1909). (3) P. A. Levene and W. A. Jacobs, Ber., 42, 3247 (1909).

135

136

ROGER W. JEANLOZ AND HEWITT G . FLETCHER, JR.

laboratories. The present review will deal primarily with the chemistry of ribose and those of its derivatives which give ribose on hydrolysis. In the interest of brevity, the nucleic acids as well as the biological aspects of ribose and its derivatives will be excluded from c~nsideration.~

11. RIBOSE 1. The Occurrence of D-Ribose Although Kossels recognized as early as 1891 that sulfuric acid hydrolysis of what is now called ribonucleic acid liberates a carbohydrate substance, eighteen years passed before Levene and Jacobs2 succeeded in identifying the sugar as D-ribose.6 These authors obtained the sugar in crystalline form and showed that it differed in its physical constants from the then-known crystalline pentoses, L-arabinose, D-xylose and D-lyxose. The phenylosazone prepared from it resembled L-arabinose phenylosazone closely save that the sign of its rotation in pyridinealcohol solution was negative while that of L-arabinose phenylosazone was known to be positive. The benzylphenylhydrazone of the new sugar differed in melting point and rotation from that derived from D-arabinose. It was evident, therefore, that the sugar from ribonucleic acid was D-ribose, a conclusion which was confirmed through comparison of a cadmium aldonate, prepared from the new sugar, with the cadmium L-ribonate prepared earlier by Fischer and Piloty. Oxidation also gave an optically inactive trihydroxyglutaric acid identical with that from L-ribose. Alberda van Ekenstein and Blanksma’ synthesized D-ribose by the method of Fischer and Pilotyl while von Brauns showed that the diphenylmethane-dimethyldihydrazones of natural and synthetic D-ribose are identical. (4) For recent reviews of the chemistry of the nucleic acids and related topics see: B. Lythgoe, “Chemistry of Nucleosides and Nucleotides,” Ann. Repts. on Progress Chem. (Chem. SOC.London), 41, 200 (1945);R. S. Tipson, “The Chemistry of the Nucleic Acids,” Advances in Carbohydrate Chemistry, 1, 193 (1945);A. R. Todd, “Synthesis in the Study of Nucleotides,” J . Chem. Soc., 647 (1946);B. Lythgoe, (‘Chemistry of Adenine Nucleotide Coenzymes,” Ann. Repts. on Progress Chem. (Chem. SCC.London), 43, 175 (1946);B. Lythgoe and A. R. Todd, “Structure and Synthesis of Nucleotides,” Spnposia Soc. Exptl. Biol. I . Nucleic Acid, 1947, 15; A. R.Todd, “Synthhse de Nucleotides,” Bull. SOC. chim. France, 1948,933:B.Lythgoe, “Some Aspects of Pyrimidine and Purine Chemistry,” Quart. Revs., 3, 181 (1949). (5) A. Kossel, Arch. Anat. Physiot., Physiol. Abt., 181 (1891). (6) The complicated history of the conflicting viewpoints and evidence regarding the sugar of nucleio acid durine, this period has been reviewed by P. A. Levene and L. W. Bass, “Nucleic Acids,” Chemical Catalogue Co., New York, 1933,p. 129 et seq. (7) W. Alberda van Ekenstein and J. J. Blanksma, Chem. Weekblad, 10,664(1913). (8) J. von Braun, Ber., 46, 3949 (1913).

THE CHEMISTRY OF RIBOSE

137

Using benzimidazole derivatives Gulland and various coworkers9,10-11 have recently restudied the problem of the identification of D-ribose in yeast nucleic acid. In addition t o its occurrence as a component of ribonucleic acid D-ribose has been found in combination with uric acid in the blood12 and with 2-hydroxy-6-aminopurine (isoguanine) in the croton bean (Croton liglium L).l3.l4 v. Euler, Karrer and Usteri15as well as SchlenkI6 have shown D-ribose t o be a component of cozymase. The discovery that D-gluconic acid 6-phosphate may be degraded enzymatically t o D-ribose 5 - p h o ~ p h a t e ~has ~ e ’thrown ~ light on a possible path for the biogenesis of D-ribose.

2 . The Preparation o j Ribose Yeast nucleic acid is the best source of D-ribose and, since the sugar is an intermediate in the synthesis of vitamin B2, its preparation from this source as well as from others has been very extensively investigated. The method of Levene and Clark,lg involving treatment of the nucleic acid with ammonia a t an elevated temperature and pressure, purification of the resulting nucleosides (guanosine and adenosine) and, finally, hydrolysis of these t o D-ribose, 2o was markedly improved by PhelpsZ1J2 who replaced the ammonia with magnesia. In this modification the nucleic acid is hydrolyzed a t 145’ for four hours, the magnesium-containing phosphates are removed by filtration and the guanosine allowed t o precipitate directly while the adenosine is recovered from the mother liquor as its picrate. After purification, the guanosine is hydrolyzed with boiling N/lO sulfuric acid, the guanine removed as its silver sulfate (9) J. M. Gulland and G. R. Barker, J . Chem. SOC.,625 (1943). (10) G. R. Barker, Kathleen R. Cooke and J. M. Gulland, J . Chem. SOC.,339 (1944). (11) G. R. Barker, Kathleen R. Farrar and J. M. Gulland, J . Chem. SOC.,21 (1947). (12) Alice R. Davis, Eleanor B. Newton and S. R. Benedict, J . Biol.Chem., 64,595 (1922). (13) E. Cherbuliez and K. Bernhard, Helv. Chim. Acta, 16, 464 (1932). (14) J. R. Spies and N. L. Drake, J . Am. Chem. SOC.,67, 774 (1935). (15) H. v. Euler, P. Karrer and E. Usteri, Helv. Chim. Acta, 26, 323 (1942). (16) F. Schlenk, J. Biol. Chem., 146, 619 (1942). (17) S.S.Cohen and D. B. McNair Scott, Science, 111, 543 (1950). (18) B. L. Horecker and Pauline Z. Smyrniotis, Arch. Biochem., 29, 232 (1950). (19) P. A. Levene and E. P. Clark, J . Biol. Chem., 46, 19 (1921). (20) P. A. Levene, J . B i d . Chem., 108, 419 (1935). (21) F. P. Phelps, U. S.Pat. 2,152,662 (1939). (22) F. J. Bates and Associates, “Polarimetry, Saccharimetry and the Sugars,” Natl. Bur. Standards Circular C440, U. S. Govt. Printing Office, Washington, D. C. (1942), p. 476.

138

ROQER W. JEANLOZ AND HEWITT Q. FLETCHER, JR.

compound and the D-ribose recovered from the mother liquor. The purified adenosine picrate is similarly hydrolyzed, the adenine picrate precipitating directly from the hydrolysis mixture. Laufer and Charney have patented two procedures for the isolation of D-ribose from yeast nucleic acid. In the first of these,2aa nucleosidecontaining hydrolysis mixture is treated with cuprous ions and the cuprous salts of the nucleosides precipitated. On subsequent hydrolysis with acid the salts are converted to D-ribose and the insoluble cuprous salts of adenine and guanine. In the second procedurez4yeast nucleic acid is hydrolyzed to a mixture of nucleotides which are then precipitated as their cuprous salts. The washed salts are hydrolyzed directly with sulfuric acid to give the insoluble cuprous salts of adenine and guanine and a solution containing sulfuric and phosphoric acids and D-ribose. Treatment of this solution with an alkaline earth hydroxide such as barium hydroxide is claimed to afford a solution of practically pure D-ribose. The hydrolysis of yeast nucleic acid by sweet almond emulsin has been found26to give high yields of guanosine and adenosine and forms a practical basis for the preparation of D-ribose.26 The purification of sirupy ribose has in the past usually been carried a costly and laborious out through the p-bromophenylhydrazone, procedure. Recent studies of the arylamine ribosides have resulted in the discovery of a cheaper and more convenient method for the purification of The procedure is based upon the fact that ribose, dissolved in aqueous alcohol containing an arylamine such &s aniline and an alkali metal salt such as sodium sulfate and having a pH of 4, is precipitated in high yield as a crystalline arylamine riboside-salt complex. The arylamine riboside may be extracted from this complex with dioxane and decomposed by boiling in water containing a trace of acetic acid. After the arylamine has been removed by steam distillation or through formation of a Schiff base with formaldehyde or benzaldehyde, the pure, crystalline ribose may be recovered. While Alberda van Ekenstein and Blanksma3' showed that L-arabinose may be converted in part directly to L-ribose through the Lobry de 1~7927

(23)L. Laufer and J. Charney, U. S. Pat. 2,379,913(1945). (24)L. Laufer and J. Charney, U. S. Pat. 2,379,914 (1945). (25) H.Bredereck and G . Rothe, Ber., 71, 408 (1938). (26) H.Bredereck, M. Kothnig and Eva Berger, Ber., 73, 956 (1940). (27) Marguerite Steiger, Helu. Chim. A d a , 19, 189 (1936). (28)L. Berger and J. Lee, J . Org. Chem., 11, 84 (1944). (29)L. Berger, U.V. Solmssen, F. Leonard, E. Wenis and J. Lee, J . Org. Chem., 11, 91 (1944). (30) J. Lee, U. V. Solmssen and L. Berger, U. S. Pat. 2,384,103 (1945). (31) W. Alberda van Ekenstein and J. J. Blanksma, Chem. Weekblad, 10,213 (1913).

THE CHEMISTRY OF RIBOSE

139

Bruyn rearrangement, the process has no preparative value as have the two indirect conversions of arabinose t o ribose which will now be described. The first of these is the original one of Fischer and Piloty' mentioned earlier. Blanksma and Alberda van E k e n ~ t e i nrepeated ~~ this work and a t first obtained a sirup contaminated with ribitol; sub~ e q u e n t l ypurification ,~~ of the crude ribose through the p-bromophenylhydrazone gave the first crystalline L-ribose. I n 1913 these authors7 repeated the synthesis in the D-series and also obtained a crystalline product. The whole process was carefully reinvestigated by Steiger in 1936.27 D-Arabinose (I), prepared from calcium ~ - g l u c o n a t e ,was ~~ oxidized ele~trolytically~~ to D-arabonic acid (11). The D-arabonic acid was partly isomerized through the action of boiling aqueous pyridine and the desired D-ribonic acid (111) isolated as its cadmium salt. Conversion to D-ribonic y-lactone (VI) and reduction with sodium amalgam gave crystalline D-ribose (VIII), more product being obtained from the mother liquors as the p-bromophenylhydrazone. By this method a yield of 17%, based on the D-arabinose, was obtained; doubtless this yield could be increased considerably by precipitating the D-ribose from the sodium sulfate-containing reduction mixture as the arylamine ribosidesodium sulfate complex mentioned earlier. D-Arabinose, a possible contaminant, does not form a similar insoluble complex.28 The second synthesis of ribose from arabinose involves arabinal (VII) as an intermediate and was first carried out by Gehrke and AichneP in both the D- and L-series. In this process D-arabinose (I) is converted t o triacetyl-@-D-arabinopyranosyl bromide (IV) which is then treated with zinc dust and acetic acid t o form diacetyl-D-arabinal (V), equally well termed diacetyl-D-ribal. After deacetylation to D-arabinal (VII) the product is hydroxylated with perbenzoic acid to give a mixture of D-arabinose and D-ribose (VIII), the latter predominating. This general procedure for the preparation of ribose has been studied and improved by several groups of workers,37*38*39 the yield of crystalline sugar obtained being about lo%, based on the arabinose used. Purification of the product was made both through direct crystallization and through forma(32) J. J. Blanksma and W. Alberda van Ekenstein, Chem. Weekblad, 6,777 (1908). (33) W:Alberda van Ekenstein and J. J. Blanksma, Chem. Weekblad, 6,373 (1909). (34) R. C. Hockett and C. S. Hudson, J . Am. Chem. Soc., 66, 1632 (1934). (35) H. S. Isbell and Harriet L. Frush, J . Research Natl. Bur. Standards, 6, 1145 (1931). (36) M. Gehrke and F. X. Aichner, Ber., 60, 918 (1927). (37) W. C. Austin and F. L. Humoller, J . Am. Chem. SOC.,66, 1152 (1934). (38) P. Karrer, B. Becker, F. Benr, P. Frei, H. Salomon and K. Schopp, Helv. Chim. Acta, 18, 1435 (1935). (39) R. Kuhn, K. Reinemund, F. Weygand and R. Strobele, Ber., 68,1765 (1935).

140

ROQER W. JEANLOZ AND HEWITT G. FLETCHER, JR.

tion of the p-bromophenylhydrazone. Again, the use of aninsoluble arylamine riboside-sodium sulfate complex to effect the separation of ribose from arabinose would probably improve the yield from this synthesis. Improvements in the Ruff degradation40 made by Hockett and Hudsona4have been applied by Hudson and Richtmyer41to the preparation of D-ribose from the calcium salt of D-altronic acid (IX) ; the latterz may be obtained from sedoheptulose, lactose, cellobiose and D - ~ ~ u c o s ~ . ~ (40) 0. Ruff, Ber., 32, 550 (1899);36, 2360 (1902): (41) C.S. Hudson and N. K. Richtmyer, U. S. Pat. 2,162,721 (1939). (42) For the preparation of calcium o-altronate from these sugars see N. K. Richtmyer, " The Altrose Group of Substances," Advances in Carbohydrate Chemistry, 1, 37 (1945).

T H E CHEMISTRY O F RIBOSE

141

A new synthetic approach t o D-ribose has recently been made by Sowden. 4 3 I n this procedure 4,6-benzylidene-~-glucose (X) was reduced catalytically to 4,6-benzylidene-~-glucitol (XI) which was then oxidized with sodium metaperiodate to 2,4-benzylidene-~-erythrose(X II). Condensation of this latter compound with nitromethane gave a mixture of epimeric, crystalline, substituted C-nitro alcohols, 3,5-benzylidenel-desoxy-l-nitro-D-arabitoland 3,5-benzylidene-l-desoxy-l-nitro-~-ribitol (XIII). After separation, the appropriate isomer was hydrolyzed to 1-nitro-l-desoxy-D-ribitol(XIV) which, in the form of its sodium salt was decomposed directly to D-ribose (XV), isolated as its benzylphenylhydrazone. This synthesis is of interest in tha t it may be used to obtain D-ribose labeled a t carbon 1 with C.I4

3. Physical Properties of Ribose D-Ribose, L-ribose and D,L-ribose crystallize without 'water of hydration. The melting point of the optically active forms is recorded by most authors as 86-87"2J3337*39 although Alberda van Ekenstein7 reported a value of 95" for D-ribose. D,L-Ribose, prepared by crystallizing a mixture of equal parts of the enantiomorphs, melts at 83-84".44 The optical crystallographic properties of D-ribose have been measured b y (43) J. C. Sowden, J . Am. Chem. SOC., 72, 808 (1950). (44) W. Alberda van Ekenstein and J. J. Blanksma, Chem. Weekblad, 11, 182 (1914).

142

ROGER W. JEANLOZ AND HEWITT

a.

FLETCHER, JR.

has meaKeenand6 and its heat of combustion by E l l i n g h a u ~ . ~Kuhnaes ~ sured the infrared absorption of D-ribose from 8 to 15 microns. The mutarotation of ribose was first observed by Phelps, Isbell and Pigman47s48 who studied both the D- and L-isomers in aqueous solution at 1". The mutarotation of L-ribose in water at 0", shown in Fig. 1, is a complex one, due probably to the existence of equilibria involving both furanose and pyranose forms. There is considerable evidence to support this view. Bredereck, Kothnig and BergerZ6found that, while the mutarotation of D-ribose in pyridine at 20" is complex, the mutarotation of &trityl-~-ribose(which can exist only in the furanose form) in pyridine at 3" is of the normal, first order type. Isbell and Pigman48

15 0

20

40

60

00

100

120

140

160 :quil.

TIME, minutes

FIG.1.-Mutarotation

of 1,-Ribose in Water a t O".4s

have studied the bromine oxidation of ribose equilibrated in aqueous solution and have shown the presence of a small quantity of some form which is more readily oxidized than the crystalline sugar. Cantor and P e n i s t ~ ninterpreted ~~ the results of a polarographic study of D-ribose as showing that 8.5 to 30% of the sugar in aqueous solution is present in the free aldehydo form. The unique nature of D-ribose as compared with the other sugars is emphasized by the fact that these authors found (45) G. T. Keenan, J . Wash. Acad. Sci., 16, 433 (1926). (46) J. Ellinghaus, 2. physiol. Chem., 164, 308 (1927). (46a) L. P. Kuhn, Anal. Chem., 22, 276 (1950). (47) F. P. Phelps, H. S. Isbell and W. W. Pigman, J . Am. Chem. SOC.,66, 747 (1934). (48) H. S. Isbell and W. W. Pigman, J . Research NatZ. Bur. Standards, 18, 141 (1937). (49) S. M. Cantor and Q. P. Peniston, J . Am. Chem. Soc., 62, 2113 (1940).

THE CHEMISTRY OF RIBOSE

143

an aldehyde content of only 0.13 to 0.4% for aqueous solutions of the typical pentose arabinose.

4. Identification of Ribose

A tentative identification of ribose may be made through the usual tests for a reducing sugar, specific tests for pentoses50 and, finally, if the sample is homogeneous and crystalline, through its melting point, specific rotation and optical crystallographic properties. Confirmation of the identity of a substance as ribose may be made through the preparation of various substituted hydrazones such as those from p-bromophenylhydrazine, 1-1*13-51benzylphenylhydra~ine~.~~ and diphenylmethanedimethyldihydrazine ([H2N-N (CH3)CeH4I2CH2) .* However, while the derivative from the last named hydrazine would appear t o be fairly effective in distinguishing ribose from the other pentoses, final identification should always be made through direct comparison with corresponding derivatives of authentic material. Ribose may be identified through the benzimidazole from ribonic acid, 2-(~-ribo-tetrahydroxybutyl)benzirnidazole~~~~~~~~ and its picrate and hydrochloride. However, caution must be used at two points in this procedure. I n the first place, the customary oxidation of ribose with alkaline hypoiodite produces both ribonic and arabonic acids, the latter being formed by the alkali-induced epimerization of the former. While this epimerization may be avoided by using a buffered oxidizing mixture such as bromine-barium benzoate,55there is, in the second place, further risk of epimerization during the condensation of the aldonic acid with o-phenylenediamine, particularly if there is insufficient acid p r e ~ e n t . ~ , ’ ~ . ~ ~ p-D-Ribopyranose tetraacetateK6has been used as a derivative for the identification of ~ - r i b o s e ’and, ~ more recently, Hardegger, Schreier and El HeweihiK7have prepared dimethyl, ethylene and dibenzyl thioacetals (mercaptals) of D-ribose for this purpose. According to ZinnerK8the di-n-propyl and diisobutyl thioacetals are particularly suitable derivatives for the identification of ribose. (50) C . A. Browne and F. W. Zerban, “Physical and Chemical Methods of Sugar Analysis,” 3rd ed., John Wiley & Sons, Inc., New York (1941), pp. 706, 715 et seq. (51) P. A. Levene and R. S.Tipson, J. Biol. Chem., 116, 731 (1936). (52) N. K. Richtmyer and C. S.Hudson, J . Am. Chem. SOC.,64, 1612 (1942). (53) R. J. Dimler and K. P. Link, J. Biol. Chem., 160, 345 (1943). (54) For a review of the substituted benzimidazoles derived from the sugar acids see N. K. Richtmyer, Aduances in Curbohydrate chemistry, 6 , 175 (1951). (55) C. S. Hudson and H. S.Isbell, J. Research NatE. Bur. Standards, 3, 57 (1929). (56) P. A. Levene and R. S. Tipson, J. Biol. Chem., 92, 109 (1931). (57) E. Hardegger, E. Schreier and Z. El Heweihi, Helu. Chim. Acta, 33,1159 (1950). (58) H. Zinner, Chem. Ber., 83, 275 (1950).

144

ROGER W. JEANLOZ AND HEWITT G. FLETCHER, JR.

The most important new tool for the identification of ribose, particularly when the sugar is present in small quantities and mixed with other substances, lies in partition chromatography, a process originally developed by Martin and SyngeSBand by Consden, Gordon and Martinao for the separation and identification of amino acids. Application of paper partition chromatography to the sugars was first made by Partridgea1Sa2who determined R, values for a variety of sugars including D-ribose and showed that as little as 30 pg. of sugar could be dealt with in this manner. Using a powdered cellulose column, Hough, Jones and Wadmana3sa4studied the separation of sugars on a 100-500 mg. scale; in their hands a synthetic mixture of galactose, rhamnose, ribose and arabinose was resolved successfully, crystalline ribose being recovered in 94% yield. The development of visible spots on paper chromatograms has received considerable attention. Partridge61*a2employed ammoniacal silver nitrate solution which, of course, reacts indiscriminately with all reducing substances and, moreover, being in aqueous solution, tends t o allow the spots t o migrate during development. As an improvement upon this reagent, Partridge has suggestede6 the use of a solution of aniline hydrogen phthalate in moist butanol. This reagent gives a bright red coloration with the pentoses while aldohexoses, desoxy sugars and uronic acids react t o give various shades of green and brown, as little as 1 pg. being detectable by this reagent. Horrocksee has studied benzidine as a developing agent for the paper chromatography of the sugars and has shown that it may be used to distinguish between pentoses and other sugars. Pacsu, Mora and Kenta7have reported an RF value for ribose as well as the use of a solution of potassium permanganate and sodium carbonate for developing sugar spots on the paper chromatogram. Hough, Jones and Wadmanas have reported RF values for ribose and have introduced various new reagents for the development of colored spots. In actual practice, final identification of a sugar by partition chromatography involves chromatographing the unknown on the same paper with authentic material. The test should be repeated with at least (59) (60) (61) (62) (63) (64) (65) (66) (67) (68)

A. J. P. Martin and R. L. M. Synge, Biochem. J., 36, 1358 (1941). R. Consden, A. H. Gordon and A. J. P. Martin, Biochem. J., 38, 224 (1944). S. M. Partridge, Nature, 168, 270 (1946). S. M. Partridge, Biochem. J., 42, 238 (1948). L. Hough, J. K. N. Jones and W. H. Wadman, Nature, 162,448 (1948). L. Hough, J. K. N. Jones and W. H. Wadman, J. Chem. SOC.,2511 (1949). S. M. Partridge, Nature, 164, 443 (1949). R. H. Horrocks, Nature, 164, 444 (1949). E. Pacsu, T. P. Mora and P. W. Kent, Science, 110, 446 (1949). L. Hough, J. K. N. Jones and W. H. Wadman, J. Chem. SOC.,1702 (1950).

THE CHEMISTRY OF RIBOSE

145

three solvents since the RF values for a given pair of sugars may be nearly identical with some solvents. Paper chromatography has been used for the quantitative determination of individual sugars in mixtures by Hirst, Hough and Jones,69 alkaline hypoiodite being used to titrate each of the sugars (including D-ribose) that was separated on the chromatogram. A closely related procedure was developed by Hirst and Jones,7o the sugars separated by paper partition chromatography being individually oxidized with sodium periodate and the formic acid thus produced being determined. A mixture of rhamnose, ribose, arabinose and galactose was thus separated and analyzed to account for a total of 102 to 106% of the original mixture. A direct application of paper partition chromatography to a problem of ribose chemistry was made by Barker and Lock71 who hydrolyzed tetraacetyl-di-D-ribose anhydride (p. 173) and showed by chromatography that only ribose was formed. Other applications of partition chromatography t o the sugars have recently been r e v i e ~ e d . ~ ~ * ~ ~ 5 . Chemical Properties of Ribose Brief mention will be made here of those reactions of ribose which do not lead t o derivatives discussed in section 111. Two years after the first preparation of L-ribose, F i ~ c h e r described ?~ the reduction of the sugar with sodium amalgam to the corresponding pentitol, which he showed to be identical with the polyol adonitol from Adonis vernalis L.76,76A process for the catalytic hydrogenation of D-ribose in the presence of magnesium-activated Raney nickel to ribitol has been patented.77 The oxidation of D-ribose t o D-ribonic acid was first carried out by Levene and Jacobs78 who used bromine in a n aqueous suspension of barium carbonate as an oxidant; more recent work bearing upon the oxidation of ribose to ribonic acid with alkaline hypoiodite63 and with bromine-barium benzoate has already been mentioned. More vigorous oxidation gives ribo-trihydroxyglutaric acid.3 The behavior of ribose in the Kiliani-Fischer synthesis has recently (69) E. L. Hirst, L. Hough and J. K. N. Jones, J. Chem. Soc., 928 (1949). (70) E. L. Hirst and J. K. N. Jones, J. Chem. SOC.,1659 (1949). (71) G. R. Barker and M. V. Lock, J . Chem. SOC.,23 (1950). (72) S. M. Partridge, Biochem. Soc. Symposia, 3, 52 (1949). (73) F. Cramer, Angew. Chem., 62, 73 (1950). (74) E. Fischer, Ber., 26, 633 (1893). (75) W. V. Podwissotzky, A w h . pharm., 227, 141 (1889). (76) E. Merck, Arch. pharm., 231, 129 (1893). (77) L. A. Flexser, U. S. Pat. 2,421,416 (1947). (78) P. A. Levene and W. A. Jacobs, Ber., 44, 746 (1911).

146

ROGER W. JEANLOZ AND HEWITT Q. FLETCHER, JR.

been revie~ed.7~~80 The condensation of nitromethane with D-ribose, a reaction which is a potential source of a wide variety of derivatives and lends itself particularly to the production of substances labeled with sotopic carbon, has been studied by Sowden and Fischer.81,82 Like the other pentoses, ribose is converted to furfural when heated with dilute aqueous acid; the quantitative aspects of this reaction have been studied by Hockett, Guttag and Smith.8a

111. RIBOSEDERIVATIVES 1. Ethers of Ribose

Complete methylation of methyl D-ribopyranoside (p. 158) leads to the formation of a trimethyl ether from which, upon hydrolysis, 2,3,4trimethyl-D-ribose has been obtained in crystalline form.84186*86 The methylation and subsequent hydrolysis of adenosineB6and guanosines7 by Levene and Tipson gave an amorphous trimethyl-D-ribose which reacted more rapidly with acidic methanol than the 2,3,4-isomer and gave, upon oxidation with nitric acid, only dimethylerythraric acid. Since 2,3,4-trimethyl-~-ribose gives 2,3,4-trimethylribaric acid on oxidation it was concluded that the new ether was 2,3,5-trimethyl-~-ribose and that the nucleosides adenosine and guanosine are ribofuranosides. Subsequently Levene and Stiller88 methylated 2,3-isopropylidene-~ribose (XVI) (see p. 168) to obtain a methyl 2,3-isopropylidene-5methyl-D-riboside (XVII) which, upon hydrolysis, gave 5-methyl-~ribose (XVIII). Further methylation to give a methyl trimethyl-Driboside (XIX), followed by a second hydrolysis, furnished 2,3,5-trimethyl-D-ribose (XX), identical with that prepared from adenosine and guanosine. The structure of 2,3,5-trimethyl-~-ribose was confirmed by Barker89 in 1948 through its synthesis from authentic methyl D-ribofuranoside. Barker and have hydrolyzed a tetramethyl-di-D-ribose anhydride (p. 173) and adduced evidence to show that the product (not isolated) was 2,3-dimethyl-~-ribose. (79) C. S. Hudson, Advances in Carbohydrate Chemistry, 1, 1 (1945). (80) N. K. Richtmyer, Advances in Carbohydrate Chemistry, 1, 37 (1945). (81) J. C. Sowden and H. 0. L. Fischer, J . Am. Chem. SOC.,69, 1048 (1947). (82) J. C. Sowden and H. 0. L. Fischer, U. S. Pat. 2,480,785 (1949). (83) R. C. Hockett, A. Guttag and M. E. Smith, J . Am. Chem. Soc., 66, 1 (1943). (84) P. A. Levene and R. S. Tipson, J . Biol. Chem., 93, 623 (1931). (85) (86) (87) (88) (89)

P. A. Levene and R. S. Tipson, J . Biol. Chem., 94, 809 (1931). P. A. Levene and J. Compton, J . Biol. Chem., 116, 169 (1936). P. A. Levene and R. S. Tipson, J . Biol. Chem., 97, 491 (1932). P. A. Levene and E. T. Stiller, J . Biol. Chem., 102, 187 (1934). G. R. Barker, J . Chem. SOC.,2036 (1948).

147

THE CHEMISTRY OF RIBOSE

CH20H

CHZOCH~

XVI

XVII

XVIII

XIX

xx

A 5-benzyl-~-ribosehas been prepared by Kenner, Taylor and Todd,90 who etherified the methyl 2,3-isopropylidene-~-ribofuranoside (XXI) of Levene and Stillers1 with benzyl chloride to obtain methyl 2,3-isopropylidene-5-benzyl-~-ribofuranoside(XXII), which was subsequently hydrolyzed to give amorphous 5-benzyl-~-ribose(XXIII). The structure of this ether was confirmed through acetylation to its triacetate (XXIV), hydrogenolysis t o 1,2,3-triacetyl-~-ribofuranose(XXV) and further acetylation to the known, crystalline tetraacetyl-D-ribofuranose (XXVI). Bredereck, Kothnig and B e r g e P obtained a crystalline monotritylD-ribose through direct tritylation of the free sugar in pyridine solution for four days at 37". I n view of the known selectivity of trityl chloride CHOCH~

I

~HOCH,

I

CHO

I

HCOH

I

HCOH

- + I I

I

H~OH

I

CHzOCHzCsHs XXI

I

CHOAc HLOAC -t

HLOAc

HA+

(90) G. W. Kenner, C. W. Taylor and A. R. Todd, J. Chem. Soc., 1620 (1949). (91) P. A. Levene and E. T. Stiller, J. Biol. Chem., 104, 299 (1934).

148

ROGER W. JEANLOZ AND HEWITT G . FLETCHER, JR.

for primary as compared with secondary hydroxyl groupsg2and the fact that the compound mutarotated t o the left in pyridine solution it was designated as 5-trityl-a-~-ribose. Barker and Lock'' have repeated this preparation and found that the yield of product is approximately tripled when the 5-trityl-~-riboseis isolated as its triacetate. Use has been made of 5-trityl-~-ribosein the synthesis of 1-(a-D-ribofuranosy1)5,6-dimethylbenzimidazole,a degradation product of vitamin B12Qa(see p. 167). 2. Esters of Ribose with Organic Acids The acetylation of D-ribose in pyridine solution at low or ordinary temperatures leads t o the formation of a crystalline tetraacetate melting at 110" and showing - 54.3" in ~hloroforrn.6~~~4 The ring structure of this substance is retained on conversion t o triacetyl-D-ribosyl bromide since the latter compound may be reconverted to it by treatment with silver acetate.60 While indirect evidence early indicated94 that the bromide as well as the tetraacetate possessed a pyranose structure the question was not settled unequivocally until the bromide was used in the synthesis of nucleosides which were known to be pyranosides through quantitative periodate oxidation. 96 While the configuration of the crystalline tetraacetate a t carbon one will not be known with certainty until its anomer is obtained, the compound may provisionally be considered p-D-ribopyranose tetraacetate because of its strong levorotation. D-Ribofuranose tetraacetate has been the object of considerable study because of its utility as an intermediate in the synthesis of nucleosides. The first successful synthesis of this ester 'was carried out by Howard, Lythgoe and Toddge who hydrogenated 1,2,3-triacetyl-5(XXVIII) trityl-D-ribofuranose (XXVII) to 1,2,3-triacetyl-~-ribofuranose which was then acetylated to give a crystalline D-ribofuranose tetraacetate (XXIX). Bredereck and Hoepfnerg7improved this process by showing that treatment of XXVII with a mixture of acetic anhydride and acetyl bromide gives D-ribofuranose tetraacetate (XXIX) directly, the trityl group being eliminated as trityl bromide. Kenner, Taylor and Todd,gousing 5-benzyl-~-riboseas an intermediate, also obtained D-ribofuranose tetraacetate as described earlier (p. 147). (92) B. Helferich, Advances in Carbohydrate Chemistry, 3, 79 (1948). (93) N. G . Brink, F. W. Holly, C. H. Shunk, Elizabeth W. Peel, J. J. Cahill and K. Fokers, J. A m . Chem. Soc., 72, 1866 (1950). (94) G . E. Hilbert and C. E. Rist, J. Biol. Chem., 117, 371 (1937). (95) R. A. Baxter, A. C. McLean and F. S. Spring, J. Chem. Soc., 523 (1948). (96) G . A. Howard, B. Lythgoe and A. R. Todd, J. Chem. Soc., 1052 (1947). (97) H. Bredereck and Eva Hoepfner, Chem. Ber., 81, 51 (1948).

:I,1 c:

149

T H E CHEMISTRY OF RIBOSE

-1 H i : I H h o

T

H :::I

- + H OAc

XXVII

- + H OAc

A

H 0-

HA0 bH2OTr

I

(!!H20H XXVIII

AH1OAc XXIX

Zinnergs has studied the acetylation of D-ribose in pyridine solution with acetic anhydride at various temperatures. At 0" the pyranose tetraacetate is the sole product, but as the temperature at which acetylation is carried out is increased, the furanose isomer is also formed, the proportions of the two isomers formed at 100"being nearly equal. These findings parallel the earlier work by Schlubach and Prochownickg9in the D-galactose series. Zinner also observed that the acetylation of D-ribose with sodium acetate and acetic anhydride at higher temperatures gives rise to the furanose tetraacetate. As confirmation of the structure of D-ribofuranose tetraacetate, may be mentioned its use in the synthesis of the naturally occurring D-ribofuranoside xanthosine.'OO Crystalline aldehyde-D-ribose tetraacetate (XXXII) has been prepared through the Rosenmund reduction of tetraacetyl-D-ribonyl chloride (XXXI),lol through the selective hydrolysis of tetraacetyl-D-ribose diethyl thioacetal (XXX) lo2and through the Raney nickel hydrogenolysis The substance of ethyl thiol-D-ribonate tetraacetate (XXXIII).103,104 and in has been used in the synthesis of 2,3,4,5-tetraacetyl-~-ribitol~~~ the synthesis of ribitylaminobenzenes.106 While various author^^^^^^^^^^^^^^ have hydrolyzed arylamine D-ribofuranoside triacetates to 2,3,5-triacetyl-~-ribose, the latter has thus far been obtained only in crude amorphous form. (98) H. Zinner, Chem. Ber., 83, 153 (1950). (99) H. H. Schlubach and Vilma Prochownick, Ber., 62, 1502 (1929). (100) G. A. Howard, A. C. McLean, G. T. Newbold, F. S. Spring and A. R. Todd, J . Chem. SOC.,232 (1949). (101) R. Pasternack and E. V. Brown, U. S. Pat. 2,237,263 (1941). (102) H. Zinner, Chem. Ber., 85, 418 (1950). (103) M. L. Wolfrom and J. V. Karabinos, J . Am. Chem. Soc., 68, 724 (1946). (104) M. L. Wolfrom and J. V. Karabinos, J . Am. Chem. Soc., 68, 1455 (1946). (105) H. H. Fox, J . Org. Chem., 13, 580 (1948). (106) R. Pasternack and E. V. Brown, U. S. Pat. 2,250,999 (1941). (107) G. A. Howard, G . W. Kenner, B. Lythgoe and A. R. Todd, J . Chem. Soc., 855 (1946). (108) J. Lee and L. Berger, U. S. Pat. 2,384,104 (1945).

(109) R. Jeanloe, H. G. Fletcher, Jr., and C. S. Hudson, J . Am. Chem. Soc., 70, 4052 (1948).

nickel gave crystalline 1,6anhydroribitol tribenzoate (XXXVII), a rneso substance and thus devoid of optical activity. Debenzoylation of XXXVII furnished ' l,&anhydroribitol (XXXVIII), the structure of which was confirmed by quantitative oxidation with periodate. The crystalline D-ribose tetrabenzoate was provisionally assigned to the IIIAXXX

IIAXXX

IAXXX

OZH?

Ho?H L H ]:

280 H +

k 8 "3 q H

2ff0?H WO H +

f

280?H

AXXX

-OZHf

AIXXX -O"f

280fH Z80fH 2 8 0

fH

+

280?H

Z80?H

Z80?H

bausx y q ! ~(IAXXX) apIsoqporyq snoyd2ours Buqnsan ayq 30 u o y o z ~ ~ n j -1nsaa 'Ioyqydsuo!yq-Z 30 q s s mnrsssqod ayq Y ~ I Mpasuapuoo SBM umq u~ q o q 'nxxx ~ 'ap!uroJq Suypuodsannoo ayq oqur (AIXXX) aqsozuaq -snqaq ayq paqnaauoa appnonq ua9oJplly :suoyman 30 sapas S U ~ M O Iayq ~OJ bq paqonqsuonrap SBM aausqsqns s q ? 30 amqonqs asonsnbd aq& m1.103 -onopp u! .ZOT - a,,[;.] P u ~ waqsozuaqsnqaq ~ auqpqsbno s pIa!d %sg u! a+% 0% eoruospnHpus naqoqai,$ ' z o p a f bq pun03 uaaq ssy annqsnaduraq M O ~B p appoiyo ILozuaq q q ! ~auypylld u! asoqp-a 30 uo!qs1bozuag

VOfH

VOTH

IIXXX WO'Hf

IIIXXX 'JVO'H?

aV0 H +

?

3V0?H

gHz3s-T

"OfHC OH3

0

IXXX VO'H? WOfH 3Vo?H 13-T

T

0

XXX aQO'H3

I

"QO?H

Z(g~z3~)~3 'ZIP 'ZI3H3L3W '9 LLIM3H a N V ZO'INV3P 'M X390ZI

0';T

T H E CHEMISTRY OF RIBOSE

151

p-D-series because of its strong levorotation and the fact that the amorphous material remaining in the mother liquor from its preparation was dextrorotatory (+%So). An amorphous 2,3,4-tribenzoyl-~-ribose has been reported as a product of the hydrolysis of aniline D-ribopyranoside tribenzoateZ9 as well as of the hydrolysis of tribenzoyl-P-D-ribopyranosyl bromide with moist acetone in the presence of silver carbonate.'1° In the latter case the structure of the product was demonstrated through methylation to the known methyl P-D-ribopyranoside tribenzoate. Recently Ness, Fletcher and Hudson"' have succeeded in obtaining a 2,3,4-tribenzoyl-~ribose in crystalline form. 3. Acylohalogenoriboses Levene and TipsonS6treated crystalline D-ribopyranose tetraacetate with hydrogen bromide and obtained a crystalline triacetyh-ribopyranosyl bromide which showed - 209.3' in chloroform and, therefore, presumably belongs to the &+series. Since the compound is markedly unstable and, moreover, need not be isolated in the course of the synthesis of ribosides95,98*112 it has received but little attention in the twenty years since its discovery. The corresponding chloride, triacetyl-P-D-ribopyranosyl chloride, has recently been prepared in crystalline form by Zinner.9* The fact that this substance, showing in chloroform a rotation of [alZzD - 169.6", is somewhat less levorotatory than the corresponding bromide tends to support the view that both compounds are members of the P-D-series.113 The acetylated D-ribofuranosyl halides, important for the synthesis of nucleosides and other ribofuranosides, are unfortunately also very unstable and, while the bromideg6vg8and c h l ~ r i d e have ~ ~ ~both ' ~ been ~ ~ ~involved ~ ~ in various researches, neither has been adequately characterized. The benzoylated D-ribopyranosyl halides appear to be considerably more stable than their acetyl analogs and tribenzoyl-P-D-ribopyranosyl bromide (XXXIX), obtained in crystalline form through the action of hydrogen bromide on p-D-ribopyranose tetrabenzoate (XLI) in glacial (110) R. Jeanloz, H. G. Fletcher, Jr., and C. S. Hudson, J . Am. Chem. SOC.,70, 4055 (1948). (111) R. K. Ness, H. G. Fletcher, Jr., and C. S. Hudson, J . Am. Chem. SOC.,73, 959 (1951). (112) D. W. Visser, I. Goodman and K. Dittmer, J . Am. Chem. SOC.,70, 1926 (1948). (113) C. S. Hudson, J . Am. Chem. SOC.,46,462 (1924). Incidentally, the assign-

ment of these two strongly levorotatory halides to the 8-D-series supports the previous allocation (p. 148) of the crystalline D-ribopyranose tetraacetate to the p-D-series. (114) J. Davoll, B. Lythgoe and A. R. Todd, J . Chem. Soc., 967 (1948).

152

ROGER W. JEANLOZ AND HEWITT G. FLETCHER, JR.

acetic acid s o 1 ~ t i 0 nappears , ~ ~ ~ to be stable indefinitely when stored over calcium chloride and potassium hydroxide a t 5". The strong levorotation of this substance, [a]20D - 199" in chloroform, justifies the tentative assumption that it belongs to the 8-D-series; its pyranose structure follows from the fact that it reacts with methanol in the absence of an acid acceptor to give methyl 8-D-ribopyranoside tribenzoate (XLII).ll0 The reaction of 8-D-ribopyranose tetrabenzoate with hydrogen bromide in glacial acetic acid solution has recently been reinvestigated by Ness, Fletcher and Hudsonlll and a new, crystalline tribenzoyl-Dribopyranosyl bromide, isomeric with that previously known, obtained in 5% yield. I n contrast to the major product of the reaction, the new halide proved to have a dextrorotation of [aI2OD 78" in chloroform and, since it reacted readily with methanol to give methyl 8-D-ribopyranoside tribenzoate (XLII), it was concluded that it is tribenzoyl-

+

I

+

L r

+

153

THE CHEMISTRY OF RIBOSE

a-D-ribopyranosyl bromide (XL). Solution of XXXIX in a glacial acetic acid solution of hydrogen bromide led to the isolation of XL in 1.3% yield; it therefore seems probable that an equilibrium is established between the two anomeric bromides in this strongly acidic medium. Treatment of 0-D-ribopyranose tetrabenzoate (XLI) with titanium tetrachloride in chloroform solution gives as a major product (56% yield) a tribenzoyl-D-ribopyranosyl chloride showing [aIzoD - 147' in chloroform and as a minor product ( 5 % yield) an isomeric chloride showing [aIzoD 60" in chloroform. Since both of these isomers react with methanol in the absence of an acid acceptor to give methyl p-Dribopyranoside tribenzoate (XLII), the dextrorotatory isomer is considered to be tribenzoyl-a-D-ribopyranosyl chloride (XLIV) and the levorotatory isomer tribenzoyl-8-D-ribopyranosyl chloride (XLIII). Comparison of the rotations in Table I tends to confirm these assignments of configuration: the a-D-bromide is more dextrorotatory than the a-D-chloride while the p-D-bromide is more levorotatory than the p-Dchloride. Further evidence in favor of the assigned configurations was obtained through a study of the reaction of the four halides with methanol. According to the present theory of the role of neighboring groups in replacement reactions1116halides such as XL and XLIV, having a halogen on carbon 1in a cis position relative to the benzoyloxy group on carbon 2, may be expected to react with methanol with simple inversion at carbon 1 to kive methyl p-D-ribopyranoside tribenzoate (XLII). On the other hand, halides such as XXXIX and XLIII, having a trans relationship between the groups on carbons 1 and 2, react with methanol, in part at least, by a different mechanism. Displacement of the halogen is here

+

TABLE1 1 1 1 Benzoylated D-Ribepyranosyl Halides

~~~

Tribensoyl-a-D-ribopyranosyl bromide Tribenzoyl-a-D-ribopyranosylchloride Tribenzoyl+D-ribopyranosyl bromide Tribenzoyl-&D-ribopyranosyl chloride

164-166' 203-204" 152-154" 162-163"

~

~~

~

+78" +60" -202" - 147"

facilitated by the neighboring acyloxy group and an intermediate ion, XLV, is formed. Under acidic conditions (i.e., in the absence of an acid acceptor) this ion reacts with a methoxyl ion, inverting a t carbon 1, to give the trans glycoside, methyl 8-D-ribopyranoside tribenzoate (115) A. E. Remick, "Electronic Interpretations of Organic Chemistry," John Wiley & Sons, New York, 2nd ed., 1949, p. 339.

154

ROGER W. JEANLOZ AND HEWITT G. FLETCHERl JR.

XLV

XXXIX (X = Br) XLIII (X = Cl)

XLII

1

I

HAOBa HAOBz AH20 XLVI

(XLII). From the foregoing it might be expected that each trans halide (XXXIX and XLIII) would react more rapidly with methanol than its cis isomer (XL and XLIV, respectively). As shown in Table 11, actual measurements confirmed this expectation and the 0-D-bromide was found to react 19 times as fast as the a-D-bromide while the /3-D-chloride reacted 85 times as fast as the a-D-chloride. T A B ~11111 ~E Reaction of Tribenzoyl-D-ribopyranosyl Halides with 1 :9-Dioxane-Methanol at 20’

k X lo4 (mins., loglo) Tribenzoyl-a-D-ribopyranosylbromide Tribenzoyl-8-D-ribopyranosyl bromide Tribenzoyl-a-D-ribopyranosyl chloride Tribenzoyl-j3-D-ribopyranosyl chloride

40 760 0.62 53

Time of “Half-change” mins. 75

4.0 4900 57

I n the presence of an acid acceptor the intermediate ion XLV may react directly with a methoxyl ion t o give a methyl 1,2-orthobenzoate such as XLVI. Experiment showed that while reaction of the a-Dbromide (XL) with methanol in the presence of silver carbonate gave the levorotatory methyl /3-D-ribopyranoside tribenzoate (XLII) in good

T H E CHEMISTRY OF RIBOSE

155

yield, both of the p-D-halides, XXXIX and XLIII, gave dextrorotatory sirups under these conditions. That these dextrorotatory sirups contained the acid-labile orthoester XLVI was rendered highly probable by the observation that they rapidly became levorotatory when dissolved in acidic methanol and that there was then obtained crystalline methyl 0-D-ribopyranoside tribenzoate (XLII). An analogous situation exists in the L-rhamnose series where crystalline 3,4-dibenzoyl-p-~-rhamnopyranose methyl 1,2-orthobenzoate was obtained from tribenzoyla-L-rhamnopyranosyl bromide. l6

4. Phosphates of Ribose While numerous phosphorylated derivatives of D-ribose are of prime importance from the biochemical point of view, the present discussion will be limited to a brief consideration of the chemistry of the known D-ribose phosphates. Kalckarll'~ll*~llY has shown that the enzymatic phosphorolysis of inosine (hypoxanthine 9-D-ribofuranoside) may give rise t o the formation of a pentose phosphate, isolable as its barium salt. The phosphate was found to be non-reducing although easily hydrolyzed by either acid or alkali to equimolar quantities of phosphate and pentose. In view of these properties and the fact that it could be used for the enzymatic synthesis of purine ribosides, Kalckar has tentatively assigned to it the D-ribose l-phosphate structure; its ring structure and configuration at carbon 1 remain undetermined. D-Ribose 2-phosphate has not been isolated as yet although some evidence has been interpreted120r121 as possibly indicating the existence of ribonucleotides having a phosphate residue in the 2 position of the sugar moiety. The 3- and 5-phosphates of D-ribose have both been obtained through the hydrolysis of naturally occurring ribosides. In 1908 Levene and Jacobs122subjected the barium salt of inosinic acid to acid hydrolysis and obtained a pentose phosphate as its barium salt. Shortly thereafter the same authors78showed that, under the conditions which normally convert a pentose to a pentaric acid, this phosphate was oxidized only to a phosphorylated D-ribonic acid and it was evident, therefore, that (116) R. K. Ness, 13. G . Fletcher, Jr., and C. S. Hudson, J. Am. Chem. SOC.,73, 296 (1951). (117) H. M. Kalckar, Federation Proc., 4, 248 (1945). (118) H. M. Kalckar, J. B i d . Chem., 167, 477 (1947). (119) H. M. Kalckar, Symposia SOC.Exptl. Biol. I . Nucleie Acid, 1947, 38. (120) C. E. Carter, J . Am. Chem. SOC.,72, 1466 (1950). (121) W. E. Cohn, J. Am. Chem. SOC.,72, 1471 (1950). (122) P. A. Levene and W. A. Jacobs, Ber., 41, 2703 (1908).

156

ROGER W. JEANLOZ AND HEWITT

a.

FLETCHER, JR.

the phosphate group was attached to the terminal position. Much later Levene and Moril28showed that the lactonization of the D-ribonic acid phosphate proceeded slowly as would be expected of a 5-phospho* 'unequivocal ~~ pentonic acid unable t o form other than a y - l a c t ~ n e . ~ ~ *An synthesis of D-ribose 5-phosphate was carried out by Levene and Stillerg1 in 1934. Condensation of D-ribose with acetone and methanol in the presence of hydrogen chloride and anhydrous copper sulfate gave methyl 2,3-isopropylidene-~-ribofuranoside (XLVII, see p. 168) as a sirup which could be purified by fractional distillation in vucuo. The structure of this substance was demonstrated through methylation and hydrolysis t o an amorphous monomethyl-D-ribose which gave a crystalline p-bromophenylosazone, identical with the p-bromophenylosazone of the authentic 5-methyl-~-ribose previously prepared by these authors88 (p. 146).

HCO-

b

H -0 h20H XLVII

Phosphorylation of XLVII with phosphorus oxychloride in pyridine solution, followed by hydrolysis to remove the methyl and isopropylidene residues, gave D-ribose 5-phosphate (XLVIII) which, as its barium salt, was found to be identical with the barium salt of the D-ribose phosphate from inosinic acid. By way of further confirmation of the structure of D-ribose 5-phosphate, Levene, Harris and Stiller'Zs showed that in methanolic hydrogen chloride solution both the natural and synthetic material mutarotated in a manner characteristic of a sugar which can form only a furanoside. The synthesis of D-ribose 5-phosphate has recently been markedly improved by Michelson and ToddlZ7through the use of dibenzylchlorophosphonate as a phosphorylating agent. Methyl 2,&isopropylidene-~(123) (124) (125) (126) (127)

P. A. Levene and T. Mori, J . Biol. Chem., 81, 215 (1929). P. A. Levene and H. S. Simms, J . Biol. Chem., 66, 31 (1925). P. A. Levene and M. L. Wolfrom, J . Biol. Chem., 17, 671 (1928). P. A. Levene, S. A. Harris and E. T. Stiller, J . Biol. Chem., 106, 153 (1934). A. M. Miohelson and A. R. Todd, J . Chem. Soc., 2476 (1949).

THE CHEMISTRY O F RIBOSE

157

ribofuranoside (XLVII) was condensed with dibenzylchlorophosphonate in pyridine solution and the protecting groups then removed from the resulting derivative (XLIX) through hydrogenation and hydrolysis to give D-ribose 5-phosphate (XLVIII) in 86% yield. In 1932 Levene and Harris12*showed that the hydrolysis of xanthylic acid gave rise to the formation of a D-ribose phosphate which was not identical with the known D-ribose 5-phosphate. Since xanthylic acid is the monophosphate derivative of a ribofuranoside of xanthine it followed that the new phosphate was either D-ribose 2-phosphate or the 3-isomer (L). Shortly thereafter the same succeeded in reducing the new D-ribose phosphate with hydrogen in the presence of platinum oxide to a ribitol phosphoric acid (LI) which was completely CHO HAOH

CHzOH HAOH

b

HAOPOIH,+ H OPO3Hz H&OH

HboH

LZOH

hHzOH

L

LI

devoid of optical activity. This finding is only compatible with a D-ribose 3-phosphate structure since the 2-isomer would give an optically active D-ribitol 2-phosphate on reduction. Later Levene and Harris'so obtained a crude methyl D-ribopyranoside 3-phosphate (LII) by the methanolysis of yeast adenylic acid. Conversion of this t o a methyl 2,4-dimethyl-~-ribopyranoside(LIII) by successive methylation and dephosphorylation was followed by hydrolysis to 2,4-dimethyl-~-ribose (LIV) which, upon reduction, gave 2,Pdimethylribitol (LV). Although the latter compound is a meso structure and would not be expected to show optical activity, the product obtained showed a rotation and the

I

CHOCH,

LII

LIII

(128) P. A. Levene and S. A. Harris, J . B i d . Chem., 96, 755 (1932). (129) P. A. Levene and S. A. Harris, J . Biol. Chem., 98, 9 (1932). (130) P. A. Levene and S. A. Harris, J . Biol. Chem., 101, 419 (1933).

158

ROGER W. JEANLOZ AND HEWITT G. FLETCHER, JR.

authors were able to demonstrate that the crude LII was contaminated with a furanoside isomer which had yielded optically active 2,5-dimethylD-ribitol as an impurity in LV. The 3- and 5-phosphates of D-ribose are readily distinguishable. Levene and StillerQ1showed that the 3-isomer hydrolyzes much more rapidly in acid solution than does the 5-isomer; a colorimetric method for distinguishing the two isomers, based on the rate of color development in the orcinol test for pentoses, has more recently been described by Albaum and Umbreit.131 5. 0-Ribosides Levene and Tipsonb6sa4warmed D-ribose with methanolic hydrogen chloride and obtained an amorphous methyl D-riboside (LVI) which upon further methyIation gave a sirupy methyl trimethyl-D-riboside

(LVII). Hydrolysis of this latter derivative gave a crystalline trimethyl-D-ribose (LVIII) from which was then prepared a trimethyl-Dribonolactone (LIX) and a trimethylpentaric acid (LX). Since L I X hydrolyzed at a rate characteristic of &lactones and L X was devoid of optical activity, it was apparent that the original glycoside, LVI, was a ribopyranoside. Shortly after the above work was published, M i n ~ a a s ' ~ ~ reported the preparation of a crystalline methyl D-riboside having [aIzoD - 113.8" in water. The structure of this crystalline compound was subsequently investigated by Jackson and who found that it consumed two moles of periodate, liberating at the same time one mole of formic acid, and was therefore a pyranoside. The dialdehyde (LXII) initially formed was further oxidized to a dibasic acid, isolated as its strontium salt (LXIII). The identity of this latter with the strontium salts from methyl p-D-arabinopyranoside and methyl p-D-xylopyranoside demonstrated that the crystalline glycoside was methyl 0-D-ribopyranoside (LXI) . (131) H. G. Albaum and W. W. Umbreit, J . Biol. Chem., 167, 369 (1947). (132) J. Minsaas, Ann., 612, 286 (1934). (133) E. L. Jackson and C. S. Hudson, J . Am. Chem. Soc., 68, 1229 (1941).

T H E CHEMISTRY OF RIBOSE

159

The investigation of the reaction of the benzohalogeno-D-riboses with methanol in the absence of an acid catalyst by Jeanloz, Fletcher and Hudsonllo as well as by Ness, Fletcher and Hudson"' has been mentioned previously. Since tribenzoyl-p-D-ribopyranosyl bromide may be prepared from D-ribose in 68% yield, since it reacts with methanol to give methyl 0-D-ribopyranoside tribenzoate in high yield and since the debenzoylation of the latter compound may be carried out in nearly quantitative yield, this path t o the synthesis of alkyl ribopyranosides is rather more attractive than the direct condensation of the sugar with a n alcohol, particularly since the latter process leads to mixtures from which the desired product is often difficult to obtain in crystalline form. Ethyl @-D-ribopyranoside has been prepared by both these methods. 110 Winter134obtained a substance from certain animal tissues which he considered t o be a n ethyl riboside; confirmation of this discovery has not yet been reported. D-Ribose reacts rapidly a t room temperature with methanol containing 1% of hydrogen chloride, and methyl D-ribofuranoside, which may be purified by vacuum distillation, is the initial The structure of the compound was shown through methylation, hydrolysis and oxidation t o 2,3,5-trimethyl-~-ribonolactone, which hydrolyzed in water at a rate characteristic of y-lactones. As mentioned above, the triacyl-P-D-ribopyranosyl halides may react with alcohols in the presence of an acid acceptor to give orthoester derivatives. Thus Levene and Tipson66 showed th a t triacetyl0-D-ribopyranosyl bromide reacts with methanol in the presence of silver carbonate t o give 3,4-diacetyl-~-ribopyranosemethyl 1,2-orthoacetate (LXIV) while Klingensmith and Evans135obtained a n analogous compound (LXV) upon condensing dihydroxyacetone monoacetate with the same halide. The structures of these two orthoesters, LXIV and LXV, have recently been discussed by Pacsu. 136 (134) L. B. Winter, Biochem. J., 21, 467 (1927). (135) C. W. Klingensmith and W. L. Evans, J . A m . Chem. Soc., 61, 3012 (1939). (13G) E. Pacsu, Advances i n Carbohydrate Chemistry, 1, 77 (1945).

160

ROGER W. JEANLOZ AND HEWITT 0. FLETCHER, JR.

0 0CHzC.CHzOAc HCO-,

I

CHa

HCOA HAOAc H AOAc AHzO LXV

6. N-Ribosides

Since D-ribose derivatives of amines occur naturally in ribonucleic acids, vitamin B12, and in cozymase and are used in t h e isolation of D-ribose as well as in the synthesis of vitamin Bz, they have attracted much attention and are currently under active investigation in a number of laboratories. As mentioned earlier, the ribonucleic acids and their component parts have been well reviewed elsewhere;* in the following discussion the syntheses of the nucleosides will be discussed only insofar as they illustrate methods of forming N-ribosides. The product from the condensation of D-ribose (LXVII) with ammonia or a primary amine might be expected to exist in a variety of tautomeric structures since the Schiff base (syn or anti form of LXX) contains the

c-

-

HAOH HAOH

A

H 0 AHnOH LXVIII

T H E CHEMISTRY OF RIBOSE

161

same potentialities for isomerism as does the free sugar and might conceivably tautomerize to the anomeric pyranosides LXVI and LXIX or to the anomeric pair of furanosides LXVIII and LXXI. The parent compound of the N-ribosides, ribosimine (LXXII or one HC=NH HbOH HbOH HbOH

bHzOH LXXII

of its cyclic tautomers), was prepared by Levene and his c ~ w o r k e r s ~ ~ ~ ~ ~ through treatment of D-ribose with dry methanolic ammonia and was used in the Kiliani synthesis for the preparation of two epimeric hexosaminic acids. When less rigorously anhydrous conditions were employed, a diribosylamine was obtained; the nature of neither of these nitrogeneous derivatives of D-ribose has been investigated further. While N-glycosides have been known for over sixty years, apparently arylamine ribosides were first prepared as a result of interest in the synthesis of vitamin Bz. In 1937 Kuhn and Strobele138condensed D-ribose with 2-nitr0-4~5-dimethylanilineby heating in alcohol in the presence of ammonium chloride, to obtain an N-riboside. This compound yielded, on acetylation, a triacetate and so was not a Schiff base of the type LXX. Furthermore, it readily yielded a monotrityl derivative in 88% yield and was therefore presumed to possess a furanose structure corresponding to LXVIII or LXXI. This evidence, like much of that pertaining t o the structures of the amine glycosides, is not convincing since the substance may well have isomerized during tritylation and, in any case, trityl chloride has been sh0wn13~to react with secondary hydroxyl groups. Furthermore, an analogous L-arabinoside prepared by Kuhn and Strobele13s is said to have been shownlo7to have a pyranose structure. and Lee, Solmssen In patents issued in 1945 Lee and Berger108s140 and Berger30."' disclosed the results of investigations of the reactions of arylamines and particularly of aniline with D-ribose. In the following year Berger and Lee2*.142 and Berger, Solmssen, Leonard, Wenis and (137)P.A. Levene and F. B. LaForge, J. B i d . Chem., 20, 433 (1915). (138) R. Kuhn and R. Strobele, Ber., 70, 773 (1937). (139) R. C. Hockett and C. S. Hudson, J. Am. Chem. Soc., 66, 945 (1934). (140)J. Lee and L. Berger, U. S. Pat. 2,383,977(1945). (141) J. Lee, U. V. Solmssen and L. Berger, U. S. Pat. 2,384,102(1945). (142)L. Berger and J. Lee, J. Org. Chem., 11, 75 (1946).

162

ROGER W. JEANLOZ AND HEWITT G. FLETCHER, JR.

Leez9 also published papers on this subject. Condensation of D-ribose with aniline in aqueous alcohol at 25" and a pH of 2-8 was found t o give an aniline pentoside while the reaction of D-ribose with aniline in boiling alcohol gave an isomeric compound. Since both of these substances were readily decomposed to D-ribose on boiling with dilute acetic acid (the aniline being removed by steam distillation or as its benzal or formal derivative) it was evident that both were aniline ribosides. The isomer prepared a t a low temperature could be isomerized to that made a t an elevated temperature simply by boiling in alcoholic solution. While acylation, tritylation and periodate studies afforded no definitive information regarding the structures of these two isomers, the authors concluded tentatively that the isomer prepared a t low temperature was a n aniline D-ribopyranoside while that prepared in boiling alcohol was an aniline D-ribofuranoside. Since both mutarotated to the left in pyridine solution they were designated as members of the a-D-series. I n 1946 Howard, Kenner, Lythgoe and Toddlo7 showed that the rotation of both isomers is constant in dry pyridine and that the presence of a trace of moisture is necessary for mutarotation. From Table I11 it may be seen that the two isomers do not come to the same end rotation under these circumstances and it is likely that each is undergoing a-Pisomerism. On the other hand, in pyridine containing 10% of acetic acid, the isomers mutarotate to the same endpoint, a phenomenon which may be explained by supposing that an equilibrium involving change in ring size is established under these conditions. This view received support from acylation studies. Acetylation of both aniline D-ribosides led to the same aniline D-riboside triacetate which, upon hydrolysis with methanolic ammonia, afforded aniline D-ribopyranoside. Evidently the ribofuranoside had rearranged to the pyranoside during acetylation. Acid hydrolysis of the aniline D-ribopyranoside triacetate removed the aniline residue and, upon further acetylation of the sugar moiety, there was obtained the known P-D-ribopyranose tetraacetate, a finding which supports the view that the aniline D-riboside prepared a t a low temperature is a pyranoside. TABLE I11 Optical Rotations of Aniline D-Ribosideslo7

I Solvent

Dry pyridine Moist pyridine Pyridine with 10% acetic acid

I

Rotation

([cY]L~-~~D)

Aniline D-ribopyranoside Aniline D-ribofuranoside +SO0 + 6 0 4 +84.4" +71- +43'

+

180" + 1 8 0 - + +161" +176 --t +44"

163

T H E CHEMISTRY O F RIBOSE

The mechanism of isomerization of amine glycosides has been discussed by Howard, Kenner, Lythgoe and Todd, lo' while the literature regarding N-glycosides in general has been briefly reviewed by Honeyman and T a t ~ h e 1 1 . l ~ ~ The insoluble complexes th at the arylamine ribopyranosides form with inorganic salts and the utility of these complexes in isolating D-ribose have been mentioned earlier. The extraction of the sodium sulfate complex of aniline D-ribopyranoside with boiling alcohol causes isomerization and the aniline D-ribofuranoside thus obtained may be hydrolyzed with dilute acid to D-ribose. In industrial practice, D-ribose for the preparation of 3,4-dimethyl-~-ribitylaminobenzene (LXXIV), a n intermediate in the synthesis of vitamin B,, need not be isolated directly. A solution containing D-ribose and sodium sulfate, obtained from the sodium amalgam or electrolytic reduction of D-ribonolactone, may be treatedzs with 3,4-dimethylaniline to give the insoluble complex of sodium sulfate with 3,4-dimethylaniline D-ribopyranoside (LXXIII).141 Either this compound or its furanose isomer (LXXV), obtained by heating in alcoho1,141~142~144 may be hydrogenated directly to the desired 3,4dimethyl-D-ribit ylaminobenzene (LXXIV). i

I

I

CHNHC6H a ( CH3)z

I

C H ~ N I - I C ~ H ~ ( C H ~ )CHNHCeHa(CH3)z Z

I

HLOH

HboH

HCOH

HboH

HAOH

- + H OH

HbOH

HAOH

HA0

b

While the melting points of the aniline glycosides, the so-called anilides," are too variable for identification purposes, the partially etherified sugars form anilides which have reliable melting points and such anilides are widely used for identification purposes. Sirupy 2,3,5-trimethyl-~-ribose,for instance, has been converted into a crystalline anilide,sg presumably aniline 2,3,5-trimethyl-~-ribofuranoside.An investigation of the configuration and properties of such derivatives would seem highly desirable. A synthesis, presumably involving a derivative of the Schiff base type (LXX), has been patented by Pasternack and Brown.'06 I n the process "

(143) J. Honeyman and A. R. Tatchell, J . Chem. Soc., 967 (1950). (144) R. Kuhn and L. Birkofer, Ber., 71, 621 (1938).

164

ROGER W. JEANLOZ AND HEWITT 0. FLETCHER, JR.

described by these authors a mixture of tetraacetyl-aldehydo-D-ribose with an arylamine is hydrogenated to give an acetylated ribitylaminobenzene. Because of the great interest in the naturally occurring nucleosides, studies of the synthesis of D-ribosides of purines and pyrimidines have been numerous. The first attempt in this direction was made by Levene and Sobotka146 who condensed the silver salt of theophylline with triacetyl-8-D-ribopyranosyl bromide to obtain what was probably triacetyl7-fl-~-ribopyranosyltheophylline (LXXVI). Subsequently Hilbert and Riste4 condensed 2,4-diethoxypyrimidine (LXXVII) with triacetyl-P-Dribopyranosyl bromide (LXXVIII) to form ethyl bromide and l-triacetyl~-ribopyranosyl-4-ethoxyuracil (LXXX), which, on deacetylation with hydrogen chloride, gave 1-D-ribopyranosyluracil (LXXIX), an isomer of

b

Br H

CiHr LXXVII

LXXVIII

1 0

HN

LXXIX

LXXX

the naturally occurring nucleoside uridine. This type of synthesis has also been used by Visser, Dittmer and Goodman for the synthesis of both uracill46 and thymine112derivatives. While, as pointed out earlier, glycosides of primary amines readily tautomerize and undergo widespread oxidation when treated with glycol-splitting reagents,147 it is to be expected that N-glycosides derived from secondary amines would more nearly resemble the 0-glycosides in their behavior. This expectation was confirmed at one point by (145)P. A. Levene and H. Sobotks, J. Biol. Chem., 66, 463 (1925). (146)D.Visser, K. Dittmer and I. Goodman, J . Biol. Chem., 171, 377 (1947). (147) 0. A. Howard, G . W. Kenner, B. Lythgoe and A. R. Todd, J. Chem. Soe.,

861 (1946).

THE CHEMISTRY OF RIBOSE

165

Lythgoe and Todd14*who found that the ring structure of the sugar residue in the purine glycosides may be ascertained through quantitative oxidation with periodate. Use was made of this fact by Baddiley, Kenner, Lythgoe and Todd149who condensed 4,6-diaminopyrimidine (LXXXI) with D-ribose in alcoholic hydrogen chloride solution to obtain an N-riboside (LXXXII) which could, of course, exist in any of a variety of structures. Through a series of reactions, which are irrelevant to the present discussion, a second ring, involving the nitrogen attached to the ribose residue, was introduced. The product, an isomer of adenosine and like the latter a riboside derived from a secondary amine, was shown to consume two moles of periodate, one mole of formic acid being liberated in the process; it is, therefore, the pyranoside 9-D-ribopyranosyladenine (LXXXIII). Comparisons based on optical rotation data indicate that the substance belongs to the p - ~ - s e r i e s . ~ ~ ~

-NHChH904

,

NHa LXXXI

I

NHa LXXXII

LXXXIII

The first successful synthesis of a naturally occurring nucleoside was reported by Howard, Lythgoe and Toddg6in 1947. Crude triacetyl-D-ribofuranosyl bromide was condensed with 2,4-diethoxypyrimidine (LXXIV) and the intermediate product, LXXXV, (not isolated) treated with methanolic ammonia. The product, LXXXVI, was identical with cytidine. The condensation of the silver salt of theophylline (LXXXVII) with triacetyl-D-ribofuranosyl bromide, followed by deacetylation, gave another synthetic N-riboside, 7-~-ribofuranosyltheophylline(LXXXVIII) ; periodate oxidation confirmed, the furanose nature of the D-ribose moiety. Similar syntheses, involving as the initial step the reaction of a silver salt of a heterocyclic secondary nitrogen compound with a triacetyl-Dribofuranosyl halide, have led to the synthesis of adenosine, 114guanosinel60 and xanthosine.lOO Davoll and L o w Y ' ~have ~ recently found that the chloromercuric derivatives of the purines give better yields of N-glyco(148) B.Lythgoe and A. R. Todd, J . Chem. Soc., 592 (1944). (149) J. Baddiley, G.W. Kenner, B. Lythgoe and A. R. Todd, J . Chem. SOC.,657 (1944). (150) J. Davoll, B. Lythgoe and A. R. Todd, J . Chem. Soc., 1685 (1948). (151) J. Davoll and B. A. Lowy, J. Am. Chem. Soc., 78,11850 (1951).

166

ROGER W. JEANLOZ AND HEWITT G. FLETCHER, JR.

0

LXXXIV

-CH

I

LXXXV

Hac-g ' 73

\\ /CH+

// N \N/

n

LXXXVI

r-

0

II ,"\

CH

\CH

H3c()

/ / N \ / /

/

HAOH HAOH

A

H 0-

sides than the silver derivatives, when condensed with acylohalogeno sugars. Thus, chloromercuri-6-benzamidopurine or chloromercuri-6acetamidopurine (LXXXIX) was condensed with triacetyl-D-ribofuranosyl chloride and the product deacetylated with methanolic ammonia to give adenosine (XC). Use of the acylaminopurine, rather than the more basic free aminopurine, resulted in less dehydrohalogenation of the acylohalogeno sugar. I

I

HgCl N

LXXXIX

xc

Efforts to condense 5-benzoyl-~-ribofuranose with a variety of pyrimidine diamines failed,1b2 although 5-benzoyl-2,3,4-triacetyl-~ribose was found to form a Schiff base with 4,6-diamino-2-methylthi0~yrimidine.l~~ Progress toward the synthesis of cozymase has been made by Haynes and Todd.164 Nicotinamide and triacetyl-D-ribofuranosyl bromide were (152) G. W. Kenner, B. Lythgoe and A. R. Todd, J . Chem. Soc., 957 (1948). (153) G.W. Kenner, H. J. Rodda and A. R. Todd, J . Chem. Soc., 1613 (1949). (154) L. J. Haynes and A. R. Todd, J . Chem. Soc., 303 (1950).

167

THE CHEMISTRY O F RIBOSE

combined in acetonitrile solution to obtain the quaternary salt (XCI) ; reduction of this with sodium dithionate, followed by removal of the acetyl groups from the sugar residue, gave an amorphous dihydronicotinamide D-ribofuranoside, N-~-ribofuranosyl-l,2(or 6)-dihydronicotinamide (XCII) which may be identical with an isomeric substance previously obtained through the hydrolysis of cozymase.

Folkers and his coworkersg3have succeeded in hydrolyzing vitamin BIZ t o a l-~-ribofuranosyl-5,6-dimethylbenzimidazole (XCVI) which they have synthesized in the following fashion. 2-Nitro-4,5-dimethylaniline (XCIII) was condensed with 5-trityl-~-ribose (XCIV) t o give the substituted N-riboside, XCV, or one of its tautomers. When this NIIz ~

3

~

0

H N-HC

CHO

I

:

H3C /l!HZOTr

XCIII

bHzOTr

xcv

XCIV

+

H3CAH,OH XCVI

168

ROQER W. JEANLOZ AND HEWITT 0 . FLETCHER, JR.

substance was successively hydrogenated, condensed with ethyl formimino ether hydrochloride and subjected to acid hydrolysis, the product, XCVI, was isolated as a picrate showing [c$'D 4- 9.1 f 1' in pyridine. When the substituted riboside XCV was acetylated prior to conversion to the benzimidazole there was obtained a product isomeric with XCVI and having in the form of its picrate a rotation of [aIzaD- 24 f 2" in pyridine. Like the dextrorotatory isomer, the substance consumed one mole of periodate and possessed, therefore, the furanose structure; for convenience, the dextrorotatory isomer was termed a-ribazole and the levorotatory isomer, 0-ribazole.

7. Acetals of Ribose The use of alkyl and alkaryl thioacetals for the identification of rib0se~7.~~ as well as for the preparation of ribose derivativesg0J02JK3 has already been mentioned. D-Ribose appears to react with thiols somewhat more rapidly than the majority of sugars, a fact which may in part be attributable to its greater solubility in hydrochloric acid.68 The condensation of D-ribose with acetone was first studied by Levene and Stiller.88 When either hydrochloric acid or anhydrous copper sulfate with sulfuric acid was used, an amorphous 2,3-isopropylidene-~ribofuranose (XCVII) was obtained. This substance was oxidized by alkaline hypoiodite, showing that carbon 1 was unsubstituted. Methylation, followed by acid hydrolysis, gave ti-methyl-~-ribose(XCIX), which reacted with acidic methanol at a rate characteristic of a sugar capable of forming only a furanoside. Further methylation of XCIX, followed by hydrolysis, afforded 2,3,&trimethyl-~-ribose (CV), a substance previously obtained through methylation and hydrolysis of the natural ribofuranoside adenosine (XC) . Confirmation of the structure of the isopropylidene-D-ribose as XCVII was obtained through the preparation of the ditosyl ester C. Reaction of this ester with sodium iodide in acetone solution resulted in the replacement of one tosyloxy group by iodine to give CIII, in which the iodine was resistant to hydrolysis and therefore not attached to position 1. In subsequent work Levene and Stillerg' showed that condensation of D-ribose with methanol and acetone in the presence of anhydrous copper sulfate and sulfuric acid gave methyl 2,3-isopropylidene-~-ribofuranoside (CI) which was identified by conversion to XCVIII, then to XCIX and, finally, to the crystalline p-bromophenylosazone of XCIX, identical with the derivative previously prepared from XCVII. When these authorslK6attempted to acetonate methyl D-ribopyranoside (CIV), (155) P. A. Levene and E. T. Stiller, J . Biol. Chem., 106, 421 (1934).

THE CHEMISTRY OF RIBOSE

169

a crude form of methyl 2,3-isopropylidene-~-ribofuranoside(CI) was obtained, the ring structure having shifted during the course of the reaction. Tosylation of the crude product gave two monotosyl derivatives; one of these reacted readily with sodium iodide in acetone solution and was, therefore, presumably the 5-tosyl derivative of CI, while the other derivative proved stable to the action of sodium iodide in acetone and may have been a derivative of methyl isopropylidene-D-ribopyranoside. As mentioned earlier, methyl 2,3-isopropylidene-~-ribofuranoside(CI) has proved useful as an intermediate in the synthesis of 5-substituted

170

ROGER W. JEANLOZ AND HEWITT G. FLETCHER, JR.

D-ribose derivatives such as 5-benzoyl-~-ribose,~~~ 5-benzyl-~-ribose~~ and D-ribose 5-ph0sphate.12~ Cyclic acetals of the naturally occurring N-ribofuranosides have found that inosine will condense been prepared. Levene and TipsonlKB with acetone in the presence of zinc chloride to give a monoisopropylidene derivative. Since this compound afforded a monotosyl ester in which the tosyloxy group was readily replaced by iodine, it was assigned structure CVI. Phosphorylation of CVI followed by hydrolytic removal

A

OH

H 0 O

H

CVI

of the isopropylidene group gave inosine 5-phosphate or "muscle inosinic acid." Similar 2,3-isopropylidene derivatives have been prepared from g ~ a n o s i n e ,adenosine, '~~ 167 ~ r i d i n e ' and ~ ~ ~cytidine. ' ~ ~ lz7 In 1940 Bredereck and BergerIK9reported that guanosine may be condensed with benzaldehyde in the presence of zinc chloride to give a monobenzylidene derivative. Since these authors were unable to obtain a trityl derivative of this latter compound, they presumed it to be 3,5-benzylideneguanosine. Subsequently Gulland and Overendlso converted benzylideneguanosine to its monoacetate. Removal of the benzylidene residue from this latter compound gave a monoacetylguanosine which was described as being resistant to the action of periodate-a fact interpreted as indicating that the original benzylidene group occupied the 2,5- or 3,5-positions. Gulland and Overend then treated acetylbenzylideneguanosine with methyl sulfate, replacing the acetyl group with a methyl group. Hydrolysis of the resulting methylated product, followed by hydrogenation of the methyl-D-ribose thus liberated, afforded an optically active methyl-D-ribitol. This evidence indicates that the benzylidene group in benzylideneguanosine is attached at the 2,3- or 3,5-positions, since, were the 3 position free, the final product (156) P.A. Levene and R. S. Tipson, J . Biol. Chem., 111, 313 (1935). (157) P.A. Levene and R. S. Tipson, J . Biol. Chem., 121, 131 (1937). (158) P.A. Levene and R. S. Tipson, J. Biol. Chem., 106, 113 (1934). (169) H.Bredereck and Eva Berger, Ber., 78, 1124 (1940). (160) J. M.Gulland and W. G. Overend, J . Chem. Soc., 1380 (1948).

171

T H E CHEMISTRY O F RIBOSE

CVII

+ CVIII II

.- .N.

P\

CH I

I

I

I

CH

N

I

cx

CH~OA~

172

ROGER W. JEANLOZ AND HEWITT G. FLETCHER, JR.

from the above-described process would be 3-methylribitol, a meso substance. With the structure accepted as 3,5-benzylideneguanosine1presumably analogous 3,bbenzylidene derivatives of the nucleosides adenosine,lZ1 uridine161 and cytidineLB2 were prepared and used in the synthesis of various supposed 2 - p h o ~ p h a t e s . ~ ~ l JIn~ ~1950, J ~ ~ however, Brown, Haynes and ToddlB4showed, through comparison of X-ray diffraction patterns, that the “ adenosine 2-phosphate” prepared from benzylideneadeno~ine~~~ was, in fact, identical with authentic adenosine 5-phosphate. Furthermore “adenosine 2-phosphate” and all the other synthetic “2-phosphates” were found to consume one mole of periodate, a finding compatible only with the conclusion that they are 5-phosphates. The evidence obtained earlier for the structure of benzylideneguanosine (CVII) was then reexamined. A crystalline monoacetylguanosine (CX) was obtained by the acid hydrolysis of acetylbenzylideneguanosine (CIX) and found to have a melting point about twenty degrees higher than that reported by Gulland and Overend. Furthermore the monoacetate CX consumed one mole of periodate and therefore could only be 5-acetylguanosine. Methylation of CIX gave a product which, upon hydrolysis, yielded an amorphous reducing sugar; paper chromatography of this latter showed it to behave like the known 5-methyl-~-ribose (CXII), It would appear, then, that the optically active methyl-n-ribitol obtained by Gulland and Overend was not 2-methyl-~-ribitol as these authors supposed but fi-methyl-~-ribitol (CXI). Brown, Haynes and Toddl64 state that tritylation of benzylideneguanosine has yielded a tritylbenzylideneguanosine (CVII1)-a finding which tends to support the conclusion that the benzylidene residue in benzylideneguanosine (and, by analogy, in the other benzylidenenucleosides) occupies the 2,3-position. 8. Anhydrides of Ribose

In the course of a study of the condensation of D-ribose with acetone, Levene and his coworkers61oS8 found that an anhydroisopropylidene-Dribose, melting at 93-94’, was obtained when hydrogen chloride was used as a catalyst, while an isomeric compound, melting at 61-62’, resulted when a mixture of sulfuric acid and anhydrous copper sulfate was employed. The structure of neither of these anhydrides has received further attention. (161) J. M.Gulland and H, Smith, J . Chem. Soc., 338 (1947). (162) J. M. Gulland and H. Smith, J . Chem. Soc., 1527 (1948). (163) J. M. Gulland and H. Smith, J . Chem. Soc., 1532 (1948). (164) D.M.Brown, L. J. Haynee and A, R. Todd, J . Chem. Soc., 408,3299 (1950).

173

T H E CHEMISTRY O F RIBOSE

In 1940 Bredereck, Kothnig and Berger2E attempted to prepare 1,2,3-triacetyl-~-ribofuranosethrough treatment of l12,3-triacetyl-5trityl-D-ribofuranose (CXIII) with hydrogen bromide in glacial acetic acid solution. Instead of the desired product, however, there was obtained an acetate, which, upon hydrolysis, gave an anhydride of D-ribose. The anhydride reduced Fehling solution only after hydrolysis with acid and, on the basis of a positive test for vicinal hydroxyl groups,las the authors assigned structure CXIV, D-ribosan (1,4)/3(1,5),to the substance. If this assignment of structure were correct it would be expected that one mole of periodate would oxidize the anhydride to produce a dialdehyde identical with that obtained from the (1,5)/3(1,6) hexosans '~~ and g a l a ~ t o s a n 'and ~ ~ showing levoglucosan, l E Ea l t r ~ s a n , mannosanlas

I HCOH 0 HAOH

HCO

I

I

I CXIV -OH& LI-OCH

-

I

I I

CXV

I

HCOH

HO~H HObH

I u CXVI

CXVII

[aI2OD- 15' in water. Barker and Lock" carried out this reaction and found, however, a rotation of [ ( Y ]-~ 48", ~ ~ no formic acid being produced in the course of the oxidation. Cryoscopic determinations (165) (166) (167) (168) (1941). (169)

J. K. Parnas and R. Klimek, 2. physiol. Chem., 217, 75 (1933). E. L. Jackson and C. S. Hudson, J . Am. Chem. Soc., 62, 958 (1940). N. K. Richtmyer and C. S. Hudson, J . Am. Chem. Soc., 62, 961 (1940). A. E. Knauf, R. M. Hann and C. S. Hudson, J . Am. Chem. Soc., 63, 1447

R. M. Hann and C. S. Hudson, J . Am. Chem. Soc., 64, 2435 (1942).

174

ROGER W. JEANLOZ AND HEWITT G. FLETCHER, J R .

of the molecular weight of the substance as well as of its acetate showed that a dimeric anhydride was in hand. Acid hydrolysis, followed by paper chromatography of the hydrolyzate, showed only ribose to be present. Methylation followed by acid hydrolysis likewise gave but one product, a substance which, with periodate, liberated formaldehyde but no formic acid and was, therefore, presumed to be 2,3-dimethyl-~ribose. In view of these facts, Barker and Lock7' assigned structure CXV to the dimeric anhydride, the while admitting that the much less probable structures CXVI and CXVII were not eliminated by the evidence obtained. 170 Various methyl 2,3-anhydroribosides have been made. Thus Honey(CXVIII) man"' treated methyl 2-tosyl-3,4-diacetyl-/3-~-arabinoside with sodium methoxide to obtain an amorphous anhydride which, in view of the well-known mechanism of the reaction of tosyl derivatives with alkali,172was assigned structure CXIX. Mukherjee and Todd,173

I

HCOCHa

I

A~OCH

1

CH20-

HO~H 1

hHa0CXVIII

CXIX

working in the L-series, and Kent, Stacey and wig gin^'^^ in the D-series, have used methyl 2,3-anhydroribopyranosides1made by this procedure, in studies of the synthesis of 2-desoxyribose. (170) The discrepancy between the specific rotation for di-D-ribose anhydride reported by Bredereck, Kothnig and Berger (reference 26) and that found by Barker and Lock (reference 71)has been corrected by R. W. Jeanloz, G . R. Barker and M. V. Lock [Nature, 167, 42 (1951)l who have pointed out an arithmetical error in the paper of reference 26. (171)J. Honeyman, J . Chem. SOC.,990 (1946). (172)S.Peat, Ann. Repts. on Progress Chem. (Chem. SOC.London), 258 (1939). (173) S. Mukherjee and A. R. Todd, J . Chem. SOC.,969 (1947). (174)P.W.Kent, M. Stacey and L. F. Wiggins, J . Chem. SOC.,1232 (1949).

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

CONTENTS I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11. Quinoxalines and Benzimidazoles from Aldoses . . . . . . . . . . . . . . . . . . . . . . . . . . 111. Benzimidazoles from Aldonic Acids. . . . . . . . . . . . . . . . . . . . . 1. Preparation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . a. From Aldonic Acids., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . b. The Special Case of Xylonic Acid, and Isolation of Benz through the Copper Salts.. . . . . . . . . . . . . . . . . . . . . . c. From Aldoses, through the Aldonic Acids.. . . . . d. From Uronic and Aric Acids. . . . . . . . . . . . . . . . . e. From Glycosides, through Simultaneous Hydroly to Aldonic and Aric Acids.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Properties, Derivatives, and Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . a. Solubilities, Recrystallization, Melting Points, and Rotations. . . . b. Hydrochlorides, Picrates, and Other Derivatives. . . . . . . . . . . . . . . c. Permanganate and Periodate Oxidations, . . . . . . . . . . . . . . . . . . . . . d. Ultraviolet Absorption Spectra. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e. Pharmacological Properties. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Anhydrobenzimidazoles.. . . . . . . . . . . . . . . . . . . . . . . . . . ........ 4. Preparation of D( -)-Tartaric Acid from D,L-Tartaric Acid through Resolution by a Benzimidazole. . . . . . . . . . . . . . . ......... 5. Determination of the Proportion of D- and L-Isomers in Samples of Lactic Acid.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6. The Benzimidazole Rule.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . IV. Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

175 176 181

186 187 187 188 188 190 190 190 194 195 196 198

I. INTRODUOTION The 2-(aZdo-polyhydroxyalkyl)benzimidazoles are weak bases derived from o-phenylenediamine by condensation with an aldonic or closely related hydroxy acid. The present review includes substances of this type containing hydroxylated side chains of one to seven carbon atoms in length. Typical is the benzimidazole from D-glucose via D-gluconic acid. The side chain is attached at position 2 of the benzimidazole nucleus, 175

176

NELSON K. RICHTMYER

(2) H O ~ H (3)

HboH

(4)

HboH

(5)

bHBOH

while the numbering of substituents in the side chain proceeds in the customary manner for sugars and their derivatives, i.e., from top to bottom in the accompanying example. The configuration of the side chain is often designated simply by a prefix referring to the sugar from which it was derived, for example, D-gluco-benzimidazole. However, the more systematic name would be 2-(~-gZuco-pentahydroxypentyl)benzimidazole, the italicized portion indicating that the configurations of the asymmetric carbon atoms are the same as in D-glucose. The benzimidazole from the corresponding 6-desoxy sugar would be named 6-desoxy-~-gluco-benzimidazole, or 2-(~-g~uco-1,2,3,4-tetrahydroxypentyl)benzimidazole.

11. QUINOXALINES AND BENZIMIDAZOLES FROM ALPOSES The discovery by Emil Fischer' that phenylhydrazine, C6HsNHNH2, unites with sugars to form characteristic derivatives prompted Peter Griess and G. Harrow2 t o try the action of the isomeric base, o-phenylenediamine, o-C6H4(NH2)2. It likewise furnished derivatives that were described as particularly interesting because of their ease of preparation and their good physical properties. Thus, a mixture of one part by weight of o-phenylenediamine and two parts of D-glucose in concentrated aqueous solution containing a few drops of hydrochloric acid was allowed to stand in a moderately warm place for about eight days. The product was a weak base that was easily soluble in dilute acid and could be precipitated from it unchanged by the addition of ammonia. It was readily recrystallizable from hot water or alcohol as beautiful, white, shining needles. In their second communication of 1887, Griess and Harrow* realized that the reaction of o-phenylenediamine was not so simple as they had assumed in their preliminary note, and that the results differed accord(1) E. Fischer, Ber., 17, 579 (1884). (2) P. Griess and G. Harrow, Ber., 90, 281 (1887). (3) P. Griess and G . Harrow, Ber., 90, 2205 (1887).

THE 2-(ALDO-POLYHYDROXYALKYL)BENZIMIDAZOLES

177

ing to whether the reaction was carried out in the presence or absence of acids. In the absence of acids, for example, two molecules of D-glucose condensed with one molecule of o-phenylenediamine t o form “digluco-oN=C eH 1 2 06

/

diaminobenzene,” which they wrote simply as CaHl

The

\

N=CeHizOs same product, obtained by Ohle and Kmyff4 in 1944 through the interaction of D-glucose and o-phenylenediamine in pyridine solution, was stated by those authors t o be a mixture of different modifications of N,N’-diglucosido-o-phenylenediamine ; that is, the compound belongs to the class of sugar anilides, which are capable of existing in solution as Schiff bases as well as in the anomeric N-glycoside forms. Apparently the only other known example of this particular type of sugar anilide is the homolog C.IHB(N=C,HI,O,), prepared by Hinsbergs by heating a mixture of 3,4-diaminotoluene and n-glucose in alcohol. Such condensation products are readily destroyed by acids, which explains why they have been obtained only under neutral or weakly basic conditions. In the presence of acids, continued Griess and Harrow,” at least two other compounds were formed and could be isolated when a reaction mixture similar to that described in their first paper was allowed t o stand for a month in a warm place. The less soluble compound mentioned earlier was named “anhydrogluco-o-diaminobenzene.” It was formed by the condensation of one molecule of glucose with one molecule of o-phenylenediamine; two molecules of water and two hydrogen atoms were eliminated during the reaction. They formulated the product N=CH

’I

correctly as CeH4

although they were puzzled

\

N=C.(CHOH) 3.CHzOH by the loss of the two hydrogen atoms. Two years later Fischers pointed out that this reaction was similir to the formation of glucose phenylosazone; the secondary alcohol group next to the aldehyde group was first oxidized to a ketone group and the resulting dicarbonyl compound could then react in the known manner with the aromatic diamine. Fischer’s experiment showing that D-glucosone (11) condensed with o-phenylenediamine within a few minutes t o the same compound that had already been described by Griess and Harrow furnished confirmatory (4) H.Ohle and J. J. Kruyff, Ber., 71, 507 (1944). (5) 0.Hinsberg, Ber., 20,495 (1887). (6) E.Fischer, Ber., 22, 87 (1889).

178

NELSON K. RICHTMYER

evidence both of the nature of the reaction with D-glucose and of the correct formulation of the product. Later, Ohle’ observed that D-frurtose and o-phenylenediamine also condensed to yield the same product. The substance thus obtained, whether from D-glucose (I), D-fructose, or D-glucosone (11), is now known as 2-(~-arabo-tetrahydroxybutyl)quinoxaline (111). It is a weak base, reduces Fehling solution, and reacts with phenylhydrazine, by oxidation and condensation, to form the yellow l-phenyl-3-(~-erythro-trihydroxypropyl)flavazole(IV) . A number of other quinoxalines and flavazoles are known, particularly through the studies of Ohle and his collaborators.8 These derivatives may be used for the identification not only of the simple sugars but also of the olirrosaccharides.

I

I

HCOH

HOCH

I

HCOH

I

CHsOH

I

I1

I11

IV

Griess and HarrowlBafter removing the crystalline “ anhydrogluco-odiaminobenzene ” or quinoxaline derivative from the weakly acidic reaction mixture of D-glucose and o-phenylenediamine acetate, and concentrating the mother liquor, obtained still another crystalline condensation product. Its composition corresponded to a molecule of glucose plus a molecule of o-phenylenediamine less a molecule of water and two atoms of hydrogen. They called it “gluco-o-diaminobenzene ” and assigned to NH

/ \

it the formula CsH4

\ CHC0.(CHOH)3.CH20H. Although /

this

NH

structure was subsequently found to be incorrect, the properties of the (7) H. Ohle, Ber., 67, 155 (1934). (8) For quinoxalines, see especially references 7 and 4, and H. Ohle and Marianne Hielscher, Ber., 74, 13 (1941). For flavazoles, see especially the series by Ohle et al. in Ber., 74, 279, 398 (1941); 76, 1536 (1942); 78, 1 (1943); reference 4; also G. Neumiiller, Arkiu Kemi, Mineral. Geol., 2lA, No. 19 (1946), and Ulla Rosenqvist, G. Neumuller and K. Myrback, ibid., 24A, No. 14 (19.46).

THE

2- (ALDO-POLY HY DROXYALKYL)BENZIMIDAZOLES

179

substance described by Griess and Harrow are sufficiently characteristic to identify it as the first known benzimidazole derived from a sugar. It crystallized from water in colorless, slender leaflets and was, in contrast t o most of the benzimidazoles prepared later, rather easily soluble even in cold water and alcohol. It had a definitely basic character and formed crystalline salts with mineral acids. Unlike the other condensation products from D-glucose and o-phenylenediamine, this base was remarkably stable, being resistant to the action of both hot acids and alkalies, and showing no reduction of Fehling solution. In fact, it was the great stability of this compound that led Hinsberg and Funckeg to state that glucose probably behaved like a simple aldehyde toward o-phenylenediamine, and that accordingly the resulting compound should N

/ \

have the formula CBH4

ISH

\ C-(CHOH)4CH20H. Although /

the

aldose is obviously oxidized t o the aldonic acid stage in the course of the condensation with the diamine, nothing is known about the mechanism of the reaction. Since the yield is not high, it is possible that oxidation of some of the aldose takes place a t the expense of the remainder. Griess and H a r r ~ w ~ reported -~O also the condensation of o-phenylenediamine with L-arabinose and D-galactose, of 3,4-diaminotoluene with L-arabinose and D-glucose, and of 2,3-diaminobenzoic acid with L-arabinose, D-glucose, D-galactose, and maltose; in all cases the products were formed in neutral or weakly acidic solutions, and through their properties were later identified as the corresponding benzimidazoles. Definite evidence that these substances really were benzimidazoles was provided in 1901 by Schilling" who subjected Griess and Harrow's product3from 2,3-diaminobenzoic acid and glucose to oxidative cleavage with permanganate. Whether formed under acid, neutral, or alkaline conditions the resulting benzimidazole carboxylic acid (VI) was identical with that produced by the condensation of 2,3-diaminobenzoic acid (VII) with formic acid, and the original substance was concluded to have, in all probability, the structure V. Dry distillation of the acid VI with calcium oxide then yielded benzimidazole itself (IX).l 2 Strangely enough, (9) 0. Hinsberg and F. Funcke, Ber., 26, 3092 (1893). (10) P. Griess and G. Harrow, Ber., 20, 3111 (1887). (11) B. Schilling, Ber., 54, 902 (1901). (12) Benzimidazole has been obtained also from the benzimidazole derived from D-galactose (ref. lo), though only in very small amount, by illumination of its alkaline solution with ultraviolet light [R. Kuhn and F. Bar, Ber., 67, 898 (1934)l. A similar irradiation of the tetrahydroxybutylquinoxalinefrom glucose gave the unsubstituted quinoxaline in 10-2074 yield.

NELSON E. RICHTMYER

180

continued Schilling, the permanganate oxidation of the condensation products of maltose and lactose with 2,3-diaminobenzoic acid gave not the benzimidazole carboxylic acid VI but the benzimidazole dicarboxylic acid VIII. Actually we should expect the latter acid to be the normal product from the permenganate oxidation of these aldo-benzimidazoles, and it is puzzling why decarboxylation should have occurred in the first oxidations cited by Schilling. COOH

O-J; COOH

KMnO: C*(CHOH),*CHaOH V

VI

VIII

;

COOH 0-N". -NH2 VII

IX

111. BENZIMIDAZOLES FROM ALDONIC ACIDS The first benzimidazoles in the sugar series, as we have seen in the preceding section, were prepared in low yields from the aldoses through a combined oxidation and condensation reaction with o-phenylenediamine. Although aromatic diamines of this type were known to condense with acids, including hydroxy acids, no one seems to have tried to prepare a benzimidazole from an aldonic acid until long after the benzimidazole structure had been established for these products. For example, Ladenburg'* condensed o-phenylenediamine with acetic acid to an "anhydro base" as early as 1875, and Georgescu14condensed the diamine with lactic acid similarly in 1892. However, it was not until 1939 that Haskins and HudsonJl6 and the following year independently Moore and Link,I6 published their valuable contributions to the chemistry of the 2-(aldo-polyhydroxyalkyl)benzimidazoles. These and subsequent papers from the laboratories of Hudson and of Link have described the preparation, properties, and reactions of nearly (13) (14) (15) (16)

A. Ladenburg, Ber., 8, 677 (1875). M. Georgeacu, Ber., 26, 952 (1892). W. T. Haskins and C. S. Hudson, J. Am. Chem. sbc., 61, 1266 (1939). S. Moore and K. P. Link, J . Biol. Chem., 183, 293 (1940,.

THE 2-(ALDO-POLYHYDROXYALKYL)BENZIMIDAZOLES

181

all the known compounds of this series; useful data on melting points and rotations will be found in the tables a t the end of this article. 1. Preparation

a. From Aldonic Acids.-The standard procedure of Haskins and Hudson16 was t o heat the aldonic lactone with a 2% molar excess of o-phenylenediamine and a small amount of water on the steam-bath for seven hours, with the occasional addition of more water whenever the cake became dry. The resulting mass of crystals was covered with ethanol and allowed to stand overnight, then filtered and recrystallized from aqueous alcohol. In this way a 41 to 75 % yield of the recrystallized benzimidazole could usually be obtained. However, in two of the twelve cases there reported, namely, with D-idonic lactone and n-manno-D-galaheptonic lactone, two molecular equivalents of concentrated hydrochloric acid were added to the reaction mixture in order to effect a satisfactory condensation to the benzimidazole stage. In the absence of a strong acid, intermediate o-aminoanilides of the type X separated shortly after heating of the reactants was begun.” The isolated and purified substances were obtained in good yields, and were identified through analyses and by their behavior toward acids. While it is probable that heating with concentrated hydrochloric acid would convert the amides to the corresponding benzimidazoles, Haskins and Hudson l7 found that the action of 6 N hydrochloric acid resulted principally in their hydrolysis. Thus, from the heptonic amide they were able to isolate both o-phenylenediamine and D-gluco-D-gdo-heptonic acid (as its phenylhydrazide) in crystalline form. Apparently the hydrochloric acid serves not only as a condensing agent in the concentrated reaction mixture but also as a solvent for the basic o-phenylenediamine, the intermediate amides, and the final benzimidazole, until the reaction is completed. When an intermediate amide is not readily soluble in the aqueous reaction mixture, conversion to the corresponding benzimidazole is very slow unless a strong acid is added. An intermediate diamide of the type XI, namely, di(D-ghco-D-tal0octony1)-o-phenylenediamine, has been described by Hann, Merrill and Hudson.ls Under the normal conditions recommended by Haskins and Hudson,16the crystalline product in this experiment was a mixture whose fractionation provided a 40 % yield of the diamide and a 39 % yield of the (17) Unpublished observations of W. T. Haskins and C. S. Hudson in this laboratory. An intermediate amide has been obtained similarly from D-gluco-L-galaoctonic lactone. (18) R. M. Hann, Alice T. Merrill and C. S. Hudson, J . Am. Chem. Soc., 66, 1912 (1944).

182

NELSON K. RICHTMYER

benzimidazole. From a condensation of the lactone with o-phenylenediamine in the presence of hydrochloric acid, only the benzimidazole was isolated. @-;~;o(cHoHi4-8cHzoH

0-

-NHCO(CHOH)eCHzOH NHCO(CH0H)aCHzOH

X

XI

The procedure of Moore and Link16 is now generally preferred for the preparation of benzimidazoles from aldonic acids, their lactones, or their salts. Their specific example starting with calcium D-gluconate is given below. Condensation with Gluconic Acid.-To 2 g. of Ca gluconate.Hs0 (0.009 mole of gluconic acid) in a test tube, add 1.1 g. (0.01mole) of o-phenylenediamine, about 4 ml. of water, 1 ml. of ethanol, and 1.7 ml. (0.02 mole) of concentrated hydrochloric acid. Warm until in solution, add a boiling chip, and heat for two hours in an oil-bath kept a t 135 f .'5 The tube should be immersed to about the level of the contained solution. During the first hour water boils off to leave a thick sirup in which bubbling gradually ceases during the second hour. Remove the tube from the bath and while still warm dissolve the sirup in about 10 ml. of water, add carbon, filter, dilute the filtrate to about 30 ml., and make alkaline with ammonium hydroxide. Crystallization is usually rapid. When it is complete, filter and wash the crystals with water, acetone, and ether. The yield of gluco-benzimidazole (m. p. 215') is 1.7 to 1.9 g. (70to 80% of theory).

In the condensation from potassium salts, Moore and LinkIs recommended that sirupy phosphoric acid (sp. gr. 1.7) be added, in amount equal to one-half the volume of concentrated hydrochloric acid that is used. While this may be of some advantage with acids, lactones, or salts of alkali metals, it tends to complicate the procedure starting with alkaline earth and other salts which will form insoluble precipitates when the reaction mixture is made basic with ammonium hydroxide. In such cases it is desirable to remove the interfering cation first. From the final alkaline solution even ammonium phosphate may crystallize during the process of concentrating a solution containing one of the more soluble benzimidazoles. The condensation of fatty acids with o-phenylenediamine has been carried out effectively by refluxing the components in 4 N hydrochloric acid.19 Moore and Link, in their second paper on the preparation of benzimidazoles,20stated that this procedure gave less satisfactory yields with the aldonic acids, the yield from D-galactonic acid being only 24%. (19) M. A. Phillips, J . Chem. Soc., 2393 (1928). (20) S. Moore and K. P. Link, J . 07g. Chem., 6, 637 (1940).

THE %(ALDO-POLYHYDR0XYALKYL)BENZIMIDAZOLES

183

However, if the reaction mixture was allowed to concentrate to a sirup during the boiling period, the yield of the same benzimidazole was 70%. The use of phosphoric acid in addition to hydrochloric acid was found to provide a reaction medium that gave more uniformly complete condensation with most aldonic acids. Concentration of a solution of the aldonic acid and a slight excess of o-phenylenediamine to a sirup at 135' in the presence of hydrochloric acid gave 60430% yields of aldo-benzimidazoles from arabonic, galactonic, gluconic, lyxonic, mannonic, and rhamnonic acids. A word of caution at this point seems most desirable. In every case where a pure aldonic acid or its derivative has been heated with o-phenylenediamine and an excess of hydrochloric acid, only a single benzimidazole has been isolated. It is well known that aldonic acids are epimerized by heating them at temperatures above 100" with organic bases such as pyridine. The heating of an aldonic acid with o-phenylenediamine at 135-150" may also result in appreciable epimerization. Thus, Moore and Linkz0reported that from the fusion of xylonic acid with o-phenylenediamine at 150°, in the absence of mineral acids, they could isolate the epimeric lyxo-benzimidazole. Barker, Farrar, and Gulland,21in a more detailed study, proved conclusively that both D-ribo- and D-arabobenzimidazoles were formed when the condensation of calcium D-ribonate with o-phenylenediamine was carried out in the presence of less than two molecular equivalents of hydrochloric acid, whereas with an excess of hydrochloric acid only the D-ribo-benzimidazole was obtained. It is important, therefore, in the condensation of o-phenylenediamine with an optically active acid at an elevated temperature that the reaction mixture always be kept on the acid side. b. T h e Special Case of Xylonic A c i d , and Isolation of Benzimidazoles through the Copper Salts.-Because xylo-benzimidazole is very soluble in water, its preparation and isolation require special modifications of the generally established methods. Huebner, Lohmar, Dimler, Moore, and Linkz2have described the procedure as follows. The barium salt from the methanol-hypoiodite oxidation of 7.5 g. (0.05 mole) of D-xylose was suspended in a small amount of water and decomposed with sulfuric acid. The barium sulfate was filtered and the solution concentrated to a sirup at reduced pressure. To the sirup dissolved in a mixture of 25 ml. of ethanol and 125 ml. of butanol, 4.6 g. (0.025 mole) of o-phenylenediamine dihydrochloride and 2.4 g. (0.022 (21) (a) G. R. Barker, Kathleen R. Farrar, and J. M. Gulland, J . Chem. SOC.,21 (1947); see also (b) J. M. Gulland and G. R. Barker, ibid., 625 (1943), and (c) G. R. Barker, Kathleen R. Cooke, and J. M . Gulland, ibid., 339 (1944). (22) C. F. Huebner, R. Lohmar, R. J. Dimler, 5. Moore, and K. P. Link, J . Biol. Chem., 169, 503 (1945).

184

NELSON I(. RICHTMYER

mole) of o-phenylenediamine (free base) were added and the mixture refluxed for eight hours. From the cooled solution 11.7 g. (85%) of the hydrochloride of D-XylObenzimidazole crystallized, m. p. 176-178'. Recrystallization (with decolorization) from twelve parts of 95% ethanol gave a mixture of anhydrous and apparently hydrated material from which the solvent was removed by drying a t 110' in uucuo. The pure anhydrous hydrochloride was obtained by recrystallization from about five parts of absolute ethanol, m. p. 181-182". An aqueous solution of the hydrochloride was shaken with an excess of silver carbonate, filtered from the silver salts, treated with hydrogen sulfide, and again filtered. Concentration of the solution gave a sirup from which D-xylo-benzimidazole crystallized. It was recrystallized from butanol, with the addition of acetone to give more complete crystallization. The melting point is 141-143'.

D-Xylo-benzimidazole has also been preparedz0 by the usual reaction at 135", although the product was not identified correctly until later.2z Its isolation was first accomplished through precipitation as the copper salt, a procedure described by Moore and Link18 that is adaptable to the isolation of other readily water-soluble benzimidazoles. In the event that little or no product crystallizes when the condensation mixture is made ammoniacal, the unreacted o-phenylenediamine is first removed by extracting the solution thrice with ether. The aqueous solution is concentrated to a small volume, and for each gram of benzimidazole estimated to be present there is added 20 ml. of a cupric ammonia solution (prepared by suspending 10 g. of cupric acetate monohydrate in water, adding sufficient aqueous ammonia to give a clear solution, and diluting to 100 ml.). The mixture is warmed on a steam-bath, with an air jet directed on the surface of the solution to insure the removal of excess ammonia and the complete precipitation of the heavy, green copper salt. The mixture is transferred to a centrifuge tube, and the product separated and washed thrice with water in the usual way. The salt is then suspended in four or five volumes of 25% ethanol and decomposed with hydrogen sulfide; the filtered and aerated solution is finally concentrated and the benzimidazole crystallized from a suitable solvent.

c. From Aldoses, through the Aldonic Acids.-The main objective of the first paper by Moore and Linkl8 was the development of a method of identifying the aldose monosaccharides by conversion t o the corresponding benzimidazoles. The general chemical and physical properties of the latter class of compounds appeared to be remarkably superior to those of the hydrazones and osazones. It was necessary, however, first to oxidize each aldose to its aldonic acid and then t o characterize the acids through their benzimidazole derivatives in a manner similar to that developed previously for a number of 'simple mono- and dicarboxylic a ~ i d s . ' ~ J ~ ' As Moore and Link showed in their second paper,2othe yields obtained

(23) (a) R.Seka and R. H. MtUler, Mbnuteh., 67, 97 (1931);(b) W.0.Pool, H. J. Harwood and A. W. Ralston, J . Am. Chem. Soc., 6B, 178 (1937);(c) Ena L. Brown and N. Campbell, J . Chem. Soc., 1699 (1937) (as picrates); (d) R. L. Shriner and R. W. Upson, J . Am. Chem. Soc., 65, 2277 (1941).

THE 2-(ALDO-POLYHYDR0XYALKYL)BENZIMIDAZOLES

185

in the direct oxidative condensation of an aldose with o-phenylenediamine are unsatisfactory, even when the reaction is carried out in the presence of copper acetatelZ4 and the method must be considered impractical in view of the 7040% over-all yields that are obtained in the usual two-stage process.26 The preliminary oxidation of the aldoses by hypoiodite in methanol is therefore recommended, the details being given in their first paper.I6 I n brief, the aldose or mixture of aldoses in a very small amount of water is added to a solution of iodine in methanol at 40°, and 4% methanolic potassium hydroxide is dropped in slowly, with stirring. The potassium salts of any arabonic, galactonic, or gluconic acids present will separate on cooling, and are filtered and used directly, without purification, for benzimidazole preparation. To the filtrate from these salts is then added a solution of barium iodide in methanol to precipitate the basic barium salts of any lyxonic, mannonic, rhamnonic, or xylonic acids, which are then filtered and condensed with o-phenylenediamine in the prescribed way. By these procedures a partial separation of acids is effected, and the resulting benzimidazoles are isolated, by fractional crystallization if necessary, and identified through their physical constants. The presence of D-fructose does not interfere with the isolation of aldo-benzimidazoles by the above method. It has no effect on the potassium salt fraction but it will precipitate with the barium salts, and later, by degradation, may give rise to small amounts of D-arabo-benzimidazole. Therefore, say Moore and Link,I6 in the examination of natural products the isolation of D-arabo-benzimidazole from the barium salt fraction, rather than from the potassium salt fraction as expected, is to be regarded with suspicion, for it may have been formed from D-fructose instead of D-arabinose. They suggest in questionable cases that pentose and ketose tests then be tried on the original sample as an aid in solving the problem. Another word of caution should be added at this point. Dimler and Link26 observed that during the oxidation of D-ribose with alkaline hypoiodite in methanol an epimerization occurred to the extent of about 5 %, the insoluble potassium D-arabonate precipitating with the potassium (24) A modification of the excellent method of R. Weidenhagen [Ber., 69, 2263 (1936)]for the preparation of 2-substituted benzimidazoles directly from an aliphatic or aromatic aldehyde and an o-diamine. (25) A striking exception, however, is that of digitoxose ( = 2,6-didesoxy-~allose), which Dimler and Link [ J . Biol. Chem., 160, 345 (1943)] converted to the corresponding benaimidazole in 70 % yield by this method of oxidative condensation whereas they could obtain only poor yields of benaimidazole by direct condensation of digitoxonic acid with o-phenylenediamine. (26) R. J. Dimler and K. P. Link, J . Biol. Chem., 160, 345 (1943); see also ref. 21.

186

NELSON K. RICHTMYER

D-ribonate. I n critical cases, such as the study of a mixture in which the presence of small quantities of D-arabinose is being considered, oxidation with bromine and a barium benzoate buffer according to Hudson and Isbel127 may be substituted, even though the procedure becomes more complicated if one wishes to fractionate the aldonic acids through their potassium and barium salts. While other examples of epimerisation under these alkaline conditions have not been reported, the possibility of such rearrangements must always be kept in mind. d. From Uronic and Aric Acids.-Concerned with the identification of uronic acids from natural sources, Lohmar, Dimler, Moore, and Link2* have studied the transformation of these substances to the corresponding dibenzimidazoles. The uronic acid must first be oxidized to the aric acid stage, preferably by the bromine and barium benzoate method of Hudson and I~be11.~' The dibasic acid is then condensed with o-phenylenediamine under conditions similar to those employed for the aldonic acids, using a molar ratio of diamine to carboxyl group of 1.3/1, with 1 mole of hydrochloric acid and 1 mole of phosphoric acid per mole of diamine for condensation. Dibenzimidasoles have thus been prepared from the naturally occurring n-glucuronic, D-mannuronic, and D-galacturonic acids through the intermediate n-glucaric ( = D-glucosaccharic), D-mannaric ( = D-mannosaccharic), and galactaric (= mucic) acids, respectively. It should be noted that the dibenzimidasole of D-glucaric acid is derivable also from L-guluronic acid, and that of galactaric acid also from L-galacturonic acid. The transformation from D-glucuronic acid to the dibenzimidasole of n-glucaric acid is shown by formulas XI1 to XIV. Melting points and rotations will be found in Table 11. COOH

x""

H OH HOAH

-+o--xH

Hk

+Ho

H

HLOH

HAOH

HbOH

HboH

LOOH

LOOH

XI1

XI11

OH

\ N//

-c-c-c-c-

H

OH

OH

OHHIp-o \N'

XIV

e. From Glycosides, through Simultaneous Hydrolysis and Oxidation to Aldonic and Aric Acids.-Lohmar, Dimler, Moore, and Linkzs have (27) C. S. Hudson and H. S. Isbell, J. Am. Chem. Soc., 61, 2225 (1929); Bur. Standards J . Research, 3, 57 (1929).

(28) R. Lohmar, R. J. Dimler, S. Moore, and K. P. Link, J . Biol. Chem., 143, 551 (1 942).

THE 2-(ALDO-POLYHYDROXYALKYL)BENZIMIDAZOLE8

187

described the treatment of bornyl D-glucuronide with a hot solution of bromine in N hydrobromic acid; the D-glucuronic acid was liberated and oxidized simultaneously, then condensed with o-phenylenediamine t o the dibenzimidazole of D-glucaric acid in a n over-all yield of 48%. Similarly, alginic acid and the barium salt of methyl D-mannuronide were converted to the dibenzimidazole of D-mannaric acid, and pectic acid to the dibenzimidazole of galactaric acid. The method has been applied also by Barker, Farrar, and Gulland2I8 to yeast nucleic acid, the final product being D-ribo-benzimidazole. The advantages of this procedure for the hydrolysis of glycosidic linkages and the simultaneous oxidation of the liberated aldoses without risk of epimerization are obvious, and the method should be useful for the study of many other substances from natural sources. 2. Properties, Derivatives, and Reactions Crystalline benzimidazoles have been obtained from all aldonic acids so far tested with only one exception that is known to the writer. Lohmar and Link29reported that the condensation of D-glucosaminic acid ( = 2-amino-2-desoxy-~-g~uconic acid) with o-phenylenediamine under a variety of conditions failed t o yield a crystalline product. The direct oxidative condensation of D-glucosamine hydrochloride with o-phenylenediamine in the presence of cupric acetate yielded only the known 2-(~-arabo-tetrahydroxybutyl)quinoxaline(111) and not the desired benzimidazole. The benzimidaeoles, as we have seen, are weak bases that are soluble in aqueous acids but may be precipitated from them by the addition of a stronger base such as ammonium hydroxide. The benzimidazoles are amphoteric substances, with acidic properties also, as shown by the formation of copper, silver, and other insoluble salts; they are soluble in an excess of a strong base such as sodium hydroxide and may be precipitated from solution in that base by the addition of carbon dioxide. a. Solubilities, Recrystallization, Melting Points, and Rotations.There is a wide range in the solubilities of the benzimidazoles varying from D-xylo-benzimidazole,22 which is very soluble both in water and ethanol, and requires butanol and acetone for its recrystallization, t o D-manno-D-gala-hepto-benzimidazole16 and a few others that are so insoluble in water and the common organic solvents that they are generally purified either by recrystallization as the hydrochloride or by dissolving in hydrochloric acid and reprecipitating in crystalline form by the addition of ammonia. Most benzimidazoles, however, are readily recrystallized from water, ethanol, or a suitable mixture of these two (29) R. Lohmar and K. P. Link, J . Biol. Chem., 160, 351 (1943).

188

NXLSON K . RICHTMYER

solvents. The dibenzimidazoles from the aric acidsz6 are among the least soluble of these substances. For additional information the reader is referred especially to the table of Haskins and Hudson,16 to the first paper by Moore and Link,16 and to the other references to the individual benzimidazoles given in the tables at the end of this review. The melting points of the various benzimidazoles (see Table I) cover a considerable range of temperatures, and with the specific rotations as observed in N hydrochloric acid or 5 % aqueous citric acid (see Table I) will serve to characterize new and identify known benzimidazoles from aldonic acids. While the substances usually melt with decomposition, the values are readily reproducible. The rotations will be discussed further in the final section of this review. b. Hydrochlorides, Picrates, and Other Derivatives.-Many of the benzimidazoles have been characterized additionally through their crystalline hydrochlorides with their usually sharp melting points (see Table I). The single apparent exception among all those examined is the benzimidazole derived from digitoxose ( = 2,6-didesoxy-~-allose),which was reported only as an oil.26 The hydrochlorides of the aldo-benzimidazoles are prepared in absolute ethanol containing dry hydrogen chloride,'e while those of the dibenzimidazoles from the aric acids are formed in hot aqueous N hydrochloric acid.28 The benzimidazoles form crystalline salts also when warmed with an equal weight of picric acid in aqueous ethanol.16 The melting points of the aldo-benzimidazole picrates (see Table I) thus furnish still another set of constants for characterization and identification purposes. The acetylation of 2-(~-arabo-tetrahydroxybutyl)benzimidazole is reported to yield a tetraacetate;' 2-(~-galacto-pentahydroxypentyl)benzimidazole, on the other hand, apparently forms a hexaacetyl derivative, 30 and the dibenzimidazole from D-mannaric acid, which contains four hydroxyl and two imino groups, forms a hexaacetyl derivative.22~28 It is not clear from these isolated cases whether N-acetylation as well as 0-acetylation is to be expected or not. The preparation of N-benzyl derivatives by replacement of the acidic hydrogen atom of the benzimidazole ring has been described by Moore and Linkz0and by Huebner, Lohmar, Dimler, Moore, and Link.22 Pertinent data on these and other miscellaneous derivatives will be found in Table I of this review. c. Permanganate and Periodate Oxidations.-The oxidative degradation of an aldo-benzimidazole by potassium permanganate, as mentioned earlier, was first reported by Schilling." Later, Bistrzycki and Prze(30) R. Kuhn and F. Bar, Ber., 67, 898 (1934).

THE 2-(ALDO-POLYHYDROXYALKYL)BENZIMIDAZOLES

189

worskial prepared what may be considered the lowest member of the series of benzimidazoles that are here under discussion, namely, 2-hydroxymethylbenzimidazole (XV), by the condensation of o-phenylenediamine with the simplest hydroxy acid, glycolic acid, CH20H.COOH. The action of potassium permanganate in sodium carbonate solution upon the benzimidazole XV was to oxidize it t o 2-benzimidasolecarboxylic acid (XVI). A similar procedure was employed by Huebner, Lohmar, Dimler, Moore, and Link22 in order to establish with certainty the presence of the benzimidazole ring in their supposed D-xylo-benzimidazole (XVII). The result was completely satisfactory, for the reaction produced a 70% yield of the 2-benzimidazolecarboxylic acid (XVI), which on subsequent decarboxylation by heating at 190’ produced benzimidazole (IX), identical with the synthetic material from o-phenylenediamine (XVIII) and formic acid. An oxidation of D-gluco-benzimidazole in the same manner gave the same end products.

xv

@: XVIII

The last-mentioned authors22 have described also the oxidation of D-xylo-benzimidazole (XVII) with sodium periodate in 35 % ethanol solution. Three molar equivalents of oxidant produced two molar equivalents of formic acid and one of formaldehyde; 60% of the latter was isolated as the dimedon derivative. The remainder of the original mole(31) A. Bistreycki and G . Preeworski, Ber., 46, 3483 (1912).

190

NELSON K. RICHTMYER

cule was recovered as solid 2-formylbenzimidazole (XIX) and characterized further through its crystalline oxime and dinitrophenylhydrazone. d. Ultraviolet Absorption Spectra.-The aldo-benzimidazoles appear to have maxima and minima in their ultraviolet absorption spectra that are characteristic of benzimidazole itself, as evidenced by measurements on that compound and D-galacto-benzimidazole by Kuhn and Bar, 30 and on the D-gluco-, D-xylo- and anhydro-D-xylo-benzimidazoles by Link's group.22 e. Pharmacological Properties.-When tested as antimalarials, the benzimidazoles derived from D-gluconic, D-gluco-D-gub-heptonic, and galactaric (= mucic) acids appeared to be quite nontoxic and i n e f f e c t i ~ e . ~ ~ The effect of D-gluco-benzimidazole on the arterial pressure of dogs anesthetized with nembutal was to cause a moderate hypotension (2 to 4 cm. of mercury) but only of short duration (about 20 3. Anhydrobenzimidazoles

Moore and believed at first that D-xylonic acid differed from the other aldonic acids that they had examined in that its acidcatalyzed condensation with o-phenylenediamine a t 135" resulted in the loss of only one molecule of water, and that further heating of the crystalline intermediate with hydrochloric acid and zinc chloride a t 180" was necessary before the benzimidazole was formed; a direct condensation of the two components at 180" in the presence of a catalyst could also be effected. However, upon a reexamination of these products it was discovered22that the analyses had been in error because of difficulties in securing complete combustion in the determination of nitrogen by the Dumas method. Kjeldahl nitrogen values obtained by the Elek and S ~ b o t k amodification, ~~ together with the carbon and hydrogen values, showed the product formed a t 135" to be the true benzimidazole, while the substance produced a t 180" had the composition of an anhydra-Dxylo-benzimidazole. In proving the structure of the anhydro compound, Huebner, Lohmar, Dimler, Moore, and Link22established first the presence of the benzimidazole moiety through its ultraviolet absorption spectrum and through its oxidative degradation by permanganate to 2-benzimidazole(32) See SN 5968, 5988, and 6860 in F. Y. Wiselogle, "A Survey of Antimalarial Drugs, 1941-1946,'' J. W. Edwards, Ann Arbor (1946). (33) A. Lespagnol, J. Vanlerenberghe, and A. Lallement, Bull. soc. pharm. Lille, 1948, No. 2, 20; Chem. Abstracts, 44, 8527c (1950). (34) A. Elek and H. Sobotka, J . Am. Chem. Soc., 48, 501 (1926). In the microanalytical laboratory at the National Institutes of Health, the Kjeldahl modification described by T. S. Ma and G. Zuazaga [Znd. Eng. Chem., Anal. Ed., 14, 280 (1942)], but with a five-hour digestion period, hits also given very satisfactory results.

THE 2-(ALDO-POLYHYDROXYALKYL)BENZIMIDAZOLES

191

carboxylic acid (XVI). Confirmatory evidence for the presence of an imino group was secured through formation of an N-benzyl derivative by refluxing the anhydro compound with benzyl chloride and sodium methoxide in absolute ethanol. The analogous anhydro-D-arabobenzimidazole was converted to a crystalline isopropylidene derivative that could not be acetylated ; hence, the parent anhydrobenzimidazole contained only two hydroxyl groups, N-acetylation apparently did not take place, and the remaining two hydroxyl groups originally present in D-arabo-benzimidazole must have been combined in an ether linkage in the anhydrobenzimidazole. Because of the stability of the anhydro ring to acid and alkali, the furan type of ring was considered most probable. This was in agreement with the easy condensation of the anhydro-D-arabo-benzimidazolewith acetone, for with a 1,4-ring in that compound the free hydroxyls on carbons 2 and 3 would then have been in the favorable cis configuration. Anhydro-D-xylo-benzimidazole was written, therefore, as structure XX. Confirmatory evidence of this formulation was gained through periodate oxidation studies. The reaction with an anhydrobenzimidazole consumed four molar equivalents of periodate, and produced 2-benzimidazolecarboxylic acid (XVI) , formaldehyde, and two molar equivalents of formic acid. Obviously the reaction did not stop at the expected dialdehyde stage (XXI). The continuing action could be explained, however, by assuming that the hydrogen atom at C I of the side chain was oxidized t o a hydroxyl group as shown in formula XXII and that subsequent oxidation of this substance in the normal manner would then produce the known degradation products. Evidence for a similar reaction, that of ethyl P-D-galactofuranoside by lead tetraacetate, was located in a paper by Hockett, Nickerson and Reeder.3s In order to obtain additional evidence for the correctness of this assumed mechanism, Huebner, Lohmar, Dimler, Moore, and Linkzz selected bornyl D-glucuronide (XXIII) as a test substance. Its oxidation with periodate should produce the dialdehyde XXIV, which contains a hydrogen atom on a carbon atom (C, of the original glucuronide) which lies between two carbonyls, those of the aldehyde and carboxylic acid groups. Oxidation of this active hydrogen to a hydroxyl group could then be expected (formula XXV), and subsequent oxidation by periodate should proceed in the normal manner. The prediction was verified: titration revealed the consumption of five molar equivalents of periodate and the liberation of five molar equivalents of acid, while the final products were bornyl (35) R. C. Hockett, M. H. Nickerson and W. H. Reeder, 111, J . Am. Chem. Soc., 66, 472 (1944). See also a subsequent paper by C. F. Huebner, S. R. Ames and E. C. Bubl, ibid., 68, 1621 (1946).

192

NELSON K. RICRTMYER

formate, oxalic acid, and formic acid. Accordingly, the two oxidations are very similar, with the hydrogen atom being activated in one caae by two C=O groups and in the other case by the combination of one C=O group and the C=N group of the imidasole ring.

+

sx

XXI

r-

ROCH

+

I€

+

+

-+

HAOH

HC=O

HC=O

H 0-

H 0-

HO 0-

bOOH XXIII R = bornyl

HCOOR

A=o

A

H =O

HbOH

A

HCHO

r I ROCH

ROCH

HoAH

XXII

b

bOOH XXIV

3 HCOOH

+

b

COOH

AOOH

AOOH

xxv

Still another indication of the 1,kanhydro ring in anhydro-D-xylobendmidasole (XX) is its conversion by two hours’ boiling with acetic anhydride to the same 2-(2-furyl)benzimidasole (XXVI) that is obtained by the direct condensation of o-phenylenediamine (XVIII) with 2-furoic acid (XXVII).

cAH

H b C H

AH

H&

AHOXXVI

LCOOH

‘ 0 ’ XXVII

THE

2- (ALDO-POLYH Y DROXY ALKY L)BENZIMIDAZOLES

193

And, finally, the synthesis of an anhydrobenzimidazole has been accomplished in a manner that proves conclusively not only the presence of the 1,4-anhydro ring but also that no inversion of configuration has occurred on any of the carbon atoms during the anhydrization. The starting material used by Huebner and Link36was the 1,4-anhydro-~glucitol (XXVIII), known also by the trivial name of “arlitan,” that was first produced by heating D-glucitol with sulfuric acid under vacuum at 130-140” until substantially one mole of water had been removed. The structure of this substance has been well established by two indeas well as by Huebner and Link’s recent definitive pendent researche~,~’ synthesis36 through the reductive desulfurization of ethyl 1-thio-a-Dglucofuranoside (XXXI) by Raney nickeLas The selective oxidation of 1,4-anhydro-~-glucitol (XXVIII) by one mole of periodate resulted in its cleavage t o formaldehyde and a five-carbon-atom aldehyde that will be recognized as 2,5-anhydro-~-xylose(XXIX). Its subsequent bromine

XXIX

xxx 1

(36) C.F. Huebner and I(.P. Link, J . Biol. Chem., 188, 387 (1950). (37) El. Soltzberg, R. M. Goepp, Jr., and W. Freudenberg, J . Am. Chem. Soc., 68, 919 (1946);R. C. Hockett, Maryalice Conley, M. Yusem and R. I. Mason, ibid., 88, 922 (1946). (38) For a review of “Applications in the Carbohydrate Field of Reductive Desulfuriaation by Raney Nickel,” see H. G. Fletcher, Jr., and N. K. Richtmyer, Advances in Carbohydrate Chem., 6, 1 (1950).

194

NELSON K. RICHTMYER

oxidation to 2,5-anhydro-~-xylonicacid (XXX), followed by condensation with o-phenylenediamine in the presence of hydrochloric and phosphoric acids at 135", afforded 2- (1,4-anhydro-~-sylo-tetrahydroxybutyl)benzimidazole (XXXII). This benzimidazole and the anhydr0-Dxylo-benzimidazole (XX) previously obtained by condensation a t 180" were identified as antipodes through their practically identical melting points and those of their respective picrates, and through their specific rotations, which were equal in magnitude but opposite in sign. Anhydrobenzimidazoles are now known22with the D-arabo-, D-lyxo-, D-ribo-, and D-xylo- configurations (see Table I). Although Moore and Link20 stated that D-gluco-benzimidazole is unstable a t 180" in the presence of zinc chloride and hydrochloric acid, it has not yet been disclosed whether this substance also undergoes formation of a similar anhydride.

4. Preparation of

D( -)-Tartaric

Acida9from D,L-Tartaric Acid through Resolution by a Benzimidazole

One of Pasteur's three classical methods of resolving a racemic acid is through salt formation with an optically active base, separation of the two diastereoisomers by a more or less tedious fractional crystallization, and liberation of the optically active acids from the individual salts by the addition of a strong base. As we have seen, theB(a1dopolyhydroxyalky1)benzimidazoles are optically active bases strong enough to be characterized further through their crystalline hydrochlorides and picrates. One of their number has been found by Haskins and Hudson'b to form a readily crystallizable acid salt with D(-)-tartaric acid, whereas the corresponding L( +)-salt did not crystallize under any of the conditions investigated. Attempts to force crystallization of the latter by addition of ethanol to its water solution resulted only (39) Ordinary tartaric acid, commonly present in grapes, is dextrorotatory and wa8 long known as d- or deztro-tartaric acid. Its configuration has been established as HO H COOH . C . C . COOH, and in accord with our modern rules of carbohydrate nomenH OH clature it is now called Irtartaric acid to indicate its relationship to the configurational

H reference standard, D-glyceric aldehyde, CH20H.C.CH0. The uncommon, levorotaOH tory tartaric acid, therefore, is now designated D-, p(leuo)-, or D ( -)-tartaric acid. It is this latter, levorotatory acid, improperly called Gtartaric acid16 in 1939 when the system of carbohydrate nomenclature was changing, whose preparation is described here. D ( -)-Tartaric acid is known also as D-threaric acid; by indicating thus its relation to D-threose, as has been suggested (W. W. Pigman and R. M. Goepp, Jr., "Chemistry of the Carbohydrates," Academic Press Inc., Publishers, New York, 1948, p. 40), we may avoid further confusion in naming the tartaric acids.

THE %(ALDO-POLYHYDR0XYALKYL)BENZIMIDAZOLES

195

in the precipitation of the free base. Hence, a practically quantitative separation of the racemic acid could be obtained in one crystallization, since the D(-)-salt is only slightly soluble in dilute ethanol. The details of this excellent method for obtaining the relatively inaccessible form of tartaric acid are as follows.16 Resolution of Racemic Tartaric Acid.-Twenty grams of racemic tartaric acid monohydrate was dissolved in 150 ml. of hot water and 35.5 g. of 2-(D-ghCO-D-gUlOhepto-hexahydroxyhexy1)benzimidszole added with stirring. To the clear solution was added 50 ml. of ethanol and crystallization was readily induced by scratching. After standing a few hours at 5" the crystals were filtered and washed successively with cold 50, 75 and 95% ethanol. The acid D ( -)-tartrate salt thus obtained (28.8 g. or 100%) occurs as the dihydrate and may be recrystallized with negligible loss from five parts of 25% ethanol if desired. Specific rotation, [ ( Y ] ~ O D , of the dihydrate is -0.5" (H20, 1 = 4, c = 0.84) and the melting point is 118-125" (corr.). The water of crystallization may be quantitatively removed a t 78" in uacuo. The D ( -)-tartaric acid was recovered b y decomposing the acid salt with excess ammonium hydroxide and removing the base by filtration. The filtrate was made barely acid with acetic acid and lead D-tartrate was precipitated with lead acetate solution. The filtered and washed lead D-tartrate was suspended in water and the lead removed by precipitation with hydrogen sulfide. The clear filtrate was evaporated t o a small volume and allowed to crystallize in a desiccator. Recovery of 96.5% of D ( -)-tartaric acid from the original acid salt was obtained; after one recrystallization from water, it showed a specific rotation [(Y]~OD of -14.2' (HzO, 2 = 4, c = 4.05) and a melting point of 168-170' (corr.), which are the known values for pure D ( -)-tartaric acid.

Some minor variations of this procedure were described later in a patent granted to S u r r n a t i ~ . ~ ~ To what extent the 2-(aZdo-polyhydroxyalkyl)benzimidazoles can be used in resolving other optically active acids has not been determined. The benzimidazoles are relatively weak bases and do not form stable salts with weakly ionized acids. Haskins and Hudson16found that when a solution of racemic lactic acid and 2-(~-gluco-~-gulo-hepto-hexahydroxyhexy1)benzimidazole was concentrated, it was the free base that precipitated rather than one of the expected salts. It seems probable, however, that the method will be found useful in other resolutions, especially of the stronger organic acids. 5 . Determination of the Proportion of D- and L-Isomers i n Samples of

Lactic Acid A practical method, based on the properties of the benzimidazole derived from lactic acid, has been described by Moore, Dimler, and Link41 (40) J. D. Surmatis (to The Brush Development Company), U. S. Pat. 2,456,752 (1948). (41) S. Moore, R. J. Dimler, and K. P. Link, Znd. Eng. Chem., Anal. Ed., 13, 160 (1941).

196

NELBON K. RICHTMYER

for the quantitative measurement of the relative amounts of the two optical isomers in preparations of lactic acid. The procedure involves condensation of the sample of lactic acid with o-phenylenediamine at 135’ in the presence of hydrochloric and phosphoric acids, followed by isolation of the benzimidazoles as the mixed crystalline silver salts. Regeneration of the mixed benzimidazoles by hydrochloric acid yields a solution from whose rotation may be calculated the percentage of the D- and L-isomers in the original sample of lactic acid. The authors state that the method is applicable, with an error of less than 1.0 in the percentage composition, to samples containing as little as 0.2 g. of lactic acid. 6. T h e Benzimidazole Rule In studying the data available in 1942 on the rotations of aldobenzimidazoles, Richtmyer and noticed a correlation between the sign of rotation and the configuration of the compound. From this observation was developed a “ benzimidazole rule ” that is now expressed in the following manner: Whenever the hydrowl group on the second (or alpha) carbon atom of a n aldonic acid i s on the right in the conventional projection formula of Fischer, the rotation of the derived benzimidazole i s positive and, conversely, when the hydroxyl group i s on the left, the rotation of the benzimidazole i s negative. Since that time a number of additional benzimidazoles have been described and we now know about thirty compounds of this type (exclusive of enantiomorphous modifications) containing from one to seven asymmetric carbon atoms. In each case the configuration of the original aldonic acid has been proved independently by a definitive method. A test of the new rule with all these compounds still reveals no exception to the correlation originally noted, and it appears that the benzimidazole rule, like the well-known amide and phenylhydrazide rules, may be used as a reliable guide in determining the configuration of new sugars and their derivatives, especially of the aldonic acids that may be generated through cyanohydrin syntheses.43 For this purpose the benzimidazoles sometimes have a decided advantage over the corresponding amides and phenylhydrazides because of the solubility relationships. Certain amides and phenylhydrazides are so nearly insoluble in water that satisfactory rotation values can be obtained only at elevated temperatures, if at all. The aldo-benzimidazoles, on the other hand, are bases, and as (42) N. K. Richtmyer and C. 8.Hudson, J . Am. Chem. SOC.,64, 1612 (1942). (43) See C. 9. Hudson, “The Fischer Cyanohydrin Synthesis and the Confiwrations of Higher-carbon Sugars and Alcohols,” Advances in Carbohydrate Chem., 1, 1 (1945).

197

THE 2-(ALDO-POLYHYDROXYALKYL)BENZIMIDAZOLES

such are readily soluble in N hydrochloric acid, the accepted solvent in which their rotations are measured. Although the benzimidazole obtained from digitoxose ( = 2,6-dibenzimidazole, desoxy-D-allose), Gamely, 2-(~-ribo-2,3,4-trihydroxypentyl) has a D-rib0 configuration and a negative specific rotation of -45.7' (see Table I), it should be noted that this does not constitute an exception to the benzimidazole rule because there is no hydroxyl group on the second (or alpha) carbon atom of the original aldonic acid. The anhydrobenzimidazoles derived from the four pentoses also have no hydroxyl group on the carbon atom in question, and their rotations (see Table I) seem t o bear no relation to their configurations. The sign of rotation of an aldo-benzimidazole having been correlated with the configuration of the second carbon atom of the corresponding aldonic acid, it is interesting t o see whether any additional relationship can be discovered through an examination of the molecular rotations of these substances (see Table I). In general it will be noted that the molecular rotations of the w-desoxy compounds are similar in magnitude to those of the completely hydroxylated analogs (exception : D-glycero, [MID 7100 and desoxy-D-glycero, [MID 2400), and that the benzimidazoles derived from the hexoses resemble in each case those from the heptoses and octoses with the same configuration for their top four asymmetric carbon atoms. Thus we have the series desoxy-L-galacto (- 10,400), D-galacto (+11,900), desoxy-L-manno-L-gala-hepto (- 11,700), D-manno-D-gala-hepto (+14,800),and D-gluco-L-gala-octo ( 14,700). Similar high rotations have been found for D-altro (- 12,900)and D-arabo (- 11,800),and from the data so far available it is seen that all benzimidazoles with an arabo configuration for &hetop three carbon atoms have absolute [MI, values greater than 10,000. Beyond this statement, and the probability that benzimidazoles with gluco or gulo configurations at top will have low absolute [MID values, no further generalizations appear a t the present time.

+

+

-

c.

IV. TABLES TABLE I

CD 00

Benzimidawlesfrom Aldonic Acids ~

R

= 2-Substituent

group

(see p . 176) Melting point, "C.

Hydroxymethylpicrate acetyl derivative D-glycero-1-Hydroxyethylhydrochloride L-glycero-1-Hydroxyethyl-

hydrochloride D,L-gl ycero-1-Hydroxyethylhydrochloride picrate wglycero-1,ZDihydroxyethylD-erythro-l,2,3-Trihydroxypropylcerythro-l,2,3-Trihydroxypropyl~-arabo-1,2,3,4-Tetrahydroxybutylhydrochloride picrate 1,4-anhydro1,4-anhydro-2,3-isopropylidene~arabo-1,2,3,4-Tetrahydroxybutylhydrochloride picrate

171-172 214 99-101 175-177 213-215 175-177 213-215 179-181 211-213 131 184-186 177-178 177-178 235 229 158 206-208 195-196 235 (d.) 230 158

[cx]*O--~~D .(solvent) c usually 2 g./100 ml. CA = 6% citric acid HCl = 1 N HC1

[MID

+33.4" (alcohol; c, 4) -32.6 (water) ; - 14.7 (CA) -2400 (CA)

+39.6 (HC1) +9 . O (CA) -8.3 (CA) -49.4 (CA); -49.7 (HC1) +2.7 (CA) - 144 (ethanol) +49.7 (CA); +49.8 (HCl)

+7100 1900

+

-11,800

+11,800

References

31, 19,44 2% 31 45 45 41,45 45 45, 14,31, 19,44 45 23c 46 47,42 47,42 16,42,26,21a 16,21a 16,21a,26 22 22 10, 16,47,42,7, 48 16 16

3

z!

z T:

2 d

2

5M

d !

tetraacetyl derivative D-1 yzo-l,2,3,4Tetrahydroxybutylhydrochloride picrate 1,Panhydro1,4anhydro-, picrate ~-ribo-l,2,3,PTetrahydroxybutylhydrochloride picrate 1,4-anhydro-, dihydrate 1,4anhydro-, picrate ~-zylo-l,2,3,4Tetrahydroxybutylhydrochloride picrate 1,4anhydro1,4anhydro-, hydrochloride l,Panhydro-, picrate 1,Panhydro-, N-benayl derivative ~-zylo-l,2,3,4Tetrahydroxybutyl1,Panhydro1,4anhydro-, picrate ~-ribo-2,3,4-Trihydroxypentylpicrate

TrgaEacto-l,2,3,4Tetrahydroxypentylhydrochloride picrate

~-g~ueo-l,2,3,4Tetrahydroxypentyl~-rnanno-l,2,3,4Tetrahydroxypentylhydrochloride picrate

141-142 189 - 12.8 (CA) 191 95-99 200-204 +62.5 (CA); +59.5 132- 138 190 (d.) +21.6 (CA); +22.5 196-198 185-186 82-83 -84.5 (ethanol) 120-125 141-143 +19.7 (CA); +20.0 181- 182 +17.3 (H20) 187-189 f64.8 (CA) 224 200-202 191 215-217 Unknown 225-228 -64.6 (CA) 190-192 207-209 -45.7 (HCl) 124-127 -41.2 (HCl) 248-249 224-225 189-191 (sinters 150) 190 (d.) t 7 . 6 (CA) 210 (d.) t 2 7 . 4 (CA); +29.1 173-175 168

-3000 (HC1) (HCl)

+5100

(HCl)

+4700

-10,400

f 1900

(HCl)

4-6900 (CA)

7 16 16 16 22 22 42, 26, 2--, 21c 26, 21a, 21c 26, 21a, 21c 22 22 22,20 22 20 16, 20, 22 16 16 22 36 36 26 26 26 26 26 42 15, 16 16 16

TABLE1 (Continued)

R

= 8-Substituent

group

(see p . 176) Melting point, "C.

198 (d.) 246 (d.)

[a]*"% (sokrent) c usually 2 g./lOO ml.

CA=6%eitricd HCl = 1 N HCl

References

-48.1 (HC1) -12,900 15 +44.5 (CA); +45.1 (HCl); +11,900 (CA) 10, 15,16,42 +50 (pyridine; c, 0.2); 30 +52.5 (acetic acid; c, 0.2) 30 16 hydrochloride 202-204 16 picrate 217 (d.) hexsscetyl derivative 179 +75 (pyridine; c, 0.75) 30 ~-g~l,2,3,4,5PentahydroPentshydroxypentyl250 (d.) -44.1 (CA); -45.0 (HCl) -11,800 (CA) 42 ~,cSa2aeto-l,2,3,4,5Pentahydro~ntyl233 inactive (CA) 49 ~-glum1,2,3,4,5Pentahydroahydrox~rpentyl210 (d.) +9.5 (CAI; +8.7 (HCl) 3, 15, 16,42 +2500 (CAI hydrochloride 180 16 picrate 203 (d.) 16 N-benzyl derivative 188 +37.0 (CA?) u) 215 (d.) ~-g1~~-1,2,3,4,5Pentahydroxypentyl-9.0 (CA); -8.3 (HCl) -2400 (CA) 47,42 ~-gulo-l,2,3,4,5Pentahydroxypentyl201 (d.) +16.7 (HCl) +4500 15 ~-&-1,2,3,4,5-PentahydroxypentyE 154-156 -19.2 (HCl) -5200 15 ~-mnw1,2,3,4,5-Pentahydroxypentyl224 (d.) -22.0 (CA); -23.7 (HCl) -5900 (CA) 15, 16 hydrochloride (hydrated) 101-150 16 picrate 205 (d.) 16 Dtalo-l,2,3,4,5Pentahydmxypentyl190-191 -23.0 (HC1) -6200 15 ~-g&-~-glueo-heptl,2,3,4,5-Pentahydroxyhexyl- 127-228 (d.) +14.6 (HCl) +4100 50 [sinters 212)

3

!i

P ?j

E

(3

13 $u

TAFILE I (Continued) ~

R = 2-Substituent group (see p. 176) Melting point, "C.

cgalo-~-manno-hepto-l,2,3,4,5Pentahydroxyhexyl243-245 (d.) mnanno-cgal.a-hepto-l,2,3,4,5Pentahydroxyhexyl- 266-268 (d.) ~-allro-~-gluco-heptl,2,3,4,5,6-Hexahydroxy193-195 (d.) h-1~-aUtcr-~manno-hepto-1,2,3,4,5,6-Hexahydroxy217-219 (d.) h-1~-gaZa-1rglueo-heptl,2,3,4,5,6-Hexahydroxyhexyl198 (d.) (=hY&OW) D-galo-MMnno-hepto-l,2,3,4,5,6-Hexahydroxy218 (d.) hexyl~ - g l ~ ~ h e p t o - 1 , 2 , 3 , 4 , 5 , 6 - H e x a h y d r o x y h e x y l215 - (d.) 118-125 *tartrate, dihydrate ~glzLeo-Dido-hepto-l,2,3,4,5,6-Hexahydro~he~l- 192 (d.) ~-manno-~-gala-hepto-1,2,3,4,5,6-Hexahydroxy241 (d.) hexyln-ga.?u-cgulo-octo-l,2,3,4,5,6,7-Heptahydroxy234-235 (d.) heptyl~-glueo-~-g&-o~l,2,3,4,5,6,7-Heptahydroxy246-247 (d.) heptyl~-glueo-~-~lo-octo-l,2,3,4,5,6,7-Heptahydroxy191-192 heDtv1-

[,]r@-25D (solvent) c uaually 2 g . / 1 0 0 ml. CA = 6% citric acid

References

H C 1 = 1 N HCI

-22.9 (HCl) -41.5 (HCl)

-6500 -11,700

50 46

+9.7 (HCI)

+2900

51

-17.7 (HC1)

-5300

51

-14.4 (HCl)

-4300

46

+18.5 (HC1) +l4.3 (HCl) -0.5 (HaO;C, 0.8) -27.6 (HC1)

+5500 +4300 -8200

15 15 15 15

+49.5 (HCI)

+14,800

15

-11.2 (HCl;C , 0.8)

-3700

18

-44.7 (HCl;C, 1.0)

-14,700

42, 52

+18.6 (HCI;c, 0.8)

+6100

52. 18

202

NELSON K. RICHTMYER

TABLETI Dibenzimidazolee from Aric Acids Melting point, "C.

Acid

[CX]zo-zsD

(solvent)

References

~~~~~

L-Threaric ( = ctartaric) dihydrochloride dihydrate Galactaric ( = mucic) dihydrochloride dipicrate D-Glucaric ( = n-saccharic) dihydrochloride tetrahydrate dipicrate trihydrate

275 (d.) 270 (d.) 298 (d.) 318 (d.) 250 (d.) 243 (d.) 265 (d.) 211 (d.) (changes form at 145") D-Mannaric ( = D-mannosaccharic) 250 (d.) dihydrochloride 256-257 (d.) dipicrate 241 (d.) hexaacetyl derivative 225-226

+ 212 (HCl; c, 0.8) f 0.0 (CA)

+60.3 (CA) 4-52.3 (HzO; C , 2)

46 46 28 28 28 28, 53, 54 28, 53, 54 28, 53, 54

28 28 28 -11.9 (CHCla; C, 2) 22, 28

-1.3 (HzO; C , 2)

TABLE I11 Bz-Substituted Benzimidazolea 8-Substituent p o u p

Melting point, "C.

References

5-methylHydroxymethyl203 31 5-methylacetyl derivative 129-132 31 D,L-glycero-1-Hydroxyethyl5-methyl178-179 14, 31 ~-arabo-l,2,3,4Tetrahydroxybutyl-~ 4carboxylic acid 235 (d.) 10 5-methyl~-arabo-1,2,3,4-Tetrahydroxybutyl10 238 n-galacto-l,2,3,4,5-Pentahydroxypentyl4carboxylic acid 10 ~-gluco-1,2,3,4,5-Pentahydroxypentyl- 4-carboxylic acid 243 3, 11 ~-gluco-l,2,3,4,5-Pentahydroxypentyl-~ 5-methyl212-214 (d.) 3, 46 ~-g~uco-3-(a-~-Glucopyranosyl)-1,2,4,54-carboxylic acid tetrahydroxypentyl235 3, 11 D-gluco-3-(8-~-GalactopyranOsy1)-1,2,4,5tetrahydroxypentyl4-carboxylic acid 206 11 Described as dextrorotatory. Has [ C ~ ] ~ ~ D9.2" in N hydrochloric acid (c, 2) ; the optical activities of the other substances in this table were not reported. 0

+

(44) H. Skolnik, J. G. Miller and A. R. Day, J. Am. Chem. SOC.,66, 1854 (1943). (45) R. J. Dimler and K. P. Link, J. Biol. Chem., 143, 557 (1942). (46) D. A. Rosenfeld, J. W. Pratt, N. K. Richtmyer and C. S. Hudson, J . A m , Chem. SOC.,in press. (47) N. I(. Richtmyer and C. S. Hudson, J. Am. Chem. Soe., 64, 1609 (1942).

TEE 2-(ALDO-POLYHYDR0XYALKYL)BENZIMIDAZOLES

203

(48) P. Karrer, B. Becker, F. Bene, P. Frei, H. Salomon and K. Schopp, Helv. Chim. Acta, 18, 1435 (1935). (49) D.J. Bell and E.Baldwin, Nature, 146,559 (1940);J . Chem. SOC.,125 (1941). (50) E. Zissis, N. K. Richtmyer and C. S. Hudson, J . Am. Chem. Soc., 72, 3882 (1950). (51) D.A. Rosenfeld, N. K. Richtmyer and C. S. Hudson, J . Am. Chem. SOC.,in press. (52) Alice T. Merrill, R. M. Hann and C. S. Hudson, J . Am. Chem. SOC.,66, 994 (1943). (53) G. A. Levvy, Biochem. J . , 42, 2 (1948). (54) J. K.Grant and G . F. Marrian, Biochem. J., 47, 1 (1950).

This Page Intentionally Left Blank

TRENDS IN THE DEVELOPMENT OF GRANULAR ADSORBENTS FOR SUGAR REFINING

BY ELLIOTTP. BARRETT Baugh and Sons Company, Philadelphia, Pennsylvania

CONTENTS I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Historical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Practical Considerations. . . . . . . . . . . . . . . ......... 3. Functions of and Requirements for Adso a. Depurative Powers.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . b. Bulk Density . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . c. Hardness . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . d. Resistance to Fluid Flow. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . e. Miscellaneous Requirements. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . f. Summary of Requirements.. . . . . . . . . . . . . . . . . . . . . 11. Factors Affecting the Depurative Powers of Adsorbents. . . . . . ...................................

2. Chemical Composition.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3. Porosity.. . . . . . . ................................ 111. Adjustment of Adsorbent Properties to Adsorbent Functions.. . . . . .

205 205 206 207 209 211 211 213 214 218 223 225

I. INTRODUCTION 1, Historical

In 1828 Dumgnt, a Paris confectioner, introduced the method of refining sucrose solutions by means of granular bone char. Prior to this time, bone char had been used in pulverized form as a contact adsorbent which was discarded after a single use. This extravagant practice rapidly exhausted the main source of supply, which was the residue from the distillation of bones to produce sal ammoniac. Dumont’s simple, but revolutionary, invention not only brought the demand for bone char into equilibrium with the potential supply, but also made possible the production of a much higher quality refined sugar, since the practice of filtration through a bed of granular bone char, followed by suitable regeneration and reuse of the char, permitted a very large increase in the ratio of char used to sugar solids treated. A detailed history of the development of the bone char process for refining raw cane sugar is beyond the scope of this discussion, and those 205

206

ELLIOTT P. BARRETT

interested are referred to the concise but thorough summary by Deitz.‘ However, it may be said that Dumont’s inveption, more than any other single factor, determined the direction in which the art and technology of cane sugar refining have evolved. As a consequence of this invention, the history of granular adsorbents for the refining of raw cane sugar is the history of bone char, in that application, punctuated by not infrequent attempts, sometimes feeble and sometimes heroic, to replace it with alternative materials or methods. The tenacity with which the sugar refining industry has clung to the bone char process for almost a century and a quarter has, not infrequently, been ascribed to ultra-conservatism. However, study of proposed bone char replacements and of alternative processes shows that the proposed materials or processes were rejected by the industry on sound economic grounds. Although many improvements in equipment and operational details have been made, and a number of supplementary refining aids have been introduced, bone char remains as the material on which the industry depends to do the major part of the refining job. 2. Practical Considerations

To understand the continuing adherence of the sugar refining industry to the bone char process, it is only necessary to realize that it is a very economical operation which, although it uses vast quantities of bone char, consumes very little of it. This desirable condition has been attained through the development of the technology of “cycling” to a point where it is one of the most efficient of industrial operations. In refinery parlance a “cycle” comprises the steps of “settling” a filter, i.e., filling a cylindrical vessel with granular adsorbent and sugar liquor in such a way as to effect maximum elimination of entrapped air, and minimum channeling in flow; “filtering,” i.e., flowing the desired quantity of liquor through the bed of adsorbent; “sweetening-off ,” i.e., displacing the sugar liquor with water; washing with water to remove, insofar as is practical, adsorbed impurities from the char; drying the char, and “reburning” it, i.e., passing the char through kilns in the presence of a minimum of air; and, finally, returning it to the filter. This complex series of operations is accomplished at a cost of only a few cents per hundred pounds of sugar refined. Moreover, these few cents represent less than one-fifth of the total cost of refining sugar. Consequently, any process which aims at lowering refining costs merely by substituting some other procedure for the conventional bone char process is limited to a maximum overall (1) V. R. Deitz, “Bibliography of Solid Adsorbents”; Bone Char Research Project, Inc., J. M. Brown, Secretary-Treasurer,care Revere Sugar Refinery, 333 Medford Street, Charlestown 29, Mass., p. xx (1944).

GRANULAR ADSORBENTS FOR SUaAR REFINING

207

saving of 20 percent (if it eliminated the adsorption technique completely) on what is already a very economical process. A factor of prime importance in effecting the high eEciency of the cycling process is large-scale operation. A survey, by the Bone Char Research Project, of 27 refineries showed a daily refining capacity of 74,000,000 poundsp2or an average, per refinery, in excess of 2,000,000 pounds per day. The investment in filters, driers, kilns, and char handling equipment of a refinery handling 2,000,000 pounds of sugar daily is considerable and serves to stress the importance of economic considerations in research on sugar refining aids. With existing equipment, an average of about half a pound of char is used per pound of sugar refined, but the efficiency of the char handling equipment is such that, on the average, less than half of one percent of “make-up” (new char added t o replace that lost as fines and dust through attrition, or that discarded because of excessively high density) per cycle is required. Therefore, the quantity of char consumed per pound of sugar refined does not exceed 0.5 X 0.005 or 0.0025 pound. 3. Functions of and Requirements for Adsorbents

a. Depurative Powers.-Broadly speaking, a sugar refining adsorbent has only one function-to separate sugar from non-sugars. In practice it is necessary to distinguish between the various non-sugars which may be present, and to take account of the particular sugar from which they are to be separated. For many years it was customary to distinguish between color, ash-forming mineral matter (commonly called “ ash ”)) and “ other non-sugars ” (an omnibus term generally interpreted as referring to proteinaceous substances, colloidal in nature, which detracted from the brilliance of the effluent from a char filter). More recently, attention has been directed to color precursors, present in the raw sugar or derived from the sugar itself, as demonstrated, for example, by Singh, Dean and C a n t ~ r . ~ From the foregoing it follows that the minimum requirements for an adsorbent include the ability to remove not only color, ash, and colloidal substances from sugar liquor, but also the ability to remove color precursors, and, since it has been shown that color precursors can be derived from the destruction of glucose13it is also desirable for the adsorbent either to prevent the destruction of glucose or, if it fails to do (2) V. R. Deitz and S. E. Cotter, “A Study of Char House Operation Observed in 1948”; Bone Char Research Project, Inc., J. M. Brown, Secretary-Treasurer, care Revere Sugar Refinery, 333 Medford Street, Charlestown 29, Mass., p. 10 (1950). (3) Bhagat Singh, G. R. Dean and S. M. Cantor, J . Am. Chem Soc., 10, 517 (1948).

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ELLIOTT P. BARRETT

so completely, to remove the products of glucose destruction from solution. If the sugar to be refined is sucrose, inversion during refining must be minimized both because the production of invert sugar decreases the yield of granulated sugar, and because, as previously noted, the invert is itself a potential source of colored substances which, if produced, must be separated from the sucrose. Since bone char performs this function in sucrose refining by maintaining the pH value of the liquor in the char filter at or near neutrality, the ability to prevent inversion must be recognized as an additional minimum requirement for any improved adsorbent proposed for use by the cane sugar refiner. The ability of bone char t o function as an alkaline buffer, so essential in sucrose refining, is a definite disadvantage in the refining of dextrose where it is desirable to operate on the acid side of pH 6. It has been shown that the optimum pH range is as low as 3.0 t o 3.5.8 However, since solutions of this acidity would attack storage vessels, char filters and pipe lines, it is impractical t o operate in the optimum pH range unless acid resistant equipment is employed. Consequently pH 5 is a practical lower limit for the process. To achieve a pH of 6 or lower for the effluent from a char filter, it is necessary t o “acid temper” the reburned bone char after it has been returned to the filter, i.e., to treat the char with dilute acid. It is evident, therefore, that bone char is not well adapted, in this respect, to dextrose refining. Consequently, one obvious direction in which an improvement in the conventional process could be made would be the devising of an adsorbent which would buffer on the acid side of neutrality instead of on the alkaline side. Alternative solutions to the problem of pH control in dextrose refining are the use of powdered activated carbon, which decolorizes the liquor but removes little ash; or the use of ion exchangers, which effect a substantially quantitative removal of ash, plus treatment with powdered activated carbon t o remove color. For convenience, the functions of granular adsorbents in sugar refining will be referred to, collectively, as depurative properties, and the ability of an adsorbent to perform the functions will be called the depurative powers of the adsorbent. Because of the large investment in equipment for the bone char process, and because bone char is used on a volume basis (filterful by filterful), it is essential that the depurative properties of any granular adsorbent proposed as a bone char replacement be at least equal to, preferably greater than, that of an equal volume of bone char. An adsorbent 10% more efficient than bone char on an equal weight basis but 20% lower in bulk density will perform less

209

GRANULAR ADSORBENTS FOR SUGAR REFINING

satisfactorily than bone char in service because a filterful of it will contain only 0.8 as many pounds of adsorbent as will a filterful of bone char. The depurative powers of bone char do not remain constant in service. Color and ash-removal power, on an equal weight basis, deteriorate from cycle to cycle of use and reactivation. An example of this deterioration is shown in Table I, which gives results of laboratory tests on TABLEI Deterioration in Color and Ash Removal Power of Two Adsorbents in Service Adsorbent into Cycle 1 4 8 12 16 20 24 28 32 38

Color Removal (%)

Ash Removal (%)

Bone Char

Synthad

Bone Char

Synthad

89.5 87.5 84.5 81.6 78.9 76.3 73.8 71.6 69.8 68.2

85.3 83.0 79.9 77.0 74.2 71.9 70.2 68.8 67.6 66.5

26.1 33.4 33.9 32.7 30.7 28.0 25.4 23.9 23.8 23.7

31 . O 31.0 30.9 29.6 27.6 25.6 24.0 23.2 22.8 22.5

Numerical values were read from smooth curves drawn on a plot of test data obtained by the laboratory of the Revere Sugar Refinery. 0

samples of bone char and Synthad (a synthetic granular adsorbent) at various stages of a full-scale refinery comparison described by Barrett, I compares the adsorbents on an equal Brown, and O l e ~ k . Table ~ weight basis although the tests were made, because the adsorbents are so used, on an equal volume basis (170 cc. of adsorbent on 200 cc. of a 47.5" Brix (1.216 specific gravity) solution of a reference sugar). The results are so expressed to emphasize the deterioration of the adsorbents as such, and to show that, although the rate of deterioration is relatively rapid for new adsorbents, it becomes much lower as their length of service increases. b. Bulk Density.-Although the pound-for-pound efficiency of bone char decreases with length of service, its performance in the refinery declines much more slowly than the data of Table I suggest because the bulk density (the weight per cubic foot) of the adsorbent increases with use. Consequently, a filter of relatively old-service char may outper(4) Elliott P. Rarrett, J. M. Brown and S. 0. Oleck, Ind. Eng. Chem., 45, 639 (1 951).

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ELLIOTT P. BARRETT

form a filter of relatively new char simply because the former contains a greater weight of adsorbent than the latter. This is illustrated in Figure 1, which compares the performance of four filters on identical liquors.* For the present purpose, it suffices to note that the adsorbents identified as Synthad and bone char had been used and reactivated 31 times prior to the experiment. “ A ” service was a bone char of an estimated average “age” of 150 cycles, and “B” service a bone char of an estimated average “age” of 300 cycles. The bulk densities of these adsorbents were 49.8, 49.5, 58.5,and 69.0 lbs./cu. ft. respectively. Inspection of the figure shows that the “ A ” service char returned appreciably less color to the refinery than did the much newer bone char. However, it is to be

FIG.1.-Color of Liquors during a Typical Filter Cycle.

noted that it was necessary to reactivate 58.5/49.5 = 1.182 times as many pounds of adsorbent to fill the filter of “ A ” service char as were required to fill the filter of relatively new bone char. The significance of the foregoing discussion is that so long as the refining industry is committed by its tremendous investment in char filters, char kilns, and char handling equipment to the use of a granular adsorbent, thermally reactivated, any proposed new granular adsorbent must possess the ability to retain its depurative powers, on a volume for volume basis, approximately as well m bone char does. Excellent initial performance is not per se a criterion of merit because the sugar refining industry does not operate with newly made adsorbents, but with service adsorbents which, statistically, have functioned for many cycles of use

GRANULAR ADSORBENTS FOR SUGAR REFINING

21 1

and reactivation. If a n adsorbent can be made which, all other factors being equal, deteriorates more slowly than bone char on a volume basis, that adsorbent is potentially capable of replacing bone char by serving the refiner more efficiently. c. Hardness.-However, it is not only by superior retention of depurative properties that a proposed new adsorbent can replace bone char. Again assuming that a n adsorbent meets all other requirements as well as bone char, superior resistance to abrasion constitutes a n improvement over the performance of bone char by reducing the amount of adsorbent consumed per cycle. The excellent resistance of bone char t o abrasion, as indicated by the smallness of “make-up” requirements, has been discussed earlier. The oniy published data on abrasion resistance of a proposed replacement material are those of Barrett, Brown, and Oleck, which show the consumption of the synthetic adsorbent called Synthad to have been about 23% smaller than that of bone char in a particular refinery test. d. Resistance to Fluid Flow.-Existing char filters are limited t o a working pressure of about 30 pounds per square inch (psi). Under average operating conditions, the pressure-drop through a bed of bone char 20 feet deep is only 3 to 4 psi. Nevertheless, it is essential t o take the resistance t o flow offered by the adsorbent into account, since in a working refinery abnormal conditions may arise which would greatly increase pressure-drop through the bed. For viscous flow, the pressure-drop produced by a fluid of constant density and viscosity through a bed of a fixed length and diameter is proportional t o the rate of flow. The magnitude of the proportionality constant under these conditions is a function of three properties of the adsorbent: (1) particle size, (2) degree of packing of the particles, and (3) particle shape. The effect of packing and particle size distribution on the pressure-drop produced by the flow of air through columns of bone char has been investigated by the Bone Char Research Project.6 I t was found that the results could be correlated, as reported by Allen for bauxite and fuller’s earth,6 by plotting the log of Fanning’s friction factor against the log of the Reynold’s number to obtain a linear relationship. The friction factor, f, is defined by the relationship

(5) First Quarterly Report for 1949. Bone Char Research Project, Inc., J. M. Brown, Secretary-Treasurer, care Revere Sugar Refinery, 333 Medford Street, Charlestown 29, Mass. (6) H. V. Allen, Jr., Petr. Ref., 23, No. 7, 247 (1944).

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ELLIOTT P. BARRETT

in which D, = average equivalent spherical particle diameter gc = gravitational acceleration, p = density of the fluid, Go = Vp = mass velocity, V = apparent linear velocity, P = pressure-drop through the column, and L = depth of bed through which P is measured. The Reynold’s number, R,, is D,G,/p, where p is the viscosity of the fluid. The applicability of the results obtained by the Bone Char Research Project, using air in one inch diameter glass tubes, to sugar liquor flowing through beds of bone char was demonstrated by A. Jonnard and J. H. Messmer in the author’s laboratory. Jonnard and Messmer used a filter one foot in diameter containing a bed of bone char six feet in depth. Figure 2 shows the close agreement between results obtained with air

XITE, FULLER‘S EARTH

m

obool

OOOI

Ro* Dp aoi%/jd

a1

10

FIG.2.-Plots of Friction Factor versus Reynold’s Number.

on bone char, using the loosest packing that could be produced, and those obtained with 70’ Brix sugar liquor in the one foot diameter filter. The latter procedure shows pressure-drops about 15 % higher than the former. The difference is ascribable to the slightly closer packing in the one foot filter. The results indicate that, to estimate pressure-drops produced by the flow of sugar liquor through beds of adsorbents other than bone char, it is not necessary to make semi-commercial scale experiments with sugar liquor and the adsorbent in question, since reliable laboratory-

GRANULAR ADSORBENTS FOR SUGAR REFINING

213

scale measurements using air as the fluid can be made with much greater facility. e. Miscellaneous Requirements.-In addition to the definite and fairly readily measured requirements already discussed, there are a number of other requirements for a good service adsorbent which are difficult to evaluate in the laboratory. For example, following filtration of the sugar liquor it is necessary to “sweeten-off” the char, i e . , to displace the sugar liquor with water. This must be accomplished with a minimum volume of water, and with a minimum of return of impurities from the char to the water, since the (‘sweetwater” is to be returned to the refinery. As a continuation of the “sweetening-off” operation, it is necessary to wash the char with more water to free it from impurities removed from the sugar liquors. In particular, it is important to accomplish the removal of the maximum practical amount of ash-forming mineral matter since any which remains in the char when it passes through the reburning kiln becomes a permanent part of the char structure and, as will be shown, reduces the porosity of the char, thereby contributing to the deterioration of its depurative properties. It is obvious that there is an inherent contradiction in the requirements just described. During sweetening-off it is desired that the adsorbent should retain its adsorbed impurities while the concentration of these impurities in the aqueous environment is decreasing. On the other hand, as soon as washing to the sewer begins, it is desired that the adsorbent release its adsorbed impurities quickly so that a minimum of wash water will be consumed. Bone char behaves so as to provide a rather good compromise between these conflicting demands. However, it has been demonstrated by full-scale experimentation that an even better compromise is ~ b t a i n a b l e . ~Nevertheless, it appears that it would be extremely difficult to investigate this sort of phenomenon adequately with laboratory-scale equipment. Also in this category is the matter of mechanical handling. The adsorbent must dump from filters, flow through driers and kiln tubes, and perform well in mechanical handling equipment. As has been shown,4 granular solids exhibit significant variations in these respects. Finally, it is essential that adsorbents proposed for sugar refinery use be capable of regeneration in existing equipment, and preferably at the same temperature as bone char in order that the proposed adsorbent can be added to the service char as “make-up.” To fulfil this latter requirement it is also necessary that the proposed adsorbent be of such a nature that it will not react chemically with bone char in filters or kilns, since such reaction would almost certainly be deleterious to both adsorbents.

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ELLIOTT P. BARRETT

f. Summary of Requirements.-Recapitulation of the foregoing considerations shows that so long as the sugar refining industry is committed by economic considerations to the existing type of equipment, improved granular adsorbents for the industry must be developed with respect to all of the following seven requirements. 1. Adequate depurative powers which do not deteriorate in service more rapidly than those of bone char. 2. A bulk density which does not change in service in such a way as to affect performance adversely. 3. Adequate mechanical strength and resistance to abrasion. 4. Distribution of particle size and shape which does not result in excessive resistance to fluid flow. 5. Satisfactory sweetening-off and washing characteristics. 6. Satisfactory mechanical handling characteristics. 7. Regenerability in existing equipment, preferably in admixture with bone char if desired.

It should be clearly understood that the alternative to developing adsorbents within the restrictions imposed by these requirements is the development of entirely new refining methods which will be sufficiently economical to justify scrapping or modifying existing equipment and installing new facilities. If expansion of refining operations is considered, then the matter of discarding existing facilities does not enter into the decision and a proposed new process can stand or fall on its economic merits. 11. FACTORS AFFECTING THE DEPURATIVE POWERS OF ADSORBENTS 1. General

Part I of this chapter leads to the conclusion that improvements in granular adsorbents are to be sought in two directions, namely, toward superior depurative powers, or superior retention of them, and toward superior hardness. The second of these aims is partly a mechanical problem, and is beyond the scope of this chapter. The first aim may appear to present a path for straightforward development, until it is realized that almost nothing is known about the fundamental mechanisms which confer depurative properties upon bone char. It is still common practice to refer to the separation of non-sugars from sugars by solids placed in contact with the solution as adsorption, but whether what occurs is chemical reaction, ionic exchange, mere increase in concentration of non-sugars at the solid-liquid interface, or a combination of all three phenomena is not known. It seems most improbable that the

GRANULAR ADSORBENTS FOR SUGAR REFINING

215

mechanisms by which color (and color precursors), ash-forming mineral matter, and acids, are removed from solution are identical. Zerban’ reviewed in 1947 the problem of color in sucrose manufacture. Examination of this survey indicates that the variety and complexity of the sources of color are so great that little progress could be made by the straightforward procedure of studying the action of various adsorbents on individual colored substances known to be present in sugar liquors. Observations of a fundamental nature with regard to the removal of ash-forming mineral matter and acidic materials have not been made. Consequently, immediate progress depends primarily on the effective utilization of observations non-fundamental in character; thus, color removal, ash removal, and pH control are to be regarded as properties of the adsorbents which, it is hoped, can be correlated with other properties in such a way that desired adjustments in the depurative properties can be effected even though the mechanisms by which the desired results are obtained are not understood. Such an approach to the problem is unscientific, and efforts t o acquire information of a fundamental character are being made. However, it seems probable that several years will be required to obtain a fundamental background adequate to influence significantly the practical development of adsorbents. Meanwhile, progress is being made as a consequence of the more empirical approach. Research in t,he field is further complicated by the lack of generally accepted methods for measuring color and ash content of sugar liquors, particularly char-treated liquors. Consequently, it is extremely difficult to correlate data from one laboratory with those from another. Progress is being made toward correcting this situation but it would serve no useful purpose to discuss it in detail a t this time since the data which must be used here have been obtained by a variety of methods; therefore, it must be understood that the results have only relative significance. Moreover, it is essential to recognize that even these relative results apply quantitatively only to the particular conditions and materials that are involved. The relative nature of measurements of color-removal and their dependence on the conditions under which they are made is illustrated by the data of Figures 3 and 4. These data were obtained in the author’s laboratory by testing the two adsorbents in three different proportions with two different sucrose solutions, a number 13 soft sugar and a Cuban raw sugar. Both liquors were made up to a concentration of 47.5’ Brix (1.216 specific gravity), The temperature and time of contact (7) F. W. Zerban, “The Color Problem in Sucrose Manufacture”; Sugar Research Foundation, Inc., New York (1947).

216

ELLIOTT P. BARRETT

were 80°C. and 4 hours. Color measurements were made on the filtrates, after buffering to pH 7, with a Cary recording spectrophotometer, and integral colors were obtained by estimating the area under adsorbency curves from 400 to 700 mp. I.aI

=

1

COLOR BAflS:

I

I

I I I I

INTEGRAL COLOR, SINGLE DILUTION BONE CHAR ON NQ 13

BONE CHAR ON CUBAN RAW

SYNTHAD ON CUBAN RAW

2

6

4

’

RESIDUAL

-COLOR

I

I

1

I

I I l l 1

loo

60

- log T units.

FIQ.3.-Decolorization Isotherms in 5.0

40

8 1 0 20 COLOR (-LOG T UNITS)

I

I

I

1

1

1

BASIS: INTEGRAL COLOR, SINGLE DILUTION

1

l

-

SYNTHAD ON CUBAN RAW BONE CHAR ON CUB

THAD ON NO. 13

RESIDUAL COLOR (%I

FIQ.4.-Decolorization Isotherms in Percentage Units.

Figure 3 shows decolorization isotherms in - log T units to illustrate the fact that the chemical nature of the colored material in the two sugars is quite different, as is evident from the greater number of color units removed per gram of adsorbent a t all concentrations of residual color from the number 13 soft sugar. The results also show that the kind of

217

GRANUCAR ADSORBENTS FOR SUGAR REFINING

colored material contained by the number 13 soft sugar is more easily removed than that contained by the Cuban raw. Although the latter sugar absorbs only about 15% as much light in the 400 to 700 mp band as the former, about 37.5% more color is removed per gram of adsorbent by bone char from the former at a residual color concentration of 5 - log T units. When the results are expressed on the more familiar basis that the color of the liquor before adsorbent treatment equals loo%, as in

0

o

SYNTHAD

"8"SERVICE

"n" SERVICE

a

5.J

b

FIQ.5.-Variation

I

10

BONE CHAR LIQUOR ON

I

I

I

- - I

20 M 40 50 VOLUME THROUGH- THOUSANDS OF GALLONS

60

70

of Liquid pH with Throughput during a Typical Filter Cycle.

Figure 4, the Cuban raw appears to be the easier of the two sugars t o decoloriee because its integral color is much smaller, but this quantitative phenomenon should not be allowed t o obscure the fact that the kind of color it contains is harder for the adsorbents to remove than the kind of color contained by the number 13 soft sugar. Inspection of Figure 4 shows that the two adsorbents are equally efficient decolorieers of the number 13 soft sugar a t a residual color of 5.2%. Above this residual color bone char, and below it Synthad, is the more efficient. For the Cuban raw the residual color for equal efficiencies is 1.7%. It is evident that a decision as to which adsorbent is the better decolorieer should be based both on the character of the sugar and on the ratio of adsorbent used to sugar treated. Even when these factors are taken into account, quantitative predictions of refinery performance cannot be made. In the laboratory, the adsorbents and the liquors were allowed to reach an approximate equilibrium. In the refinery, equilibrium is never attained. Before the laboratory color measurements were made, the liquors were all buffered to the same pH value. Char

218

ELLIOTT P. BARRETT

filter effluents are not usually buffered in a refinery before comparing them with color standards. The bone char and Synthad of Figures 3 and 4 are the same as those for which filter effluent color curves are given in Figure 1. Examination of that figure shows that the performance of both adsorbents on the high test liquor applied to the filters in the first part of the operation was substantially identical. The bone char performance was superior to that of the Synthad on the low test (3B) liquor applied in the second part. However, Figure 5 shows that while the 3B liquor was being applied to the filter, Synthad was maintaining the effluent a t a higher pH than bone char, which circumstance would cause the Synthad effluent to appear more highly colored than would be the case had it been a t the same pH as the bone char effluent. 2. Chemical Composition The mineral, or inorganic, portion of bone is an hydroxyapatite in the crystal lattice of which some magnesium and sodium are substituted for calcium, and some carbonate ions for phosphate ions.* The organic portion consists principally of proteinaceous matter. When bone is subjected to destructive distillation, the organic portion is converted to carbon and a combustible, nitrogenous residue. The ability of bone char to decolorize sugar liquors has been ascribed to the nitrogeneous residue plus the c a r b ~ n , ~ ,to ~ Oactive carbon supplied by progressive decomposition of the nitrogenous residue,l1 and to the inorganic component plus the carbon.12Ja Horne’s results have been interpreted as indicating that the carbon of bone char was responsible for its decolorizing action, and that the hydroxyapatite was the ash remover. Knowles’ data suggest that a carbon content of about 6% is optimum from the standpoint of decolorizing power. Experiments by the research staff of the Bone Char Research Project on the decolorizing power of progressively decarbonized service chars reveal maximum decolorizing power a t carbon contents varying from 2 to 9%.14 Barrett, Brown, and Oleck show4 for a number 13 (8) Sterling B. Hendricks and William L. Hill, Science, Be, no. 2489 (Sept. 11, 1942). (9) T. L. Patterson, J . SOC.Chem. I d . , 22, 608 (1903). (10) Claude M. Hall, Jr., Ind. Eng. Chem., 14, 18 (1922). (11) P. M. Horton, Ind. Eng. Chem., 15, 519 (1923). (12) W. D. Horne, Ind. Eng. Chem., 14, 1134 (1922). (13) H. I. Knowles, Znd. Eng. Chem., 19, 222 (1927). (14) Fourth Quarterly Report for 1949. Bone Char Research Project, Inc., J. M. Brown, Secretary-Treasurer, care Revere Sugar Refinery, 333 Medford Street, Charleston 29, Mass.

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GRANULAR ADSORBENTS FOR SUGAR REFINING

soft sugar liquor, decolorizations by a new bone char, by bone ash from the same char, and by a synthetic hydroxyapatite of 90.8, 88.0 and 88.8%, respectively. This seems to indicate that for new adsorbents the carbon contributes little to the decolorizing power of the mineral component of bone char. Some light is thrown on this rather obscure situation by the data of Table 11, obtained in the author's laboratory. Evidently when a TABLE I1 Depurative Powers of a New Granular Activated Carbon and a New Bone Char Adsorbent

Bone Char Bone Char Bone Char Activated Carbon Activated Carbon Activated Carbon

Weight" (vams)

Per Cent Color Removedb

125 100 75

94.8 93.4 90.3

80 65 50

97.2 96.4 93.5

Per Cent Ash Removed 34.2 30.4 26.6 -21.6 -17.4 -13.2

pH of Sugar Liquor after Contact0

7.31 7.20 7.08 5.40 5.30 5.21

Weight of water washed (3 cc H 2 0 per gram of adsorbent at 80°C. for 1 hour) and dried (100'-110°C.) adsorbent contacted with 200 cc of 47.5" Brix (1.216 sp. 9.) no. 13 soft sugar liquor for 4 hours at 80°C. b Based on integral color estimated from absorbency curve from 400 to 700 mp determined with a Cary recording spectrophotometer. All liquors were buffered to pH 7 prior to measurement. 0 The pH of the control (200 cc of liquor maintained at 80°C. for 4 hours i n the absence of adsorbent) was 5.22. 0

granular adsorbent consists principally of carbon, it is possible t o develop in it much greater decolorizing power than can be obtained when the carbon is formed in the presence of, or is deposited on, a porous inorganic framework such as the hydroxyapatite of bone. Decolorization isotherms, constructed from the data of the Table 11, are given in Figure 6. These show that under the test conditions the activated carbon is twice as efficient a decolorizer, gram for gram, as bone char a t a residual color of lo%, and 3.5 times as efficient at a residual color of 1%. It will be shown later that the superior decolorizing power of the activated carbon is probably not due to the fact that it contains more carbon than bone char, but rather to structural differences. The negative ash removal exhibited by the activated carbon merely indicates that it contains impurities soluble in the sugar liquor. That active carbon, properly prepared, is capable of removing ash-forming

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ELLIOTT P. BARRETT

mineral matter is well known (see, for example, the work of Horton and Sengsen16). However, the low alkalizing power exhibited by the activated carbon is characteristic of carbons in general, and shows that the bone char possesses this capacity because of its inorganic components. That synthetic hydroxyapatite also possesses this alkalizing power has been shown elsewhere.*

c

40-

i 0

n -

n

-

-

x

RESIDUAL

FIG. 6.-Decolorization Activated Carbon.

COLOR YX)

Isotherms for a New Bone Char and a New Granular

The foregoing observations suggest that the depurative properties of bone char reside primarily in its inorganic component, although the decolorizing power is significantly augmented by the presence of some carbon. This raises a question as to whether or not similar properties reside, or can be developed, in other pubstances. In the author's laboratory it has been found that they can be developed to some extent in many clays, but to a much smaller degree than in bone char. Also, no granular adsorbent has ever been made from inorganic materials which exhibits such high decolorizing power as that possessed by new granular activated carbons. However, La Lande has shown that properly calcined bauxite develops color removal, ash removal, and alkaline buffering powers comparable to those of bone char.lB Bauxite and hydroxyapatite therefore appear (15) P. M. Horton and P. T. Sengsen, I d . Eng. Chem., 16, 165 (1924). (16) W. A. La Lande, Jr., Ind. Eng. Chem., 88, 108 (1941).

GRANULAR ADSORBENTS FOR SUGAR REFINING

22 1

to be unique in this respect. Nevertheless, unpublished results of refinery tests of calcined bauxite showed it to be inferior to bone char in some other respects, notably in resistance to abrasion. Unless some other substance possessing alkaline buffering power for sugar liquors is discovered, development of improved adsorbents for sucrose refining, where control of pH is essential to prevent inversion, appears to be confined in the immediate future to adsorbents based on hydroxyapatite. This restriction does not apply to the development of adsorbents for refining dextrose, for reasons that have been discussed previously (see page 208). If the immediate, limited objective in developing improved adsorbents for sucrose refining is taken to be the production of an adsorbent which will deteriorate more slowly in service than does bone char, then one is concerned with the changes which occur in the complex system hydroxyapatite-carbonaceous matter-minor impurities from cycle to cycle. The principal minor impurities are silica, calcium sulfate, calcium sulphide, and iron oxide. The percentages of all of these increase with increasing length of service." There is no evidence that these substances have any specific chemical effect on the rate of deterioration of the adsorbent, but they do contribute to it by progressively filling the pores. There is no evidence that the decrease in organically combined nitrogen is a factor in char deteri~ration,'~ and Synthad, which contains no nitrogen when made, deteriorates more slowly than bone char.4 Calcium carbonate is not to be regarded as an impurity, but as part of the apatite lattice.* The decrease in carbonate content which occurs in service1' may therefore contribute to the deterioration in depurative powers, but this has not been demonstrated. The effect of carbon content has already been discussed generally, but it should be noted that if carbon is allowed to accumulate in the pores of the adsorbent it will block them quite as effectively as will inorganic impurities, and hence contribute to the deterioration. That moderate variations in carbon content have no effect on the rate of deterioration of adsorbents is shown in Figure 7, which presents results of some of the laboratory tests made on the adsorbents during the fullscale comparison of Synthad and bone char, to which reference has already been made.4 Figure 7 (diagram A) shows the rate of deterioration of the decolorizing power of the adsorbents, for a particular sugar under a particular set of conditions, with increasing length of service. Figure 7 (diagram B) traces the variation in carbon content of the adsorbents. Figure 7 (17) Guilford L. Spencer and George P. Meade, "Cane Sugar Handbook"; John Wiley and Sons, Inc., New York, 8th. ed., p. 321 (1945).

I

222

ELLIOTT P. BARRETT

(diagram C) shows the loss in area per unit weight of adsorbent, and Figure 7 (diagram D) the change in color removing power per unit area. It is obvious that neither the decolorizing power per unit weight, nor the area per unit weight, nor the decolorizing power per unit area bears any functional relationship to the carbon content over the range through which it varied during the course of the comparison. On the contrary, it is apparent that the three properties varied in a systematic manner

ADSORBENT INTO CYCLE

FIG.7.-Effect

of Service on Some Properties of a New Bone Char and a New

Synthad.

with the number of cycles of use and reactivation. Of still greater interest is the observation that the decolorizing power per unit area increased in service. Stated another ~ a y the , adsorbents lose area progressively in service, but the activity of the area which remains becomes progressively greater. This last observation suggests one, or both, of two possibilities. Either chemical changes occur in the surface of the adsorbents which increase its activity per unit area, or the surface which is disappearing is less active or less available than the surface that remains. At all events,

GRANULAR ADSORBENT8 FOR SUGAR REFINING

223

it is apparent that the surface which adsorbents of this sort possess after being subjected to service is more active, not less active, with respect to color removal than is the surface of the new, unused material. Therefore, the most obvious way to effect an immediate improvement in granular adsorbents is to produce a substance which will retain area as tenaciously as possible. This requires investigation of the intragranular structure of the adsorbents and the effect of service upon it. 3. Porosity Barrett, Brown, and Oleck have shown that when bone char is cycled in service it first loses a large portion of the volume contained in pores smaller than 90 A radius.4 Simultaneously the volume in larger pores increases. With further service, the ability t o develop new large pore volume decreases until a condition is reached in which the char slowly, but progressively, loses volume in pores of all sizes. These changes are illustrated in Figure 8. Their influence on the area physically available to

FIG.&-Effect

of Service on Pore Volume Distribution of Bone Char.

molecules of various sizes is shown in Figure 9. Barrett, Joyner, and Halenda studied these phenomena under controlled conditions, l* and showed that the gain in large pore volume was associated with increasing size of the hydroxyapatite crystallites composing the non-carbonaceous portion of the char. It was also observed that the loss in small pore (18) Elliott P. Barrett, L. G. Joyner and P. P. Halenda, ‘‘Some Factors Affecting the Porosity and Activity of Granular Adsorbents for Sugar Refining in Service.” Paper presented at the Tenth Annual Meeting of Sugar Industry Technicians, Inc., 150 Nassau Street, New York 7, N. Y.

224

ELLIOTT P. BARRETT

volume was much less when the char was merely subjected to thermal treatment comparable to that which it would receive in several hundred cycles of service than it was when the char was actually used as an adsorbent. From this it was concluded that pores of all sizes function in the removal of impurities from sugar liquors. I

r

n

m

FIG.9.-Cumulative Area Curves for Bone Chars of Various Lengths of Service.

If the foregoing conclusion is correct, it follows that the increase in decolorizing power per unit area with increasing length of service, shown in Figure 7, results from a change in the character of the surface, not from a change in its physical availability. Consequently, the ability to retain area in service appears to be of primary importance. Impurities taken up by an adsorbent, which are not removed from it either by washing or in the reburning kiln, remain in the pores and, in general, decrease their area. Thus a given area (or volume) in large pores will be retained more tenaciously than the same area (or volume) in small pores, if the service conditions are the same in both cases. Pore volume distributions for the “adsorbents into cycle 1” of Figure 7 are shown in Figure 10, Curves 1 and 2. If the bone char had merely lost pore volume and area as a consequence of retained impurities partially

GRANULAR ADSORBENTS FOR SUGAR REFINING

225

filling the pores, the rate of loss of area shown in Figure 7 would have been much more rapid than that actually observed. However, as a consequence of the development of large pores through the mechanism of crystallite growth, the bone char retained area (and consequently color and ash removal power) more tenaciously than might be anticipated from the pore volume distribution curve of Figure 10. Nevertheless,

FIG.10.-Pore Volume Distribution Curves for Three New Adsorbents.

the Synthad was initially so much more coarsely porous than the bone char that the latter lost area much more rapidly than the former. These observations appear to indicate that although the Synthad referred to in Figures 7 and 10 was initi,ally much more coarsely porous than the bone char, it would be desirable to produce a synthetic adsorbent still more coarsely porous. That progress in this direction is being made is shown by curve 3 of Figure 10.

111. ADJUSTMENT OF ADSORBENT PROPERTIES TO ADSORBENT FUNCTIONS The background which has thus far been developed makes it possible to predict with some assurance how well a particular granular adsorbent is adapted to a particular use. Also it indicates the directions which

226

ELLIOTT P. BARRETT

may most profitably be followed in developing new adsorbents better adapted to their uses than are the present ones. These applications of the background material will be illustrated by means of the bone char and the granular activated carbon referred to in Table I1 and Figure 6. Inspection of the data shows that the activated carbon is a much more efficient decolorizer than bone char. Data, not shown, indicate that its abrasion resistance is excellent and that its bulk density is such that in the first cycle of use it would be about 25% more efficient in decolorizing performance than bone char. The very low pH of the sugar liquor after contact with the activated carbon indicates that it could not be used for sucrose refining without excessive inversion losses unless the liquor was heavily limed to raise its pH. The low alkalizing power of the carbon recommends it for use in dextrose refining, but the fact that it adds mineral matter to the liquor, rather than removing it, is unfavorable. It is possible that after several cycles of use and reactivation this condition might correct itself, but if it was necessary to use this carbon it would be desirable to be prepared to supplement it with ion exchange treatment of the liquor to remove ash-forming mineral matter. In addition to this “short range” estimate of the probable merit of the granular activated carbon, an estimate of its ability to retain activity is required. Relevent data are provided by Figure 11. These show the carbon to possess a very large volume in pores smaller than 25 &. radius. Consequently its total area is very large, about 1100 square meters per gram, roughly ten times as great as the area of new bone char. However, nearly 90% of this area is contained in pores smaller than 15 A radius. It is apparent from the relative performance of Synthad and bone char that unless some variation in conditions or operating procedure were introduced, the carbon could not retain its large area throughout many cycles of use and reactivation. One variation in conditions favorable to the carbon is its negative ash removal. By failing to remove ash the adsorbent escapes the loss in area consequent upon the filling of its pores with mineral matter. Presumably therefore it could be used for many cycles, in conjunction with ion exchangers for ash removal. There would, of course, occur some loss in area due to the deposition of carbon in the pores of the adsorbent as a consequence of the carbonization of organic residue incompletely removed in washing. This could be overcome by the installation of regenerating equipment which would permit reburning in an atmosphere of controlled oxidation potential so that, instead of merely carbonizing the organic residue, it would be oxidized, leaving the pores essentially unaffected. Unfortunately, operating data on the performance of this carbon in

GRANULAR ADSORBENTS FOR SUGAR REFINING

227

service are not presently available and consequently the foregoing estimate of its potentialities is speculative. Nevertheless, it appears that in view of the fundamental concepts developed in this chapter, the carbon will not continue to perform well in existing reburning equipment. For Synthad, in contrast to the granular activated carbon, both laboratory and operating data are available. Some of these, reported

GRANULAR ACTIVATED CARBON 557

NE CHAR 412

PORE RADIUS, r ( A )

FIG.11.-Pore Volume Distribution Curves for Three Types of Adsorbent.

by Barrett, Brown, and O l e ~ kand , ~ by Barrett,Ig are assembled in Tables 111, IV, V and VI. Comparison of the pore volume distribution curves for new Synthad and new bone char (curves 1 and 2, Figure 10) leads to the prediction that Synthad will retain its area more tenaciously in service than will bone char. It is thus not unreasonable to suppose that the color and ash removal powers of Synthad will deteriorate more slowly than those of bone char. Inspection of the tabulated data confirms both predictions. It should be remarked that the somewhat inferior performance of new Synthad shown in Tables IV, V, and VI is not ascribable solely to (19) Elliott P. Barrett, “Synthad as a Refining Aid in Cane Sugar Production.” Paper presented at the Symposium on Refking Aids, 119th Meeting Am. Chem. SOC., 1951.

N N

00

TABLEI11 Comparison of Some Physical Properties of Sydhad C 5 8 and Bone Char

Property and Units Reported

0

a

a

Specific Heat lb./OF.)

Description of Adsorbents Used for Measurements

synthad Ratio of Results (Synthad/B.C.) C58 M

(Btu/

Thermal Conductivity (Btu/hr./ft.'/"F./ft.) Heat of Wetting (calories/gram)

Bulk Density (lbsJft.8) Specific Surface (m.*/g.) *Shrinkage in service (lbs./cycle) a

Temperature Range ("F.)of Meaeurementa

8MOO

New Adsorbents dried, pulverized, and evacuated in a quartz bulb

0.24

0.24

1.00

90-210

Average of samples into cycles 1J10J15J 20 of refinery test

0.1w

0.101

1.01

70-72

New adsorbents heated to 1100°F. and cooled in a 15.9 dry atmosphere 38.6 New adsorbents through 10 on 28 mesh 49.8 Adsorbents after 32 cycles of refinery test 112.5 New adsorbents 66.0 Adsorbents after 32 cycles of refinery test

9.3

0.58

40.4 50.0 82.5 70.5

1.045 1.002 0.732 1.068

663

0.775

3

Meaaurements by A. Jonnard in the author's laboratory.

* Sum of average weight lost per cycle plus average weight added per cycle.

v P

{ {

Average for the adsorbents during refinery test

!?

855

cd cd

Fl

3

229

GRANULAR ADSORBENTS FOR SUGAR REFINING

TABLEIV Summary of Relative Color Removals CyCk8 1-10 11-15 16-20 21-25 26-30 31-32

Loading

Relative Removal (%) aunthad Removal (Bone Char Removal)

Light Normal Heavy Very heavy Very heavy Normal

loo

95.7 96.0 92.7 97.6 97.6 99.0

TABLEV Summary of Relative Color Removals (Washed Raw Sugar LiquoT Only) Cycles 1-10 11-15 31 32 33

Loading

Relative Removal (%) Synthad Removal (Eons Char Removal)

Light Normal Normal Normal Normal

loo

99.1 98.9 101.1 99.8 103.0

TABLEVI Summary of Relative Net Ash Removals Cycles

Loading

1-10 11-15 16-20 21-25 25-30 31-32

Light Normal Heavy Very heavy Very heavy Normal

95.0 64.7 86.5 95.5 90.0 105.5

its relatively smaller specific surface. As a consequence of more precise control of carbonizing temperature and of rate of carbonization it has been found possible t o produce Synthad which equals bone char in initial performance although no significant increase in specific surface accompanied the gain in activity.

230

ELLIOTT P. BARRETT

The granular activated carbon described above and Synthad represent two extremes of thought in the development of granular adsorbents for sugar refining. Economics, rather than technology, will determine whether fine pored or coarse pored adsorbents will be used in the future, or whether or not both types will find advantageous applications. There remains the possibility that ion exchangers will render both types of adsorbent obsolescent.

ACONITIC ACID, A BY-PRODUCT IN THE MANUFACTURE OF SUGAR BY ROBERTELLSWORTH MILLERA N D SIDNEYM. CANTOR Research and Development Division, American Sugar Refining Company, Philadelphia, Pennsylvania

CONTENTS I. 11. 111. IV. V.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Physical Properties of Aconitic Acid.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analytical Estimation of Aconitic Acid.. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The Recovery of Aconitic Acid in the Manufacture of Sugar... . . . . . . . . . . . Chemistry and Uses of Aconitic Acid., . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

231 234 236 239 244

I. INTRODUCTION For many years, aconitic acid (I), an unsaturated tribasic aliphatic H2C-COOH A-COOH

II

HC-COOH

I

acid, l12,3-propenetricarboxylicacid, has been recognized as a constituent of extracts from sugar-containing plants. Only in the past ten years, however, has it become apparent that the recovery of aconitic acid as a by-product in the manufacture of sugar was feasible. Recently this recovery has assumed greater importance with the realization that aconitic acid, its salts, and its esters are important chemical intermediates in the preparation of plasticizers for various types of resins and also in the preparation of surface-active agents. Aconitic acid was first isolated in 1820 by Peschier' and during the early years after its discovery a variety of names, e.g., aconitic acid,' equisetic acid, 2,a achillea acid14 " Brenzcitronsaure1116and "Citridin(1) Anon., Ann., 28, 243-46 (1838). (2) H.Braconnot, Ann. chim. phys., 58, 5-24 (1828). (3) V. Regnault, Ann., 19, 145-54 (1836);Ann. chim. phys., 62, 208-17 (1836). (4) B.Zanon, Ann., 68, 21-36 (1846). (5) G.L. Crasso, Ann., 54, 53-84 (1840). 231

232

ROBERT ELLSWORTH MILLER AND SIDNEY M. CANTOR

were assigned to the acid. It had been named originally as aconitic acid by Peschier due to his isolation of the acid from Aconitum napellus and paniculatum and this name became the adopted common name for the acid. Very little quantitative data have been reported in relation to the concentration of aconitic acid in various plant juices other than from cane sorghum and from sugar cane varieties although the acid has been identified in the juices from many other species of plants. It has been ,~~~~ isolated from a variety of species of A ~ o n i t u m , ' , ~D- e~ l~p h i n i ~ mand E q ~ i s e t u r nand , ~ also ~ ~ ~from ~ ~ Achillea ~ rnillef~lium,~~'~ Adonis vernalis, 1**16 Helinus ovatus, l6 Sansevieria zeylancia, l7 wheat ,la and from barley, maize, oat and rye plants.1° It can indeed be said that aconitic acid, at least qualitatively, is a commonly occurring constituent in the plant kingdom. BehrP2Oin 1877, identified aconitic acid as a constituent of sugar cane molasses while its occurrence in sugar beet products was demonstrated in 1879 by von Lippmann.21 Numerous other investigators since then have isolated aconitic acid from sugar cane sugar cane molas77, 293-305 (1851). (7) Anon., Wyoming Agr. Expt. Sta. Repts., 131 (1920);Ezpt. Sta. Record, 46, 410 (Chem. Abstracts, 16, 3500 (1922)). (8) D. Wasowicz, Arch. Pharm., 214, 193 (1879). (9) 0.A. Beath, J . Am. Chem. SOC.,48,2155-58 (1926). (10) A. Jermstad, Medd. Norsk. farm. Selsk., 6, 81-86 (1944) (Chem. Zentr., 1944,11, 1198). (11) H. A. D . Jowett, J . Chem. SOC.,69, 1518-26 (1896). (12) W. Wiche, Ann., 90, 98-99 (1854). (124 W. Wohlbier and S. Beckmann, Ber., 83, 310-14 (1950). (13) H.Hlasiwetz, Jahresber. Fortschritte der Chem., 331 (1857);J . prakt. Chem., 72, 429-31 (1867). (14) F. Linderos, Ann., 182, 365-66 (1876);F. W.Heyl, M. C. Hart and J. M. Schmidt, J . Am. Chem. Soc., 40, 436-53 (1918)report that they were unable to find any aconitic acid in Adonis vernalis. (16) N. Orlow, Pharm. 2.f. Russland, 33, 771 (Chem. Zentr., 1895, I, 202). (16) J. A. Goodson, J . Chem. SOC.,117, 140-44 (1920). (17) S. Scheindlin and A, A. Dodge, Am. J . Pharm., 119, 232-53 (1947). (18) E. K.Nelson and H. Hasselbring, J. Am. Chem. SOC.,63, 104043 (1931). (19) E.K. Nelson and H. H. Mottern, J . Am. Chem. SOC.,63, 3046-48 (1931). (20) A. Behr., Ber., 10, 361-65 (1877). (21) E. 0.von Lippmann, Ber., 12, 1649-61 (1879). (22) P.A. Yoder, J . Znd. Eng. Chem., 3, 640-46 (1911). (23) C.8. Taylor, J . Chem. SOC.,116, 886-89 (1919). (24) F. W.Zerban, J . Ind. Eng. Chem., 11, 103436 (1919). (6) S. Baup, Ann. chim. phys., [3]30, 312-24 (1850);Ann.,

ACONITIC ACID I N T H E M A N U F A C T U R E O F SUGAR

233

ses,25--28 and from sorghum product^^^-^^^ and it has been reported that the average aconitic acid content of sugar cane is about 25 to 40 percent of the amount in sorgho.82 Several workers have observed the deposition of alkaline earth aconitates as a sediment in molasses, as scale in sugarhouse evaporators and vacuum pans, and in some cases as a precipitate in concentrated sugar liquors during the crystallization procedure^.^^,^^-^^ It was not until the comparatively recent work of McCalip and Seibert,34 and of Balch, Broeg and Ambler,37however, that quantitative data on the amount of aconitic acid in various sugar cane products were available. These workers found that the amount of aconitic acid in the sugar cane juice was only a few tenths of a percent of the total weight of the juice. The acid concentration, however, became higher as the sugar liquors were processed and various molasses samples were found t o contain from 1.8 to 6 percent aconitic acid based on the Brix solids of the molasses. The actual function of aconitic acid in the plant physiology is not clearly understood. Cis-aconitic acid undoubtedly is present t o a certain extent in the plant because of its role in the citric acid cycle but the factors which cause the accumulation of comparatively large quantities of aconitic acid have not been clearly defined. Whether the concentration of aconitic acid which is formed in the plant is the cis-form exclusively or is a mixture of the cis- and the trans- acids is also unknown. Balch, Broeg and Ambler,37in their investigations, reported considerable variation in the aconitic acid content of various crusher juices of Louisiana (25) E.K.Nelson, J . Am. Chem. SOC.,61, 280&10 (1929). (26) E.K.Nelson and C. A. Greenleaf, Ind. Eng. Chem., 21, 857-59 (1929). (27) H.C. Prinsen-Geerligs, Arch. Suikerind., 41, 720-21 (1933). (28) K.Miti, Bull. Inst. Phys. Chem. Research (Japan),22, 671-73 (1943). (29) H.B. Parsons, Amer. Chem. J . , 4, 39-42 (1882-3). (30) H.W. Wiley and W. Maxwell, Amer. Chem. J., 12, 216 (1890). (31)J. J. Willaman, R. M. West and G. E. Holm, J . Agr. Research, 18, 1-33 (1919)[Chem. Abstracts, 14, 961 (1920)l. (31a) R. H. Cotton, L. W. Norman, G. Rorabaugh and H. F. Haney, Znd. Eng. Chem., 48, 62l3-35 (1951). (32) Anon., Louisiana State Univ. Eng. Ezpt. Station News, 1, No. 2, 9 (1945). (33)E.K.Ventre, Sug. Jour., 8, No. 7, 23-30 (1940). (34) M.A. McCalip and A. H. Seibert, Ind. Eng. Chem., 38, 637-40 (1941). (35) W.L. McCleery, Repts. of 62nd meeting of Hawaiian Sugar Planters Assoc., pp. 83-84;as reported in Intern. Sugar J . , 46, 244 (1943). (36) H.A. Cook, Hawaiian Planter's Record, 47, No. 2, 71-73 (1943). (37) R.T.Balch, C. B. Broeg and J. A. Ambler, Sugar, 40, No. 10, 32-35 (1945); 41, No. 1, 46 (1946). (38)Anon., Intern. Sugar J., 47, 112 (1945). (39) J. McGlashan, Proc. 16th Conv. Sugar Tech. Assoc. India, 1,83-93;as reported in Intern. Sugar J., 61, 31-32 (1949).

234

ROBERT ELLSWORTH MILLER AND SIDNEY M. CANTOR

sugar canes. This fact led these authors to suggest that an important factor which may affect the aconitic acid concentration in the plant is the composition of the soil and that the acid may play an important part in stabilizing the reactions of the plant ~ a p . 4 I~n their opinion the function of the aconitic acid may be to neutralize the basic elements which are absorbed from the soil-in order to maintain the normally acid condition of the juice (pH value about 5.4). There also may be a relationship between the aconitic acid content and the alkaloid content of the plant. These authors also observed that the juice from the immature growing portions of the sugar cane stalk-the tops which are normally discarded-contained from three to five times as much aconitic acid as the juice from the mature and millable portions of the cane. On the basis of the above findings the growing of sugar cane under carefully controlled conditions (e.g. soil composition and maturity of the cane) primarily for the production of aconitic acid is a distinct possibilitya’ although economic considerations would point away from this.

11. PHYSICAL PROPERTIES OF ACONITIC ACID Aconitic acid, a white crystalline solid, exists as either the transor the cis-form with the trans-aconitic acid being the more stable form41 while the cis-acid is the stronger acid. The trans-aconitic acid exhibits a decomposition point rather than a true melting point. The values reported in the literature vary over a range from 185’ t o 208’ and the observed decomposition point is a function not only of the purity of the acid but also of the temperature of the melting point bath when the sample is introduced and of the rate of heating.a4*42 The trans-aconitic acid is easily soluble in water and the solubility increases as the temperature rises. The acid is quite soluble in methanol, ethanol, aqueous ethanol, dioxane, slightly soluble in diethyl ether and can be recrystallized from water, ether or concentrated hydrochloric acid. (40) Analyses of numerous molasses samples from various geographical areas as carried out in the research laboratories of The American Sugar Refining Co. also have revealed a considerable fluctuation of the aconitic acid concentration. A comparison of the aconitic acid concentration in these blackstrap molasses should serve as an indication of the variation in the aconitic acid concentration of the sugar cane juices from which the respective molasses were derived. Louisiana molasses in general contain more aconitic acid than Cuban blackstraps. Thus in a series of ten Louisiana samples the aconitic acid content ranged from 2.10 to 7.39 percent with an average value of 4.83 percent (based on dry solids). In a series of forty-four samples of Cuban molasses the aconitic acid content ranged from 1.64 to 4.37 percent with an average value of 3.20 percent (based on dry solids). (41) For a discussion of this cis-trans relationship see page 244. (42) W. F. Bruce in “Organic Syntheses” (H. A. Blatt, editor), John Wiley and Sons, Inc., New York, Coll. Vol. 11, 12-14 (1943).

ACONITIC ACID I N THE MANUFACTURE O F SUGAR

235

The physical properties of aconitic acid are listed in Table I. TABLEI Physical Properties of Aconitic Acid trans-Aconitic Acid

cis-Aconitic Acid

Melting Point

Reported in range from 180' to 208" (dec.) Refs. 11, 16, 17, 21, 34, 39, 42-48

125" 49

Solubility in Water

18.6 g./100 ml. at 13" 5o 26.4 g./100 ml. a t 25" 5 L 110.7 g./100 ml. at 90" 5 1

Ionization Constants ki

ki

1.31 X at 20" 6 2 1 . 3 6 x 10-846 1 . 5 8 X 10-8 a t 25" 53 3.5 X 1.1 X

1.19 X 10-3 at 20" 1.13 X lo-' 66

a t 25" I4 a t 15" 6 5

Molecular Heat of Com481.3 kcal. (constant volume)5' bustion 476.3 kcal. (constant volume)6* 475.4 kcal. (constant pressure)&* Refractive Indices of Crystals

n, 1.4906g;1.47534 np indeterminate ny 1.610L8;1.64234

(43) M. Conrad, Ber., 32, 1007 (1899). (44) W. Hentschel, J. prakt. Chem., [2] 36, 205-6 (1887). (45) L. Claisen and E. Hori, Ber., 24, 12CL27 (1891). (46) T. H. Easterfield and W. J. Sell, J. Chem. SOC., 61, 1003-12 (1892). (47) H. 0. L. Fischer and Gerda Dangschat, Helu. Chim.Acta, 18, 1204-6 (1935). (48) P. Walden, Z.physik. Chem., 10,563-79 (1892). (49) R. Malachowski and M. Maslowski, Ber., 61, 2521-25 (1928). (50) V. Dessaignes, Ann., Suppl., 2, 189 (1862). (51) Taken from a catalogue published by Chas. Pfieer and Co. (52) R. Malachowski, Bull. intern acad. polon., 1931A,369-82. (53) J. Walker, J. Chem. Soc., 61, 696-717 (1892). (54) R. Wegscheider, Monats., 23, 599-668 (1902). (55) I. M. Kolthoff, "The Use of Color Indicators," 2nd Ed. (Berlin 1923) p. 166 (Bedstein, Z I , 2nd suppl., p. 693). (56) G. Semerano and L. Sartori, Gazz. chim. ital., 68, 167-73 (1938). (57) W. Louguinine, Ann. chim. phys. [6], 23, 206 (1891). (58) F. Stohmann and C. Kleker, Z.physik. chem., 10, 417 (1892). (59) E. K. Nelson, J. Am. Chem. SOC., 47, 568-72 (1925).

236

ROBERT ELLSWORTH MILLER AND SIDNEY M. CANTOR

111. ANALYTICAL ESTIMATION OF ACONITIC ACID Three separate and distinct methods have been utilised for the determination of aconitic acid in sugar cane and/or sorghum products. One involves the extraction of aconitic acid from the sample with an organic solvent, the second is based upon the decarboxylation of aconitic acid while the third employs the polarographic t e c h n i q ~ e . ~ ~ " The first of these, utilized by YoderJa5McCalip and SeibertJa4and by Balch, Broeg and Ambler,a7provides for the extraction of the aconitic acid from the sample being investigated, usually with diethyl ether, and the subsequent isolation of the acid from the solvent. In dealing with solid samples, e.g. alkaline earth aconitates, evaporator scale, etc., the prescribed procedure is to dissolve the material in aqueous mineral acid and to extract the acid solution exhaustively with ether. The ether extract is then evaporated under reduced pressure, the dried residue titrated with standard alkali and the titratable acid calculated as aconitic acid. In dealing with such solid samples it is often necessary to make an additional determination for oxalic acid which otherwise would be assumed to be aconitic The aconitic acid in liquid samples is usually precipitated as the insoluble lead salt which is separated and treated as any other solid sample. In some cases this procedure is unnecessary and the liquid samples are merely acidified with a mineral acid and then extracted with ether.a7 This method for the determination of aconitic acid, however, requires a considerable amount of time and is further complicated by the interference of ether-soluble waxes and non-volatile acids. The second method, developed by Ambler and Robert~,~@-~~ involves the decarboxylation of aconitic acid. These workers found that aconitic (59a) A fourth method has recently been reported by K. Lauer and S. M. Makar (Anal. Chem., 23, 587-89 (1951)). These authors have reported an analytical procedure for the determination of aconitic acid which involves titration of an acidified (sulfuric acid) aqueous solution of aconitic acid a t the boiling point with a standard potassium permanganate solution. Since the oxygen consumption was found to vary with the concentration of the potassium permanganate solution this latter solution must be standardized against a pure known sample of aconitic acid. Procedures are described for the determination of aconitic acid in pure solutions, in technical aconitates and in molasses. While itaconic acid and its salts constitute an interference the authors outline a procedure in which the aconitic acid is separated from the itaconic acid as its mercurous salt before the aconitic acid determination is carried out. (60) E. J. Roberts and J. A. Ambler, Anal. Chem., 19, 118-20 (1947). (61) J. A. Ambler and E. J. Roberts, Anal. Chem., 19, 877-78 (1947). (62) J. A. Ambler and E. J. Roberts, Anal. Chem., 19, 879-80 (1947). (63) J. A. Ambler and E. J. Roberts, Anal. Chem., 20, 880 (1948).

ACONITIC ACID IN THE MANUFACTURE O F SUGAR

237

acid and certain aconitates undergo a rapid decarboxylation when refluxed with anhydrous acetic acid-potassium acetate mixtures and one mole of carbon dioxide is liberated per mole of original aconitic acid. The carbon dioxide is collected and determined by any standard method. With liquid samples the aconitic acid is isolated as the lead salt which is carefully dried and then added to the acetic acid reagent. A number of materialslsOwater, certain organic acids, the most important of which is citric acid, and certain inorganic salts, interfere with the determination. The decarboxylation cannot be conducted in the presence of nitrates and when carbonates are present two separate determinations of carbon dioxide are necessary. The procedure is also inapplicable when oxidizing compounds which are soluble in the hot reagent are present. Another interfering substance, sulfur dioxidelB1 can be eliminated by the use of a saturated, acidified (sulfuric acid) solution of potassium dichromate to wash the gases evolved by the decarboxylation procedure. Ambler and Robertslszon further examination of the interference of citric acid, found that the addition of boric acid t o the acetic acidpotassium acetate reagent prevented the decarboxylation of the citric acid. When boric acid was used in the reagent, however, it was found that oxalic acid, galacturonic acid and mucic acid were slowly decarboxylated. Polyuronic acids were insoluble in the acetic acid reagent and were not decarboxylated by the procedure.63 I n addition, when the decarboxylation procedure was applied to methylgalacturonide dihydrate it was found that the compound was easily soluble in the reagent but gave no carbon dioxide even after refluxing for three hours. The evidence indicated, therefore, that only the free galacturonic acid was decarboxylated in the aconitic acid method and that the potassium acetateacetic acid reagent, being practically anhydrous, is unable t o hydrolyze soluble uronides to the free uronic acids. Although polarographic studies of aconitic acid in pure solutions had been made by several investigators, the application of such techniques to the determination of aconitic acid in sugarhouse products had been n e g l e ~ t e d . ~ ~Recently, -~~ however, a procedure has been developed (64) L. Schwaer, Chem. Listy, 26, 485-89 (1932). (65) K. Shoji, Bull. Inst. Phys. Chem. Research (Tokyo), 9, 69-78 (1930); Absts. 9-11 pub. with Sci. Papers Inst. Phys. Chem. Research (Tokyo), 12, No. 221-27. (66) L. Schwaer, Coll. Czechoslou. Chem. Commun., 7 , 326-35 (1935). (67) G. Semerano and L. Sartori, Mikrochemie, 24, 130-33 (1938). (68) H. Siebert, 2.Elektrochem., 44, 768-69 (1938). (69) A. Miolati and G. Semerano, 2. Electrochem., 46, 226-28 (1939).

238

ROBERT ELLSWORTH MILLER AND SIDNEY M. CANTOR

whereby the amount of aconitic acid in sugar products can be quantitatively determined polar~graphically.~~ The determination of aconitic acid in comparatively pure solutions is not difficult and a well defined wave having a half-wave potential of -0.55 volt (referred to a saturated calomel electrode) is obtained when normal hydrochloric acid is used as the supporting electrolyte. 'For using most automatic recording polarographs with pure solutions a range in aconitic acid concentration of two to ten milligrams of acid per 100ml. is chosen as the most optimum conditions from the standpoint of sensitivity range and in order to obtain wave heights which are sufficiently large to minimize the errors due to measurement. With pure solutions a simple dilution with normal hydrochloric acid to the desired concentration is satisfactory. In applying the procedure to blackstrap molasses a comparative method is employed in which the concentration of the unknown solution is determined by comparison of the wave height with that from a known concentration. Interfering substances are present in blackstrap molasses, however, which prevent the formation of a well defined currentvoltage relationship and special treatment of such samples is therefore required. The removal of the interfering substances can be accomplished by treating the molasses sample with activated carbon. The conditions under which the samples are prepared must be rigidly standardized in order to obtain reproducible results and the following procedure is recommended : A sample of the blackstrap molasses (25 9.) is transferred quantitatively to a 500 ml. Kohlrausch flask using only sufficient water to make the transfer; concentrated hydrochloric acid (20 ml.) is added, the contents of the flask are thoroughly mixed and then made up to volume with distilled water. An aliquot (20ml.) of this solution is adjusted to a pH value of 10 f 0.2 with six normal sodium hydroxide and then diluted to 50 ml. with distilled water. The entire 50 ml. is transferred to a 125 ml. Erlenmeyer flask to which is added a carbon-filter aid mixture (approximately 2 9.) composed of 40% Darco KB and 60% filter aid. (The type of filter aid used is not critical.) The flask is placed upon a hot plate (at approximately 150°),allowed to remain for exactly four minutes and then immediately filtered, using a very rapid filter paper. An aliquot (20 ml.) of the filtrate is made up to 50 ml. with normal hydrochloric acid and the solution is then ready for the electrolysis cell. The sample is placed in the cell, a current of nitrogen is bubbled through it for ten minutes, the bridge is placed in operation and the polarogram is obtained. The wave height of the polarogram is measured, corrected for the sensitivity employed and then by comparison with the standard solutions the aconitio acid concentration is calculated. The usual precautionary measures apply which are necessary for all polarographic procedures (e.g. temperature control, drop rate, protection from vibration, etc.). (70) R. W. Liggett, J. A. Devlin and S. M. Cantor, Unpublished work from laboratories of American Sugar Refining Co.

ACONITIC ACID I N THE MANUFACTURE O F SUGAR

239

Numerous other methods, many of which are useful only in special cases, have been utilized to determine aconitic acid in various solutions. The color reaction of aconitic acid with acetic anhydride has been ~~~~~~ employed to a very minor extent in sugar t e c h n o l 0 g y . ~ 3MalachowskilS2in analyzing solutions of cis- and trans-aconitic acid, made use of the difference in the specific conductance of the two compounds to determine the composition of the solutions. Krebs and Eggle~ton,?~ seeking a method for the determination of cis-aconitic acid, used aconitase t o convert the cis-aconitic acid to citric acid which was then analyzed according to the method of Pucher, Vickery and Lea~enworth.?~Ksebs and Eggleston also utilized this procedure for studies of the equilibrium between the cis- and trans-aconitic acid in aqueous solutions. Ambler and Roberts,7s who were studying the stability of cis-aconitic acid in aqueous solutions, made use of the difference in the solubilities of the st,rontium salts of the cis- and trans-acids to determine the composition of the equilibrium mixtures obtained. The latter procedures, however, are inapplicable t o the determination of aconitic acid in sugarhouse products.

IV. THERECOVERY OF ACONITIC ACID IN THE MANUFACTURE OF SUGAR During the last ten years considerable interest has developed in connection with the commercial recovery of aconitic acid from sugarcontaining liquors such as sorghum juice or sugar cane juice. The isolation of aconitic acid from raw sorghum juice, which contains a considerable amount of aconitic acid, can be carried out before the sugar is crystallized. In sugar cane juice, however, the amount of aconitic acid is much lower and usual starting points for the isolation of aconitic acid from this source are the “ B ” molasses which is obtained after two crops of sugar have been crystallized from the juice, and the final blackstrap molasses. The first indication that the recovery of insoluble aconitates from these sugar-containing juices was feasible was the initial work by Ventr433*76 and Ventre and Paine.?? These workers found that during the evaporation of sorghum juice an insoluble aconitate salt separated in amounts (71) 0. Furth and H. Hermann, Biochem. Z.,280, 448-57 (1935). (72) E. K. Ventre, J. A. Ambler, H. C. Henry, S. Byall and H. S. Paine, I d . Eng. Chem., 38, 201-4 (1946). (73) H. A. Krebs and L. V. Eggleston, Biochem. J., 38, 426-37 (1944). (74) G. W. Pucher, H. B. Vickery and C. S. Leavenworth, Ind. Eng. Chem., Anal. Ed., 6, 190 (1934). (75) J. A. Ambler and E. J. Roberts, J . Org. Chem., 13, 399-402 (1948). (76) E. K. Ventre, Sugar, 36, No. 1, 36-37 (1941). (77) E. K. Ventre and H. S. Paine, U. S. Pat. 2,280,085 (Apr. 21, 1942).

240

ROBERT ELLSWORTH MILLER AND SIDNEY M. CANTOR

which .made it practicable to recover this salt as a by-product. The only chemical addition involved in this early work was that of an alkaline earth clarifying agent which was employed to adjust the pH value of the juice to within the range 6.8 to 7.2. Since the alkaline earth aconitates are more insoluble at higher temperatures, the temperatures employed subsequently in the evaporation of the sorghum juice, were of the proper range to cause the formation of the insoluble aconitates. Ventre and c o - w o r k e r ~in , ~later ~ ~ ~work, ~ found that the addition of calcium chloride greatly increased the amount of aconitates thus recovered. The procedure used was as follows: lime was added to a quantity of sorghum juice to adjust the pH value to approximately 6.9. The amount of lime required for this treatment was calculated as equivalents of aconitic acid and this portion of the aconitic acid in the original sample of juice was assumed to be free aconitic acid. The remaining aconitic acid was assumed to be bound in the form of a soluble aconitate. An amount of calcium chloride equivalent to the bound aconitate was then added to the juice for the precipitation. The insoluble aconitates which precipitated during the subsequent evaporation of the juices were removed by some appropriate means at a later point in the sugar recovery system. Following this initial work on the isolation of aconitates from sorghum juice the same process was applied to sugar cane "B" molasses.82~37~88~Te Ambler, Turer and Keenan,80in 1945 investigated various salts of aconitic acid and reported that the dicalcium magnesium aconitate hexahydrate and aconitates containing lesser amounts of magnesium were less soluble than either of the hydrates of tricalcium aconitate. Thus Ambler, Roberts and Weissborn, Jr.,81 and Ambler and Roberts,82soon reported an improved process for the recovery of aconitates from molasses in which both calcium chloride and magnesium chloride were added t o the molasses. According to these workers the optimum conditions for aconitate recovery were fivefold: 0

a. The molasses was diluted to 50" to 55" Brix. b. Calcium oxide or hydroxide were the best agents for adjustment of the pH value. The optimum pH values were found t o be within the range of 6.5 to 6.8. (78) E. K. Ventre, J. A. Ambler, S. Byall and H. C. Henry, U. S. Pat. 2,359,537 (Oct. 3, 1944). (79) Anon., Sugar Bull., 23, No. 19, 173-74 (1945). (80) J. A. Ambler, J. Turer and G. L. Keenan, J . Am. Chem. SOC.,67, 1-4 (1945). (81) J. A. Ambler, E. J. Roberts and F. W. Weissborn, Jr., U.S. Bur. Agr. I d . Chem., Mimeographed Circ. Ser. AIC 196 (1946). (82) J. A. Ambler and E. J. Roberts, U. 5. Pat. 2,481,557 (Sept. 13, 1949).

.4CONITIC ACID I N THE MANUFACTURE OF SUGAR

24 1

c. Calcium chloride and magnesium chloride were used to increase the calcium and magnesium content of the molasses sample. The most satisfactory results were obtained by adding a solution containing three parts of anhydrous calcium chloride and one part of anhydrous magnesium chloride for every five parts of aconitic acid in the solution. These were the least amounts required. Larger quantities had no affect upon the aconitate recovery but increased unnecessarily the amount of ash and particularly chlorides in the molasses returned to the sugarhouse. d. Best results were obtained if the precipitation were carried out at temperatures between 93" and 99". e. The reaction temperature was maintained for at least forty-five minutes. Extension of the reaction time beyond one hour was found to have very little affect upon the recovery.

The findings of G o d ~ h a u x ~ 3agreed 9 ~ ~ well in most respects with the above optimum conditions but differed in respect of the chemical addition required. The latter worker and his associates indicated that magnesium chloride was not necessary for the precipitation of the aconitic acid but actually was detrimental to sugar recovery. More important was the realization that a definite chemical addition could not be used for all molasses samples. Certain molasses when limed and heated precipitated a large percentage of aconitic acid as insoluble alkaline earth aconitates whereas other molasses required excessive amounts of chemical addition. This inability t o designate a definite chemical addition for all molasses was also discussed by Ventre;85the suggested resolution for this problem was the use of preliminary laboratory experiments to determine the optimum conditions for each molasses. A more recent investigation86 has also indicated that it is impossible to state a specific procedure for the recovery of aconitates which is applicable to all molasses but that each type of molasses must be investigated and handled as a separate entity. The samples of Cuban b1ackstra.p molasses which were studied gave good recoveries of insoluble aconitates by simple dilution and heating, and the addition of soluble calcium salts in the usual manner to these molasses did not materially improve the aconitate recoveries. Louisiana blackstrap molasses in general, however, were found to require the addition of large amounts of chemicals (83) R. J. Fume and L. Godchaux, 11, Sugar Research Foundation (New York), BUZZ., 4, NO.20, 78-81 (1948). (84) Anon., DeLauaZ Centrzfugul Rev., 16, No. 1, pp. 3, 4, 1 1 (1949). (85) E.K.Ventre, U. S. Pat. 2,469,090(May 3, 1949). (86) R. E. Miller, R. Netsch and R. W. Liggett, unpublished data.

242

ROBERT ELLSWORTH MILLER AND SIDNEY M. CANTOR

before satisfactory yields of aconitate could be recovered. Typical results in relation to the precipitation of aconitates from Cuban and Louisiana blackstrap molasses are presented in Table 11. TABLE I1 Precipitation of Aconitates from Cuban and Louisiana Blackstrap Molasses

Molasses Sample

Percent of Total Aconitic Acid Precipitated as Insoluble Aconitates Procedure

10

1

Procedure IP

Louisiana Molasses Samples 1 2 3 4 5 6

7 8 9 10

41 27 6 19 0 32 42 2 4 12

66 67 61 67 66

68 68 55 57

74 75 65 64

74 48 61 57 70

Cuban Molasses Samples 13 14 15 16

0 Procedure I: The molasses was diluted to 53" Brix and heated for one hour a t 9 0' with mechanical stirring. A portion of the reaction mixture was then centrifuged and the exhausted molasses (supernatant liquor) was analyzed for aconitic acid. * Procedure 11: The molasses was diluted to 53" Brix and a CaO slurry (10% by weight) was added to a pH value of 7.0. The desired amount of 3M CaCll solution was added (enough to bring the total equivalents of calcium ion up to 1.5 times the number of equivalents of aconitic acid present), and the reaction mixture was heated at 90" for several hours with mechanical stirring. The reaction mixture was then centrifuged and the exhausted molasses was analyzed for aconitic acid.

The insoluble aconitate salts isolated by the aforementioned procedures usually crystallize as hexahydrates and generally contain both calcium and magnesium even when magnesium salts have not been added to the molasses prior to the aconitate precipitation. It is reportedso that the salts have the optical-crystallographic characteristics of dicalcium magnesium aconitate hexahydrate, CazMgAcon2.6H20,although their magnesium content is usually less than that of this salt. Ambler, Turer and Keenanso made several preparations of this substance which contained magnesium in quantities ranging from almost theoretical down to

ACONITIC ACID I N T H E MANUFACTURE O F SUGAR

243

approximately 25% of theory, and which, regardless of the magnesium content within these limits, were homogeneous and showed identical optical-crystallographic properties. These crystalline hexahydrates obtained from molasses show no indication of being physical mixtures of insoluble calcium aconitate with soluble magnesium aconitate since it is impossible to separate magnesium aconitate from the salts by leaching with hot water.72 The salts, therefore, are believed to be members of a series of mixed crystals or solid solutions of dicalcium magnesium aconitate hexahydrate and tricalcium aconitate hexahydrate.s0ss2 D. W. C0llier,~7in a recent patent, reports that the use of a small amount of barium and/or strontium salts in conjunction with the calcium and/or magnesium salts ordinarily used in the precipitation of the aconitic acid from molasses gives much higher aconitate recoveries than those previously reported. The use of a small amount of either barium or strontium salts causes much greater precipitation than an equivalent amount of calcium ion. Thus the use of a mixture of a calcium salt and a barium salt which contained cations equivalent to the aconitic acid (90% equivalence of calcium ion and 10% equivalence of barium ion) in a trisodium aconitate solution was found to give a residual aconitate solubility (3.1 g./liter) much lower than that (12.6 g./liter) obtained when an equivalent amount of calcium ion was used alone. The procedure as outlined by Collier is very similar to that previously described. The molasses is neutralized with lime to a pH value of 6.8, heated, and the desired amount of an aqueous calcium chloride solution is added. This mixture is subjected t o the usual precipitation conditions (90-95', mechanical agitation) for approximately forty-five minutes and the soluble barium and/or strontium salts are then added. The heating is continued for another forty-five minutes and the insoluble aconitates are recovered from the molasses. The salts obtained from this latter process thus contain barium and/or strontium ions in addition to the calcium and magnesium cations usually present. From a consideration of these data, it would appear that precipitation of insoluble aconitates from molasses is an extremely complicated reaction and is a function not only of the relative amounts of acid and metallic ions present but also the status of the acid in solution. I n this latter respect, it would seem that aconitic acid exists in molasses not only as free ionized acid but also as soluble complexes and the conversion of these soluble complexes to insoluble salts is an important yield-governing consideration. One phase of the aconitate precipitation process which has not been previously mentioned but is extremely important is the disposal of the (87)

D.W. Collier, U. S. Pat. 2,513,287 (July 4, 1950).

244

ROBERT ELLSWORTH MILLER AND SIDNEY

M. CANTOR

molasses after the insoluble aconitates have been removed. With the present demand for blackstrap molasses for.fermentations and livestock feed and the comparatively high price level of molasses it is quite evident that a careful examination of the effect of the various cations employed for the precipitation upon the final use of the molasses is necessary. In large scale operations the aconitic acid is usually recovered from the crude calcium magnesium aconitates by acidification with a mineral acid followed by the crystallization of the aconitic acid from the liquors obtained. Thus Ventre, Henry and Gayle,88 acidified the crude salts with dilute sulfuric acid. The insoluble calcium sulfate was removed by filtration and the aconitic acid was separated from the magnesium sulfate by fractional crystallization. Ambler and R o b e r t ~ ,in~subsequent ~,~~ work, found that if the calcium magnesium salts were heated to remove a portion of the water of hydration the magnesium content could be replaced by calcium by treating the dried salts with a hot concentrated calcium chloride solution. Thus the aconitates could be converted into tricalcium aconitate and subsequent treatment of this salt with sulfuric acid enabled the removal of the cations as insoluble calcium sulfate. The crystallization of aconitic acid from such a filtrate was therefore not complicated by the necessity of a fractional crystallization to separate the aconitic acid and the magnesium sulfate formerly obtained. Hydrochloric acid has also been used for the acidifi~ation.~~ I n this case the aconitic acid is then crystallized from the solution of aconitic acid and alkaline earth chlorides. AND USES OF ACONITIC ACID V. CHEMISTRY

Because of the polyfunctional character of aconitic acid, it being both an unsaturated acid and a polybasic acid, the compound can undergo a variety of chemical reactions. Application of derivatives obtained by such reactions has aroused considerable interest in the plasticizer, wetting agent and resin manufacturing fields. Much of the chemical behavior of aconitic acid is closely related t o the chemistry of maleic and fumaric acids. As mentioned earlier, aconitic acid can exist as either the trans- oqthe cis-isomer. It was not until 1928, over one hundred years after its initiaI discovery, that the trans-aconitic (88) E. K. Ventre, H. C. Henry and F. L. Gayle, U. S. Pat. 2,345,079 (Mar. 28, 1944). (89)J. A. Ambler and E. J. Roberts, U. S. Pat. 2,432,223 (Dec. 9, 1947). (90) H. F.Reeves, Jr., U. S. Pat. 2,614,010(July 14, 1950).

ACONITIC ACID I N T H E MANUFACTURE OF SUGAR

245

acid was identified as the more stable form,46~48~49~91-g7 the so-called “ordinary” aconitic acid. Only a few investigations have been made, however, in connection with the cis-trans equilibrium and the factors which affect this equilibrium. Malachowskils2 working with aqueous solutions of cis- and trans-aconitic acid, has reported that the equilibrated solutions contain approximately 85 per cent trans-aconitic acid. The amount of cis-aconitic acid increases slightly with increasing temperatures and with dilution of the solution. Krebs and Eggle~ton’~ found that in neutral solution sodium cis-aconitate is quite stable and that the most rapid and extensive conversion of the cis- to the trans-acid takes place in ‘strongly acidic or strongly alkaline solutions. Ambler and R ~ b e r t s , ’in~ a further investigation of the affect of the pH value of the solution upon the stability of cis-aconitic acid, found that cis-aconitates are stable in neutral and slightly alkaline solution, but unstable at high alkalinities, especially if the solutions are heated. In acid solutions the stability decreases as the acidity of the solution increases. As a result of the cis-trans isomerization two isomeric aconitic anhydrides are known. Treatment of the trans-aconitic acid with acetyl ~hloride,46JJ6*~6 or with acetic anhydridelg60g7 leads to the formation of both the cis-aconitic anhydride (11) and the trans-aconitic anhydride (111). More recently it has been reported that good yields of the cis-anhydride HC-C=O

/I

‘0

I1

/ c-c=o

A

HC-C=O €IOOC--c ‘1, ( ‘) I121:-C=0/

Hz -COOH

I1

I11

can be obtained by refluxing a mixture of trans-aconitic acid in xylene with catalytic amounts of p-toluenesulfonic The cis-aconitic acid can be prepared by the hydrolysis of the cis-anhydride under carefully controlled conditions49while the trans-acid is prepared in the laboratory by the sulfuric acid dehydration of citric Aconitic acid is easily esterified by conventional methods and physical properties of some of the trialkyl aconitates are presented in Table 111. (91) (92) (93) (94) (95) (96) (97) (98)

A. Michael, Ber., 19, 1381-86 (1886); Amer. Chem. J., 9, 193 (1887). S. Ruhemann and K. J. 1’. Orton, Ber., 27, 3449-57 (1894). R. Anschtitz and W. Bertram, Ber., 37, 3967-70 (1904). H. Rogerson and Jocelyn F. Thorpe, J . Chem. SOC.,89, 631-52 (1906). N. Bland and Jocelyn F. Thorpe, J . Chem. SOC.,101, 1490-98 (1912). P. E. Verkade, Rec. trau. chim., 40, 381-86 (1921). R. Malachowski, M. Giedroyc and Z. Jerznianowska, Ber. 61,2525-38 (1928). W. P. Ericks and E. R. Meincke, U. S. Pat. 2,345,041 (Mar. 28, 1944).

246

ROBERT ELLSWORTH MILLER AND SIDNEY M. CANTOR

Certain of these trialkyl aconitates are reported to be effective for controlling soft-bodied and sucking insects.eQ The six isomeric monomethyl cis- and trans-aconitates were prepared by Malachowski, Giedroyc and Jerzmanowskas7 and were obtained as crystalline solids melting sharply within the range of 100" to 150". The monomethyl anhydro-cis-aconitate (IV) also prepared by these workers was a low melting solid (37-38"). Ericks and Meinckes8 have reported the use of cis-aconitic anhydride to prepare monoalkyl aconitates and also dialkyl aconitates although the resulting esters were not described fully nor were the physical properties reported. HC-C=O

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).

This Page Intentionally Left Blank

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

FRIEDEL-CRAFTS AND GRIGNARD PROCESSES

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).

FRIEDEL-CRAFTS AND GRIGNARD PROCESSES

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

FRIEDEL-CRAFTS AND GRIGNARD PROCESSES

:"

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).

FRIEDEL-CRAFTS AND GRIGNARD PROCESSES

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).

FRIEDEL-CRAFTS AND GRIGNARD PROCESSES

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

FRIEDEL-CRAFTS AND GRIGNARD PROCESSES

(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

This Page Intentionally Left Blank

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 ><

H O

CH

b’

CHCsII6

Hz 0

The configuration of the anhydronitroalcohol at the positions of closure of the anhydro ring (2- and 6-) is not known. However, since the anhydro ring bridges the same carbon atoms as did the pyranose ring of the interesting possithe reactant, 4,6-benzylidene-a-~-glucopyranose, bility arises that the anhydronitro compound may have been produced by direct elimination of water between sodium mi-nitromethane and the benzylidene sugar without disruption of the hemiacetal ring. The anhydronitroalcohol would then have the D-gluco-D-gulo- or D-gluco-Dido- configuration. b. From Unsubstituted A1doses.-The successful condensation of unsubstituted aldose sugars with nitromethane to produce carbohydrate C-nitroalcohols appears to depend to a large extent upon certain solubility relationships in the reaction mixture. Methanol is usually satisfactory as the reaction solvent but it is probable that other solvents may be preferable in instances where the use of methanol leads t o low yields. Aldose sugars of greater chain length than the tetroses are only sparingly soluble in cold mixtures of methanol and nitromethane. However, when sodium methoxide is added to suspensions of certain aldoses in this mixture, rapid solution of the sugar occurs. In the most favorable examples of the condensation reaction, this rapid solution of the sugar is accompanied by, or quickly followed by, precipitation of the sodium salts of the carbohydrate C-nitroalcohols. Thus, if the sugar is sufficiently soluble in the alkaline reaction mixture and the sodium mi-nitroalcohols are

NITROMETHANE A N D

%NITROETHANOL

SYNTHESES

305

sufficiently insoluble, the condensation reaction may proceed well toward completion. These solubility relationships are true for D-erythrose, D- and L-arabinose and D-mannose. In contrast, the sodium aci-nitroalcohols resulting from the condensation of D-glucose and nitromethane are moderately soluble in the reaction mixture and the reacting sugar also is only moderately soluble. Consequently the reaction does not proceed to any great extent with this hexose. Reaction solvents other than methanol may improve such situations. A relatively large excess of nitromethane normally is employed in order to favor the formation of the carbohydrate C-nitroalcohols in the equilibrium and to allow for some destruction of nitromethane by the alkali. From one and one-half to two molecular-equivalents of sodium methoxide, based on the reacting sugar, usually are sufficient to promote a reasonably rapid condensation reaction. The minimum time required for completion of the condensation, which may be expected to vary from one aldose sugar to another, has not been determined. As judged visually, the precipitation of the sodium aci-nitroalcohols is essentially complete in less than one hour in the most favorable instances. However, a total reaction time of from six to eighteen hours has been employed. D-Erythrose.-sirupy D-erythrose, prepared by mild acid hydrolysis from 2,4-benzylidene-~-erythrose,30 is readily soluble in cold mixtures of methanol and nitromethane. When sodium methoxide is added t o the resulting solution, precipitation of amorphous sodium aci-nitroalcohols begins in a few minutes. Removal of the sodium from these salts by ion-exchange then gives, in 70-75 percent yield, based on the tetrose component, a mixture of crystalline 1-nitro-1-desoxy-D-arabitoland amorphous 1-nitro-1-desoxy-D-ribitol. CHO H bI o H

D-Erythrose

CHaNOz

HobH I

bHa0H l-Nitro-1desoxy-Darabitol

CHiNOa HAOH I

hHaOH 1-Nitro-ldesoxy-Dribitol

D- and L-Arabinose.-Unlike D-erythrose, the arabinoses are virtually insoluble in cold,mixtures of methanol and nitromethane. However, when sodium methoxide is added to a suspension of the powdered sugar

306

JOHN C. SOWDEN

in this mixture, the pentose dissolves at once and the sodium aci-nitroalcohols begin to precipitate a few minutes thereafter. Removal of the sodium from these salts by ion-exchange gives, in 45 to 60 percent yield, based on the starting sugar, a crystalline mixture of the corresponding 1-nitro-1-desoxyglucitol and 1-nitro-1-desoxymannitol. The mixed nitroalcohols are readily separated into the pure components by fractional crystallization. CHO

CHiNOz

HAOH

HoAH

HOAH HobH

HboH +HobH

AH20H

L-Arabinose

CHiNOg

HoAH bHzOH l-Nitro-1dW0xy-Lglucitol

HAOH and

HboH H oAH

b

HO H AH20H l-Nitro-1desox y -Lmannitol

Experimental Detail~.~'-Asuspension of 25 g. of barabinose in 50 CC. of methanol and 90 cc. of nitromethane was shaken with a solution containing 5.3 g. of sodium in 175 cc. of methanol. After eighteen hours, the precipitated, hygroscopic sodium salts (43 9.) were collected by filtration and washed with cold methanol, ether and petroleum ether. A typical analysis of the dried salts showed 9.1% of sodium and 5.7% of nitrogen (theory for the pure sodium nitroalcohols: Na, 9.9%; N, 6.1%). The sodium salts were dissolved in 200 cc. of cold water and immediately passed over a cation-exchange resin. Concentration of the resulting sodium-free solution a t reduced pressure followed by concentration with absolute ethanol produced a crystalline residue. Fractional crystallization of this residue from absolute ethanol yielded 6.5 g. (18.5 %) of 1-nitro-1-desoxy-tmannitol and 6.6 g. (18.8%) of l-nitro-l-desoxytglucitol. After recrystallization from absolute ethanol, the former compound showed m. p. 133-134", [a];' 7.0°, in water, while the latter compound showed m. p. 107-108", [a];69.5", in water. From the combined filtrates of the fractional crystallization there was obtained approximately 5 g. (14%) of the mixed nitroalcohols which are useful for the preparation of the corresponding acetylated nitroolefin (see page 313).

~-Mannose.~~-Incontrast t o the arabinoses and D-erythrose, the alkaline condensation reaction mixture of D-mannose and nitromethane in methanol remains heterogeneous throughout. However, visual inspection shows a moderately rapid replacement of the crystalline sugar in the insoluble phase by the amorphous sodium aci-nitroalcohols. Both epimeric nitroalcohols are obtained in the crystalline state in a combined yield of approximately 55 percent. The separation of l-nitro(41) J. C. Sowden and H. 0. L. Fischer, J . Am. Chem. Soc., 69, 1963 (1947). (42) J. C. Sowden and R. Schaffer, J . Am. C L m . Soc., 73, 4662 (1951).

NITROMETHANE AND

%NITROETHANOL

SYNTHESES

307

1-desoxy-D-manno-D-gala-heptitol (m. p. 197-198'), which is the preponderant product, from the epimeric 1-nitro-1-desoxy-D-manno-D-taloheptitol (m. p. 141-142') is facilitated by the surprisingly low solubility of the former in water. The latter nitroalcohol can be obtained from the aqueous recrystallisation filtrates by crystallization from ethanol. CHO I

HOCH HObH

HCOH bH,OH D-Mannose

CHzNOi I

HCOH

b

CHzNOz HOhH

-iHO H

HCOH

HbOH

HbOH

HboH

bHzOH l-Nitro-1desoxy-Dmanno+gala-heptitol

&H~OH l-Nitro-1desoxy-nmann0-Dtalo-heptitol

2. Conversion to Aldose Sugars by the Nef Reaction

The conversion of a carbohydrate C-nitroalcohol to the corresponding sugar is achieved simply by adding an aqueous solution of the sodium mi-nitroalcohol to a moderately concentrated aqueous sulfuric acid solution at room temperature. A copious evolution of nitrous oxide occurs during the addition and the resulting sugar then can be obtained from the reaction solution in yields of from 60 to 80 percent, depending upon the ease of isolation of the particular aldose produced. L-Glucose.-The preparation of L-glucose from L-arabinose by the cyanohydrin synthesis43is long and tedious, due primarily to the difficulty of separating L-gluconic acid from the preponderant L-mannonic acid. The y-lactone of the latter is readily separated in crystalline form but L-gluconic acid must be converted to the phenylhydrazide and then the calcium or barium salt to effect isolation. Accordingly, the final yield of L-glucose is small. I n contrast, the epimeric C-nitroalcohols resulting from the condensation of L-arabinose with nitromethane are readily separated by fractional crystallization and the 1-nitro-1-desoxy-L-glucitol thus obtained can be converted in good yield to L-glucose by the Nef reaction. Thus, the preparation of comparatively large amounts of pure L-glucose by the nitromethane synthesis involves a reasonable outlay of time and material. (43) E. Fkcher, Ber., 23, 2611 (1890).

308

JOHN C. SOWDEN

CH=N02Na

c:

HO H

CHO HobH

LnOH Sodium l-aci-Nitro1-desoxy-cglucitol Experimental, Details.41-Forty-five grams of 1-nitro-1-desoxy-bglucitol, m. p. 104-106", was dissolved in 125 cc. of 2 N sodium hydroxide and the solution added dropwise to a stirred solution containing 63 cc. of sulfuric acid and 73 cc. of water, at room temperature. The resulting solution was neutralized to Congo red with warm barium hydroxide solution. The barium sulfate was removed by centrifuging and the remaining sulfate ion was then precipitated from the solution by the addition of a slight excess of barium acetate solution. The finely divided barium sulfate was removed by filtration through filter-aid and the resulting solution was then passed over a cation-exchange resin to remove sodium and barium ions. Concentration of the effluent a t reduced pressure and crystallization of the resulting sirup from ethanol produced 22.1 g. (58%) of bglucose, m. p. 146-147' and [a]F - 52.6" (equil.) in water, c 2.6. These constants for L-glucose compare favorably with the corresponding constants for D-glucose of highest purity.

L-Mannose.-This sugar, reasonably accessible from L-arabinose by the cyanohydrin synthesis,44 is even more quickly and economically available by the nitromethane synthesk41 Due to the ease of separating the mannoses from other carbohydrates as the insoluble phenylhydrazone, no separation of the epimeric nitroalcohols arising from L-arabinose is necessary for the preparation of L-mannose and thus the mixed, amorphous sodium aci-nitroalcohols can be used directly in the Nef reaction. I n this way, L-mannose phenylhydrazone, from which L-mannose is easily obtainable, can be prepared from L-arabinose in 20 to 25 percent yield in about one day. L-Culose.-This sugar results when the Nef reaction is applied to 6-nitro-6-desoxysorbitol.8s Since the latter can be prepared in fair yield starting from commercial sorbitol (see page 302), this method of preparing L-gulose is considerably more attractive than the only previously known method that depended on the following successive reductions of D-glucaric acid (D-glucosaccharic acid) with sodium amalgam :8e D-glucaric acid + D-glucuronic acid + L-gulonic y-Ihctone 4 L-gulose. The nitromethane synthesis, in this instance, employs reagents that (44) E. Fischer, Ber., 23, 370 (1890);ibid., 24, 2683 (1891);W. Alberda van Ekenstein and J. J. Blanksma, Chem. Weekblad, 11, 902 (1914),cj. Chem. Zenlr., 86, 11, 1265 (1914).

NITROMETHANE AND %NITROETHANOL SYNTHESES

309

are readily available and the preparation of relatively large amounts of L-gulose is now quite practicable. 1-C14-~4?hcose,I-C14-~-Mannoseand l-C14-~-Xylose.-Isotopically labeled sugars are finding extensive application in the elucidation of both biological and chemical processes involving the carbohydrates. Of these labeled sugars, D-glucose understandably is of greatest interest, especially for biological studies. Radioactive D-glucose is currently available with t,hree different types of Cl4-labeling. Biosynthetic C14-~-glucosewith random distribution of the radioactive tracer is obtained via photosynthesis in plants in the presence of carbon-14 dio~ide.4~A biosynthetic 3,4-C14-~-glucoseresults from the hydrolysis of the liver glycogen of animals after injection of C14-bicarbonate i0n.4~ Finally, l-C14-~glucose has been prepared from D-arabinose by the n i t r ~ m e t h a n eand ~~ cyanohydrin4*syntheses. -4 comparison of the two synthetic methods for l-C14-~-glu~ose reveals that each has certain advantages as well as some disadvantages. The cyanohydrin synthesis, which employs commercially available sodium C14-cyanide, gives a somewhat higher radio-chemical yield but the l-C14-~-glucose must be recrystallized several times to effect complete separation from the concomitant l-C14-~-mannose. The nitromethane synthesis employs commercially available C14-methyl iodide which can be converted readily in about 70 percent yield t o C14-nitromethane by the Victor Meyer reactiong with silver nitrite. Approximately 15 percent of the isomeric C14-methyl nitrite is obtained as a by-product. The yield of nitroalcohols from the aldose-nitromethane condensation is lowered somewhat in this instance since no excess of the valuable C14-nitromethane is employed. The epimeric nitroalcohols are separated by fractional crystallization and converted individually by the Nef reaction to the corresponding radioactive sugars. After the initial crystallization, the l-C14-~-glucose(m. p. 142-145') px-epared in this way from l-C14-l-nitro-l-desoxysorbitolwas found to be free from radioactive impurities when examined chromatographically on paper.49 (45) L. G . Livingston and G. J. Medes, J. Gen. Physiol., 31, 75 (1947); S. Aronoff, A. Benson, W. Z. Hassid and M. Calvin, Science, 106, 644 (1947); E. W. Putman, G. Krotkov and H. A. Barker, J. Biol. Chem., 173, 785 (1948). (46) A. I(.Solomon, B. Vennesland, F. W. Klemperer, J. M. Buchanan and A. B. Hastings, J. Biol. Chem., 140, 171 (1941); H. G . Wood, N. Lifson and V. Lorber, J. Bid. Chem., 169, 475 (1945); D. B. Zilversmit, I. J. Chaikoff, D. D. Feller and E. J. Masoro, J. Bid. Chem., 176, 389 (1948); Y. J. Topper and A. B. Hastings, J. B i d . Chem., 179, 1255 (1949). (47) J. C. Sowden, Science, 109, 229 (1949); J . Biol. Chem., 180, 55 (1949). (48) D. E. Koshland, Jr., and F. H. Westheimer, J . Am. Chem. SOC.,71, 1139 (1949); 72, 3383 (1950). (49) M. Gibbs, J. Am. Chem. Soe., 72,3964 (1950).

310

JOHN C. SOWDEN

Approximately twice as much l-C'LD-mannose as l-C14-~-glucose is obtainable from D-arabinose by the nitromethane synthesis when no excess of C"-nitromethane is employed in the initial condensation reaction. ~-C14-~-Xylose.60_Thissugar is prepared readily from ~-C"-Dglucose by the 5,6-glycol cleavage of l-C14-1,2-isopropylidene-~-glucofuranose with sodium metaperiodate, followed by reduction of the free carbonyl group to the alcohol and subsequent hydrolysis of the isopropylidene acetal.

HbOH *CHo

A

HO H

H*Fc 1 H*

H -0

HC-0

c:

HboH

H oAH

HO H

0

HAOH

HA

Hb

I-

AH,OH l-Cl'-~Glucose

HbOH

bHO

AHnOH l-C~4-l,2-Ieopropylidene-l-C14-1,2-Ieopropylidenea-D-glucofuranose 5-aldo-c~-~-xylofuranoee

HC-0 HbOH HA

I

bHpOH l-C"-l,2-I80 ropylidenea-D-xyloRranoee

&HIOH 1-c14D-Xylose

The over-all yield of l-C14-~-xylosefrom l-C'*-~-glucose is approximately 60 percent.

V. C-NITRODESOXY SUGARSAND C-NITRODESOXY INOSITOLS A clever application of the aldehyde-nitroparaffin condensation reaction was employed by Grosheintz and Fischer!' to effect the cyclization of sugar derivatives to inositol derivatives. Actually, the two (50) J. 0. Lampen, H. Geet and J. C. Sowden, J . Bact., 61, 97 (1951). p . ( 5 1 ) J. M. Grosheints and H. 0. L. Fiacher, J . Am. Chem. Soc., 70, 1476, 1479 (1948).

NITROMETHANE AND %NITROETHANOL SYNTHESES

31 1

carbonyl functions of a five-carbon sugar dhldehyde were condensed successively with the same molecule of nitromethane to produce a mixture of cyclic six-carbon nitrodesoxy inositols. The stepwise condensation of the dialdehyde with one molecule of nitromethane was made possible by the blocking of one of the carbonyl functions during the initial condensation with the nitroparaffin. with lead Glycol cleavage of 1,2-isopropylidene-~-g~ucofuranose tetraacetate6z gives 1,2-isopropylidene-5-aldo-~-xylofuranose.This acetonated dialdehyde is noteworthy in that it retains asymmetry only by virtue of the isopropylidene substitution. Removal of the substituent would give xylaric dialdehyde, a meso compound. Condensation of the aldehydo function of the acetonated dialdehyde with nitromethane gave a urancrystalline mixture of 1,2-isopropylidene-6-nitro-6-desoxy-~-glucof uranose : ose and 1,2-isopropylidene-6-nitro-6-desoxy-~-idof

1,2-Isopro ylidene-5aldo-n-xyfof uranose

1,2-Isopro ylidene-6nitro-6-8esoxy-~glucofuranose

l,2-hopro ylidene-6nitro-6-&soxy-~idofuranose

These isomeric acetonated nitrodesoxy sugars could not be separated by fractional crystallization but a selective re-acetonation of the mixture gave mainly the di-isopropylidene derivative of the nitrodesoxy-L-idose, which then could be separated readily from the unchanged mono-isopropylidene nitrodesoxy-D-glucose. Hydrolysis of the isopropylidene substituents with dilute acid then gave, respectively, &nitro-6-desoxy-I,idose and 6-nitro-6-desoxy-~-glucose. When either of the unsubstituted nitrodesoxy sugars was treated with mild alkali, intramolecular condensation of the carbonyl and nitromethylene functions occurred to give a complex mixture of opticallyinactive nitrodesoxy i n o s i t ~ l s . ~ The ' ~ ~ ~ring closure in each instance might be expected to give four diastereoisomers, since two new asymmetric centers are produced, at carbons one and six. However, the (52) K. Iwadare, Bull. Chem. SOC.Japan, 16, 40 (1941). (63) B. Iselin and H. 0. L. Fischer, J . Am. Chem. Soc., 70, 3946 (1948).

312

JOHN C. SOWDEN

actual situation is probably even more complex because of the reversibility of the aldehyde-nitromethylene condensation. In the alkaline condensation reaction mixture, reversible ring-opening of the nitrodesoxy inositols may be expected between carbons five and six, as well as between carbons one and six, resulting in randomization of the original configuration of carbon five:

/"I

OH 1

/

CHO

H / H

/

I

HOH 1\

\

I\/

6)HNOi

/

\

\I

l/6

11

6-Ni tro-6-desoxy-~-glucose

I

HOH 1\

/'2

\ \

\

OH

H

/"I / H

/' s!\ HO \ OH

~

~

a

CHO 6

\'4 Isomeric Nitrodesoxy-inositols

6

17

1 CHO

H /

CHzNOz /6

61/

HO 6-Nitro-6desoxy-1.Adose

Thus, either of the nitrodesoxy sugars may be expected to give a mixture containing any of eight possible diastereoisomeric nitrodesoxy inositols. Actually, three individual nitrodesoxy inositols were isolated, and all three were obtained from the cyclization of either 6-nitro-6desoxy-D-glucose or 6-nitro-6-desoxy-~-idose. It is remarkable that the nitrodesoxy inositols, when subjected to the conditions of the Nef reaction in the hope of obtaining inososes, did not react and were recovered ~nchanged.~3 The cyclic nature of the nitrodesoxy inositols was demonstrated by the quantitative transformation of their pentaacetates to diacetyl-5nitroresorcinol when treated with warm pyridine. Such ready aromatiration is typical of the inositols and their derivatives.

~

~

z

NITROMETHANE AND

%NITROETHANOL

SYNTHESES

313

VI. THE ACETYLATED CARBOHYDRATE C-NITROOLEFINS 1. Preparation

a. From Carbohydrate C-Nitroa1cohols.-The carbohydrate C-nitroalcohols undergo smooth acetylation with acetic anhydride containing a trace of sulfuric acid. The resulting polyacetates contain the grouping -CHOAc.CHZNOz and consequently form nitroolefins when treated with a mild base (Schmidt and Rutz reactionz2). The acetylated nitroolefins are formed in excellent yield and usually are obtained readily in crystalline condition. CHzNO2

a

H d H

b

HO H

CHzNOz

CHNOz

AcObH -+

b

AH

AcO H

b

AcO H 4

HboH

HAOAc

HAOAc

HbOH

H bOAc

HLOAc

bH,OH I-Nitro-1desoxy-Dmannitol

LH20Ac l-Nitro-1desoxyD-mannitol pentaacetate

I

CHZOAC u-aroboTetraacetoxy1-nitrohexene-1

Experimental Delails.6'-Three grams of 1-nitro-1-desoxy-D-mannitol was acetylated on the steam bath for one-half hour with 20 cc. of acetic anhydride containing one drop of sulfuric acid to give 5.26 g. (88%) of the crystalline pentaacetate. After recrystallization from a mixture of ether and petroleum ether, the product melted a t 88-89" and showed [a]: 37.8" in absolute chloroform, c 7.3. Neither pyridine nor sodium acetate was found to be satisfactory for catalysis of the acetylation, both yielding dark colored sirups. One gram of I-nitro-1-desoxy-D-mannitol pentaacetate in 20 cc. of dry benzene was refluxed for two and one-half hours with 1 g. of sodium bicarbonate. The mixture was cooled, filtered and concentrated to dryness. The resulting residue, on recrystallization from a mixture of ether and petroleum ether, yielded 0.74 g. (86%) of the acetylated nitroolefin. D-arabo-Tetraacetoxy-1-nitrohexene-1melts a t 115-1 16" and shows 32.4" in absolute chloroform, c 5.2.

In similar fashion, 6-nitro-6-desoxysorbitol gives 87 percent of the acetylated nitroolefin, L-xylo-tetraacetoxy-1-nitrohexene-1,without purification of the intermediate, sirupy nitroalcohol p e n t a a ~ e t a t e . ~1-Nitro~ 1-desoxy-D-arabitol t e t r a a ~ e t a t egives, ~ ~ in the Schmidt and Rutz reaction, 81 percent of D-erythro-triacetoxy-1-nitropentene-1; 1-nitro-1desoxy-D-manno-D-gala-heptitol h e x a a ~ e t a t esimilarly ~~ gives 90 percent of D-manno-pentaacetoxy-1-nitroheptene-1. (54) J. C. Sowden and H. 0. L. Fischer, J. A m . Chem. SOC.,69, 1048 (194i); J. C. Sowden, U. S. Pat. 2,530,342 (1950).

3 14

JOHN C. SOWDEN

b. From Aldose Sugars.-The preparation of an acetylated carbohydrate C-nitroolefin frequently can be accomplished conveniently, without the isolation of intermediates, by condensing the related next-lower aldose sugar with nitromethane and then applying the Schmidt and Ruts reaction to the acetylated crude mixture of nitroalcohols. It will be noted that, while the condensation of nitromethane with any individual aldose produces two epimeric carbohydrate C-nitroalcohols, the latter in turn give the same nitroolefin, since the formation of the double bond destroys the asymmetry of carbon atom 2 of the nitroalcohols. Indeed, it has at times been possible to obtain the single acetylated nitroolefin in pure, crystalline condition when the separation and purification of the two intermediate nitroalcohols or their polyacetates could not be realized. CHO

b

HO H bH oH

L20H

1 ]:$I CHzNOa

+

zkz

HobH

HboH bH,OH

D-Xylose

CHNOz

and

+

HAOH hHZOH

AH c ko rhA c

H b oAc bHzOAc D-sybTetraacetoxy-1nitrohexene-1

Experimental Details."-A suspension of 10 g. of D-xylose in 50 cc. of absolute methanol and 50 cc. of nitromethane was shaken for twenty hours with 75 cc. of methanol containing 2.1 g. of sodium. Ethyl ether (60 cc.) was then added and the precipitated sodium aci-nitroalcohols filtered and washed successively with cold methanol, ether and petroleum ether. The resulting powder was dissolved in 100 cc. of water and the solution passed immediately over a cation-exchange resin. Concentration of the sodium-free effluent a t reduced pressure and thorough drying over phosphorus pentoxide yielded a light yellow sirup. The mixed, sirupy nitroalcohols were acetylated on the steam-bath for one hour with 120 cc. of acetic anhydride containing one drop of sulfuric acid. After separation and thorough drying, the crude, sirupy acetates were refluxed in benzene solution (250 cc.) with 20 g. of sodium bicarbonate for two and one-half hours. Filtration followed by concentration then yielded a partly crystalline residue. Recrystallization from absolute ethanol gave 8.45 g. (35%) of D-sylo-tetraacetoxy-1-nitrohexene-1,m. p. 115-116" and [a];*10.2" in absolute chloroform.

Acetylated nitroolefins have been prepared in similar fashion from D-erythroselB0D-arabinose, D-ribose and D-glucose. The ease with which the acetylated nitroolefins usually crystallize is exemplified by the experience with =glucose. Here, the product, D-gluco-pentaacetoxy-lnitroheptene-1, was obtained in the crystalline state from a sirupy mixture containing approximately twenty times the nitroolefin's weight of other acetylated carbohydrate material, formed from the original

NITROMETHANE AND

%NITROETHANOL

SYNTHESES

315

D-glucose, the bulk of the latter having failed to condense with the nitromethane. 2. The 2-Desoxy Aldose Synthesis The acetylated carbohydrate C-nitroolefins, having an olefinic double bond conjugated to the nitro group, should undergo many of the interesting reactions already known for the simpler aliphatic nitroolefins. lo Currently, their most useful reaction sequence gives rise to the 2-desoxy aldose sugars. This transformation is made possible by the selective hydrogenation of the olefinic double bond in the presence of the nitro group. The resulting acetylated 1,2-didesoxy-1-nitroalcoholthen can be converted, by de-acetylation followed by the Nef reaction, t o the corresponding 2-desoxy aldose sugar. CHNOz AH HboAc

[ ] CHzNOi

-,

HbOAc bHlOAc D-erythroTriacetoxy1-nitropentene-1

CHO AH,

HbOAc

--+HAOH

H:~ic

HboH

AIIIOAC AH2OH l-Nitro-l,2~-erylhro-!& didesoxy-DDesoxy-pentose erythro-pentitol (“ 2-Desoxytriacetate D-ribose”)66

Experimental Delails.aOSa1-A solution of 2.2 g. of D-erythro-triacetoxy-1-nitropentene-1 (m. p. 63-65”, prepared in 44% yield from sirupy D-erythrose without the isolation of intermediates) in 50 cc. of absolute ethanol was shaken with hydrogen a t room temperature and atmospheric pressure in the presence of 0.2 g. of freshly prepared palladium black.66 The hydrogenation was interrupted after twenty minutes when 1.05 mole-equivalents of hydrogen had been absorbed and the rate had become slow. The sirup obtained after filtration and concentration was stirred with a mixture of 40 cc. of 1 N sodium hydroxide solution and 10 cc. of ethanol. After the sirup had dissolved, the solution was added dropwise to a stirred mixture of 5 cc. of sulfuric acid and 7.5 cc. of water a t 0’. The reaction mixture was then diluted with ice-water and neutralized by stirring with solid barium carbonate. After filtration, a few drops of glacial acetic acid were added to the filtrate and it was concentrated a t reduced pressure to a sirup. The sirup was taken up in a small volume of 75% ethanol and 1.5 cc. of a-benzyl-a-phenylhydrazine added. Slow evaporation of this solution then gave 1.4 g. (59 %) of ~-erythro-2-desoxypentosebenzylphenylhydrazone.6’ After recrystalliaation from aqueous ethanol, the pure hydrazone melted a t 127-128” and showed [a];’- 17.7” in pyridine, c 2. Cleavage of the hydrazone with benzaldehyde as described by Meisenheimer and Jungs* gave D-erythro-Zdesoxypentose (“2-desoxy-~-ribose”), in 82 % yield (55) (56) (57) (58)

Cf. J. C. Sowden, J. Am. Chem. Soc., 60, 1047 (1947) for nomenclature. J. Tausz and N. von Putnoky, Ber., 62, 1673 (1919). P. A. Levene and T. Mori, J. Biol. Chem., 88, 803 (1929). J. Meisenheimer and H. Jung, Ber., 60, 1462 (1927).

316

J O H N C. SOWDEN

as a colorless sirup showing [a]$- 50” in water, c, 1. After standing several days in a desiccator, the sugar crystallized spontaneously. After recrystallization from a few drops of isopropyl alcohol, the desoxy pentose melted a t 83-85’ and showed [a];’ - 56” in water, c, 1. Mutarotation was not detected.

The synthesis of ~-erythro-2-desoxypentose from D-erythrose via the nitromethane condensation and the acetylated nitroolefin also has been reported, however in extremely low yield, by Overend, Stacey and Wiggins.6g The D-erythrose used in this instance was obtained by a Ruff type degradation of calcium D-arabonate. The intermediate nitroolefin, D-erythro-triacetoxy-l-nitropentene-1,apparently was not obtained in pure form. No attempt was made to hydrogenate selectively the olefinic double bond but, rather, the hydrogenation, carried out in methanol, was allowed to continue until no further absorption of hydrogen occurred. Finally, the Nef reaction, giving rise to the acid-labile desoxy pentose, was conducted at room temperature. The recorded yield of ~-erythro-2-desoxypentose, isolated via the anilide, was only 0.5 percent, based on n-erythrose. The selective hydrogenation of the olefinic double bond in the acetylated carbohydrate C-nitroolefins, using palladium black as catalyst, depends to a marked degree on the solvent employed. I n absolute ethanol a sharp decrease in the rate of hydrogen absorption usually occurs when the double bond has been saturated. This decrease in rate is not sharply defined in 95 percent ethanol and is not detectable when absolute ethyl acetate is employed as the hydrogenation solvent. In the six-carbon serieslb4 the selective hydrogenation of D-arabotetraacetoxy-l-nitrohexene-1 gave crystalline l-nitro-l,2-didesoxy-~arabo-hexitol tetraacetate in 79 percent yield. This product, on de-acetylation followed by the Nef reaction, then gave ~-arabo-2-desoxyhexose ( “ ~ - ~ ~ s o x ~ - D - ~ ~ u cisolated o s ~ ” ) , as the benzylphenylhydrazone,sO in high yield. VII. THE !&NITROETHANOLSYNTHESIS OF HIGHER-CARBON KETOSES When the conditions of the nitromethane-aldose condensation reaction, with the exception that nitromethane was replaced by 2-nitroethanol, were applied to D-arabinoSelB1the condensation reaction proceeded normally with rapid solution of the pentose followed by precipitation of the amorphous sodium aci-nitroalcohols. No attempt was made to isolate and separate the four isomeric nitroalcohols t o be expected from the removal of sodium from these salts but, rather, they were sub(59) W.G.Overend, M. Stacey and L. F. Wiggins, J . Chem. SOC.,1358 (1949). (60) M. Bergmann and H. Schotte, Ber., 64,440 (1921). (61)J. C. Sowden, J . Am. Chem. SOC.,72, 3325 (1950).

NITROMETHANE AND

%NITROETHANOL

8YNTHESES

317

jected directly t o the Nef reaction. From the crude product thus obtained, unchanged aldose sugar was removed by oxidation with bromine followed by de-ionization with appropriate ion-exchange resins. The resulting mixture of ketose sugars was fractionated readily by crystallization, in a combined yield of 23 percent, into nearly equal amounts of D-mannoheptulose and D-glucoheptulose.

D-Mannolieptulose

D-Glucoheptulose

Thus, the 2-nitroethanol synthesis results in the addition of two carbon atoms t o an aldose sugar to produce two higher-carbon ketose sugars epimeric a t carbon 3. While the synthesis is general in nature, the two ketoses produced from any one aldose are seldom as readily separable as is fortunately the case with D-mannoheptulose and D-glUC0heptulose. However, the newly developed techniques of adsorption and partition chromatography will undoubtedly be of service for the more difficult separations. A word of caution regarding the preparation of 2-nitroethanol for the above synthesis is in order. When 2-nitroethanol is produced by the condensation of nitromethane and formaldehyde, it is accompanied by large amounts of higher-boiling by-products and its separation from these by distillation is attended b y some hazard of explosion. As emphasized by Gorski and Makarov, l 3 the alkaline condensation reaction mixture should be made definitely acidic before fractionation is attempted. Moreover, all the usual explosion precautions should be observed during the actual distillation of the product. Two recent syntheses of 2-nitroethanol, one from barium nitrite and ethylene oxide,62 the other from nitrogen dioxide and ethylene have been reported and may circumvent much of the danger of this preparation. It will be noted th at not only are higher-carbon aldose sugars and ketose sugars available through the nitromethane and 2-nitroethanol (62) Tanabe Chemical Industries Co., Japanese Pat. 156,256 (1943), cj. Chem. Abstracts, 44, 2008 (1950). (63) G . Darzens, Compt. rend., 229, 1148 (1949).

318

JOHN C. SOWDEN

syntheses, respectively, but other interesting sugar structures should be available by suitable modifications of the aldose-nitroparaffin condensation in combination with the Nef reaction. Thus, aldose-nitroacetic acid condensations should lead via the Nef reaction to analogs of ascorbic acid while aldose-nitroethane condensations would make available the 1-desoxy-2-ketose sugars.

ERRATA VOLUME 3 Page 100, first paragraph. Supporting references are B. Helferich and M. Vock, Ber., 74, 1807 (1941) and B. Helferich and A. Gniichtel, German Pat. 710, 129 (1941). B. Helferich. VOLUME 4 Page 229, eighth entry in table. The compound melting a t 174-176" has been shown by E. J. Bourne and W. F. Wiggins [J.Chem. SOC.,1933 (1948)l to be! triethylidene-D-mannitol, of 1.11"~ - 72.3' in chloroform. Rolland Lohmar. Page 229, eighth entry from bottom of table. Delete the m. p. 195196' and the rotation +5.6'; they apply to a higher substituted benzylidene acetal and to an incompletely purified sample, respectively (reference 76). Rolland Lohmar. Page 249, reference 22. Change volume number from 63 t o 73. J. K. N. Jones and F. Smith. Page 273, reference 104. For authors read P. A. Levene and L. C. Kreider. J. K. N. Jones and F. Smith.

319

This Page Intentionally Left Blank

Cumulative Subject Index for Vols. I-V A -, methyl-n-butyl-, from glutose, 111, 118, 123 Acetal, reaction with Br, 111, 167 -, trichloro-, starch estcr, I, 301 Acetaldehyde, effect on ketonuria, 11, Acetoacetaldehyde, phytochemical reduc148 tion of, IV, 85 as intermediate in fat formation, 11, Acetoacetic acid, 11, 145 123 effect of D-glucose on ketonuria from, reduction of, IV, 77 11, 152 -, chloro-, 11, 109, 110, 113 ethyl ester, labelled with Cla, 111, 232 -, methylethyl-, phytochemical reduclabelled with isotopic C, 111,247,248 tion of, IV, 80, 106 oxidation of, 11, 147; 111, 249 -, thio-, phytochemical reduction of, phytochemical reduction of, IV, 85 IV, 93 Acetobacter pasteurianum, cellulose formaAcetaldol, IV, 117 tion by, 11, 206 phytochemical reduction of, IV, 81 Acetobacter rancens, cellulose formation Acetals, of carbohydrates, 111, 97 by, 11, 206 cyclic, 111, 51 Acetobacter suboxydans, I, 17; V, 7 herni-, in cellulose, 111, 191 Acetobacter xylinum, cellulose formation of hexitols, IV, 223 by, 11, 206 Acetic acid, as acetonation catalyst with Acetoin, IV, 86 zinc chloride, 111, 51 Acetoisovanillone, IV, 64 glacial, for laboratory crystallization Acetol, 111, 127 of B-glucopyranose, V, 136 phytochemical reduction of, IV, 80,84 as intermediate in fat formation, 11, from sucrose, IV, 299 124 Acetolysis, of starch, I, 287 as intermediate in fat oxidation and Acetonation, of meso-inositol, 111, 50 carbohydrate formation, 11, 129 -, selective, 111, 54 labelled with C13, 111, 236, 245 Acetone, I, 145 labelled with CI4, 111, 236 from carbohydrates, IV, 109 labelled with isotopic C, 111, 231, 232, reaction with Br, 111, 168 238, 249 reaction with inosine, I, 206 oxidation of, 111, 249 reaction with uridine, I, 210 reduction of, 111, 108, 109 from sucrose, IV, 322, 323 as solvent for sugars, I, 24 Acetone, acetyl-. See 2,CPentanedione. from sucrose, IV, 322 Acetone, allyl-, phytochemical reduction from wood saccharification, IV, 177, of, IV, 92 183 -, benzyl-, IV, 92 -, cellulose ester. See Cellulose acetate. -, benzylidene-, phytochemical reduc-, starch ester. See Starch acetate. tion of, IV, 92 -, chloro-, anhydride, effect on esterifica- -, bromo-, 111, 168 tion of cellulose, I, 319 -, a,a-dichloro-, phytochemical reducstarch ester, I, 301 tion of, IV, 81 -, dichloro-, starch ester, I, 301 -, dihydroxy-, 111, 53, 166 32 I

322

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Acetone-soluble fats, from lipids of M. tUberCdOSi8, 111, 326, 327 Acetophenone, phytochemical reduction of, IV, 83 Acetophenone ketazine, hydrogenation of, 111, 40 Acetyl bromide, in acetylation of starch, I, 288 Acetyl chloride, in acetylation of starch, I, 288 8-N-Acetyl glucosaminidaae, V, 61 Acetyl phosphate, 111, 237 Acetyl propionyl. See 2,bPropanedione. Acetyl value, determination of, for starch acetates, I, 290 Acetylation, of cellulose, I, 311 rates for various cellulosic fibers, V, 122, 123 of starch, I, 284-290 of xylan, V, 286 Acetylene, 11, 109, 110, 112 -, divinyl-, dichlorohydrin, 11, 109, 110, 113 -, divinyl-, dioxide, 11, 110, 112, 113 Acids, hydroxy, synthesis of, I, 2 -, 2-keto, preparation of, 11, 84 -, 2-keto-3,4dihydroxy1 lactonization and enolization of, 11, 83, 87 Aconitic acid, IV, 326 cis-Aconitic acid, labelled with isotopic C, 111, 241, 242, 249 trans-Aconitic acid, 111, 73 Acridine, 9-hydrazino-, streptomycin hydrazone from, 111, 379 Acrolein, 11, 115, 116 dichloride, 11, 115, 116 hydrogenation of, 11, 108, 109 a-Acrose, IV, 27 Actidione, 111, 344 Actinomyces griseus. See Streptomyces griseus. Actinomyces lauendulae. See Streptomyces lauendulae. Actinomycetes, levan formed by, 11, 228; 111, 338 Activated carbon, use in manufacture of dextrose, V, 140, 143 Activity factor, for antibiotic production, 111, 341 Acyl migration, I, 109, 113

Acylation, tritylation and, 111, 90 of polyuronides, I, 334 Adenine, from desoxyribosenucleic acid, I, 237 from molasses, IV, 336 from nucleic acids, I, 195 from ribosenucleic acid, I, 198, 200 Adenine, desoxyribosyl-, I, 240 -, phosphodesoxyribosylnucleo&de, I, 241 -, 9’- (bphospho-D-ribofuranosy1)-. See Adenylic acid from ribosenucleic acid. -, 9’-(5-phospho-D-ribofuranosyl)-. See Adenylic acid, muscle. -, 9-8-D-ribofuranosyl-, v, 74 -, 9’-(5-tritylribofuranosyl)-6’-iV-trityl-, I, 205 -, 7’-(5-trityl-~-ribofuranosyl)-,111, 110 Adenine glycoside, I, 141 Adenosine, V, 74 from ribosenucleic acid, I, 198, 200 spectrum and structure of, I, 202, 204 Adenosine, 2,bdiacetyl-, I, 205, 206 -, diacetylditosyl-, I, 206 -, diacetylditrityl-, I, 205, 206 -, N,6-diphospho-2,3-isopropylidene-,I, 213 -, ditrityl-, I, 205, 206 -, isopropylidene-, I, 207 -, bphospho-, I, 217 -, bphospho-. See Adenylic acid, muscle. -, trimethyl-N-methyl-, I, 203, 204 -, 5’-triphosphate (ATP). See Adenylic acid, muscle. -, tritosyl-, I, 205, 206 -, 5trityl-, I, 205, 206 Adenylic acid, I, 196 boric acid complex of muscle, I, 213 muscle, I, 212, 213; V, (ATP) 49, 50, 73, 74 from ribose nucleic acid, I, 214, 217 Adhesives, dextrin, I, 274 starch xanthates as, I, 307 Adipic acid, IV, 316; V, 288 Adipo-cellulose, V, 104 Adonitol, I, 10, 180; 11, 86, 115, 117 effect on conductivity of boric acid, IV, 191

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

323

r.-Adonose, 11, 86 Aldehydes, phytochemical reduction of, L-Adonoside, methyl, 11, 86 IV, 77-81 -, methyl 3,4-isopropylidene-, 11, 86, reaction with hexitols, IV, 223 87 Aldehydes, hydroxy, 11, 89 Adrenalin. See Epinephrin. Aldobionic acids, 11, 175; 111, 132 Adsorption, of iodine by starch, I, 256 Aldobiuronic acid, in hemicellulose of molecular configuration and, I, 277 English oak, V , 280 by starch, I, 252, 255 Aldofuranose, 111, 130 Adynerin, I, 148, 171 Aldohexoses, 111, 4 Aerobacler aeroqenes, in fermentation of Aldonic acids, 111, 130, 133, 157 wood sugars, IV, 184 keto, 111, 131, 147, 148, 155 Aerobacter lmanicum, levan formed by, oxidation of, 11, 85 11, 228 preparation of, 111, 141, 161 Agar-agar, IV, 275, 278 Ruff degradation of, 111, 149 Agglutinins, IV, 37, 38 Aldonic acid nitriles, acylated, IV, 119Agglutinogens, IV, 37, 38, 41 151 Aircraft fabrics, cellulose ester coatings Aldonic l,Clactone, 111, 131 for, I, 324 Aldonic 1,5-lactone, 111, 130 Alanine, IV, 101 Aldonic lactones, from aldonic phenyl-, phenyl-, in blood group substances, hydrazides, I, 22 Aldopentofuranose, 2-(N-methyl-a-~-gluIV, 49 labelled with (314, 111, 233 copyranosaminido)-bC-formyl-5(destro)-Alanine, N-acetyl-, V , 11 desoxy-, meao(3,5-diguanidino-2,4,6configuration, V , 11 trihydroxycyclohexyl) a-glycoside. o,lrAlanine, metabolism of, 111, 229, See Streptomycin. 247 Aldopyranose, 111, 130 Albumin, 11, 194 Aldose alkyl orthoesters, I, 113, 121 Alcohols, biochemical production from Aldose orthoacyl halide, I, 118 carboxylic acids, IV, 108, 109 Aldoses, 111, 11, 130 effect on aqueous leaching of starch, I, degradation of, I, 254 263 oxidation of, 111, 133, 140, 147, 151. hexahydric, ethylene oxide derivatives 154, 157, 162, 181 of, V , 218 structure of, 111, 152 starch precipitation by, I, 258, 263 Aldoximes, nitriles from, IV, 120 -, polyhydric, bacterial cellulose from, Alfalfa, V, 93, 95, 96 11, 207 Algae, marine, presence of xylan in, V , oxidation of, 111, 132, 150, 166 270 -, sugar, configuration of, I, 1-36 Alginic acid, 11, 176, 237; 111, 146 identification of higher-C, I, 34 hydrolysis of, I, 336 metabolism of, I, 175-192 structure of, I, 342 oxidation of, 111, 132, 150, 166 Alhagi manna. See under Manna. from sugars by reduction with Raney Alkali cellulose, 11, 282; V , 113 Ni, I, 24 Alkali lability, of starch, I, 253, 267 tritylation of, 111, 85 Alkali number, of starch, I, 254 -, unsaturated, hexitols and pentitols Alkalies, reaction with osazones, 111, 40 from, 11, 107 reaction with sugars, 111, 113 Alcoholysis, of trityl ethers, 111, 81 reaction with trityl ethers, 111, 84 Aldehyde content, of starch, I, 276 Alkylation, of carbohydrates, 111, 96 Aldehyde group, in starch molecule, I, Allitol, I, 36, 64, 65, 181; 11, 109, 111, 112, 114; 111, xx, 4, 114; IV, 216,217 253

324

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

hexaacetate, 11, 114 Allosaccharic acid, 2,5-anhydro-, calcium oxidation of, IV, 226 salt, 11, 74 physical properties of, IV, 219 DAllo(?)saccharic acid, 2,5-anhydro-, -, 1,6-diacetyl-2,4: 3,5-dimethylene-, IV, and calcium salt, 11, 74 (possibly 241 D-talo-). -, 1,4: 3,6-dianhydro, stereochemical u-Allose, I, 10, 37, 39, 65 model of, V, 215 phenylosazone, I, 72 -, dibenzylidene-, 11, 112; IV, 241 reduction of, IV, 217 -, 2,4: 3,5-dimethylene-, IV, 241 -, 3,6-anhydro-, phenylosaeone, 11, 77 -, 2,4 :3,5-dimethylene-1 ,bdilauroyl-, -, 3,6-anhydro-2-methyl-, 11, 77 IV, 241 -, 2-desoxy-, V, 20 -, 2,4: 3,5-dimethylene-l,B-ditosyl-, IV, -, 2,6-didesoxy-. See Digitoxose. 241 -, %rnethyl-2,6-didesoxy-. See CymaD-Allitol, 2-desoxy-, V, 6 rose. L-Alloascorbic acid, I, 64,65; 11,83,96 L-Allose, I, 42 Allodulcitol. See Allitol. phenylosazone, I, 72 19-D-Allofuranoside, methyl 2,Sanhydro- D,L-Allose, phenylosazone, I , 72 5,6-dibenzoyl-, 11, 71 D-Alloside, methyl 2,3-anhydro-beneyli-, methyl 2,3-anhydro-5,6-ditosyl,11, dene-, 11, 50 71 -, methyl 2,3-anhydro-dimethyl-, 11, -, methyl 2,3-anhydro-5-tosyl-6-ben49 ~ o y l - 11, , 71 -, methyl 3,4anhydro-dimethyl-, 11, 50 D-Allofuranoside, methyl 2,3-isopropyl- L-Allosone, I, 64 idene-6-desoxy-, 11, 55 Allulose and derivatives. See Psicose D-Alloheptulose, I, 48 and derivatives. Allolactose, 111, 95 Almond gum, IV, 246 D-Allomethylose, 2-desoxy-. See Digi- D-Altritol, 1,4 :3,6-dianhydro-, stereotoxose. chemical model of, V, 215 Allomucic acid, I, 37, 39; 111, 49, 50, 58 D-Altrofuranose, 1,2,5,6(?)-diisopropyliD-Allonic acid, I, 38, 39 dene-, I, 72 p-Allono-ylactone, I, 38 D-Altro-D-gluco-heptitol. See 8-SedohepAllonucleic acid, I, 196 titol. cY-D-Allopyranoside, methyl 2,3-anhydro- D-Altro-D-manno-heptitol. See Vole4,6-benzylidene-, I, 55, 57; 11, 71; mitol. v , 20 D-Altro-D-fructo-heptose. See Sedo-, methyl 2,3-anhydro-4,6-dimethyl-, heptulose. 11, 71 D-Altroheptose phenylosotriazole, 111, 38 -, methyl 2,3-anhydro-4,6-ethylidene, n-Altroheptulose. See Sedoheptulose. 11, 71 D-Altromethylose, specific rotation of, I, -, methyl 2-desoxy-, V, 20, 27 155 -, methyl %methyl-, V, 20, 27 -, 2-desoxy-. See Digitoxose. 8-D-Allopyranoside, methyl 2,3-anhydro-, -, 2-methyl-, I, 62, 63, 64, 153, 154 11, 53, 71 specific rotation of, I, 155 -, methyl 2,3-anhydro-4,6-benzylidene, L-Altromethylose, I, 62 11, 71 and phenylosaeone, I, 161, 162 -, methyl 2,3-anhydro-4,6-dimethyl-, D-Altronic acid, I, 38, 39, 73 11, 71 brucine salt, I, 73 -, methyl 3,4-anhydro-, 11, 53 and calcium salt, I, 67, 68, 70, 73 -, methyl 3,4-anhydro-2,6-dimethyl-, sodium salt, I, 73 11, 48, 72 D-Altronic acid, 5-keto-, I, 69

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

325

o-Altronic acid lactonc. See D-Altrono- -, methyl 2,3-ditosyl-4,6-dimethyl-, 74 lactone. -, methyl Z-hydraein0-4,6-benzylidene-, L-Altronic acid, I, 73 I, 74 brucine salt, I, 73 -, methyl 3-hydrazino-4,6-benzylidene-, calcium salt, I, 73 I, 75 L-Altronic acid lactone. See cAltrono- -, methyl 2-methyl-, I, 62, 74, 154 lactone. -, methyl 3-methyl-, I, 75 D-Altronic acid 1,5-lactone, 3,4,6-tri- -, methyl 2-methyl-3,6-anhydro-, I, 74 methyl-, I, 73 -, methyl 2-methyl-3-benzoyl-4,bbenD-Altronic phenylhydrazide, I, 73 zylidene-, I, 74 L-Altronic phenylhydrazide, I, 73 -, methyl 2-methyl-4,6-benzylidene-, I, D-Altronolactone, I, 73 74 L-Altronolactone, I, 73 -, methyl 3-methyl-4,6-benzylidene-, T, D-Altrosan. See 8-D-Altropyranose, 1,675 anhydro-. -, methyl Z-methyl-6-desoxy-, I, 63, 74 -, 2,3,4-triacetyl-, I, 53 -, methyl 2-methyl-3,4diacetyl-, I, 74 ol-D-Altropyranoside, methyl, I, 54,56,74 -, methyl 2-methyl-3,4-diacetyl-6-iodo8-D-Altropyranose, 1,6-anhydro-, I, 44, B-d-oxy-, I, 63, 74, 154 45, 50, 52, 56, 72; 11, 65, 70 -, methyl 2-methyl-3,4-di-, 1,6-anhydro-3-amino-, HClsalt, I I , 7 0 acetyl-6-trityl-, I, 62, 63, 74, 154 -, 1,6-anhydro-2,3,4-triacetyl-, I, 53,72; -, methyl 2-methyl-6-iodo-6-desoxy-, I, 11, 70 154 ru-D-Altropyranoside, methyl, I, 54, 56, 74 -, methyl 2-methyl-3-methylthio-4,6-, methyl Z-acetamino-3-acetyl-, I, 74 benzylidene-, V, 27 -, methyl 2-acetamino-3-acetyl-4,6-ben- -, methyl 2-methyl-3-tosyl-, I, 74 zylidene-, I, 74 -, methyl 2-methyl-6-tosyl-, I, 154 -, methyl 2-acetamino-3,4,5-triacetyl-, -, methyl 2-methyl-3-tosyl-4-acetyl-6I, 74 trityl-, I, 74 -, methyl 2-acetyl-3-acetamino-, I, 74 -, methyl 2-methyl-3-tosyl-4,6-benzyli-, methyl 2-acetyl-3-acetamino-4,6-bendene-, I, 74 zylidene-, I, 74 -, methyl 2-methyl-3-tosyl-4,6-diben-, methyl 2-amino-, and hydrochloride, zoyl-, I, 74 I, 74 -, methyl 2-methylthio-4,6-benzyli-, methyl 2-amino-4,6-benzylidene-, hydene-, V, 20 drochloride, I, 74 3-methylthio-4,bbenzyli-, methyl 3-amino-4,6-benzylidene-, I, -, methyl dene-, V, 27 61 -, methyl 2-methylthio-3-methy1-4,6hydrochloride, I, 75 benzylidene-, V, 20, 27 -, methyl 3,6-anhydro-2,4dimethyl-, -, methyl 2,3,4,6-tetraacetyl-, I, 53, 74 I, 75; 11, 77 -, methyl 3,6-anhydro-2-methyl-, 11, 77 -, methyl 2,3,4,6-tetramethyl-, I, 75 -, methyl 2,4,6-triacetyl-3-acetamino-, -, methyl 4,6-benzylidene-, I, 56, 75 I, 75 -, methyl 2,3-dimethyl-, I, 74 -, methyl 2,4,6-trimethyl-, I, 75 -, methyl 4,6-dimethyl-, I, 54, 75 -, methyl 4,6-dimethyl-3-acetamido-, j3-n-Altropyranoside methyl, I, 75 -, methyl 3,4-anhydro-2,6-dimethyl-, I, 11, 168 75; 11, 72 -, methyl 2,3-dimethyl-4,6-benzylidene-, -, methyl 3-acetamino-, I, 75 I, 74 -, methyl 2,3-ditosyl-4,6-benzylidene-, -, methyl 3-acetamino-4,6-dimethyl-, I, 75 I, 74

326

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

-,

methyl 3-amino-, I, 58, 59, 60 acetate, I, 75 hydrobromide, I, 75 hydrochloride, I, 75 possible identity with “methyl epiglucosamine,” I, 61 -, methyl 4,&benzylidene-, I, 75 -, methyl 4,6dimethyl-, I, 76 -, methyl 2-methyl-4,6-benzylidene-, I, 75 -, methyl 2,3,4,&tetraacetyl-, I, 53, 75 -, methyl 2,3,4,&tetramethyl-, I, 75 -, methyl 2,4,6-triacetyl-3-acetamino-, I, 75 -, methyl 2,4,6-trimethyl-, I, 75 -, methyl 3,4,&trimethyl-, I, 75 -, methyl 2,4,6trimethyl-3-acetamino-, I, 61, 75 D-Altrose, I, 2, 10, 38, 39, 45, 56 benzylphenylhydrazone, I, 72 dibenzyl mercaptal, I, 72 formation of anhydride by acids, I, 44 from its dibenzyl mercaptal, I, 43 from methyl a-D-glucopyranoside, I, 54 origin of name, I, 38 oxime, I, 72; IV, 122 phenylosazone, I, 72 -, phenylosotriazole from, 111, 38 -, 3-amino-, I, 60; 11, 65 phenylosazone, I, 73 -, 1,6-anhydro-3-amino-, hydrochloride, I, 72 -, 6-desoxy-2-methyl-, I, 62, 63, 64, 72 -, 2,8didesoxy-. See Digitoxose. -, 4-(p-D-glucopyranosyl)-. See Celtrobiose. -, 3-methyl-, phenylosazone, I, 73 -, 2-methyl-3,6-anhydro-, I, 72 -, 2,3,4,64etramethyl-, I, 73 -, 2,4,6trimethyl-, I, 73 -, 3,4,64rimethyl-, I, 73 a-D-Altrose, 4,6-dimethyl-, and phenylosazone, I, 73 -, 1,2,3,4,6-~entaacetyl-,I, 53, 72 p-D-Altrose, I, 72 -, 1,2,3,4,&pentaacetyl-, I, 53 -, 2,3,4,&tetraacetyl-, I, 53, 73 cAltrose, I, 42, 72 reduction of. IV. 217 benzylphenylhydraeone, I, 72 I

,

dibenzyl mercaptal, I, 43, 72 phenylosazone, I, 72 -, 6-desoxy-, I, 62, 72 p-bromophenylhydrazone, I, 72, 75 phenylhydrazone, I, 72 phenylosazone, I, 72 D,L-Altrose, phenylosazone, I, 72 Altrose group of substances, I, 37-76 D-Altroside, methyl isopropylideneanhydro-, I, 71 D-Altruronic acid, I, 67, 68 Aluminum chloride, in orthoacyl chloride formation, I, 119 reaction with cellobiose octaacetate, I, 44 reaction with glucopyranose pentaacetate, I, 46 reaction with lactose octaacetate, I, 40-43 reaction with maltose octaacetate, I, 82 in rearrangement of sugar acetates, I, 40-46 Amadori rearrangement, 111, 42, 43 Amide rule of rotation, I, 21, 163 Amides, of sugar acids, oxidation of, 111, 165 tritylated, 111, 105 Amines, tritylated, 111, 105 Amino acid amides, in cane juice, 111, 124 Amino acids, biosynthesis of, IV, 101 in blood group substances, IV, 49 in cane juice, 111, 124 effect on ketonuria, 11, 148 labelled with C14, 111, 233 Amino group, effect on oxidation by halogens, 111, 145 Amino sugars, 11, 49, 167, 221. See also individual sugar amines, such as Glucosamine. in polysaccharides of M. tuberculosis, 111, 333, 334 Amy1 alcohol, IV, 78 as starch precipitant, I, 259 tert-Amy1 alcohol, as starch precipitant, I, 259 Ammonia, in cane juice, 111, 124 Ammonium compounds, p-D-glucopyranosyltrimethyl-bromide, 111, 86

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

327

6-trityl-~-~-g~ucopyranosyltrimethyl--, salivary, 111,276 bromide, 111,86, 107 action on arrow-root starch, 111, 299, Amygdalin, V,60 300 Amylase, crystalline beta, of sweet glycogen and starch hydrolysis by, 111, 278 potato, V, 234 -, crystalline pancreatic alpha, V, 235, phosphatase activity of, 111,305 -, Taka, action on starch, 111,295 236, 241 -, crystalline salivary alpha, V,265 phosphatase activity of, 111,305 Amylases, action on starch, I, 276; 111, Amyloamylose, I,250 Amylobiose, 111,308 252, 301 Amylocellulose, I,252 starch conversion by, I,269,270 Amylopectin. See also “B-fraction’’ U I L starch fractionation by, I,252 der Starch. -, a-,111,262;V,229-268 Amylopectin, I, 250; 111, 256; V, 106, action on starch, 111,307 231, 245,246 phosphatase activity of, 305 purification by differential inactiva&amylase action on, 111, 268 chain length in, 111,260 tion, V,234,256 constitution (calculated) of, 111,268 -, of Bacillus macerans, action on cyclocycloamyloses from, 111,306 amyloses, 111,305 methylation of, I,268 action on starch, 111,306 the term, I,280 -, bacterial, action on starch, 111,301 Amylopectin, phosphate, I, 305 -, 8-, 111,216,268;V,231-235,268 Amylopectin triacetate, films and plastics action on 8-dextrin, 111,286 of, I, 300 action on starch, 111,307 viscosity and osmotic pressure of, I, glycogen and starch hydrolysis by, 111,

278 phosphataae activity of, 111,305 purification by differential inactivation, V,234,256 -, dextrinogenic, 111,262 -, endo and exo, 111, 301 -, malt, action on starch, 111,287 phosphatase activity of, 111,305 -, malt a-,111,269 action on amylose, 111,271, 281, 282 action on arrow-root starch, 111,280 action on barley starch, 111,281 action on corn starch, 111,279 action on 8-dextrin, 111,281, 282,285, 286 action on glycogen, 111,287 action on potato starch, 111,274 glycogen and starch hydrolysis by, 111, 278 -, pancreatic, action on potato starch, 111,298, 300 phosphatase activity of, 111,305 -, saccharogenic, 111,261

294,295 Amylophosphatase, 111,270 Amylose. See also “A fraction l 1 under Starch. Amylose, I, 250; 111, 256; V, 231, 241, 245,246,263 cycloamyloses from, 111,306 a-dextrins from, 111,284 malt a-amylase action on, 111, 271, 281,282 methylation of, I, 268 phosphoric acid in, 111,303 saccharification of, 111,263,264 the term, I,280 a-Amylose, I,250 8-Amylose, I,250 Amylose triacetate, films of, I,297, 298, 299 plastics of, I,300 viscosity and osmotic pressure of, I, 294,295 Anaesthetics, local, IV, 314 Analgesics, IV,313 As-Androstenediol, IV,93 A1-Androstene-3,i7-dione, IV,93

328

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

A4-Androstenedione, IV, 93 As-Androstenedione, IV, 93 A’-Androstene-17-01-3-one, IV, 93 &Angelica lactone, IV, 312 Anhydrides, of disaccharide osazones, 111, 36 of hydrazones and osazones, 111, 31 of osazones, 111, 31 of pentitols and hexitols, V, 191-228 Anhydro-. For anhydro- derivatives see inverted entries under the name of the parent compound, e.g., P-D-Mtropyranose, 1,6-anhydro-. Anhydro ring formation, by transexchange, 11, 43 inversion of configuration, 11, 45 mechanism of, 11, 41 Anhydro ring scission, by acids, 11, 49 by alkali, 11, 47 Anhydro sugars, 11, 37-77; 111, 101 classification of, 11, 40 of ethylene oxide type, 11, 47-56 of glycosan type, 11, 64-66 of hydrofuranol type, 11, 56-64 as intermediates in interconversion of configurational isomers, 11, 51 in synthesis, 11, 67 Aniline, IV, $18 -, m-nitro-, IV, 99 Animal gum, 11, 185 Animal sinistrin, 11, 191 Animal tissues, carbohydrate synthesis in, 111, 243 carbon dioxide rassimilation in, 111, 238 Anomerization, 111, 98 h o m e r s , 111, 1, 15 Ansolvo acid, as catalyst for acetonations, 111, 51 l14,9,10-Anthradiquinone,phytochemical reduction of, IV, 90 Anthraquinone, IV, 89 Anthrax, polysaccharide formation by bacillus of, 11, 223 Antiarol, 111, 64 Antibiotic activity, 111, 338, 342 Antifreeze, 2,a-butylene glycol, IV, 328 glycols from sucrose, IV, 301 sodium levulinate, IV, 310

Antigenic properties, of blood group substances, IV, 52 Antigens, 11, 199; IV, 37, 39 artificial, from blood group substances, IV, 53 bacterial somatic, 11, 166 dextrans as, 11, 214 Forsmann, 11, 166, 199; IV, 41, 50, 53 pneumococcus polysaccharide as, 11, 221 Wassermann’s, 11, 166 Antiketogenesis, 11, 120, 126, 146, 149, 156. 158 Antiketogenic, 11, 146 Antipyretics, IV, 313 Apigenin, IV, 58, 59, 61, 62 7-Apigenin apiofuranosyl-pu-glucopyranoside, IV, 73 7-Apigenin 8-D-glucopyranoside, IV, 66, 68, 72, 73, 74 Apiin, IV, 58, 59, 61, 70, 72, 73 Apiinibiose, IV, 73, 74 Apionic acid, IV, 68, 69, 70, 71 optical rotation of, IV, 72 aldehydo-D-Apiose, discussion of configurational formula of, 111, 21 Apiose, IV, 57-74 a-benzyl-a-phenylhydrazone, IV, 69, 70 p-bromophenylosazone and phenylosazone, IV, 68 “Apioseglucosephoroglucin,” IV, 74 Apozymase, IV, 103 Apple wood, L-arabinose and u-xylose in hemicellulose of, V, 279 optical rotation of xylan from, V, 282 hpples, pectin-esterases in, V, 85, 99 Araban, I, 342; 11, 237, 238, 239, 245248, 251; IV, 262 Arabic acid, IV, 250 Arabic gum, IV, 246, 250 L-Arabinal, 3,5-diaeetyl, bromination of, 111, 169 bArabinodesose, 111, 144 L-Arabinofuranoside, methyl 2,3,5-trimethyl-, V, 281, 283 L-Arabinopyranose, 3-(a-~-glucopyranOsyl)-, V, 43, 46, 71, 72 a-D-Arabinopyranoside, 2’-naphthyl 1thio, triacetate, V, 14, 27

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

8-L-Arabinopyranoside, phenyl, V, 66, 67 a-o-Arabinopyranoside, phenyl 1-thio-, triacetate, V, 14, 27 8-D-Arabinopyranosyl bromide, 2,3,4triacetyl-, V, 23 Arabinose, origin of early D and L classification of, 111, 10, 12 n-Arahinose, I, 2; IV, 144, 146; V, 8 from calcium D-gluconate, 111, 149 diphenylhydrazone of, IV, 142, 143 from firmly bound liped of M . tuberculosis, 111, 329 from Mycobactariri m tuberculosis polysaccharides, 111, 316, 317, 318, 333, 334, 335 phenylosotriazole from, 111, 38 specific rotation of, I, 155 from tuberculin polysaccharides, I1 I, 322, 323 from waxes of M . tuberculosis lipids, 111, 328 -, diethyl thioacetal, tetraacetate, V, 7, 26 -, 3-(fi-~-galactopyranosyl)-,IV, 148 henzylphenylhydrazone, IV, 142 -, 5-(~~-galactopyranosyl)-, IV, 148 -, I-(D-glucopyranosy1)-, ( 1 ) IV, 148 heptaacetate (?), IV, 148 -, 2-(~-glucopyranosyl)-, IV, 148 hrptaacetate, IV, 148 -, 3-(a-~-glucopyranosyl)-, 11, 25; I V , 148 phenylosazone, 11, 25 -, 3-(~-~-glncopyranosyl)-, 111, 194; I V , 147 heptaacetate, IV, 147 oxime, IV, 147 -, 2-methyl-, specific rotation of, I, 155 1,-Arabinose, I, 3; 11, 239, 240; IV, 144, 204 from araban, 11, 245 a-benzyl-a-phenylhydrazone, V, 279 enzymatic reaction with a-o-glucose-lphosphate, V, 43 in gums, IV, 245, 246, 250, 253, 256, 258, 259, 261 ( 1 interaction with boric acid, IV, 204 in mucilages, IV, 268, 270, 274, 275 oxidation of, 111, 176, 180 from pectins, 11, 236

329

in polyuronides, I, 338 phenylosazone anhydride, 111, 31 phenylosotriazole from, 111, 38 -, diethyl thioacetal, tetraacetate, V, 7, 26 -, 2-desoxy-, I, 239; 111,144 -, 5-desoxy-, IV, 146 -, 1,2: 3,4-diisopropylidene-, IV, 205 -, 2,3-dimcthyl-, 11, 246; IV, 254 -, 2,4-dimethyl-, IV, 248; V, 44 -, 2,5-dimethyl-, IV, 251, 257 -, 3,5-dimethyl-, IV, 259 phenylosazone, IV, 284 -, 3-(~-galactopyranosyl)-,IV, 250 -, ditrityl, 111, 85 -, ditrityldiacetyl-, 111, 109 -, ditrityldibenzoyl-, 111, 109 -, methyl-, 11, 247 -, 2-methyl-, methyl 8-glycoside and its hydrate, IV, 284 -, 3-methyl-, I, 246 phenylosazone, IV, 284 -, 2-methyl-3,4-isopropylidene-, IV, 284 -, 2,3,4-triacetyl-5-trityl-,diethyl mercaptal, 111, 109 -, 2,3,4-tribenzoyl-5-trityl-,diethyl mercaptal, 111, 109 -, 2,3,5-trimethyl, IV, 251, 254, 257, 259 o,L-Arabinose phenylosotriazole, 111, 38 L-Arabinose anilide, 2,3-dimethyl-, IV 284 -, 3-methyl-, IV, 284 D-kabinose diacetamide, IV, 130, 146, 151 -, 5-benzoyl-, IV, 146 -, tetraacetyl-, IV, 151 L-Arabinose diacetamide, IV, 133 -, 5-desoxy-, IV, 145, 151 D-Arabinose dibenzamide, IV, 131 -, 5-benzoyl-, IV, 151 -, triacetyl-5-benzoyl-, IV, 151 r>-Arabinose dibenzamide, 5-desoxy-, IV, 131, 146, 151 -, triacetyl-5-desoxy-, IV, 151 -, tribenzoyl-5-desoxy-, IV, 151 D-Arabinose dipropionamide, IV, 146,151 -, tetraacetyl-, IV, 151 D-Arabinose oxime, IV, 122 L-Arabinose oxime, IV, 124 -, tetraacetyl-, IV, 124

330

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Arabinosecarboxylic acid, I, 3, 4 Arabinoside. See also Arabinofuranoside and Arabinopyranoside. L-Arabinoside, methyl 2,bdimethyl-, 11, 245 -, methyl monomethyl-, 11, 245 L-Arabinosylamine, N-methyl-, 111, 354, 382 Arabitol, effect on conductivity of boric acid, IV, 191 D-Arabitol, I, 180 configuration, V, 8 -, 1,5-anhydro-, V, 14, 23, 27, 221, 222, 225 2,3,4triacetate, V, 225 2,3,4tribenzoate, V, 225 -, 1-desoxy, tetraacetate, V, 7, 26 L-Arabitol, I, 180 -, 1-desoxy-, tetraacetate, V, 7, 26 -, 1,5-ditrityl-, 111, 111 D,L-habitol, 11, 115, 117 pentaacetate, 11, 117, 118 D-Araboascorbic acid, 11, 87, 95, 98 -, 2,3-dimethyl-, 11, 98;lOO -, 2-methyl-, 11, 100 -, 3-methyl-, 11, 98 -, 2,3,5-trimethyl-, 11, 100 -, 2,3,5-trimethyl-6-trityl-, 11, 100 L-Araboascorbic acid, 11, 83, 96 L-Arabofuranose, 2,3-dimethyl-, 11, 246 -, 2,3,btrimethyl-, 11, 246 a-L-Arabofuranose, 11, 240 n-habofuranoside, methyl 3,5-dimethyl-, 111, 331 L-Arabofuranoside,methyl trimethyl-, 11, 245 L-Araboketose, enzymatic reaction with a-D-glucose-1-phosphate, V, 41 L-Araboketoside, a-D-glucopyranosyl-, V, 35, 41 L-Arabonamide, 2,bdimethyl-, 11, 246; IV, 284 -, 2,4dimethyl-, IV, 284 -, 2,54imethyl-, IV, 284 -, 3,5-dimethyl-, IV, 284 -, 3-methyl-, IV, 284 -, 2,3,4-trimethyl-, IV, 284 -, 2,3,5-trimethyl-; 111, 165; IV, 284 D-Arabomethylose, and p-bromophenylhydrazone and phenylosazone, I, 162

L-Arabomethylose, and pbromopheilylhydrazone and phenylosazone, 1,162 D-Arabonic acid, 111, 144, 163 from sucrose, IV, 298 -, 3,4,btrimethyl-, 11, 97 L-Arabonic acid, 111, 144, 152 -, 2-desoxy-, 111, 144 -, 2,4dimethyl-, and lactone, V, 45 -, 2,bdimethyl-, phenylhydrazide, IV, 284 D-habonk lactone, trimethyl-, IV, 14 L-Arabonic lactone, 6-desoxy-, 111, 144 -, 2,3-dimethyl-, 11, 246; IV, 284 -, 2,S-dimethyl-, IV, 284 -, 3,bdimethyl-, IV, 284 -, 3-methyl-, IV, 284 -, 2,3,4-trimethyl-, 111, 146 -, 2,3,5-trimethyl-, IV, 284 D-Arabononitrile, heptaacetyl-3-(8-~galactopyranosy1)-, IV, 148, 150 -, heptaacetyl-2-(~-glucopyranosyl)-, IV, 148 -, heptaacetyl-3-(a-~-glucopyranosyl)-, IV, 148 -, heptaacetyl-3-(~-~-giucopyranosyl)-, IV, 147 -, heptaacetyl-2-(~-glucosyl)-,Iv, 150 -, tetraacetyl-, IV, 126, 144, 149 L-Arabononitrile, tetraacetyl-, IV, 140, 144, 149 a-chabopyranose, structural formula of, 11, 240 L-Arabopyranose, 2,3-dimethyl-, 11, 246 GArabopyranosyl bromide, triacetyl-, 111, 95 Arlitan, 111, xviii; V, 194, 226 Aromatization, of inosose esters, 111, 64, 65 of streptamine, 111, 350 Arsenic acid, hexitol complexes of, IV. 225 Artichoke tubers, inulin from, 11, 254 L-Ascorbicacid.(Vitamin C ) , I, 71; II,79, 88; 111, 164; IV, 128 amino derivatives, 11, 92, 94 use of D-galacturonic acid in synthesis of, v, 102 -, 2-desoxy-, 11, 93 -, 6-desoxy-, 11, 92, 95 -, trityl-, 111, 108

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

D-Ascorbic acid, synthesis of, IV, 128 Ascorbic acid analogs, 11, 79-106 nomenclature of, 11, 82 physiological activity of, 11, 94 structure of, 11, 97 synthesis of, 11, 79 Asparagine, 111, 125, 126 Asparagosin, 11, 260, 273 Aspartic acid, in blood group substances,

IV, 49 LAspartic acid, IV, 101 Aspen, pentoean content, V, 27 Aspergillus niger, emulsis, V, 63 xylanase enzyme from, V, 288 Aspergillus oryzae, amylase of, V, 250255, 265

Aspergillus aydowi. levan produced by,

11, 226 Asphodelin, 11, 260, 273 Asymmetric carbon atom, Van’t HoffLe Be1 theory, I, 2, 4, 18; 111, 2-9 ATP. See Adenylic acid, muscle. Avocado, heptose (D-mannoheptulose) from, I, 12 Azobenzene, IV, 98 -, p-amino-, IV, 100 -, 2,4diamino-, IV, 100 -, p-dimethylamino-, IV, 100 Azotobacter, polysaccbaridee of, 11, 165, 189

Azdobacter chroococcum, polysaccharide formation by, IV, 220 Aaoxybenzene, IV, 98 -, m-dinitro-, IV, 99

B Bacillus delbrueki, emulsins, V, 63 Bacillue krzemieniewski, polysaccharide formation by, 11, 220 Bacillus levaniformans, levan formed by, 11, 226 Bacillus macerana, action on starch, I, 269 amylase of, V, 266 Bacillus megatherium, levan formed by, 11, 227 Bacillus mesentericus, levan formed by, 11, 226, 228 Bacillus polymyza, levan formed by, 11, 228

33 1

Bacillus shigae, antigens, 11, 166 Bacillus subtilis, V, 48 amylase of, V, 265 effect on polysaccharides in potato plant, 11, 228 levan formed by, 11, 226, 228 Bacillua typhimurium, antigens, 11, 166, 200

Bacillus typhosum, antigens, 11, 166, 200 Bacillus vulgatus, levan formed by, 11,226 Bacteria, carbon dioxide assimilation by,

111, 235 phytochemical reduction by, IV, 106 Bacterial amylases, V, 265 Bacterial cellulose. See under Cellulose. Bacterial polysaccharides. See under Polysaccharides. Bacteriological culture media, dulcitol, mannitol and sorbitol in, I, 192 Bacterium amylobacter, in fermentation of wood sugars, IV, 184 Bacterium dysenteriae, antigens, 11, 199 Bacterium xylinoides, cellulose formation by, 11, 206 Bacterium xylinum, cellulose formation by, 11, 206 Bagasse, IV, 295 tarabinose and D-xylose in hemicellulose of sugar cane, V, 279 Banana starch. See under Starch. Barium acid heparinate, 111, 146 Barium 2-desoxy-~-gluconate, 111, 144 Barium D-gluconate, 111, 144 Barium hypobromite, 111, 163 Barium salts, in preparation of aldonic acids with NaCN, I, 23 Bark, tree, pentosan content, V, 271 Barley, alpha amylase of malted, V, 255-

-,

265

beta amylase of ungerminated, V, 231-234

Barley shoots, sucrose formation in, V, 34 “Bastose,” V, 104 Beechwood, tarabinose in xylan from, V,

-,

279

pentosan content of, V, 271 Beechwood xylan, V, 285 Beer, made with dextran, IV, 333 Beets, hexose phosphates. in, V, 33 -, pectinic acids of, V, 83

332

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Bentonite, use in manufacture of dextrose, V, 139, 142 Benzaldehyde, enzymatic formation from amygdalin, V, 60 -, phytochemical reduction of, IV, 79 -, dibenzyl thioacetal, V, 4 -, o-nitro-, phytochemical reduction of, IV, 80 Benzene, lJ2-dihydroxy-, effect on conductivity of boric acid, IV, 191 -, lJ3-dihydroxy-. See Resorcinol. -, 1,4dihydroxy-. See Hydroquinone. -, 1-hydroxy-2,3,5-tribenzoxy-,111, 64, ’ 65 -, 2-hydroxy-1,3,5-tribenzoxy-,111, 65 -, nitro-, phytochemical reduction of, IV, 98 -, nitroso-, IV, 98 -, 1,2,3,5-tetraacetoxy-, 111,64 -, lJ2,3-trihydroxy-, effect on conductivity of boric acid, IV, 191 -, 1,2,4trihydroxy-, effect on conductivity of boric acid, IV, 191 -, lJ3,5-trihydroxy-. See Phloroglucinol. Benzene hexahalides, hydrolysis of, 111, 58 Benzenesulfonic acid, 3,4.-dichloro-, starch ester, I, 303 -, p-(2-hydroxy-l-naphthylazo)-,streptamine salt, 111, 348 Benzil, phenylosazone, hydrogenation of , 111, 40 -, phytochemical reduction of, IV, 87 Benzilic acid, effect on conductivity of boric acid, IV, 195 Benzimidazole, 2-(~-aho-pentahydroxyamy1)-, I, 73 Benzimidazole derivatives, 111, 161 Benzimidazole rule of rotation, I, 21 1,bBenl;odioxan, 8,8’-methylenebis (6* nitro-), 111, xvii Benzoic acid, cellulose esters, I, 320 labelled with isotopic C, 111, 231 starch esters, I, 302, 303 -, 2,4.dihydroxy-, effect on’conductivity of boric acid, IV, 195 -, 2,4,5-trihydroxy-, effect on conductivity of bopic acid, IV, 195 -, 3,4,5trihydroxy-. See Gallic acid.

Benzoin, IV, 87 Benzoquinone, oxime, IV, 101 -, phytochemical reduction of, IV, 89 o-Benzoquinone, tetrabromo-, IV, 89 p-Benzoquinone, tetrahydroxy-, 111, 48 Benzoxazole, 5-acetamido-2-methyl-, 111, 351 Benzyl alcohol, as starch precipitant, I, 259 S-Benzylthiuronium salts, I, 168, 171 Bertrands’s rule, IV, 226 Betabacterium vermiforme, polysaccharide formation by, 11, 219 Betitol, 111, 69 Bibenzyl, from benzaldehyde dibenzyl thioacetal, V, 4 Biochemical reductions, a t expense of sugars, IV, 75-117 Biochemical syntheses, in sucrose series, IV, 31 Biolase, source of a crystalline alpha amylase, V, 265 Bios I, identity with meso-inositol, 111, 47 Biosan, 111, 200 “Biosyn,” from wood sugars, IV, 186 Biotin, IV, 97 Birectifier, IV, 78 Bis(diacetoneg1ucosg)disulfide, I, 143 Bleaching powder, 111, 139 Bleibtreu’s equation for conversion of Dglucose to palmitic acid, 11, 121 Blood groups, IV, 37, 38 Blood group polysaccharides, IV, 37-

65 Blood group specific substances, 11, 164, 186 Blood group substances, amino acids in, IV, 49 -, antigenic properties of, IV, 52 -, artificial antigens from, IV, 53 -, destruction by enzymes, IV, 55 -, from erythrocytes, IV, 41, 46 -, from gastric juice, IV, 43, 46, 48 -, from hog stomach, IV, 53 -, from hog stomach, hog much and pepsin, IV, 43, 46, 48 -, from ovarian cyst fluids, IV, 44, 46 -, from peptone, IV, 43, 46 -, properties and chemistry of, IV, 45

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

-, -, -,

from saliva, IV, 45, 46 sources of, IV, 42 from urine, IV, 42, 46 Blood proteins, IV, 37 Blood transfusion, IV, 37, 38, 54 Borates, of hexitols, IV, 220 Boric acid, complex with muscle adenylic acid, I, 213 -, in determination of configuration of carbohydrat$s, IV, 189-210 -, hexitol complexes, IV, 224 d-Borneol, trityl ether, 111, 86 Borneo1 D-glucuronoside, 111, 146 dl-Borneol, as starch precipitant, I, 259 Borneolcarboxylic acid, cis- and trans-, effect on conductivity of boric acid, IV, 195 Bornesitol, 111, 46 Bourguel's catalyst, 11, 109, 110, 113 Bread staling, I, 273 Bromate, 111, 138 Bromine, as oxidant, 111, 145, 169 solubility of, 111, 136 Bromine oxidation, mechanism of, 111, 152 Bromine water, 111, 133, 140, 150 p-Bromophenylhydrazine, in identification of uronic acids, I, 339 Brucella melitensis, antigens, 11, 166, 200 Brucellosis, 111, 339 Brucine D-altronate, I, 73 Brucine Iraltronate, I, 73 Brucine salts, 111, 143, 144, 164 -, with iironic acids, I, 339 Buffered solutions, carbohydrate oxidation in, 111, 151 Butadiene, 2,3-dimethyl-, IV, 323 1,a-Butanediol, IV, 85 2,bButanediol. See 2,3-Butylene glycol. I-Butanol, 2-ethyl-, as starch precipitant, I, 259 I-Butanol, 2-methyl-, IV, 78 as starch precipitant, I, 259 4-Butanol, 2-methyl-, IV, 78 2-Butanone, 3-hydroxy-, benzoate, bromination of, 111, 168 3-Butanone, 1-hydroxy-, phytochemical reduction of, IV, 85 3-Butene-1-01, phytochemical reduction of, IV, 106-

333

Butterfat, effect of lactose on metabolism of, 11, 160 feeding experiments with, 11, 134 Butyl alcohol, IV, 91, 106 from butyric acid, IV, 108 from carbohydrates, IV, 109 leaching of starch with, I, 263 as starch precipitant, I, 258, 259, 263 from sucrose, IV, 322, 323 from wood sugarq, IV, 182 sec-Butyl alcohol, as starch precipitant, I, 259 Butyl mercaptan, IV, 95 2,a-Butylene glycol, IV, 86, 106 from sucrose, IV, 322, 328 from wood sugars, IV, 184 Butyraldehyde, phytochemical reduction of, IV, 78 -, a-methyl-, phytochemical reduction of, IV, 80 -, thio-, IV, 95 -, a,a,fl-triohloro-, phytochemical reduction of, IV, 81 Butyramide, hydroxydimethoxy-, IV, 13, 14 Butyric acid, from carbohydrates, IV, 107 from glycerol, IV, 110 as intermediate in fat oxidation and carbohydrate formation, 11, 130 labelled with C'a, 111, 245 labelled with C14, 111, 237 labelled with isotopic C, 111, 231, 247 metabolism of, 11, 152 reduction of, IV, 108 from sucrose, IV, 322, 324 from wood sugars, IV, 183 -, cellulose esters, I, 310, 317, 322, 324. 326 --, starch ester, I, 301 -, dimethoxyhydroxy-, and methyl ester, IV, 13, 14 -, 8-hydroxy-, 11, 139, 145, 151, 152, 154, 157; IV, 85, 116 -, fl-hydroxy-r,r,r-trichloro-,effect on conductivity of boric acid, IV, 195 -, trihydroxy-, 111, 131, 148, 149 yButyrobetainelJV, 107

334

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

C

Cadmium D-galactonate, 111, 142, 143 Cadmium D-ribonate, 111, 144 Cadmium D-xylonate, cadmium bromide. double salt, 111, 152 Calcium caltronate, I, 73 Calcium D-arabonate, 111, 144 Calcium carabonate, 111, 144 Calcium boro-gluconate, IV, 331 Calcium D-galactonate, 111, 143, 151, 155 Calcium cgalactonate, I, 70 Calcium D-gluconate, 111, 141, 142, 149, 152, 155, 156, 161; IV, 331 Calcium hypochlorite, 111, 165 Calcium %keto-D-gluconate, 111,148, 155 Calcium 5-keto-D-gluconate,111, 156 Calcium lactobionate, calcium bromide double salt, 111, 155 Calcium levulinate, IV, 311 Calcium maltobionate, 111, 161 Calcium D-mannonate, 111, 152 Calcium pectate, I, 334 Calcium brhamnonate, 111, 144 Calcium salts, in preparation of aldonic acids with NaCN, I, 23 Calcium vicianobionate, 111, 154 Calcium D-xylonate, 111, 155 Camphor, optically active, formed from inactive (racemic) camphor carboxylic acid in the presence of quinine, quinidine or nicotine, V, 53 Camphor carboxylic acid. See Camphor. Camphor, 3-hydroxy-, IV, 89 Camphorquinone, pliytochemical reduction of, IV, 89 Canna starch. See under Starch. Capric acid, as glycogenic agent, 11, 134 Caproaldehyde, phytochemical reduction of, IV, 78 Caproic acid, aa glycogenic agent, 11, 134 labelled with isotopic C, 111, 231 -, deuterio-, metabolism of, 11, 152 Caprylic acid, as glycogenic agent, 11,134 labelled with isotopic C, 111, 231 metaboliam of, 11, 152 Carbamic acid, N-phenyl. See Carbanilic acid. Carbanilic acid, cellulose esters, I, 321

Carbanilic acid, thio-, phenyl ester glucoside, I, 133 Carbinol, acetylfuryl-, phytochemical reduction of, IV, 91 -, acetylmethyl-, 111, 127; IV, 86 phytochemical reduction of, IV, 106 from sucrose, IV, 322, 328 -, sec-butyl-, IV, 78 -, divinyl-, 11, 118 -, isobutyl-, IV, 78 -, methylbenzoyl-, phytochemical reduction of, IV, 87 -, phenylacetyl-, IV, 87 -, propionylmethyl-, IV, 88 Carbohydrases, V, 59 Carbohydrate chemisorption, V, 56 Carbohydrate derivatives, formation from thio-carbohydrates through reductive desulfurization by Raney nickel, V, 1-28 Carbohydrates, enzyme specificity in the domain of, V, 49-78 enzymatic syntheeis of, 11, 205 from fat, 11, 125-145 from fat in plants, 11, 144 from fatty acids, 11, 128, 129 forces of attraction to enzymes, V, 55 metabolism of, 11, 119-160 oxidation of, relation to ketosis, 11, 145-159 protein complexes with, 11, 162 sulfuric acid esters of, 11, 178 transformation to fat, 11, 120-125 union:of enzyme and substrate, V, 54, 56 Carbon dioxide, assimilation in animal t k u e s , 111, 238 assimilation in microorganisms, 111, 235 assimilation in plants, 111, 233 labelled with C~1,111,232,233,238,239 labelled with C**,111, 235 labelled with 0 4 , 111, 236 Carbon iaotope CIS, 11, 124 Carbon isotopes, in carbohydrate metaboliam, 111, 230 Carbon monoxide, labelled with isotopic C, 111, 233 Carbon tetrachloride, as solvent for acetylation of cellulose, I, 314

.

CUMU+4TIVE SUBJECT INDEX FOR VOLS. I-V

Carbonium cation, 11, 41, 42 Carbonium ion, in orthoester formation, I, 115 Carbonyl compounds, reduction of, 111, 355

Carboxyl groups, in cellulose, 111. 192. 210

Cardiac glycosides, I, 147-173 Cardiolipin, 11, 166, 198 Carlic acid, 11, 99 Carnitin, IV, 107 Carragheen mucilage, IV, 275, 277 Carvone, IV, 92 Cascara, pentosan content, V, 271 Catabolism, fat, 11, 150, 151 Catalase, theory of action on ethyl hydroperoxide, V, 53 Catalysis, enzyme-substrate and intermediate compound theory in homoand heterogeneous, V, 51 Catalysts, for acetonation, 111, 51 for acetylation of starch, I, 284, 286 Bourguel’s, 11, 109, 110, 113 for esterification of cellulose, I, 312 in oxidation of carbohydrates by halogens, 111, 177 Raney nickel for reductive desulfurization, V, 3 ultraviolet light as oxidation, 111, 162, 177

Catechol, boric acid complex, IV, 194 effect on conductivity of boric acid, IV, 191

Cationogen, the term, 11, 42 Cattle food, from bagasse, IV, 296 molasses as, IV, 334 from sugar beet pulp, IV, 297 Cedar bark, Western Red, pentosan content of, V, 271 Cellobial, 11, 67 hexaacetate, 111, 195 -, 2-hydroxy-, heptaacetate, V, 16 Cellobiitol, 1,5anhydro-, heptaacetste, V, 2, 27 Cellobionic acid, 111, 161 Cellobiononitrile, octaacetyl-, IV, 147, 150

Cellobiose, 11, 67; 111, 193, 198; IV, 147 AlCl, rearrangement of octaacetate, I, 46

335

constitution and configuration of, 111, 95

effect on ketonuria, 11, 148 hydrolysis by 8-glucosidase, V, 61 hydrolysis rate of, 111, 197 molecular rotation of, 111, 200 octaacetate, 111, 194, 195 phenylosazone anhydride, 111, 31, 36 phenylosazone, reaction with .KOH, 111, 40 phenylosotriazole, 111, 38 synthesis of, 111, 85 Cellobiose, acetobromo-, 111, 95 -, octamethyl-, 111, 194 a-Cellobiose, octaacetate, 111, 377 8-Cellobiose, octaacetate, 111, 377 Cellobiose oxime, nonaacetyl-, IV, 147, 150

Cellobiose, thio-, I, 136 8-Cellobiosedieenide, methyl, 111, 104 8-Cellobioside, methyl, 111, 91, 104 -, methyl 6,6‘-diiodo-6,6’-didesoxy-, pentaacetate, 111, 98, 99 -, methyl 6,6’-ditosyl-, pentaacetate, 111, 98, 99 -, methyl 6,6’-ditrityl-, 111, 98, 99, 111 pentaacetate, 111, 98, 99, 111 -, methyl heptaacetyl-, 111, 95, 193,

-, -, -,

377

methyl heptamethyl-, 111, 194 methyl pentaacetyl-, 111, 98, 99 phenyl 1-thio-, heptaacetate, V, 2, 27

a-Cellobiosyl chloride, heptaacetate, 111, 377

Cellobiuronic acid, 11, 175 Cellohexaose, IV, 160 Cellopentaose, 111, 195, 198, 200 Cellotetraose, 111, 195, 198, 199,200; IV, 160

Cellotetraoside, methyl tridecamethyl-, 111, 196 Cellotriose, 111, 195, 197, 198, 200; IV, 160

@-Cellotrioside,methyl decamethyl-, 111, 196

Cellular reaction, of lipid fraction of M. tuberculosis, 111, 330 Cellulosans, 111, 187; V, 270 separation from polyuronides, I, 334

336

CUMULATIVE SUBJECT INDEX FOR VOI+S. I-V

Cellulose, a,8, and y, I, 311; 111, 188;V, 275 alkali, 11, 282 bacterial, 11, 206-209 bacterial, early studies of, 11, 206 bacterial, industrial importance of, 11, 209 bacterial, structure of, 11, 207 bacterial, X-ray and electron microscope investigations of, 11, 208 from bagasse, IV, 296 constitution of, 111, 185-228 crystalline, X-ray diffractions, V, 106 crystallites and non-crystalline, V, 107 definition of, 111, 186 mercerized, V, 110, 113, 116, 119, 126 origin and history of name, 111, 186; V, 103 sources of, for ester preparation, I, 310 stable, IV, 162 stable, hydrolysis of, IV, 173 structure of, 11, 283; 111, 185-228; V, 105 Cellulose, carboxyl groups in, 111, 192, 210 -, combination with formaldehyde, V, 126 -, decomposition of hydrolysis products of, IV, 164 -, decomposition by Vibrio perimastriz, v, 122 -, degraded, 111, 205 -, deuterium exchange applied to,V, 122 -, dispersion in quaternary ammonium bases, 11, 286 -, etherification of, 11, 281, 282, 283, 285, 287 -, etherifying agents for, 11, 281, 285 -, 8-D-glucose basic unit of, 111, 189 -, hemiacetal groups of, 111, 191 -, hydrolysis of, IV, 162 -, hydroxyl groups of, 111, 190 -, methods of estimation of crystalline and noncrystalline portions of, V, 109-124 -, methylation of, 111, 207 -, methyl ethers, V, 123 -, mode of linkage of basic units in, 111, 193, 201 -, molecular rotation of, 111, 200, 202

-,

mucoproteins produced from, by Cytophagae, 11, 189 -, non-reducing end groups in, 111, 207, 209 -, polydispersity of, 111, 224 -, polymerization, degree of, 111, 202, 205, 212 -, reducing end groups in, 111, 206, 209 -, regenerated, 11, 281, 285 -, sodium cupri-, 11, 286 Cellulose, benzyl-, 11, 286, 288, 290 polymerization, degree of, 111, 214 -, carboxymethyl-, 11, 293, 294 -, ethyl-, 11, 286, 288, 293 polymerization, degree of, 111,214, 218 -, hydroxyethyl-, 11, 286, 292, 294 -, methyl-, 11, 286, 291, 293 polymerization, degree of, 111, 206, 214,222 -, trityl-, 111, 82, 96, 111 Cellulose acetate, I, 309; 11,280; 111, 190, 226 accessibility of saponified, V, 114 commercial, V, 106, 122 commercial, degree of polymerization, V, 106 crystallinity of saponified, V, 116 deacetylation and etherification of, 11, 286 films of, I, 300 industrial applications, I, 322 manufacture of, I, 311-314 polymerization, degree of, 111, 213 preparation of, I, 289 salt effect on, I, 317 viscosity of solutions of, I, 294 viscosity and strength of, I, 316 Cellulose acetate butyrate, I, 310, 317, 322, 324, 326 Cellulose acetate linoleate, I, 319 Cellulose acetate phthalate, I, 321 Cellulose acetate propionate, I, 310, 317, 322 Cellulose acid phthalate, I, 320 Cellulose acid succinate, I, 320 Cellulose benzoate, I, 320 Cellulose carbamates, N-derivatives, I, 321 Cellulose carbanilate, I, 321 Cellulose crotonate, I, 319

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Cellulose esters, of aromatic acids, I, 320 of dibasic acids, I, 320 of higher aliphatic acids, I, 319 industrial applications, I, 322 mixed, I, 317 of organic acids, I, 309-327 salt effect on, I, 317 of substituted aliphatic acids, I, 319 of sulfonic acids, I, 321 of unsaturated acids, I, 319 Cellulose ethers, 11, 279-294 as intermediates, 11, 294 polymerization of, 11, 287, 289, 291 properties of, 11, 280 raw materials for, 11, 281 viscosity of, 11, 287 Cellulose formate, I, 310 Cellulose glycolic acid. See Cellulose, carboxymethyl-. Cellulose nitrate, I, 325, 326; 11, 280; 111, 190, 213, 218, 225 salt effect on, I, 317 Cellulose sulfonates, I, 321 Cellulose p-toluenesulfonate, I, 321 Cellulose xanthate, 11, 280 Celluloses, acid hydrolysis of, V, 109-120 -, commercial regenerated, degree of polymerization, V, 106 -, crystalline and non-crystalline regions of, V, 109-126 -, esterification and etherification, V, 122-124 -, oxidation by periodate, V, 121 -, relative crystallinity of, V, 103-126 -, swelling and density of, V, 107, 120, 121 Cellulosic fibers, density of, V, 121 Celtrobionic acid, I, 44 Celtrobiose, I, 44 8-glucosidase action on, V, 61 orthoesters of, I, 91 Celtrobiose, hexaacetyl-, 1,2 or 1,6-orthoacetic acid, I, 92, 112 e-Celtrobiose, acetochloro-, I, 44, 76 -, heptaacetyl-, and E t 2 0 compound, I, 76 -, octaacetyl-, two forms, I, 76 crystalline molecular compound with pceltrobiose octaacetate and EtlO, I, 76

337

8-Celtrobiose, monohydrate, I, 76 heptaacetate-, and Et,O compound, I, 76 -, hexaacetyl-, 1,2+rthoacetate(?), I, 76 -, octaacetyl-, two forms, I, 76 monohydrate, I, 76 Cement mortars, sucrose in, IV, 321 Chaulmoograte, ethyl, V, 223 Cheirolin, I, 132 Chelation, in osazone formation, 111, 43 Chemical constitution, physiological activity and, of ascorbic acid analogs, 11, 94 Chemical properties, configuration and, of similar sugars, I, 26 Chemisorption, between enzyme and substrate, V, 56 Cherry gum, I, 343; IV, 246, 256 Chicory, inulin from, 11, 254 Chitaric acid, 11, 61, 63 and calcium and brucine salts, 11, 73 Chitin, 11, 164, 184 Chitobiose, 11, 185 Chitonic acid, 111, 145 Chitosamine, I, 60, 61; 11, 60, 61, 62, 68, 167 Chitosan, 11, 185 Chitose, 11, 39, 60, 62, 63, 73 oxidation of, 111, 145 Chitose, methyl glycoside monohydrate from, 11, 73 Chitotriose, hendecaacetyl-, 11, 185 Chloral hydrate, phytochemical reduction of, IV, 81 Chloramine, as oxidant, 111, 165 Chlorates, 111, 137, 178 Chloric acid, as oxidant, 111, 178 Chlorine, as oxidant, 111, 169, 184 solubility of, 111, 136 Chlorine dioxide, use in delignification, V, 274 Chlorine monoxide, 111, 135 Chlorine water, 111, 136, 150 Chlorites, as oxidants, 111, 179 Chlorohydrins, of divinylacetylene, 11, 109, 110, 113 of divinylglycol, 11, 108 Chlorophyll, 111, 234 Chlorous acid, as oxidant, 111, 179 Cholanic acid, 3-hydroxy-12-keto-, IV, 92

-,

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

338

Cholera, polysaccharide formed by organism of, 11, 222 Cholestenone, labelled with 0 4 , 111, 233 Cholesterol, trityl ether, 111, 86 Cholic acid, phytochemical reduction of,

-,

IV, 92

7-hydroxy-3,12-diketo-, IV, 106 Choline esterase, 11, 166, 196, 197 Cholla gum, IV, 246 Chondroitin, sulfate, 11, 104, 182 Chondrosamine, 11, 167, 169 Chondrosaminide, methyl N-acetyltrimethyl-, 11, 169 Chondrose, 11, 73 Chondrosic acid, and calcium salt, 11, 74

Chondrosine, 11, 183 Chromatin, I, 193 Chromatographic adsorption, of sugars and derivatives, 11, 232 Chromatography, in hexitol analysis, IV, 227

of trityl ethers, 111, 80 of tuberculin, 111, 324 Chrysin, IV, 67 Cinchonine, salts with uronic acids, I, 339

Cinnamic acid, starch ester, I, 303 Cinnamaldehyde, phytochemical reduction of, IV, 79, 91 Cinnamyl alcohol, IV, 91 phytochemical reduction of, IV, 92 Citraconic acid, IV, 327 Citral, phytochemical reduction of, IV, 79

Citric acid, 11, 148; 111, 238, 242, 248 labelled with Cl*, 111, 238 labelled with isotopic C, 111, 241 from molasses, IV, 336 from sucrose, IV, 322, 324 Citric acid cycle, in carbohydrate oxidation, 111, 238 Citrogenaee, 11, 148; 111, 248 Citronellal, phytochemical reduction of,

IV, 79 Citrus nobilis, emulsins, V, 63 Cloetridiztm p a s t k n u m , in fermentation of wood sugars, IV, 184 Clostridium perfringens, polysaccharide formation by, 11, 223

Clostridium welchii, enzymes, effect on blood group eubstances, IV, 56 Coacervation, I, 277 Coatings, cellulose eater, I, 323 Co-carboxylase, 11, 124 Coccidioides immitie, polysaccharide formed by, 11, 226 Cocositol, 111, 60 Coir, xylan peroentage in, V, 271 Collagenase, effect on blood group substances, IV, 55 Colonial Products Research Council, IV, 293 Conduritol, 111, 58, 59, 60, 68 -, dihydro-, 111, 68 -, tetraacetyl-, 111, 60 Configuration, of alcohols (sugar) and higher-C sugars, I, 1-36 amide, benzimidazole, and phenylhydrazide rules of rotation and, I, 21 boric acid in determination of, of carbohydrates, IV, 189-210 determination of, of a-hydroxy acids, I, 71 lactone rule of rotation and, I, 18, 19 and orthoester formation, I, 124 physical and chemical properties and, of similar sugars, I, 26 proof of, in glucose and galactose series, I, 33 Coniferyl aldehyde, phytochemical reduction of, IV, 80 -, methoxymethyl-, phytochemical reduction of, IV, 80 Convallatoxin, I, 148 Copper, removal in manufacture of dextrose, V, 139 Cori ester. See also D-Glucose-1-phoephate. Cori ester, 111, 258, 264; IV, 31 Corn cobs, optical rotation of xylan from, V, 282 pentosan content of, V, 271 as source of D-xylose, V, 279 Corn seedlings, optical rotation of xylan from, V, 282 Corn stalk, pentosan content of, V, 271 Corn starch. See Starch.

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Cotton. See also Cellulose and Cotton linters. Cotton, V, 104-126 low xylan content, V, 271 Cotton linters, 11, 281, 282; V, 106-124 as cellulose source, I, 310 Cottonseed hulls, as source of D-xylose, V, 279 Cozymase, I, 213; IV, 103 Cress seed mucilage, IV, 270 Crotonaldehyde, phytochemical reduction of, IV, 91 Crotonbetaine, IV, 107 Crotonic acid, cellulose ester, I, 319 Crotonic acid, polymer, produced by certain bacilli, IV, 117 Crotonic acid, reduction by microorganisms, IV, 108 Crotyl alcohol, IV, 91 phytochemical reduction of, IV, 92,106 Crystalbumin. See Albumin. Crystalline dextrose, commercial production, V, 127-143 Crystallinity, relative, of celluloses, V, 103-126 Crystallization of sugars, solvents for, I, 24 Crystallography, of melezitose, 11, 14 Cub-cellulose, 111, 187 Cyanohydrins, in synthesis of higher-C sugars, I, 1-36, 37, 38 Cyclization, of hexose derivatives, 111,53 Cycloamyloses, 111, 254; 305; V, 266 Cyclohexane, 1,3-diamino-2,4,5,6-tetrahydroxy-. See Streptarnine. -, 1,2,3,Pdiepoxy-, 111, 70 -, 1,3-diguanidino-2,4,5,6-tetrahydroxy-. See Streptidine. -, 1,3-diureido-2,4,5,6-tetrahydroxy-. See Strepturea. -, hexahydroxy-. See Inositol. -, tetrahydroxy-, 111, 69, 70 1,2-Cyclohexanedione, tetrahydroxy-, 111, 57 " Cyclohexane-erythritol," 111, 70 Cyclohexanol, effect on leaching of starch, I, 263 effect on starch paste, I, 272 as starch precipitant, I, 259 Cyclohexanol, 2-methyl-, IV, 83

-,

339

3-methyl-, IV, 92 Cyclohexanol, trityl ether, 111, 86 Cyclohexanone, 4,5-isopropylidene-3,4,5trihydroxy-, 111, 69, 70, 72 -, 2-methyl-, phytochemical reduction of, IV, 83 -, pentahydroxy-, 111, 50, 61 Cyclohexene, tetrahydroxy-, 111, 59 Cyclohexen-3-one, 1-methyl-, IV, 92 Cyclopentane-1,2-diol, cis- and trans-, effect on conductivity of boric acid, IV, 192 Cyclopentane, 1-methyl-, cia- and trans-, effect on conductivity of boric acid, IV, 192 Cyclopentanecarboxaldehyde, 1hydroxy-, rearrangement of, 111, 374 Cyclopentanecarboxylic acid, Zhydroxy-, cia- and trans-, effect on conductivity of boric acid, IV, 195 Cyclopentanecarboxylic acid, 5-methylZhydroxy-, cis- and trans-, effect on conductivity of boric acid, IV, 195 Cyclopentanol, IV, 84 Cyclopentanone, phytochemical reduction of, IV, 84 Cyclopentanophenanthene, perhydro-3hydroxy-, glycosides, I, 147 Cymarin, I, 148, 166 Cymaronic acid, phenylhydraride and S benzylthiuronium salt, I, 168 Cymaronic lactone, I, 165 Cymaronic lactone (1,4), 5-methyl-, I, 165 Cymaronic lactone (1,5), 4-methyl-, I, 165 Cymarose, I, 63, 64, 148, 149, 164-166, 168, 169 Cysteine, effect on ketonuria, 11, 149 inactivation of streptomycin by, 111, 352 phytochemical reduction of, IV, 97 -, thiosugar derivative, I, 134 Cystine, effect on ketonuria, 11, 148, 149 Cytidine, I, 207-210 Cytidilic acid, I, 196, 217 Cytophagae, mucoprotein formation from cellulose by, 11,189 polysaccharides of, 11, 165

340

CUMULATrVE SUBJECT INDEX FOR VOLS. I-V

Cytosine, from desoxyribosenucleic acid, Desoxyribosenucleic acid, I, 195, 236-245 I, 237 Desoxyribose nucleosides, I, 238 desoxyribose nucleoside, I, 238, 240 Desoxyribosyladenine, I, 240 from nucleic acids, I, 195 3'-Desoxyribosylcytosine, I, 240 phosphodesoxyribosyl nucleotide, I, Desoxyribosylguanine, I, 240 241 Desoxyribosylpurinea, I, 238 from ribose nucleic acid, I, 198 .Desoxyribosylpyrimidines, I, 240 Cytosine, 3'-desoxyribosyl-, I, 240 3'-Desoxyribosylthymine, I, 240 -, diphosphodesoxyribosyl-, I, 242 2-Desoxy sugars, I, 148; 111, 101 -, 1'-(5-trityl-~-ribofuranosyl)-,111, 110 Desulfurization, reductive, by Raney nickel in the carbohydrate field, V, D 1-28 Detergent, phenylmercury levulinate, D and L symbols, in Fischer-Rosanoff sysIV, 312 tem for enantiomorphous series in Detritylation, 111, 81 carbohydrate group, origin of, 111, halogenation and, 111, 98 12-18 Deuteriocaproic acid, metabolism of, 11, Dahlia tubers, inulin from, 11, 254 152 Dambonitol, 111, 46 Deuteriotributyrin, 11, 152 Damson gum, I, 343; IV, 246, 247 Deuterium, in carbohydrate metabolism structure of, IV, 253 study, 111, 230 blood group activity of, IV, 50, 52 Deuterium-labelled glycogen, 111, 246 Deamination, mechanism of, 11, 62 Dextran, 2,3-dimethyl-~-glucose from Degradation, of acylated nitriles of almethylated, V, 161 donic acids, IV, 119-151 Dextran acetate, 11, 218 of aldonic acids, 111, 149 Dextran beers, IV, 333 of aldose sugars, I, 254 Dextran esters, 11, 218 enzymatic, of starch and glycogen, 111, Dextran ethers, 11, 218 251-310 Dextran triacetate, 11, 210, 212 of starch, I, 254 Dextran tribenzoate, 11, 210, 212 Wohl, of nitriles of aldonic acids, IV, Dextrans 129 as antigens, 11, 214 Zemplh, of aldononitriles, IV, 138 bacterial, 11, 165, 190 As-Dehydroandrosterone, IV, 93 enzymatic synthesis o€, 11, 205, 216 Dehydrocholic acid, IV, 106 as haptenes, 11, 215 Dehydrodesoxycholic acid, IV, 92 history of, 11, 209 Dehydrohalogenation, of halo carboimmunological properties of, 11, 214 hydrates, 111, 102 industrial applications of, 11, 218; IV, Density of cellulosic fibers, V, 121 333 Depolymerase, action on pectic acids, V, as industrial nuisance, 11, 217 82, 92 of Leuconostoc dextranicum, 11, 214; IV, Depolymerizafion, of polytetranucleo333 tides, I, 227 of Leuconostoc mesenteroides, 11, 211; Desoxy-. For desoxy- (or deoxy-) derivIV, 333 atives see also inverted entries undm of Leuconostoc organisms, IV, 333; V, 47 the name of the parent compound, medical application of, 11, 219; IV, 333 e.g., D-Glucose, 2-desoxy-. structure of, 11, 211 6-Desoxyaltroses, I, 62 vermiforme, 11, 219 Desoxyfuroin, IV, 90 Dextrinic acid, @-amylaseaction on, 111, Desoxyribonucleo-depolymerase, I, 245 265

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Dextrinization, 111, 271, 307 Dextrinogenic amylase, 111, 282; V, 230 Dextrins, I, 269, 273 from action of amylases, 111, 251-310; V,229-268 &amylase action on, 111, 265 limit, 111, 274 limit, from arrow-root starch, 111, 292, 293, 298, 300;V, 257, 260 limit, from barley starch, 111, 293, 299 limit, from corn amylose, V, 247-262 limit, from corn starch, 111, 289, 290, 295;V, 241, 262 limit, phosphoric acid in, 111, 303, 304 limit, from potato starch, 111,293,294, 297,300; V, 232, 241, 243, 253 limit, from rice starch, 111, 292, 293, 297 limit, from starch, 111,252,254;V, 232 limit, from waxy maize starch, V, 241 limit, from wheat starch, 111, 292, 293 nature of limit, 111, 289 Dextrins, Schardinger. See Cycloam yloses. a-Dextrins, 111, 273,274 from amylose, 111, 284 from arrow-root starch, 111, 281 from barley starch, 111, 281 from corn starch, 111, 280 a-Dextrins, hydrolysis rate of, by 8amylase, salivary amylase, and malt 0-amylase, 111, 278 from potato starch, 111, 275 saccharification of, 111, 276, 277 8-Dextrins, 111, 265 &amylase action on, 111, 286 malt a-amylase action on, 111,271,281, 282, 285, 286 Dextrose. See also D-Glucose. brewer’s sugar, V, 128 chip sugar, V, 128 “70” sugar, V, 128 c‘80”sugar, V, 128 Dextrose, addition compound with NaCl, V, 132 Dextrose, alpha anhydrous, V, 135 photograph of crystala of, V, 135 Dextrose, alpha, monohydrate, V, 131 photograph of crystals of, V, 133, 134. 141

341

Dextrose, beta, V, 136 photograph of crystals of, V, 137 Dextrose, commercial production of crystalline, V, 127-143 process of ion-exchange refining, V, 137-143 Dextrose, diagram of solubility in water, V, 130 “Dextrosecarboxylic” acid, I, 3 Diabetes, effect of glycerol on insulin shock, I, 177 u-mannitol as sweetening agent in, I, 181 D-sorbitol as sweetening agent in, I, 187, 189 Diabetes mellitus, 11, 125 respiratory quotient in, 11, 138 Diacetyl, 111, 127 Diacetyl, phytochemical reduction of, IV, 86, 106 Dialdosyl disulfide, octaacetate, V, 5 Dialysis, in purification of polyuronides, I, 333 Diazouracil, IV, 35 1,2,5,6-Dibenzanthracene,labelled with Ct4, 111, 233 Dicarbonyl sugars, 111, 103 Dichroism of flow, of starch-iodine complex of A fraction, I, 266 Diffusion constants, of starch acetates, I, 295 Diffusion measurements, for determination of degree of polymerization of cellulose, 111, 222 Di-D-fructofuranose anhydride, 111, 122, 123 2,1’:1,2’-Di-~-fructofuranose,11, 275 2,l‘:1,2’-Di-~-fructofuranoseanhydride, 11, 269 1,2’:2,3’-Di-~-fructofuranoseanhydride, 11, 269 2,l’:1,2’-Di-~-fructopyranose, 11, 275 1,2‘:2,1’-Di-~-fructopyranoseanhydride, 11, 268 Di-u-fructose anhydride, 111, 118 hexaacetate, 111, 122 hexabenzoate, 111, 123 -, hexamethyl-, 111, 122 Di-D-fructose anhvdride “I ”,, 11.. 265 268, 274, 275

342

-,

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

6,6’-dimethyl-3,4 :3’,4’-tetraacetyl-, 11, 266 -, 6,6’-ditrityl-, 11, 265 -, 6,6’-ditrityl-3,4 :3’,4’-tetraacetyl-, 11, 266 -, hexaacetyl-, 11, 265 -, hexamethyl-, 11, 265, 268 -, 3,4: 3’,4‘-tetraacetyl-, 11, 266 Di-D-fructose anhydride “I1”, 11, 266, 268, 269, 273, 274, 276 -, hexamethyl-, 11, 266 Di-D-fructose anhydride “111”, 11, 266, 268, 269, 274, 275 -, hexamethyl-, 11, 266, 270 -, 6,1’,6’-tri(trityl)-, 11, 266, 271, 272 -, tri(trity1)trimethyl-, 11, 271, 272 Difructose anhydrides, 11, 263, 267-277 from inulin, 11, 256, 274 oxidation by periodic acid, 11, 276 Diginigenin, I, 168 Diginin, I, 148, 168, 170 Diginonic acid, S-benzylthiuronium salt, I, 171 and phenylhydrazide and S-benzylthiuronium salt, I, 168, 169 Diginose, I, 148, 167-170 Digitaligenin, I, 158 Digitalis glycosides, I, 148 Digitalonic lactone, I, 150, 168 Digitalose, I, 62, 148, 150-158 Digitoxal, I, 160-163 Digitoxide, methyl, I, 165 -, methyl dimethyl-, I, 166 Digitoxin, I , 163 Digitoxonic acid, I, 160 Digitoxonic lactone, I, 163 Digitoxonic lactone (1,4), dimethyl-, I, 165 Digitoxose, I, 63, 64, 148, 149, 159163 Digitoxosecarboxyliclactone, I, 163 B,B-Di-D-glucopyranosyl disulfide, octaacetate, V, 5, 26, 202 Diglycolic acid, derivatives, 111, 131 -, methoxyhydroxymethyl-, 111, 131 dihydrate of strontium salt, 111, 164 Diglycolic acid, D,rchydroxymethyl-, strontium salt, V, 221 Di(glucosyl-3)disulfide,I, 143 Di(glucosyl-6)disulfide,I, 141

Diheterolevulosan, 11, 265, 267, 274, 275; 111, 119, 120 -, hexaacetyl-, 11, 265 -, hexamethyl-, 11, 265, 267 Diketones, phytochemical reduction of, IV, 86 Diosmetin, IV, 58, 69, 63, 66 Diosmin, IV, 60 Dioxane, as solvent in sugar research, I, 24 Diphosphodesoxyribosylcytosine, I, 242 Diphosphodesoxyribosyl pyrimidines, I, 241 Diphosphothymidine, I, 242 Diplococcua pneumoniae, polysaccharides formed by, 11, 221 Disaccharides, 111, 130 enzymatic syntheses of, V, 29-48 oxidation of, 111, 132, 145 Dismutation, the term, IV, 101 Disproportionation, IV, 102 Dissociation constants, of hypobromous, hypochlorous and hypoiodous acids, 111, 135 Disulfides, phytochemical reduction of, IV, 93 Disulfides, of sugars, I, 136, 144; V, 5 Divinylcarbinol, 11, 118 D/N ratio, in metabolism studies, 11, 135 Dogwood, pentosan content of Pacific, V, 271 Douglrts fir, pentosan content, V, 271 Douglas fir manna, 11, 11 DP. Definition as degree of ,polymerization, V, 106 Dual affinity, in theory of enzyme action, v, 64 Dulcitan, metabolism of, I, 191 Dulcitol. See also Galactitol. Dulcitol, I, 181; 11, 109, 111, 114; 111, 4; IV, 212, 216 effect on conductivity of boric acid, IV, 191 metabolism of, I, 191 oxidation of, 111, 166; IV, 227 physical properties of, IV, 219 D-Dulcitol, 1,banhydro-, V, 203 tetraacetate, V, 204 D-Dulcitol, 3,6-anhydro-, V, 203, 204

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

343

Dulcitol, 2,5-bis(dichloroacetyl)-l,3 :4,6- -, 1,6-dit~syldiisopropylidene-, IV, 238 dibenzylidene-, IV, 237 -, 1,6-ditrityl-, 111, 81, 84, 110; IV, 237 -, l,bdiacetyl-, IV, 237 -, 1,6-ditrityl-2,3,4,5-dibenzylidene-, -, 1,64iacetyldibenzylidene-,IV, 237 111, 97, 110; IV, 238 -, 2,5-diacetyl-1,3: 4,&dibenrylidene-, -, 1,6-ditrityl-diisopropylidene-,IV, 238 IV, 237 -, 1,6-ditrity1-2,3,4,5-tetraacetyl-,111, -, 1,64iacetyldiisopropylidene-,IV, 238 100, 110; IV, 238 -, 1,4:3,6-dianhydro-, V, 215 -, hexaacetyl-, 11, 114 -, l,Bdibenzoyl-, IV, 237 -, hexaallyl-, IV, 237 -, l,&dibenzoyldibenzylidene-,IV, 237 -, hexabenzoyl-, IV, 237 -, 2,5-dibenzoyl-1,3 :4,6-&beneylidene-, -, hexa(p-chlorobenzoy1)-, IV, 237 IV, 237 -, hexa(phenylcarbamy1)-, IV, 237 -, 1,6dibenroyldiisopropylidene-, IV, -, mono (m-nitrobenzylidene), IV, 237 238 -, mono(p-nitroben2ylidene)-, IV, 237 -, 1,6-dibenzoyl-2,3,4,5-tetraacetyl-, IV, -, tetraacetyl-, 11, 114 237 -, tri(o-nitrobenzy1idene)-, IV, 237 -, 2,5-dibenzoyl-1,3,4,6-tetraacetyl-,IV, Dulcitols, anhydro-, V, 203-204 237 Dyes, phytochemical reduction of, IV, -, 2,5-dibenzyl-, IV, 237 100 -, 1,3:4,6-dibenzylidene-, IV, 237 -, 2,3,4,5-dibenzylidene-, and isomer, E IV, 237 -, 1,3:4,6-dibenzylidene-2-benzyl-,IV, Eberthella typhosa, polysaccharide formed 238 by, 11, 223 -, 1,3:4,6-dibenzylidene-2,5-dibenzyl-, Egg plum gum, V, 246, 258 Eggplant, pectin-methylesterase (PM) IV, 237 -, 1,6-dibromo-l,6-didesoxy-2,3,4,6in, v, 93 tetraacetyl-, 111, 100 Electrodialysis, in purification of poly-, diisopropylidene-, IV, 237 uronides, I, 333 -, 2,3,4,5-diisopropylidene,IV, 237 Electrolytic oxidation, of carbohydrates, -, 1,3:4,6dimethylene-, IV, 237 111, 154 -, 1,3:4,6-dimethylene-2,5-diacetyl-,IV, Electrophoresis, of starch, I, 251 Emicymarin, I, 148, 156 237 -, 1,3:4,6-dimethylene-2,5-dibenzoyl-, Emulsin. 8ee also 8-Glucosidase. IV, 237 Emulsins, V, 60-66 -, 1,3:4,6-dimethylene-2,5-dibenzyl-, Enanthaldehyde, phytochemical reducIV, 237 tion of, IV, 78 -, 1,3:4,6-dimethylene-2,5-ditosyl-,IV, Enanthic acid, glycogen formation from, 11, 128 237 -, 1,3: 4,6-di(o-nitrobenzylidene)-, IV, Enediols, 111, 114 237 Enolization, of 2-keto-3,4-dihydroxy acids or esters, 11, 83, 87 -, 1,3: 4,6-di(o-nitrobenzylidene)-2,5Enzymatic degradation, of nucleic acids, diacetyl-, IV, 237 -, 1,3: 4,6-di(o-nitrobenzylidene)-2,5I, 226 Enzymatic degradation, of pectin, 11, dibenzoyl-, IV, 237 -, 1,3: 4,6-di(o-nitrobenzylidene)-2,5241; V, 79-102 Enzymatic degradation, of starch and ditosyl-, IV, 237 glycogen, I, 252, 269, 270; 111, 251-, l,&ditosyldibenzylidene-, IV, 238 -, 2,5-ditosyl-l,3 :4,6-dibenzylidene-, 310; V, 229-268 Enzymatic reduction, IV, 79 IV, 237

344

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Enzymatic synthesis, of disaccharides, V, Epimaltitol, 11, 26 29-48 nonaacetate, 11, 23, 26 of starch and glycogen, 111, 258; V, Epimaltose, 11, 23, 24, 26 32 . Epimers, I, 4 Enzyme, diagram of postulated union of Epinephrin, effect on fat metabolism, 11, substrate with, V, 56 139 Enzyme specificity, principles under- LEpirhamnitol, 1-trityl-, 111, 110 lying, in the domain of carbohy- 1,2-Epoxides, hydrogenation, V. 22 Ergosterol, IV, 334 drates, V, 49-78 Enzyme value, definition, V, 62 Erythritan, metabolism of, I, 179 comparative values from rates of hy- Erythritol, effect on conductivity of drolysis of phenyl hexosides and boric acid, IV, 191 pentosides, V, 62 metabolism of, I, 178 Enzyme-substrate unions, V, 53-57, 60 oxidation of, 111, 150, 166 diagram illustrating sucrose-saccharase .-, 1,4ditrityl-, 111, 111 combination, V, 56 -, tetranitrate, I, 179, 185 Enzymes, action on pectic substances, Erythroamylose, I, 250 V, 79-102 r.-Erythroascorbic acid, 11, 86, 96 -, amylolytic. See Amylaaes. Erythrocytes, blood group substances -, blood group substances, destruction from, IV, 41, 46 by, IV, 55 D-Erythrofuranoside, 1-(Do-glucopyrano-, carbohydrate synthesis by, 11, 205 syl)-, IV, 139, 148 -, carbohydrates and their specific, V, hexaacetate, IV, 148 76 D-Erythronamide, 2,4dimethyl-, 111, 165 -, dextran synthesis by, 11, 205, 216 D-Erythronic acid, 3-methyl-, 11, 100 -, in fractionation of starch, I, 252 LErythronic acid, and brucine salt, 111, -, gentirtnose hydrolysis by, 11, 34 144 -, kinetics and mechanism of activation r.-Erythropentulose, 11, 86 of, v, 59 Erythrose, 111, 150 -, levan synthesis by, 11, 205 D-Erythrose, I v , 144 -, melezitose hydrolysis by, 11, 32, 34 -, 2-(&~-galactopyranosyl)-,IV, 148 -, nucleoclastic, I, 226 -, 2-(~~-glucopyranosyl)-, IV, 148 -, pectic, V, 79-102 -, 2-(p-~-glucopyranosyl)-,IV, 147 -, raffinose hydrolysis by, 11, 34 -, glycosyl-, 111, 194 -, starch conversion by, I, 269, 270. -, 34’-hydroxymethyl-, 111, 21 See also Amylases. -, triacetyl-, IV, 144 -, sucrose hydrolysis by, 11, 34 IV, 144 -, synthesis of sucrose and other disac- LErythrose, oxidation of, 111, 144 charides by, V, 29-48 -, Pdesoxy-, phenylosazone, 111, 367 -, turanose hydrolysis by, 11, 33 -, triacetyl-, IV, 141 Epicellobiose, octaacetate, 111, 195 D-Erythrose diacetamide, IV, 143, 144, Epichitose, 11, 73 151 Epichondrosic acid, 11, 74 -, triacetyl-, IV, 151. Epiglucosamine, I, 57, 60 LErythrose diacetamide, IV, 133, 144, -, anhydro-, 11, 65, 70 151 hydrochloride, I, 59, 61 -, methyl-, and hydrochloride, I, 58, 59, -, triacetyl-, IV, 151 D-Erythroside, methyl, IV, 144 60, 61 Esparto xylan, optical rotation of, V, Epi-isosaccharic acid, 11, 61 282 and calcium and KH salts, 11, 74

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Esterification, catalysts for, of cellulose, I, 312 -, of cellulose, I, 318 -, of hexitols, IV, 220 -, partial, of cellulose, I, 314 -, solvents for, of cellulose, I, 313 -, of starch, I, 281 Esters. See also Orthoesters. of cellulose with organic acids, I, 309327 of hydroxy acids, condensation of, II,91 of starch, I, 279-307 a-Estradiol, IV, 93 Estrone, phytochemical reduction of, IV, 93 Ethanol, 2-methoxy-, (“methyl cellosolve”), as solvent in sugar research, I, 24 Ethanolamine, use in delignification, V, 274 Etherification, of cellulose, 11, 281-283, 285, 287 of hexitols, IV, 223 Etherifying agents, for cellulose, 11, 281, 285 Ethers, trityl. See Trityl ethers. Ethocel, 11, 289 Ethyl alcohol, effect on ketonuria, 11, 148, 149 leaching of starch with, I, 263 metabolism of, 11, 147 from molasses, IV, 336 as starch precipitant, I, 259 from sucrose, IV, 322, 323 from sugar cane tofis, IV, 295 from sulfite waste liquor, IV, 178 from wood saccharification sugars, IV, 178 Ethyl disulfide, IV, 95 Ethyl hydroperoxide, decomposition by catalase, V, 53 Ethyl lactate, as solvent in sugar research, I, 24 Ethyl mercaptan, IV, 93, 94 Ethyl sulfuric acid, catalytic formation, V, 52 Ethylene glycol, IV, 299 effect on conductivity of boric acid, IV, 191 effect on ketonuria, 11, 148, 149

345

-, -,

methylfuryl-, IV, 91 a-methyl-8-phenyl-, IV, 87 Ethylene glycol monomethyl ether, (,“methyl cellosolve”) as solvent in sugar research, I, 24 Ethylene oxide, dimethyl-, IV, 328, 329 Ethylene oxide-mannitan monolaurate, I, 187 Ethylene oxide rings, formation and cleavage of, I, 57 Ethylenic linkages, phytochemical reduction of, IV, 91 Ethynylenedimagnesium bromide, 11, 109, 110,112 Ethynylmagnesium bromide, 11, 115, 116 Euxanthic acid, 111, 97 Explosives, starch nitrates as, I, 303

F Fat, from carbohydrates, 11, 120-125 feeding experiments with, 11, 134 metabolism of, 11, 119-160 metabolism, effect of lactose on, 11,159 nutritive values of, 11, 160 from sugars, IV, 114 transformation to carbohydrate, 11, 125-145 vegetable, carbohydrate from, 11, 144 Fat coefficient, IV, 116 Fatty acids, adsorption by starch, I, 255 conversion to carbohydrates, 11, 125, 128, 129 effect on starch paste, I, 252 as glycogenic agents, 11, 133 metabolism of, 111, 247 oxidation of, 111, 249 removal from starch, I, 256 synthesis of, IV, 114 Feculose, I, 289 Fehling’s solution, use in purification of xylan, V, 278, 289 Fermentation, alcoholic, I, 213; IV, 75 of carbohydrates, IV, 107 of furanose form of D-fructose, V, 74 of only monosaccharides by Torula nzonosa, V, 38 phytochemical reduction and, IV, 105 of sucrose, IV, 322 of wood saccharification sugars, IV, 178

346

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Film, cellulose acetate, I, 300 cellulose ester, I, 325 starch acetate, I, 297 Fischer cyanohydrin synthesis of higherC sugars, I, 1-38 Fischer, fundamental conventions of E. - for writing stereochemical formulas in a plane, 111, 1-22 Flavone, 5,7,3',4'-tetrahydroxy-. See Luteolin. -, 5,7,4'-trihydroxy-. See Apigenin. -, 5,7,3'-trihydroxy-4'-methoxy-. 8ee Diosmetin. Flax, V, 104 speed of acetylation, V, 122 low xylan content, V, 271 Flax, New Zealand, polysaccharide of, V, 283 Floridose, IV, 275 Fluorine, as oxidant, 111, 133 Fluorine derivatives of carbohydrates, 111, 100 Folinerin, identity with oleandrin, I, 171 Forces of attraction between enzyme and substrate groupings, V, 56 Formaldehyde, combination with cellulose, V, 126 Formic acid, cellulose ester, I, 310 from inositol oxidation, 111, 52 labelled with C", 111, 237 labelled with isotopic C, 111, 231, 232 starch ester, I, 300 from sucrose, IV, 309 Formose, IV, 27 Forsmann antigens, I, 166, 199; IV, 41, 50, 53 Fractionation of starch, I, 247-277 by adsorption (selective), I, 252, 255 by aqueous leaching, I, 261, 261,276 by electrophoresis, I, 251 by enzymes, I, 252 by precipitation (selective), I, 252,265, 258, 263, 276 by retrogradation (selective), I, 25 Friedliinder's bacillus, polysaccharides of, 11, 165, 189 Frog spawn mucin, blood group activity of, IV, 50, 52 D-Fructofuranose, V, 31 8-D-Fructofuranose, V, 42, 68, 69, 74, 75

n-Fructofuranose anhydride, 111, 122, 123 8-D-Fructofuranosidase, I, 257;V, 32,33, 55, 67-69 diagram of postulated union with sucrose, V, 56 D-Fructofuranoside, benzyl, IV, 23, 24 -, ethyl, IV, 28 -, methyl, IV, 22-24 a-D-Fructofuranoside, benzyl, V, 69 -, 8-D-glucopyranosyl, (Isosucrose), V, 69 octaacetate, V, 30 -, methyl, V, 69 8-D-Fructof uranoside,-a-D-ghcopyranosyl (Sucrose), 11, 29-34; IV, 1-31; V, 29-39, 67-71 octaacetate, V, 38 octamethyl-, V, 31 -, methyl, IV, 22, 25;V, 32, 67 D-Fructofuranosyl chloride, tetraacetyl-, IV, 28, 29 D-Fructoheptononitrile, IV, 126, 149 D-Fructopyranose anomers, IV, 209 o-Fructopyranose phenylosazone, 111, 29 -, tetramethyl-, 111, 29 a-D-hctopyranoside, methyl, acetylated, IV, 29 D-Fructopyranosyl chloride, tetraacetyl-, IV, 29 Fructosans, bacterial, 11, 225 D-FrUCtose, I, 2, 3, 16; 111, 11, 114;IV, 5 alkali action on, 111, 113, 123 bacterial cellulose from, 11, 207 calcium bromide compound, 111, 154 determination of, 111, 161 effect on conductivity of boric acid, IV, 207,208 effect on ketonuria, 11, 148 enzymatic syntheses with, V, 29-39, 46-48 fermentation of furanose form, V, 74, 75 heat action on solutions of, 111, 119 from inulin, 11, 256 from D-mannitol, IV, 226 methyl l,%rthoacetate, I, 91 methylphenylhydrazone, 111, 35 methylphenylhydrazones, and their pentascetates, 111, 26

CUMULATIVE SUBJECT INDEX FOR VOLS. I--V

methylphenyl-p-nitrophenylosazone, 111, 30 methylphenylosazone, 111, 30 methylphenyl-phenylosazone, 111, 30 in mucilage, IV, 268 mutarotation, IV, 18-25; V, 32, 75 orthoesters of, I, 90 osazone formation with, 111, 44 oxidation of, 11, 84; 111, 141, 149, 151, 165 reaction with asparagine, 111, 126 reaction with bromine, 111, 154 reaction with lead hydroxide, 111, 115, 116 reaction with sodium hypoiodite, 111, 160 from sorbitol, 111, 160 from etyracitol, V, 200 synthesis of, 111, 53 from wood, IV, 160 D-Fructose anhydride, trimethyl-, I11 122 D-Fructose 1,2-anhydride, 111, 123 D-Fructose 1,6-diphosphate, IV, 26 D-Fructose, 5-keto-, fermentation of, IV, 87 D-Fructose, anhydro-, 111, 118 D-Fructose, diethyl thioacetal, pentaacetate, V, 6, 26 -, 2,3: 4,5-diisopropylidene-, 11, 85 -, 3,4-dimethyl-, 11, 271, 272 D-Fructose, 1 (&D-glucopyranosyl)-, 11, 21; 111, 95 D-Fructose, 3-(a-~-glucopyranosyl)-. See Turanose. -, 1,bditrityl-, 111, 84 dipyridine compound, 111, 108 oxime, 111, 108 -, 4methyl-, 11, 271, 272 -, tetraacetyl-, IV, 28 -, 2,3,4,5tetraacetyl-l-trityl-,111, 108 -, tetramethyl-, IV, 10, 12, 13 -, 1,3,4,5-tetramethyl-, IV, 14 -, 1,3,4,6-tetramethyl-, IV, 14; V, 31 -, 3,4,5triacetyl-, methyl 1,2-orthoacetate, I, 90, 91 -, 1,3,4trimethyl-, 11, 20, 276 -, 1,4,&trimethyl-, 11, 20, 270, 272, 276 -, 3,4,5trimethyl-, 111, 29, 123 -, 3,4,6trimethyl-, 11, 270, 272, 277

-

-, -,

347

l,a,d-tritrityl-, 111, 108 1-trityl-, 111, 108 DL-Fructose, IV, 27 j3-D-Fructoside, ethyl thio-, I, 138 8-D-Fructoside, methyl 3-mono-acetyl-, and triacetate, I, 91 D-Fructosylbromide, tetrabenzoyl-, IV, 28 D-Fructoxazoline, 1-trityl-p-mercapto-, 111, 108 Fruit juices, pectin-methylesterase (PM) in, V, 93 -, removal of pectin from, V, 101 cFucito1, acylation of, 111, 91 pentaacetate, V, 6 L-Fucitol, 1-bromo-1-desoxy-2,3,4,5tetraacetyl-, 111, 100 -, 2,3,4,5-tetraacetyl-l-trityl-,111, 100, 110 -, 1-trityl-, 111, 110 bficoascorbic acid, 11, 83, 95 “a-Fucohexitol,” V, 9 “Fucohexonic” acids, I, 30; V, 9 “~-Fucohexose,”V, 9 Fucoidin, IV, 275 L-Fuconamide, 2,3,4trimethyl-, IV, 286 D-Fucononitrile, tetraacetyl-, I v , 145, 149 L-Fucononitrile, tetraacetyl-, IV, 145, 149 a-cFucopyranoside, methyl 2,3,4-trimethyl-, 11, 188; IV, 47 a-L-Fucopyranoside, methyl trityl-, 111, 87, 108 n-ficopyranoside, methyl 3,4isopropylidene-, I, 154 -, methyl 2-methyl-3,4-isopropylidene-, I, 154 Fucosan, IV, 275 D-FuCOse, I, 62; V, 145 specific rotation of, I, 155 -, 2-methyl-, specific rotation of, I, 155 synthesis of, I, 152-154 -, 3-methyl-. See Digitalose. L-Fucose, I, 28,30; 11,236, 237; V, 9 from blood group substances, IV, 45, 46

configuration of, I, 19 in gums, IV, 245, 246, 262 in mucilages, IV, 275 oxidation of, 111, 144 phenylosotriazole from, 111, 38

348

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

LFucose, 2-methyl-, specific rotation of, I, 155 synthesis of, I, 152-154 IrFucose, 2,3,4-trimethyl-, IV, 286 anilide, IV, 286 a- and 8-glycoside, IV, 286 hydrate, I, 150; IV, 286 L-Fucose, 2,3,4-trimethyl-, IV, 286 L-Fucose anilide, 2,3,4trimethyl-, IV, 286 D-Fucose oxime, pentaacetyl-, Iv, 123, 150 L-Fucose oxime, IV, 124 pentaacetate, IV, 124, 150 Fumaric acid, 111, 238, 241 labelled with C11,111, 238 labelled with isotopic C,111,240,248, 249 from sucrose, IV, 322, 329 Furaldehyde, 5-(bromomethy1)-, 111, 167 -, hydroxymethyl-, 111, 127 Furan, 3,4-dihydroxy-2,3-dimethyltetrahydro-, 111, 360 -, 2,5-dimethyltetrahydro-, IV, 301 -, 2-ethyltetrahydro-, V, 192 -, 2-vinyldihydro-, V, 192 2-Furancarboxylic acid, bhydroxymethyl-, and ethyl ester, IV, 316 -, 6-hydroxymethyltetrahydro-,and ethyl ester, IV, 316 2,5-Furandicarbinol, IV, 315 -, tetrahydro-, IV, 300, 301, 316 2,5-Furandicarboxy!ic acid, tetrahydro-, IV, 316 Furanose and pyranose, origin and definition of terms, 111, 18 Furanose and pyranose rings, method of distinction in some cases, 111, 103 Furfural, commercial production from pentosans, V, 288 from bagasse, IV, 296 from wood saccharification, IV, 178 -, 5-hydroxymethyl-, IV, 5, 307, 314, 336 Furfural-5-carboxylic acid, IV, 332 Furfuryl alcohol, a-methyl-4-hydroxytetrahydro-, IV, 300 -, ti-methyltetrahydro-, IV, 300, 301 Furil, IV, 90

Furoin, phytochemical reduction of, IV, 90 Fususarium h i , in fermentation of wood sugars, IV, 181 G

D-Galactal, 2-hydroxy-, tetraacetate, v, 17 Galactan, in pectin, I, 342; 11, 237-239, 248-251 cGalactan, of larch wood, 11,249 D-Galactitol, 1,5-anhydro-, V, 17, 226 tetraacetate, V, 17, 27, 226 -, 3,5-anhydro-, V, 226 tetraacetate, V, 226 -, 4-benzoyl-2,3,5,6-tetramethyl-,IV, 239 -, Pbenzoyl-pentamethyl-, IV, 239 -, 1-desoxy-, V, 26 pentaacetafe, V, 6, 26 -, 1,~dibenzoyl-2,3,5,6-tetramethyl-, IV, 239 -, 1,2,3,5,6-pentamethyl-, IV, 239 -, 2,3,5,6-tetramethyl-, IV, 239 D-Galactoascorbic acid, 11, 82, 83, 96 -, imino-, 11, 82 Galactocarolose, 11, 224 Galactogen, 11, 191 Galactokinase, V, 49, 50 D-Galactonamide, 3,6-anhydro-2,4-dimethyl-, 11, 77 -, 2,4-dimethyl-, IV, 287 -, 2,6-dimethyl-, IV, 288 -, 2,3,4,6-tetramethyl-, IV, 288 -, 2,3,4-trimethyl-, IV, 288 -, 2,3,6-trimethyl-, 11, 249; IV, 288 -, 2,4,6-trimethyl-, IV, 288 GGalactonamide, 3,6-anhydro-2,4-dimethyl-, 11, 77 -, 3,6-anhydro-2,bdimethyl-,11, 77 D-Galactonic acid, I, 67, 68; 111, 143 lactone, 111, 140 from lactose, 111, 140 D-Galactonic acid, 2,5-anhydro-, and brucine salt, 11, 73 -, 3,6-anhydro-, and methyl ester, 11,77 -, 3,6-anhydro-2,4-dimethyl-, and methyl ester, 11, 77 -, 3,0-anhydro-2,&dimethyl-, IV,279

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

-,

<

349

3,6-anhydro-2,4,5-trimethyl-, and -, 1,6-anhydro-3,4isopropylidene-, 11, methyl ester and brucine salt, 11, 70 77 -, 1,6-anhydro-3,4-isopropylidene-2-, 2,4dimethyl-, phenylhydrazide, IV, methyl-, 11, 70 287 -, 1,6-anhydro-3,4-isopropylidene-2-, 2,4dimethyl-, lactone, IV, 287 tosyl-, 11, 70 -, 2,6-dimethyl-, phenylhydrazide, IV, -, 1,6-mhydr0-2-methyl-, 11, 70 288 -, 1,6-anhydro-2-tosyl-, 11, 70 -, 2-keto-, 11, 84; 111, 148 -, 1,3-anhydro-2,4,6-triacetyl-,11, 69 -, pentaacetyl-, 111, 153 -, 1,6-anhydro-2,3,4acetyl-, 11, 70 -, pentamethyl-, methyl ester, IV,288 -, 1,6-anhydro-2,3,4tribenzoyl-,11, 70 -, 2,3,4,6tetrarnethyl-, 111, 146 -, 1,6-anhydro-2,3,4trimethyl-,11, 70 and phenylhydrazide, IV, 288 -, 1,6-anhydr0-2,3,4-tritoeyl-,11, 70 -, 2,3,4trimethyl-, phenylhydraeide, -, 2,3,6-trimethyl-, 11, 249 IV, 288 a-D-Galactopyranosidase,V, 61, 66 -, 2,3,&trimethyl-, pbenylhydraeide, D-Galactopyranoside, methyl 3,6-anhyIV, 288 dro-2,4-dimethyi-, 11, 59 -, 2,3,6-trimethyl-, lactone, 11, 249; IV, -, methyl 2,4-dimethyl-6-(2,3,4-tri288 methyl-&D-glucuronosyl)-, IV, 261 L-Galactonic acid, I, 69 -, metbyl tetramethyl-, 11, 249 and calcium salt, I, 70 D-Galactopyranoside, methyl trimethyl-, -, 3,6-anhydro-2,4-dimathyl-, methyl 11, 55 ester, 11, 77 -, methyl 2,3,4trimethyl-, IV, 247 -, 3,6-anhydro-2,Bdimethyl-,11, 77 -, methyl 2,3,6-trimethyl-, 11, 249 L-Galactonic acid, Bketo-, I, 69, 70; 11, a-D-Gabctopyranoside, methyl, oxidation 241,242 of, 111, 155 -, 2,4,5,6tetramethyl-, IV, 279 enzymatic hydrolysis of, V, 66, 67 D-Galactononitrile, pentaacetyl-, Iv, 146, -, methyl 3,6-anhydro-, 11, 76 149 -, methyl 3,6-anhydro-2,4-dimethyl-, -, pentabenzoyl-, IV, 126, 129,130, 147, 11, 76 149 -, methyl 3,6-anhydro-2-methyl-, 11, 76 -, pentapropionyl-, IV, 147, 149 -, methyl 3,6-anhydro-Prnethyl-, 11, 76 D-Galactopyranose anilide, tetramethyl-, -, methyl 3,6-anhydro-4-methy1-2IV, 279 tosyl-, 11, 76 D-Galactopyranose, 1,2:3,4diisopropyli- -, methyl 3,6-anhydro-2-tosyl-, 11, 76 dene-€i-trityl-, 111, 108 -, methyl 3,4i~opropylidene-6-t~syl-, D-Galactopyranose, 3-tosyl-trimethyl-, I, 154 11, 54 -, methyl 6tosyl-, I, 154 8-D-Galactopyranose, 11, 240 -, phenyl, enzymatic hydrolysis of, V, -, 2-acety’l-1,6-anhydroro-3,4-isopropyli66, 67 dene-, 11, To @-D-Galactopyranoside,methyl, 111, 104 -, 1,3-anhydro-, 11, 66, 69 -, methyl 3,Panhydro-, 11, 43, 49, 72 -, l,banhydro-, 11, 64, 65, 70 -, methyl 3,6-anhydro-, 11, 58, 59, 76 -, 1,6-anhydro-2-benzoyl, 11, 70 -, 1,6-anhydro-2-benzoyl-3,4-diacetyl-, -, methyl 3,4-anhydro-2-acetyl-6-trityl-, 11, 72 11, 70 -, 1,6-anhydr0-2-benzoyl-3,4ditosyl-, -, methyl 3,4-anhydro-2,6-diacetyl-,11, 72 11, 70 -, 1,6-anhydro-2-benzoyl-3,4-isopropyli- -, methyl 3,4anhydro-2,6-dibenzoyl-, 11, 72 dene-, 11, 70

350

-,

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

methyl 3,4-anhydro-2,6-dimethyl-, -, 2,3,5-trimethyl-, &methyl ester, IV, 11, 72 288 -, methyl 3,6-anhydro-2,4-dimethyl-, D-Galactosaccharic 3,6-lactone, 2,4-dimethyl-, 1-methyl ester, IV, 289 11, 76 -, methyl 3,4-anhydro-6(?)-methyl-,11, -, 2,4,5-trimethyl-, 1-methyl ester, IV, 72 289 -, methyl 2,3,4-triacetyl-&trityl-, 111, D-Galactosan, 11, 64, 65, 70 108 -, 2-acetyl-3,4-isopropylidene, 11, 70 -, methyl 2,3,4-tribenzoyl-6-trityl-, 111, -, 2-benzoyl-, 11, 70 108 -, 2-benzoyl-3,4-diacetyl-,11, 70 -, methyl &trityl-, 111, 107 -, 2-benzoyl-3,4-ditosyl-, 11, 70 -, 2'-naphthyl 1-thio-, V, 203 -, 2-benzoyl-3,4-isopropylidene-, 11, 70 tetraacetate, V, 17, 27 -, 3,44~opropylidene-,11, 70 -, phenyl3,4anhydro-, 11, 72 -, 3,4-isopropylidene-2-methyl-,11, 70 -, phenyl 3,4-anhydro-2,6-diacetyl-,11, -, 3,4isopropylidene-2-tosyl-, 11, 70 72 -, 2-methyl-, I&,70 -, phenyl, enzymatic hydrolysis of, V, -, 2-to~yl-,11, 70 62, 63 -, 2,3,4-triacetyl-, 11, 70 @+Galactopyranoside, methyl 3,B-anhy- -, 2,3,4-tribenzoyl-, 11, 70 dro-, 11, 77 -, 2,3,4-trimethyl-, 11, 70 -, methyl 3,6-anhydro-2,4-dimethyl-, -, 2,3,4tritosyl-, 11, 70 11, 77 D-Galactose, I, 3; 11, 239, 240; 111, 14: 4-(@-D-Galactopyranosyl)-~-altrose. See IV, 146 Neolactose. alkali action on, 111, 113 a-D-Galactopyranosyl bromide, tetrafrom araban, 11, 247 acetyl-, 111, 95 bacterial cellulose from, 11, 207 fl-D-Galactopyruronoside,methyl monofrom blood group substances, IV, 45, methyl-, methyl ester, IV, 263 46, 51 Galactosaccharic acid, 2,5-anhydro-, 11, calcium D-altronate from, I, 67, 68 74 configuration of, I, 7, 33 Galactosaccharic acid, 2,3,4,5-tetrain damson gum, IV, 62 methyl-, dimethyl ester, IV, 289 effect of CY and B anomers on condiamide, IV, 289 ductivity of boric acid, IV, 200 D-Galactosaccharicacid, 2,3,4-trimethyl-, effect on ketonuria, 11,148,160 and dimethyl ester, IV, 289 from h l y bound lipids of M. tuberD-Galactosaccharic 1-amide, 2,3,PtriCUlOSi8, 111, 329 methyl-, 6-methyl ester, IV, 289 n-glucose conversion into, 11, 54 n-Galactosaccharic bis (methylamide), in gums, IV, 246, 246, 250, 253, 266, 2,3-dimethyl-, IV, 288 258, 259, 262 -, 2,4dimethyl-, IV, 289 higher4 sugars from, I, 8 -, 2,3,4trimethyl-, IV, 289 in mucilages, IV, 264, 268, 270, 274, -, 2,4,5-trimethyl-, IV, 289 276 D-Galactosaccharic diamide, 2,3-diorthoesters of, I, 96 methyl-, IV, 288 in ovomucoid, IV, 52 -, 2,4-dimethyl-, IV, 289 oxidation of, 111, 143, 147, 151, 162, -, 2,3,4-trimethyl-, IV, 289 176 -, 2,3,5trimethyl-, IV, 288 from pectins, 11,236 -, 2,4,5-trimethyl-, IV, 289 from polysaccharides of &f. tuberD-Galactosacchario 1,4-lactone, 2,3-dinCl08i8, 111, 317, 333-335 methyl-, &methyl ester, IV, 288 in polyuronides, I, 338

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

reduction to dulcitol, IV, 215 specific rotation of, I, 155 transphosphorylation between adenosine triphosphate and, V, 49, 50 from waxes of M. tuberculosis lipids, 111, 328 from wood, IV, 160 >Galactose, in mucilages, IV, 270 D-Galactose, 3,6anhydro-, phenylosazone, 111, 39 phenylosazone, and diacetate, 111, 33 D-Galactose, %amino-, 11, 167, 169 -, l,banhydro-, 11, 67 -, 3,6-anhydro-, 11, 44, 76 dimethyl acetal, 11, 59, 76 -, 3,6-anhydro-2,4-dimethyl-,and anilide and dimethyl acetal, 11, 76 -, 3,6-anhydro-2,4,5-tribenzoyl-,dimethyl acetal, 11, 76 -, 3,6-anhydro-2,4,5-trimethyl-,and dimethyl acetal, 11, 76 D-Galactose, Bdesoxy-. See also D-

351

-,

methy~-6-(~-glucuronosyl)-, IV, 259 -, 2,3,4,6-tetraacetyl-, and methyl-

phenylhydrazone and phenylhydrazone, 111, 27 -, 2,3,5,6-tetraacetyl-, and methylphenylhydrazone and phenylhydrazone, 111, 27 -, 2,3,4,5-tetraacetyl-6-trityl-, diethyl mercaptal, 111, 108 -, 2,3,4,5-tetrabenroyl-6-trityl-,diethyl mercaptal, 111, 108 D-Galactose, 2,3,4,6-tetramethyl, IV, 248, 251, 254, 267, 268, 274 and methyl p-glycoside, IV, 287 -, thio-, I, 136 -, trimethyl-, methylphenylphenylosazone, 111, 29 -, 2,3,Ctrirnethyl-, IV, 251, 254, 261, 274, 287 -, 2,3,6-trimethyl-, IV, 274 -, 2,4,8trimethyl-, IV, 248, 254, 257, 261, 268, 274, 279 Fumae. and hydrate and methyl (Y and p oxidation of, 111, 144 glycosides, IV, 287 -, Meaoxy-1,2 :3,4-diisopropylidene-6- -, 6-(2,3,4-trimethyl-~-~-glucuronosyl)iodo-, I, 62 2,3,4-trimethyl-, methyl p-glycoside -, 1,2:3,4-diisopropylidene-, tritylation methyl ester, IV, 289 of, 111, 87 amide, IV, 289 -, 1,2: 3,4-diisopropylidene-6-trityl-, 111, -, trithiodi-, I, 136 87 -, 6-trityl-, 111, 84, 107 D-Galactose, 2,Cdimethyl-, IV, 251, 254, L-Galactose, 3,6-anhydro-2,4-dimethyl-, 257, 259 IV, 279 hydrate, (Y and B methyl glycosides, and anilide, 11, 77 IV, 287 -, Mesoxy-, V, 9 D-Galactose anilide, 2,Cdimethyl-, IV, -, 2,5-dimethyl-, IV, 278 and methyl 8-glycoside, IV, 287 287 -, 4,6-dimethyl-, IV, 254 -, 2,6-dimethyl-, IV, 287 phenylosazone, IV, 287 -, Zmethyl-, IV, 287 -, 3-(D-galactopyranosyl)-,IV, 248 -, 4-methyl-, IV, 287 -, ~ - ( D - ~ ~ u c w o ~ oIV, s ~259 ~)-, -, 2,3,4,64etramethyl-, IV, 287 -, 6-(~-~-glucuronosy~)-, Iv, 250, 258 -, 2,3,4-trimethyl-, IV, 287 -, hexamethyl-(BD-glucuronosyl)-, IV, -, 2,4,6-trimethyl-, IV, 287 251 D-Galactose benzylphenylhydrazone, 111, -, %methyl-, IV, 254, 278 26 and methyl pglycoside, IV, 287 n-Galactose diethyl monothioacetal penspecific rotation of, I, 155 taacetate, I, 96 -, Cmethyl-, IV, 254 D-Galactose diethyl thioacetal, V, 26 and phenylosazone, IV, 287 pentaacetate, V, 6, 26 -, &methyl, and methyl 8-glycoside D-Galactosemethylphenylhydrazone, 111, and phenylosazone, IV, 87 26

352

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

D-Galactose methylphenyl-phenyl-osazone anhydride, 111, 34 D-Galactose methylphenyl-phenyl-osazone tetraacetate, 111, 34 D-Galactose p-nitrophenylhydrazone, 111, 26 D-Galactose oxime, I v , 122, 124 -, hexaacetyl-, IV, 123, 150 D-Galactose phenylhydrazones, and their pentaacetates, 111, 26 D-Galactose phenylosazone, 111, 29, 34 D-Galactose phenylosazone anhydride, 111, 31, 39 D-Galactose phenylosrtzone anhydride and diacetate, 111, 32, 33 D-Galactose phenylosazone tetraacetate, 111, 30 D-Galactose phenylosotriazole, 111, 38 a-D-Galactose 1-phosphate, V, 71 D-Galactose sulfates, 11, 178 aldehyde-n-Galactose, l-chloro-l-thioethoxy-, pentaacetate, I, 96 aldehydo-D-Galactose, 1-thioethoxy-3,4,B,&tetraacetyl-, ethyl 1,2-orthoacetate, I, 96, 121 aldehydo-D-Galactose, ethyl hemiacetal pentaacetate, 111, 26 -, 2,3,4,5-tetraacetyl-6-trityl-,ethyl hemiacetal and semicarbasone, 111, 108 aldehydo-D-Galactose aldehydrol, 2,3,4,5tetraacetyl-&trityl-, 111, 108 L-Galactose anilide, 2,3,4,6-tetrametliyl-, IV, 287 “Galactosecarboxylic acid,” I, 3 D-Gdactoseptanose, pentaacetyl-, 111, 102 a-Galactosidase. See a-D-Galactopyranosidase. j%Galactosidaae. See &D-Galactopyranosidaae. D-Galactosone, 11, 82 oxidation of, 11, 84 D-Galacturonamide, methyl a-pyruronoside, IV, 288 -, 2,3-dimethyl-, methyl 8-fururonoside, IV, 288 -, 2,3,4trimethyl-, methyl a-pyruronoside, IV, 288

-,

2,3,5trimethyl-, methyl @-fururonoside, IV, 288 D-Galacturonic acid, 11,175,236,238-242 in gums, IV, 246 in gum tragacanth, IV, 202 in mucilages, IV, 245, 269, 270, 274 poly-a-pyranose anomer in pectins, V, 80

in polyuronosides, I, 338 and sodium calcium salt, I, 70; V, 102 use in ascorbic acid synthesis, V, 102 D-Galacturonic acid, 2,3-dimethyl-, IV, 262, 274 methyl @-pyruronoside,IV, 288 methyl uronoside methyl ester, 11, 176, 243,244 -, methyl-, IV, 262 -, methyl a-pyruronoside, 11, 175; 111, 155 -, methyl a-pyruronoside methyl ester, and hydrate, 11, 175, 176; IV, 288 -, 2,3,4trimethyl-, IV, 272, 273 methyl a- and &pyruronoside methyl esters, 11, 176; IV, 288 -, 2,3,5-trimethyl-, 11, 176 -, 2,3,5-trimethyl-, methyl 8-fururonoside methyl ester, IV, 288 Galacturonides. See under deriuuliues of Galacturonic acid. L-Gala-D-fructo-heptose. See L-Perseulose. n-Galaheptose, origin of name, 111, 12 D-Gala-bgala-octario acid, I, 29 L-Gala-D-gala-octaric acid, I, 29 D-Gala-L-gala-octitol, and octaacetate, I, 35 D-Gala-L-gala-octonic acid, I, 29 D-Gala-L-gala-octononitrile, heptaacetyl-, IV, 150 D-Gala-bgala-octose oxime, IV, 124 heptaacetate, IV, 124 octaacetate, IV, 150 D-Gala-Irgluco-heptitol, I, 9, 11 and heptaacetate, I, 35 L-Gala-D-glwo-heptitol, I, 14 and heptaacetate, I, 35 L-Gala-wgluco-heptonic acid, 7-desoxy-, I, 30 *Gala-bglwo-heptose, I, 9, 20, 21

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

D-Gala-bgulo-octitol, I, 22 and octaacetate, I, 35 D-Gala-cgulwctose, I, 22 “a-Galaheptitol,” I, 8 “B-Galaheptitol,” I, 8 “a-Galaheptose,” I, 8 “8-Galaheptose,” I, 8 D-Galaheptose phenylosotriazole, 111, 38 L-Galaheptulose, See IcPerseulose. D-Gala-edo-octitol, I, 22 D-Gala-bido-octose, I, 22 o-Gala-manno-heptitol. See bPerseitol. D-Gala-bmanno-heptitol, 1-desoxy-, V, 10 LGala-D-manno-heptitl, 7-desoxy-, V, 9 D-Gala-bmanno-heptonic acid, I, 3 cGala-D-manno-heptonic acid, 7-desoxy-, I, 30; V, 9 D-Gala-bmanno-heptononitrile,hexaacetate, IV, 149 D-Gala-cmanno-heptose, I, 9; V, 10 D-Gala-cmnno-heptose, 7-desoxy-, I, 31 D-Gala-bmanno-heptose oxime, heptaacetate, IV, 122, 125, 150 D-Gala-D-mnno-nonitol, I, 31 Galaoctose, I, 8 origin of name, 111, 12 Gallic acid, 111, 75 effect on conductivity of boric acid, IV, 191 D-mannitol and D-sorbitol esters, IV, 302 Galtose, 111, 115 Galuteose, 11, 224 Gastric juice, blood group substances from, IV, 43, 46, 48 Gelatinization, of starch, I, 275 Gelation, configuration and, I, 277 of starch, I, 264, 272 Gel-forming substances, I, 331 Gels, pectin, 11, 238 Gentianose, 11, 29, 34 hydrolysis by &D-fructofuranosidase, V, 68 Gentiobial, 2-hydroxy-, heptaacetate, V, 16 a-Gentiobiopyranoside, methyl, 111, 93, 94 heptaacetate, 111, 93

353

fl-Gentiobiopyranoside, phenyl 1-thio-, heptaacetate, V, 16, 17, 27 Gentiobiose, 111, 93, 94 hydrolysis by fl-D-glucopyranosidase, V, 61 from starch, 111, 252 Gentiobioside. See Gentiobiopyranoside. Germicidal soap, phenylmercury levulinate in, IV, 312 Gitoxin, I, 163 Glass, from bagasse ash, IV, 296 Glaucoma, D-sorbitol in treatment of, I, 189 Globoglycoid, 11, 165, 195 Globulin, 11, 194 D-Glucal, 2-hydroxy-, tetraacetate, V, 15, 198 -, triacetate, 111, 169 Glucic acid, 111, 127 Glucitol. See also Sorbitol. D-Glucitol, 1-desoxy-, pentaacetate, V, 6 DbGlucitol, 111, xxii physical properties of, IV, 219 D-Glucitol, 1,4-anhydro-, 111, xv% -, 2,5-anhydro-l,6-dibenzoyl-,111, xviii -, 2-desoxy-, 111, xx -, 1,4:3,6-dianhydro-, 111, xx GGlucitol, 111, xxii; IV, 216 physical properties of, IV, 219 -, 6-desoxy-1-trityl-, 111, 110 -, dibenzylidene-, IV, 240 -, hexaacetyl-, IV, 240 -, trimethylene-, IV, 240 D-Glucoascorbic acid, 11, 81-83, 96, 97 -, 2,3-dimethyl-, 11, 97 -, imino-, 11, 81 -, 2,3,5,6,7-~entamethyl-,11, 97 L-Glucoascorbic acid, 11, 83, 91, 95 Glucocheirolin, I, 131, 132 Glucoconiferyl aldehyde, tetraacetyl-, IV, 80 “D-a,a,Cy,a-Glucodeconic” lactone, I, 18, 20 “D-a,a,a,fl-Glucodeconic ” lactone, I, 18, 20 “D-a,a,cr,a-G1ucodecose,” I, 17, 29 D-Glucofuranose, 3-acetyl-1,2-kopropyfidene-, I, 111

384

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

-,

3-acetyl-l,%isopropylidene-6-trityl-, -, methyl 3,6-anhydro-2,5-dimethyl-,11, 111, 106 75 -, 5-acetyl-3,6anhydro-1,2-isopropyli- -, methyl 3,6-anhydro-2,5-ditosyl-,11, dene-, 11, 75 75 -, 3,6-anhydro-5-benzoyl-l~2-isopropyli--, methyl 5-bensoyl-2,3,6-trimethyl-, dene-, 11, 75 V, 178 -, 3,6-anhydro-l,2-isopropylidene-, 11, -, methyl 2,3,5,6-tetramethyl-, V, 190 75 -, methyl 3-tosyl-2,5,6-triacetyl-,11, 51 -, 3,6-anhydro-1,2-isopropylidene-5-, methyl 5-tosyl-2,3,6-trimethyl-, V, methyl-, 11, 76 178 -, 3,6-anhydro-1,2-isopropylidene-b -, methyl 2,3,6-trimethyl-, V, 178 tosyl-, 11, 44, 75 -, methyl 3,5,6-trimethyl-, V, 185 -, 3,6-anhydro-1,2,5-triacetyl-,11, 75 a-D-Ghcofuranosyl bromide, 2-acetyl-, 5,6-anhydro-1,2-isopropylidene-,11, 3,6-anhydro-&tosyl-, 11, 75 40, 48, 68, 72 3-beneoyl-1,2-isopropylidene-,I, 110 6-desoxy-l,2 :3,5-diisopropylidene-6nitro-, 111, 54 -, 6-desoxy-1,2-isopropylidene-6-nitro-, 111, 54 -, 3,5-diacetyl-6-desoxy-6-iodo-l,2-isopropylidene-, 111, 103, 104 -, 3,5-diacetyl-l,2-isopropylidene-6-trityl-, 111, 107 -, 3,5-dibenzoyl-l,2-isopropylidene-6trityl-, 111, 107 -, 1,2: 5,6-diisopropylidene-, IV, 198 tritylation of, 111, 87 -, 1,2: 5,6-diisopropylidene-3-trityl-,111, 87, 107 -, 1,2-isopropylidene-, 111, 54 -, 1,2-isopropylidene-3tosyl-,11, 51 -, 1,2-isopropylidene-6-trityl-,3-phosphate, 111, 107 -, tetramethyl-, V, 194 a-D-Glucofuranose, 3,6-anhydro-5-tosyl-, 11, 75 a-n-Glucofuranoside, ethyl thio-, I, 139, 140 -, methyl 3,6-anhydro-, 11, 75 -, methyl 3,6-anhydro-2,5-dimethyl-, 11, 75 -, methyl 2,3,5,6-tetramethyl-, V, 190 -, methyl 3,5,6-trimethyl-, V, 186 a-n-Glucofuranoside, propyl thio-, I, 138-140 fl-n-Glucofuranoside, methyl 3,g-anhydro-, 11, 52, 58, 75 -, methyl 3,6-anhydro-2,5-dibenzoyl-, 11, 75

-, -,

u-D-Glucofuranosyl chloride, 2-acetyl3,6-anhydro-5-tosyl-, 11, 75 n-Glucofuranosylamine, N-acetyl-, IV, 135-137, 147 D-Glucofururonolactone, 1-chloro-2.5-diacetyl-, 11, 171 ~-~~ucofururono-3,6-~aotone, 1,2-isopropylidene-, 11, 173 8-D-Glucofururonoside, methyl 2,5-dimethyl-, V, 165 amide, V, 165 8-n-Glucof ururonoside-3,6-lactone, methyl, 11, 172 fl-n-Glucof ururonoside-3,6-lactone, methyl 2,5-dimethyl-, 11, 172; V, 165 D-Gluco-D-gala-decose, I, 29 I, 20, 22 D-G~uco-L-ga~a-octitol, and octaacetate, I, 35 D-Gluco-L-gala-octose, I, 20, 22 Gluco-gulo-heptitol, and heptaacetate, I, 9, 34, 35 -, L,7-ditrityl-, 111, 110 D-Gluco-D-gulo-heptonic acid, I, 3, 24 lactone, I, 23 n-Gluco-n-guto-heptononitrile, hexaacetyl-, IV, 126, 130. 147, 149 D-Gluco-D-gulo-heptose, I, 9, is; 111, 12; IV. 147 n-Gluco-D-guto-heptose, orthoesters of, I, 88 ~-Gluco-~-gu~o-heptse, tetraacetyl-, methyl 1,2-orthoacetate, I, 88 n-Gluco-D-guh-heptose oxime, I v , 125 D-Gluco-j3-D-guto-heptosyl chloride, pentaacetyl-, I, 88

CUMULATIVE BUBJECT INDEX FOR VOLS. I-V

355

D-Glucoheptoascorbic acid, 11, 83, 90, 95 -, bmethyl-, V, 155 Glucoheptose, origin of name, 111, 12 phenylhydrazide, V, 155 “a-Glucoheptose,” I, 7. See a180 Dsodium salt, V, 155 Glum-D-gulo-heptose. -, 4-methyl-, &lactone, V, 156 D-Gluco-D-ido-heptose, 111, 12 D-Gluconic acid, pentaacetyl-, 111, 153 D-Gluco-n-manno-nonitol,I, 31 -, 2,3,4,6-tetramethyl-, V, 188 D-Glum-D-manno-nonose, I, 29 amide, V, 188 Glucon, V, 61 &lactone, IV, 12; V, 188 D-Gluconamide, 3,6-anhydro-, 11, 76 phenylhydrazide, V, 188 -, 3,6anhydro-2,Pdimethyl-, 11, 76 -, 2,3,5,6-tetramethyl-, V, 190 -, 3,6-anhydro-2,5-dimethyl-,11, 76 amide, V, 190 -, 3,&anhydro-4-methyl-, 11, 76 b-lactone, 111, 194; V, 190 -, 3,6-anhydro-5-methyl-, 11, 76 phenylhydrazide, V, 190 -, 2,4,6-trimethyl-, V, 181 -, 2,3,Ptrimethyl-, V, 175 D-Gluconasturtiin, I, 131 -, 2,3,54rirnethyl-, V, 174, 176 D-Gluconate, methyl thiol-, V, 23, 28 y-lactone, V, 176 D - G ~ U C acid, O ~ ~I, C 24; 111,140,141,150, phenylhydrazide, V, 176 151,154, 155, 161, 163 -, 2,3,6trimethyl-, V, 178 y-lactone, reduction to D-sorbitol, IV, y-lactone, V, 178 214 I-lactone, V, 178 manufacture of, 111, 152 phenylhydrazide, V, 178 optical rotation of, IV, 72 -, 2,4,6trimethyl-, amide, V, 181 oxidation of, 111, 147 -, 3,4,6-trimethyl-, V, 184 from aucrose, IV, 322, 330 phenylhydrazide, V, 184 LGluconic acid, I, 4 -, 3,5,6-trimethyl-, V, 185 D-Gluconic acid, 2-amino-2-desoxy-, 11, amide, V, 185 63; 111, 145 y-lactone, V, 185 -, 2,5-anhydro-. See Chitaric acid. sodium salt, V, 185 -, 3,6anhydro-, 11, 70 D-Gluconic acid nitrile, 111, 354; Iv, 127, -, 3,6-anhydro-2,4-dimethyl-,11, 76 141, 149 -, 3,6-anhydro-Prnethyl-, methyl ester, -, 2-(~-glucopyranosyl)-, octaacetate, 11, 76 IV, 148 D-Gluconic acid, 2-desoxy-, 111, 73, 74 -, 3-(~-glucopyranosyl)-, octaacetate, -, 2,3: 4,5-diisopropylidene-2-keto-,11, IV, 148 85, 86 -, 2-(D-glUCOSyl)-, octaacetate, IV, 150 -, 3,4,5,6-diisopropylidene-2-methyl-, -, 3-(D-glUCOSyl)-, octaacetate, IV, 150 methyl eater, V, 150 -, pentaacetyl-, IV, 120, 121, 126, 128, -, 2,Bdimethyl-, phenylhydrazide, V, 141, 143, 146, 149 163 Wohl degradation of, IV, 129 -, 2,6-dimethyl-, phenylhydrazide, V, Zemplbn degradation of, IV, 139 166 -, pentabenzoyl-, IV, 126, 146, 149 -, 2-keto-, 11, 84-86; 111, 148, 163 degradation of, IV, 130 methyl ester, 11, 87 -, pentapropionyl-, IV, 129, 142, 146, in mucilage, IV, 275 149 from sucrose, IV, 322, 330 D-Gluconic y-lactone, 3,6-anhydro-, II,76 -, 5-keto-, from sucrose, IV, 322, 330 -, 3,6-anhydro-2,5-dimethyl-,11, 76 GGluconic acid, 5-keto-, 111, 149 -, 3,6anhydro-5-methyl-, 11, 76 D-Gluconic acid, 2-methyl-, V, 150 L-Gluconic lactone, 6-desoxy-, 111, 144 amide, V, 150 D-Glucononose, I, 7, 29 y-lactone, V, 150 D-Glucooctitol, and octaacetate, I, 21

356

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

D-Ghcooctose, I, 7; 111, 12 a-~-Glucopyranoseenide(6,6), methyl 2,3,4-triacetyl-, 111, 103 D-Glucopyranose, 111, 18 -, 6-(~-carabopyranosyl)-. See Vicianose. -, 3-benzyl-l,2,4-triacetyl-6-trityl-,111, 106 -, 8-(a-D-galactopyranosyl)-. See Melibiose. -, 6(&D-galactopyranosyl)-, 111, 96 -, 4-(p-~-glucopyranosyl)-.See Cellobiose. -, 6methyl-, 111, 96 -, 2,3,4,6-tetramethyl-, from amylose, 111, 266 from corn starch, 111, 296 from dextrin, 111, 292 from starch, 111, 267 -, 2,3,4,6-tetramethyl-, III,18, 146,194, 196, 201; IV, 10, 11, 123 from cellulose, 111, 190, 207 reducing power of, 111, 160 -, Ptosyl-2,3,6-trimethyl-, 11, 65 -, 2,4,6-trimethyl-, IV, 282, 289 -, 6-(8-D-XylOpyranOSyl)-. See Primeverose. a-D-Ghcopyranose, 1,2,3,4-tetraacetyl-6trityl-, 111, 106 -, 6-trityl-, 111, 106 D-Glucopyranose, &trityl-, 111, 90 p-D-Glucopyranose, 1,2,3,&tetraacetyl-, 111, 90, 91, 93,94 -, 1,2,3,4-tetraacetyl-6-trityl-,111, 90, 106 -, 4-to~yl-,111, 92 D-Glucopyranose. see also D-Glucose and Dextrose. D-Glucopyranose, a- and 8-, IV, 198 -, 1,2-anhydro-, 11, 38, 64, 69 -, 1,2-anhydro-3,4,6-triacetyl-,11, 69 -, 1,2-anhydro-3,4,6-tribenzoyl-,11, 69 -, 1,2-anhydro-3,4,6-trimethyl-,11, 69 -, 2(~-glucopyranosyl)-,IV, 148 -, 3-(~-glucopyranosyl)-,IV, 139, 148 D-Glucopyranose, 4-(~-~glucopyranosy1)-. See Maltose. a-D-Glucopyranose, 1-phosphate, 111, 268, 264; IV, 31; V, 29-46, 68, 69, 71

D-Glucopyranose, 2,3,4,6-tetraacetyl-, IV, 28 D-Glucopyranose,2,3,4trimethyl-, V, 175 anilide, V, 176 a-l,Bdi-azobenzoate, V, 176 l,&dinitrate, V, 175 a-D-Glucopyranose, 1,4-anhydr0-2,3,6trimethyl-, 111, 66, 69 8-D-Glucopyranose, 11, 40, 240 &D-Glucopyranose, l,&anhydro-, 11, 38, 40, 64, 66, 69 -, l,B-anhydro-2,&diacetyl-~~osyl-,11, 69 -, 1,6-anhydr0-2,4-dibenzoyl-,11, 69

-,

-,

-, -,

1,6-anhydro-2,4-dibensoyl-3-tosyl-, 11, 69 1,6-anhydro-2,3,4-triacetyl-,11, 69 1,6-anhydro-2,3,4-tribenzoyl-, 11, 69 1,6-anhydro-2,3,4-tribenzyl-, 11, 69

@-D-Glucopyranose, 1,2,3,4 and 1,2,3,6tetraacetates, structures of, I, 109 @-D-Glucopyranosidase,IV, 30; V, 60-65 D-Glucopyranoside,benzyl 1-thio-, u-and 8-anomers, I, 138 -, ethyl 1-thio-, a- and @-anomers, I, 138 -, methyl, a- and 8-, effect on conductivity of boric acid, IV, 198 -, methyl 3,6-anhydro-, 11, 44 -, methyl 3,&anhydro-2,4-dimethyl-, 11, 69 -, methyl 3-benzyl-2,4-dimethyI-6-trityl- (anomeric mixture), 111, 106 -, methyl tetramethyl-, a-and 8-, effect on conductivity of boric acid, IV, 197, 198 -, methyl Sthio-, Q- and 8-anomers, I, 138 -, phenyl 1-thio-, I, 132 a-D-Glucopyranoside, ethyl 1-thio-, I, 139 -, 1,2-ethylene-6-trityl-, 111, 107 a-D-Glucopyranonde, ho-menthyl-, 111, 377 -, methyl, acylation of, 111, 91 configurational formula, III,1,2,18-20 D-altrose from, I, 54, 65 tritylation of, speed of, 111, 86 a-D-Glucopyranoside, methyl, 111, 15 from cellulose, 111, 189, 190 oxidation of, 111, 164

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

-,

357

methyl 2-acetamido-4,6-dimethyl-, 11, -, methyl 4,6-dirnethyl-, V, 171 168 -, methyl 4,6-dimethyl-2,3-di-p-nitro-, methyl 4acetyl-2,3-dimethyl-6-tribenzoate, V, 171 tyl-, V, 163 -, methyl 4,6-dimethyl-2,3-ditosyl-, V, -, methyl 2-amino-4,6-benzylidene-, I, 171 61 -, methyl 4-(3,5-dinitrobenzoy1)-2,3,6-, methyl 3,6-anhydro-, 11, 75 trimethyl-, V, 178 -, methyl 3,Banhydro-, 111, 101 -, methyl 3,4di-N-phenylcarbamy1-2,6-, methyl 3,6-anhydro-2,4-dimethyl-, 11, dimethyl-, V, 166 75 -, methyl 2-methyl-, V, 150 -, methyl 3,6-anhydro-4methyl-, 11, 75 -, methyl 2-methyl-3,4,6-triacetate, V, -, methy1 2-azobenzoyl-3,4,6-trimethyl-, 150 V, 184 -, methyl 3-methyl-, V, 155 -, methyl 4azobenzoyl-2,3,6-trimethyl-, -, methyl Bmethyl-, V, 161 V, 178 -, methyl 6-methyl-2,3,4tribenzoate, V, -, methyl 4benzoyl-2,3-dimethyl-6-tri161 tyl-, V, 163 -, methyl 2,3,4,6-tetramethyl-, V, 188 -, methyl 4,6-benzylidene-2,3-dimethyl-, -, methyl 3-tosyl-2,4,6-trimethyl-, V, V, 163 181 -, methyl 4,6-benzylidene-2,3-ditosyl-,I, -, methyl 2,3,4triacetyl-, 111, 93 54, 55 -, methyl 2,3,4triacetyl-6-trityl-, 111. -, methyl 4,6-benzylidene-3-methyI-, V, 84, 98, 106 155 -, methyl 2,3,4-tribenzoyl-6-trityl-,111. -, methyl 4,6-benzylidene-3-methyl-2106 tosyl-, V, 155 -, methyl 2,3,4trimethyl-, 111, 97; V, -, methyl 6-bromo-6-desoxy-2,3,4-tri175 acetyl-, 111, 103 -, methyl 2,3,4trimethyl-6-trityl-, 111, -, methyl 6-chloro-6-desoxy, 111, 98 106; V, 175 -, methyl 6-chloro-6-desoxy-2,3,4tri- -, methyl 2,3,6-trimethyl-, V, 178 acetyl-, 111, 98 -, methyl 2,4,6-trimethyl-, V, 181 -, methyl Bdesoxy-6-iodo-2,3,4tri-, methyl 3,4,6-trimethyl-, V, 184 acetyl-, 111, 103 -, methyl 6-trityl-, 111, 106 -, methyl 2,4diacetyl-&tosyl-6-trityl-, -, 6-phosphate, 111, 92 111, 106 8-D-Glucopyranoside, benryl 2,4,6-tri-, methyl 2,3-di-azobenzoyl-4,6-dimethyl-, V, 181 methyl-, V, 171 -, ethyl, IV, 31 -, methyl 4,6-di-azobenzoyl-2,3-di-, ethyl 1-thio-, I, 137, 139 methyl-, V, 163 -, 1,2-ethylene-6-trityl-, 111, 107 -, methyl 2,3-dibenzoyl-4,6-dimethyl-, -, Zevo-menthyl-, 111, 377 V, 171 8-D-Glucopyranoside, methyl, 111, 15 -, methyl 2,3-dibenzyl-4,6-dimethyl-, V, acylation of, 111, 91 171 from cellulose, 111, 189, 190 -, methyl 2,3-dimethyl-, V, 163 configurational formula, 111,1,2,18-20 -, methyl 2,3-dimethyl-4,6-furylidene-, 8-D-Glucopyranoside, methyl 2-acetylV, 163 4,6-ethylidene-3-methyl-, V, 155 -, methyl 2,3-dimethyl-4tosyl-6-trityl-, -, methyl 3-acetyl-2,4dimethy1-6-niV. 163 trate, V, 164 -, methyl 2,3-dimethyl-&trityl-, V, 163 -, methyl 3,4(?)-anhydro-6-trityl-, methyl 2,4dimethyl-, V, 164 acetyl-, 111, 107 -, methyl 2,6-dimethyl-, V, 166 -, methyl 3,6-anhydro-, 111, 101

358

CUMULATIVE SUBJECT INDEX FOR VOCS. I-V

methyl 3,6-anhydro-, 11, 38, 58, 59, -, 76 -, methyl 3,6-anhydro-2,4-diaoetyl-,11, -, 76 -, -,methyl 3,6-anhydro-2,Cdimethyl-, 11, -, 76 -, methyl 2-azobenzoyl-3,4,btrimethyl-, -, V, 184 -, -, methyl 4-azobenzoyl-2,3,6-trimethyl-, V. 178 -, -, methyl 6-azobenzoyl-2,3,4-trimethyl-, V, 175 -, -, methyl 4benzeneaulfonyl-2,3,btrimethyl-, V, 178 -, -, methyl 2-benzoyl-3,4-dimethyl-b -, trityl-, V, 168 -, methyl 2-benzyl-3,4,6-trimethyl-, V, -, 184 -, methyl 4,bbenzylidene-, V, 163 -, -, methyl 4,6-benzylidene-2-methyl-, V, 150 -, -, methyl bbromo-bdesoxy-2,3,4tri- -, methyl-, V, 175 -, methyl 2-chloro-2-desoxy-, I, 58 -, -, methyl 2,4-diacetyl-3-tosyl-6-trityl-, 111, 106 -, -, methyl 4,6-dibenzenesulfony1-2,3-di- -, methyl-, V, 163 -, methyl 2,4dibenzoyl-3,bdimethyl-, -, V, 169 -, methyl 4,6-dibenzoyl-2,3-dimethyl-, -, V, 163 -, methyl 2,3-dimethyl-, V, 163 -, -, methyl 2,3-dimethyl-4,6-ethylidene-, -, V, 163 -, methyl 2,3-dimethyl-3-tosyl-btrityl-, -, 111, 106 -, methyl 2,4-dimethyl-, 111, 89, 97; V, -, 164 -, -, methyl 2,4-dimethyl-3,6-dinitrate, V, -, 164 -, -, methyl 2,4-dimethyl-bnitrate, V, 164 -, -, methyl 2,4-dirnethyl-&tosyl-, V, 164 -, methyl 2,4dimethyl-&tosy1-6-trityl-, -, V, 164 -, -, methyl 2,6-dimethyl-3,4-dinitrate,V, 166 -, -, methyl 2,6-dimethyE3,4ditosyl, V, -, 106 -, methyl 3,Pdimethyl-, V, 168 -,

-,

methyl 3,4dimethyL2,bdinitrate, V, 168 methyl 3,4-dimethyl-btrityl-, V, 168 methyl 3,6-dimethyl-, V, 169 methyl 3,6-dimethyl-2,4-ditosyl-, V, 169 methyl 4,6-dimethyl-, V, 171 methyl 4,6-dimethyl-2,3-ditosyl, V, 171 methyl 4,6-ethylidene-2-methyl-, V, 150 methyl 4,6-ethylidene-&rnethy1-2to~yl-,V, 165 methyl 2-methyl-, V, 150 methyl 2-methyl-3,4,6-triscetate, V, 150 .methyl 2-methyl-3,4,6-tribenzoate,V, 150 methyl 2-methyl-3,4,6-tritosylate, V, 150 methyl &methyl-, V, 155 methyl &methyl-2,4,6-triacetate, V, 155 methyl &methyl-2,4,&tribenzoate,V, 155 methyl Cmethyl-, V, 156 methyl 4methyl-2,3,btriacetate, V, 156 methyl 4-methyl-2,3,6-tribenzoate, V, 156 methyl 4-methyl-2,3,6-trinitrate, V, 156 methyl bmethyl-, V, 161 methyl bmethyl-2,3,Ctriaoetate, V, 101 methyl bmethyl-2,3,4-tribenzoate,V, 161 methyl tetraacetyl-, I, 109 methyl 2,3,4,6-tetramethyl-, V, 188 methyl 2-tosyl-, I, 60 methyl 2-tosyl-3,4,btriacetyl-, 11, 51 methyl 2-tosyl-3,4,6-trimethyl-, V, 184 methyl 3-tosyl-, 11, 53 methyl 3-tosyl-2,4,btrimethyl-, V, 181 methyl 3-toayl-btrityl-, 111, 97, 106 methyl 4-tosyl-2,3,6triacetyl-, 111, 102 methyl 2,3,Ptriacetyl-, 111, 85

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

-,

methyl 2,3,4-triacetyl-6-trityl-, 111, 85, 106 -, methyl 2,3,6-triacetyl-, 111, 85, 95 -, methyl 3,4,6-triacetyl-, I, 60; 111, 18 -, methyl 2,3,Ptrimethyl-, V, 175 -, methyl 2,3,4-trimethyl-6-nitrate, V, 176 -, methyl 2,3,6trimethyl-, V, 178 -, methyl 2,4,6-trimethyl-, V, 181 -, methyl 3,4,6trimethyl-, V, 184 -, methyl &trityl-, 111, 86, 106 -, phenyl, enzymatic hydrolysis, V, 62, 63 -, phenyl 1-thio-, V, 65 tetraacetate, V, 16, 27 -, phenyl 2,3,4-triacetyl-6-trityl-, 111, 106 -, phenyl 2,4,6-trimethyl-, V, 181 -, ptolyl 1-thio-, tetraacetate. V, 16,27 a-L-Glucopyranoside, methyl, 111, 16 0-L-Glucopyranoside, methyl, 111, 16 8-D-Gluoopyranosides, enzymatic synthesis of, V, 57 D-Glucopyranosyl chloride, 2,3,4-triacetyl-, 111, 91 -, 2,3,&trimethyl-, 11, 60 o-Glucopyranosyl fluoride, 2,3,4-triacetyl-6-trityl-, 111, 107 -, 2,3,4tribenzoyl-, 111, 93, 94 -, 2,3,4-tribenzoyl-6-trityl-,111, 107 -, 6-trityl-, 111, 107 a-D-Glucopyranosyl bromide, 4-acetyl-6desoxy-2,3-ditosyl-6-iodo-, I, 302 -, Pacetyl-2,3,&tritosyl-, I, 302 -, 6-bromo-6-desoxy-2,3, Mriacetyl-, 111, 84, 89 -, tetraacetyl-, 111, 93, 95 D-Glucopyranosylamhe, N-benzoyL(2thioethy1)-, IV, 136 ~-D-Glucopyranosyltrimethylammonium bromide, and 6-trityl ether, 111, 86 D-Glucopyruronoside, methyl, methyl ester, 11, 173 8+-Glucopyruronoside, methyl 2,3,4-trimethyl-, methyl ester, 11, 172 D-Glucosaccharic acid, 11, 103, 104; 111, 57, 146 from sucrose, IV, 298 ~,L-Glucosaccharicacid, 111, 49, 50, 63

359

D-Glucwccharic acid, 2,5-anhydro-, 11, 62 and Ca and KH salts, 11, 74 L-Glucosaccharic acid, 2,3-anhydro-, and potassium hydrogen salt, 11, 74 D-Glucosaccharic acid, dilactone, 11, 103 -, 1,4-lactone, 2,3,btrimethyl-, 11, 172 -, 2,4:3,5-dimethylene, IV, 298; V, 217 D-Glucosaccharic acid amide, 2,3-dimethyl-, IV, 289; V, 163 -, 2,5-dimethyl-, V, 165 -, 2,3,5-trimethyl-, IV, 290; V, 176 D-Glucosaccharic acid 1,4-lactone, 11, 103, 104 -, 2,3-dimethyl-, 6-methyl ester, IV, 289 -, 2,3,5-trimethyl-, 6-methyl ester, IV, 290; V, 176 D-Glucosaccharic acid l,blactone, 2,3,4trimethyl-, 6-methyl ester, IV, 289; V, 175 D-Glucosaccharic acid 3,64actone, 11, 103, 104 -, 2,4methylene-, IV, 298 A4-~-Glucosaccharic acid, 3,6-lactone, 2,bdimethyl-, methyl ester, 11, 104, 105, 172 Glucosaccharo-. See derivatives of Glucosaccharic acid. D-Ghcosamine, I, 30, 60, 61; 11, 60-62, 68, 167; 111, 353 from blood group substances, IV, 45,46 from firmly bound lipids of M.tuberculosis, 111, 329 from M. tubercu~oeis polysaccharides, 111, 318, 335 oxidation of, 111, 145, 177. from waxes of M. tuberculosis lipids, 111, 328 D-Glucosamine, N-acetyl-, in blood group substances, IV, 45, 46, 51 in ovomucoid, IV, 52 -, N-acetyl-, diethyl thioacetal, 111, 384 -, pentaacetyl-, diethyl thioacetal, 111, 384 D-Glucosamine, pentaacetyl-N-methyl-, 111, 353 a-D-Glucosamine, N-methyl-, 111, 353, 382 -, pentaacetyl-N-methyl-, 111, 382 ~-Glucosamine,111, 353, 382

360

-, -,

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

N-acetyl-N-methyl-, 111, 354, 382 N-methyl-, 111, 352-354, 356, 359361, 382 a-cGlucosamine, N-methyl-, hydrochloride, 111, 382 -, pentaacetyl-N-methyl-, 111,353, 354, 356, 375, 382 8-L-Glucosamine, pentaacetyl-N-methyl-, 111, 354, 375, 382 a-n,bGlucoaamine, pentaacetyl-Nmethyl-, 111, 382 o-Glucosamine diethyl thioacetal, pentaacetate, V, 11, 26 D-Glucosamine oxime, IV, 125 n-Glucosaminic acid, 11, 63 -, N-methyl-, 111, 353, 382 L-Glucosaminic acid, 111, 353 -, N-methyl-, 111, 353, 354, 382 L-Glucosaminic acid nitrile, N-methyl-, 111, 354, 382 -, pentaacetyl-N-methyl-, 111, 382 D-Glucosaminide, methyl, 11, 168 -, methyl N-acetyl-, 11, 168 -, methyl N-acetyl-3,4,6-trimethyl-,IV, 47 D-Glucosaminonitrile, pentaacetyl-, IV, 129, 149 cGlucosaminonitrile, N-methyl-, IV, 127, 149 -, pentaacetyl-N-methyl-, IV, 126, 149 a-Glucosan, 11, 38, 64, 69 -, 3,4,6-triacetyl-, 11,69 -, 3,4,6-tribenzoyl-, 11, 69 -, 3,4,6-trimethyl-, 11,69 D-Glucose (See also D-Glucopyranose and Dextrose), I, 2,3, 17; 11,240; 111, 14, 75, 114 from acetic acid, 11, 130 alcoholic fermentation, V, 50 alkali action on, 111, 113, 116, 123 from alpha dextrins, 111, 277 from amygdalin, V, 60 from arrow-root starch, 111, 274 bacterial cellulose from, 11, 207 biological synthesis of, 111, 246, 249 from butyric acid, 11, 132 in cardiac glycosides, I, 148 as cellulose basic unit, 111, 189 configuration of, I, 18, 33; 111,5, 8 configuration in sucrose, IV, 1-35; V, 39

convereion into D-galactose, 11, 54 conversion into palmitic acid, 11,121 dehydrophenylosazone, 111, 39 effect on conductivity of boric acid, IV, 196, 198 effect on ketonuria, 11, 148, 152, 158 effect on rate of disappearance of ketone bodies, 11, 153 bglucitol from,,IV, 216 from glycerol, 11, 126 higher-carbon sugars from, I, 7 hydrogenation of, IV, 300 from inulin, 11, 256 labelled with isotopic C, 111, 244 methylphenyl-phenylhydrazone and anhydride, 111, 35 in mucilage, IV, 268, 275 from Mycobacterium tuberculosis polysaccharides, 111, 317, 320 -nitrogen ratio in fat metabolism, 11, 135 oxidation of, 111, 140, 141, 147, 148, 150-152, 156, 162, 163, 165, 172, 173, 176, 180 oxime hexaacetate, 111, 30 pentaacetate, IV, 28 pentaacetate, AlCls rearrangement of, I, 46 phenylhydraeones, and their pentaacetates, 111, 24 phenyl-methylphenylosazone and anhydride, 111, 35 phenylosazone, 111, 29, 34, 121, 353 phenylosazone anhydride, 111, 31, 39 phenylwazone anhydride diacetate, 111, 32 phenylosazone, reaction with KOH, 111, 40 phenylosazone, tetraacetate, 111, 30 phenylosotriazole, 111, 38, 121, 353 &phosphate, I, 306; 111, 303 in polyuronides, I, 338 reducing power of, 111, 160 reduction with asparagine, 111, 126 reduction to D-sorbitol, IV, 213 refractive index of, 11, 17 relation to meso-inositol, 111, 53 from soluble starch, 111, 272 from wsorbitol, 111, 150 specific rotation of, I, 155

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

from starch, 111, 254, 269, 308 sulfuric acid esters, 11, 178 from wood, IV, 160, 186 from wood sugars, IV, 146 D-Glucose, formed from starch, by acid hydrolysis, V, 127-143 by amylase of Aapergillua wyzae, V, 250-255 by amylase of malted barley, V, 255265 by pancreatic amylase, V, 235,247-250 by salivary amylase, V, 265 D-Glucose, aceto-, ieothiocyanate and thiocyanate, I, 133 -, acetobromo-, V, 202 -, 5-acetyl-3,6-anhydro-, 11, 75 -, 2-amino-2-desoxy-, I, 61; 11, 167 -, bamino-bdesoxy-, I, 59, 60 -, anhydro-, as celluloae units, 111, 192 -, 1,2-anhydro-, 11, 40, 65 -, 3,banhydro-, 11, 44, 75; V, 197 -, 3,Banhydro-, phenylosazone, 111, 31, 32, 39 -, 3,6anhydro-2,4-dimethyl-,11, 75 -, 3,6-anhydro-2,5-dimethyl, and anilide, 11, 75; V, 165 -, 3,6-anhydro-4-methyl-, 11, 75 -, 3,6-anhydro-2,4,5-trimethyl-,and dimethyl acetal, 11, 59, 75 D-Glucose, &(a-tarabinosyl)-. See Vicianose. -, bbenzyl-Btrityl-, 111, 106 -, 2-desoxy, oxidation of, 111, 144 -, 2-desoxy, 2-thioethyl-, I, 143 -, 3-desoxy-3-thiomethyI-, I, 142 -, 6-desoxy-, tetraacetate, V, 24 -, 6-desoxy-biodo, tetraacetate, V, 24 -, 6-desoxy-6-nitr0, 111, 54, 55 -, Bdesoxy-6-thiomethyl-, I, 144 -, diethyl thioacetal, pentaacetate, V, 6, 26 -, dimethyl-, from methylated starch, I, 269 -, 2,bdimethyl-, reducing power of, 111, 160 -, 2,bdimethyl, and derivatives, V, 160163 anilide, V, 163 phenylhydrazone, V, 163 1,4,6-triazobenzoate, V, 163

-,

361

2,bdimethyl-, from methylated starch and glycogen, 111, 257 -, 2,ldimethyl, and derivatives, V, 162164 -, 2,5-dimethylJ derivatives of, V, 164165 -, 2,6-&methyl-, and derivatives, V, 165-167 1,3,4-triazobenzoateJV, 166 -, 3,Pdimethyl, and derivatives, V, 167, 168 phenylosazone, V, 168 -, 3,5-dimethyl-, V, 168 -, 3,Bdimethyl-, and derivatives, V, 168, 169 1,2-isopropylidene-, V, 169 -, 4,6-&methyl-, and derivatives, V, 170, 171 1,2,btriazobenzoate, V, 171 -, 5,&dimethyl-, and derivatives, V, 171, 172 3-benzoxymethyl-lJ2-~opropylidene-, V, 172 3-benzyl-1,2-isopropylidene-,V, 172 pbromophenylhydrazone, V, 172 3-carbanilyl-l,2-isopropylidene-,V, 172 1,2-isopropylidene-, V, 172 1,2,btriazobenzoate, V, 172 1,2,3-tri-p-nitrobenzoate1V, 172 D-Glucose, methyl ethers of, V, 145-190 dimethyl ethers, V, 160-172 monomethyl ethers, V, 148-160 tetramethyl ethers, V, 186-190 trimethyl ethers, V, 172-186 D-Glucose, 2-methyl-, and derivatives, V, 148-151 phenylhydrazone, V, 150 specific rotation of, I, 155 1,3,4,6-tetraacetateJ V, 150 ptoluidide, V, 150 D-Glucose, 2-methyl-, diethyl thioacetal tetraacetate, V, 11 -, bmethyl-, reducing power of, 111, 160 D-Glucose, bmethyl-, and derivatives, V, 151-155 a-form, V, 155 6-form, V, 155 anilide, V, 155 1,2: 5,6-diisopropylidene-, V, 155

382

CUMULATIVE SUBJECT INDEX FOR POLS. I-V

D-Glucose, 2,3,4-trimethyl-, 111, 96 phenylosazone, V, 155 from methylated corn starch, 111, 297 p-tetraacetate, V, 155 from methylated dextrin, 111, 293 1,2,4,6-tetraazobenzoate,V, 155 D-Glucose, 2,3,4-trimethyl-, and derivaptetrabenzoate, V, 155 tives, V, 172-175 D-Ghcose, Cmethyl, and derivatives, V, anilide, V, 175 154-157 a-l,&di-azobenzoate, V, 175 phenylosazone, V, 156 1,6-dinitrateJ V, 175 1,2,3,6-tetraacetateJ V, 156 -, Cmethyl-, dibenzyl thioacetal, V, 156 D-Glucose, 2,3,&trimethyl-, and derivatives, V, 174-176 2,3,4,5-pentaacetate, V, 156 l,&anhydro-, V, 176 D-Glucose-bmethyl-, and derivatives, V, d-Glucose, 2,3,6trimethyl-, 111, 146, 157, 158 194, 196, 201; IV, 10 6-benzoyl-1,2-isopropylidene-3-tosyl-, from methylated cellulose, 111, 190 V, 158 from methylated corn starch, 111, 297 3,6-diacetyl-1,2-isopropylidena,V, 158 from methylated dextrin, 111, 292 l,2-isopropylidene-, V, 158 from methylated starch, 111, 252, 257 phenylosazone, 111, 28; V, 158 methylphenylosarone, 111, 28 D-Ghcose, bmethyl-, and derivatives, V, methylphenyl-phenylosarone, 111, 28, 158-161 29 1,2-isopropylidene-, V, 161 n-Glucose, 2,3,Btrimethyl-, and derivaphenylosazone, V, 161 tives, V, 176-179 ~-1,2,3,4-tetraacetate, V, 161 Bbenzoyl-l-chloro, V, 178 8-lJ2,3,4tetraacetate,V, 161 @-1,4-diacetate,V, 178 1,2,3,4tetraazobenzoate,V, 161 1,4-di-aeobenroateJ V, 178 ~~-1,2,3,4-tetrabenroate, V, 161 dibenzoate, V, 178 8-1,2,3,4tetrabenzoate, V, 161 diethyl thioacetal, V, 178 D-Glucose, monoisopropylidene-, specD-Glucose, 2,4,btrimethyl-, and derivatrum of, I, 107 tivea, V, 179-183 -, 1-phosphate, enzymatic reactions anilide, V, 181 with, V, 33, 35, 45-47, 58, 71 3-benzyl, V, 181 -, 2,3,4,5,6pentamethyl-, reducing 1,3,-di-azobenzoate, V, 181 power of, 111, 160 -, 2,5,&trimethyl-, V, 182 8-D-Glucose 1,2,3,4-tetraacetate-~-mannose 3’,4‘,6‘-triacetate 6,1’,2’-ortho- -, 3,4,btrimethyl-, and derivatives, V, 182-184 acetate (two forms), I, 97 a-form, V, 184 D-Glucose, 2,3,4,5-tetrabenzoyl-6-trityl-, @-form,V, 184 diethyl thioacetal, 111, 107 a-f,2-di-azobenzoate, V, 184 D-Glucose, 2,3,4,&tetramethyl-, and dephenylosazone, V, 184 rivatives, V, 31, 44, 186-188 -, 3,5,&trimethyl-, and derivatives, V, anilide, V, 188 184-186 8-azobenzoate, V, 188 1,2-dichloroethylidene-,V, 185 p-toluidide, V, 188 1,2-isopropylidene-, V, 18.5 D-Glucose, 2,3,5,6-tetramethyl-, and dephenylosazone, V, 185 rivatives, V, 189, 190 1,2-trichloroethylidene-,V, 186 -, 1-thio-, I, 130, 134, 135 -, 3,6,&trimethyl-, reducing power of, -, 1-thio-, 8-tetraacetate, V, 3, 26 111, 160 -, 3-thio-, I, 142 -, g-trityl-, 111, 84 P-D-Glucose, 2,3,4triacetyl-, 1,6-ortho- L-Glucose, 2-desoxy-, N-methyl-2acetic acid, I, 110 amino-, 111, 353

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

L-Glucose, phenylosasone, 111, 352 phenylosotriasole, 111, 353 Glucoseens, 111, 103 n-Glucose-l,2-enediol, 111, xxii ~-Gluoose-2,3-enedio1,111, xxii D-Glucose dibensamide, IV, 132, 151 D-Glucose oxime, IV, 122, 125 D-Glucose oxime, hexaacetyl-, IV, 121123, 150 “Glucoseapigenin,” IV, 66, 68, 72, 74 “d-Glucosephlorogluci,” IV, 74 a-Glucosidase (maltase), V, 31, 64 8-Glucosidase, V, 57, 60-65, 67 “ 1,4-Glucosido-styracitol,” V, 16 “ 1,6-Glucosido-styracitol,”V, 16 D-Glucosone, 11, 81 ; 111, 148, 163, 373 D-Glucosotriasole, phenyl-, I, 25; 111, 38, 121, 353 D-Gluco-L-taZooctitol, I, 22 and octaacetate, I, 35 D-Gluco-btalo-octose, I, 22 a-D-Gluco-1-thio-furanoside, ethyl 2-acetamido-2-desoxy-, 111, 384 -, ethyl 2-acetamido-2,6didesoxy-6nitro, 111, 384 D-Glucothiose, tetraacetyl-, v, 202 Glucotropaeolin, I, 131 Glucuralone, trimethyl-, 11, 172 D-Ghcuronamide, 2,3,4trimethyl-, methyl a- and 8-glucuronides of, IV, .289 D-Glucurone. See n-Glucuronic acid 3,6lactone. D-Glucuronic acid, 11, 171; 111, 146, 147 D-Glucuronicacid, in damson gum, IV, 52 in gums, IV, 244, 246, 250, 253, 256, 258 in hemicellulose of cottonseed hulls, corn stalks, wheat straw and alfalfa hay, V, 280 in mucilage, IV, 270 in polyuronides, I, 338 in xylans of corn cobs and esparto, V, 280 P-D-Glucuronic acid, 11, 240 D-Glucuronic acid, 2,3-dimethyl-, IV, 251, 254, 257; V, 284 -, 3,6lactone, 11, 171, 174 -, 2,3,4trimethyl-, IV, 247, 251, 254, 257, 259

-,

363

amide of methyl a-uronoside, V, 175 amide of methyl 8-uronoside, V, 175 methyl 8-uronoside, V, 175 8-Glucuronidase, V, 61 Glucuronides. See Glucuronosides. D-Glucuronolactone. See D-Glucuronic acid, 3,6-lactone. D-Glucuronoside, methyl, 111, 164 -, methyl diacetyl-, 11, 172 -, methyl 2,3-dimethyl-, methyl ester p nitrobensoate, IV, 289 -, methyl 2,3-dimethyl, phenylhydraside, IV, 289 -, methyl 2,3,4-trimethyl-, methyl ester, IV, 247 a-n-Glucuronoside, menthyl, from oxidation of menthyl a-wglucopyranoside, 111, 164 0-n-Glucuronoside, methyl 2,3,4-trimethyl-, 11, 174; IV, 289 D-Glucuronosides, 11, 171 Glutamic acid, in blood group substances, IV, 49 Glutaraldehyde, zyto-trihydroxy-, 111, 153 Glutaramide, zylo-trimethoxy-, IV, 11 Glutaric acid, L-arabo-a,ydimethoxy-, IV, 282 -, D-arabo-trimethoxy-, IV, 15 dimethyl ester, IV, 11 -, carabo-trimethoxy-, I, 151; 11, 176 -, dibensamidohydroxy-, 111, 349 -, a-keto-, 111, 238 labelled with C11, 111, 239 labelled with isotopic C, 111, 242, 248, 249 -, ribo-trihydroxy-, I, 199 -, ribo-trimethoxy-, I, 203 -, zylo-trihydroxy-, IV, 332 strontium salt, 111, 153 -, zyZo-trihydroxy-, from oxidation of xylan, V, 285 Glutaric dialdehyde, 1,2-isopropyIideneD-zylofurano-trihydroxy-, 111, 54 Glutaric di(methylamide), ribo-trimethOXY-, I, 48, 50 Glutathione, V, 54 Glutosasone, 111, 121 Glutose, 111, 113-128 biochemistry of, 111, 118

364

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

chemistry of, 111, 116 fermentation of, 111, 118 a-Glutose, 111, 114 8-Glutose, 111, 114 Glyceraldehyde, 111, 8, 13 o-Glyceraldehyde, 111, 14, 21 phenylosazone, 111, 29 reaction with dihydroxyacetone, 111, 53 -, 3-bis(C-hydroxymethyl)-, III,21 D-Glyceraldehyde, dibenzoyl-, IV, 222 tGlyceraldehyde, dibenzoyl-, IV, 223 Bis(L-Glyceraldehyde,btosyl-) 2,2’ether, V, 206 t(Zeuo)-Glyceraldehyde and deztro-alanine, correlation of configurations, V, 11 t(Zeuo)-Glyceraldehyde and deztro-lactic acid, correlation of Configurations, V, 11 D,cGlyceraldehyde, 111, 166 Glyceric acid, effect on conductivity of boric acid, IV, 195 reduction of, IV, 109 D-Glyceric acid, 111, 21 D,L-Glyceric acid, 111, 132, 167 Glycerides, trityl ethers, 111, 105 -, unsaturated, 11, 125 Glycerol, butyric acid from, IV, 110 effect on conductivity of boric acid, IV, 191 effect on ketonuria, 11, 146 effect on insulin shock, I, 177 formation of, IV, 113 metabolism of, I, 177 oxidation of, 111, 132, 166, 177 reduction of, IV, 114 from sucrose, IV, 299, 300, 322, 329 transformation to D-glucose, 11, 126 trinitrate, I, 185 trityl ethers, 111, 86, 105 Glycerol, 1,3-dimethyl-, IV, 89 -, 1,bditrityl-, 111, 105 Glycerose, 111, 166 cGlycerotetrulose, 3-acetyl-l-diazo-1,4didesoxy-, 111, 367 -, 4-desoxy-l,bdiacetyl-, 111, 367 Glycidol, metabolism of, I, 178 Glycine, in blood group substances, IV, 49 labelled with Cl*, 111, 232, 246

Glycine soya emulsins, V, 63 Glycitols, l,&anhydro-, V, 18 -, o-desoxy-, V, 9 Glycofuranosides, from glycose thioacetals, I, 138-141 Glycogen, 8-amylase action on, 111, 267, 268; V, 231, 232 biological synthesia of, 111, 246, 249 chain length in, 111, 260 constitution of, 111, 252, 268 cycloamyloses from, 111, 306 enzymatic degradation of, 111,261-308 enzymatic synthesis of, 111, 258 labelled with deuterium, 111, 246 labelled with isotopic C, 111, 243, 244 malt a-amylase action on, 111,271, 287 from Mycobacterium tuberculosis, 111, 314, 315, 319 phosphorolysis of, V, 34 products of enzymatic degradation of, 111, 251-310 synthesis of, IV, 34 Glycogen, trityl-, 111, 96, 111 Glycogenesis, 11, 127-129 from butyric acid, 11, 131 Glyooids, 11, 162 Glycol. See Ethylene glycol. Glycol, divinyl-, 11, 108-111; IV, 84 dichlorohydrin, 11, 108 Glycol cellulose. See Cellulose, hydroxyethyl-. Glycolaldehyde, 11, 147 Glycolaldehyde, a,a-diphenyl-, 111, 374 Glycolaldehyde, cY,a-dicyclohexyl-, 111, 374 Glycolaldehyde, fat formation from, IV, 116 Glycolic acid, 111, 141, 149 from inositol oxidation, 111, 52 Glycolic acid, effeet on conductivity of boric acid, IV, 195 Glycols, from sucrose, IV, 301 Glycoproteins, 11, 162 Glycopyranoside, 111, 130 Glycosans, 11, 64 constitution and properties of, 11, 66 Glycosidaaes, V, 55, 69, 61 Glycosides, a-, occasional formation in ICljnigs-Knorr reaction, I, 84 alkaline hydrolysis of some, 11, 64

CUMULATIVE SUBJECT INDJX FOR VOLS. I-V

365

cardiac, I, 147-173 L-Gulomethylitol. See D-Glucitol, 1digitalis, I, 148 desoxy-. enzymatic hydrolysis of, V, 49-78 D-Gulomethylose. See D-Gulose, 6-desnitrogen, I, 202 oxy-. oxidation of, 111, 131 D - G u ~ oacid, ~ ~ c 2-amino-2-desoxy-, 11, 62 of parsley plant, IV, 57-74 -, 5-keto-, 111, 147 thio-. See Thioglycosides. -, 1,4-lactone, oxidation of, 111, 147 tritylation of, 111, 80 -, 1,4-lactone, reduction of, IV, 216 Glycosides, 1-thio-, hydrogenolysis, V, D-Gulo-L-talo-heptitol, I, 11, 17 14 L-Gulonic acid, oxidation of, 11, 85 Glycothioses, I, 135 L-Gulonic acid, 6-desoxy-2-keto-, 11, 87 Glycuronide, 111, 131 -, 2,3: 4,6-diisopropylidene-2-keto-, 111, Glyoxal, methyl-, phytochemical reduc164 tion of, IV, 80 -, 2-keto-, 11, 84-86 -, methyl-, 111, 127 -, 5-keto-, 111, 149 phenylosazone, 111, 117, 122 a-D-Gulopyranoside, methyl 4,6benzyliGlyoxylic acid, ethyl ester, II,89; IV, 128 dene-2-desoxy-, V, 21, 28 Goepp, Rudolf Maximilian, Jr., obituary, -, methyl 2-desoxy-, V, 21, 28 111, xv-xxiii D-Gulosaccharic acid, 2,5-anhydro-, II,62 Gonadotropic substances, 11, 165, 196 Gulose, historical reversal of D and L Graminin, 11, 260, 261, 273 symbols, 111, 14 -, methyl, 11, 262 D-Gulose, I, 4 Grape sugar, as historical name for D- -, oxidation of, 111, 176 glucose, V, 128 -, phenylosazone, 111, 34 Grapefruit gum, IV, 246 D-Gulose, 6-desoxy-, I, 30, 155 Guanine, I, 195, 198, 200, 237 -, bdesoxy-2-methyl-, I, 155 desoxyribose nucleoside, I, 238 L-Gulose, I, 17 phosphodesoxyribosylnucleotide, I, 241 from oxidation of D-sorbitol, 111, 150 Guanine, from molasses, IV, 336 L-Gulosone, oxidation of, 11, 85 Guanine, desoxyribosyl-, I, 240 L-Gulo-n-tagdo-heptose, I, 17 -, 9’-(3-phospho-D-ribofuranosyl)-. See L-Gulo-D-tabheptitol. See fl-SedohepGuanylic acid. titol. -, 7’-(5-trityl-~-ribofuranosyl)-,111, 110 D-Gulo-L-tab-heptose, I, 11 -, uridylic acid, I, 223-226 -, 3,4,6,7-tetraacetyl-, methyl 1,amthoGuanosine, I, 198, 200, 201 acetate, I, 94 spectrum and structure of, I, 202 D-Gulo-L-talo-heptosyl chloride, pentaGuanosine, isopropylidene-, I, 207 acetyl-, I, 95 -, trimethyl-N-methyl-, I, 203 Gum arabic, structure of, I, 343 Guanylic acid, I, 196, 214, 216 Gum gatto, IV, 266 D-Gulitol. See L-Glucitol. Gum tragacanth, araban from, 11, 247 L-Guloascorbic acid, 11, 83, 96 Gums, composition of, IV, 243 8-D-Gulofuranoside, methyl, 111, 19 Damson, blood group activity of, IV, D-Gulo-L-gala-heptitl, I, 11 50, 52 L-Gulo-D-gala-heptitol, I, 16 plant, IV, 243-291 D-Gulo-L-gala-heptose, I, 11 Gums, plant, I, 331 tj3-Guloheptitol. See 8-Sedoheptitol. structure of, from plants, I, 342, 343 ~-“(a)”-Guloheptose,of Isbelland Frush, H identical with LaForge’s D-fl-guloheptose (D-gulo-L-tala-heptose), I, Halogen acids, oxidation with, in acid 11,94 solution, 111, 178

366

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Halogen derivatives, of carbohydrates, 111, 97 Halogen oxidation, mechanism of, 111, 169 Halogen oxidation systems, oxidation potentials of, 111, 132 Halogenation, of inositols, 111, 57 Halogens, miscellaneous action on carbohydrates, 111, 167 in oxidation of carbohydrates, 111, 129-184 Halohydrocarbons, as solvents for acetylation of cellulose, I, 313 Haptenes, dextrans as, 11, 215 pneumococcus polysaccharide as, 11, 221 Haworth’s perspective formulas, 111, 18 Heat of combustion, of sucrose, IV, 16 Helianthate, of streptomycin, 111, 345, 346 Helix pomatia, action of digestive juices on hemicellulose, V, 288 Hematoporphyrins, phytochemical reduction of, IV, 100 Hemiacetal groups, in cellulose, 111, 191 Hemicellulose, I, 252; IV, 161,173 action of Helix pomatia digestive juices on, V, 288 -, of apple wood, V, 282 -, of English oak, presence of monomethylhexuronic acid in, V, 280 -, of raw corn cob, V, 276, 282 xylan as component of, V, 270 Hemicelluloses, I, 332, 343; 111, 187 Hemlock, Western, V, 107, 113, 285 Hemoglobin, hydroxy-, phytochemical reduction of, IV, 100 Hemp, V, 107, 122 -, Manila, xylan percentage in, V, 270 Heparin, 11, 164, 181 n-Heptanal, phytochemical reduction of, IV, 78 l,Z-Heptanediol,. IV,. 85 Heptanoic acid, glycogen formation from, 11. 128 2-Heptanone, 1-hydroxy-, phytochemical reduction of, IV, 85 Heptasaccharide, from potato starch, 111, 275 5-Hepten-2-01, &methyl-, IV, 82, 92 -]

5-Hepten-2-0ne, &methyl-, phytochemical reduction of, IV, 82 Heptonitrile, 7-desoxy-, IV, 149 Heptose, origin of name, 111, 11 Heterocyclic compounds, phytochemical reduction of, IV, 90 Heterolevulosan, 111, 119, 120 1,5-Hexadiene-3,4-diolJ 11, 108-111 Hexahexosan Pringsheim, @-amylaseaction on, 111, 267 Hexamethylenediamine, V, 288 Hexanal, a-hydroxy-, phytochemical reduction of, IV, 81 1,4-HexanediolJ V, 192 2,3,4,5-Hexanetetrol, 1,6-dichloro-, 11, 108 Hexanetetrol, l,&(erythro-3,4)-, V, 6 1-Hexanol, 2-ethyl-, as starch precipitant, I, 259 Hexaric acids, 111, 49, 60, 63 Hexasaccharides, from potato starch, 111, 275 3-HexeneJ 1,2,5,6-tetraacetoxy-, 11, 114 -, 1,2,5,&tetrahydroxy-, 11, 109, 110, 113 3-Hexene-2,5,&tetrol, 11, 109, 110, 113 tetraacetate, 11, 114 Hexenolactone, 11, 89 1-Hexen-5-01, IV, 92 4-Hexen-1-01, IV, 91 l-Hexen-5-0ne, IV, 92 Hexitols, I, 180; 11, 107, 109-114, 148; 111, 4, 131; IV, 211-241; V, 191-228 analysis of, IV, 227 anhydrides of, V, 191-228 chemical properties of, IV, 218 and derivatives, IV, 211-241 esterification of, IV, 220 etherification of, IV, 223 history of, IV, 211 industrial uses of, V, 222 metal complexes of, IV, 224 occurrence and preparation of, IV, 212 oxidation of, IV, 226 physical properties of, IV, 218 reaction with aldehydes and ketones, IV, 223 synthesis of, IV, 217 Hexobiose, 111, 12 Hexokinase of yeast, V, 73

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

(?)Hexopyranose, 1,4-anhydro-2,3,6-trimethyl-, 11, 69 Hexose phosphates, in leaves of sucroseproducing plants, V, 33 Hexotriose, 111, 12 Hexuronic acid, monomethyl-, in hemicellulose of English oak, V, 280 Hexuronic acids, 11, 170 Hexyl alcohol, as starch precipitant, I, 259 3-Hexyne, 1,2,5,6-diepoxy-, 11, 110, 112, 113 -, 1,2,5,6-tetrahydroxy-, 11, 109, 110, 113 3-Hexyne-2,5-diol, 1,6-dichloro-, 11, 109, 110, 113 3-Hexyne-1,2,5,6-tetrol,11, 109, 110, 113 Histidine, in blood group substances, IV, 49 HMF. See 5-Hydroxymethylfurfural. Hog mucin, blood group substances from, IV, 43, 46 Hog stomach, blood group substances from, IV, 43, 46, 48, 53 Holocellulose, I, 333; 111, 188 as source of xylan, V, 274 Honey, melezitose in, 11, 12 Honeydew, melezitose in, 11, 8 Hormones, 11, 165, 196 Horse carboxyhemoglobin, dipole moment of, V, 55 Hudson isorotation rules, 111, 17 Hyaluronic acid, 11, 164, 179 sulfate, 11, 164, 184 Hyaluronidase, effect on blood group substances, IV, 55 Hydration, of starch, I, 275 Hydratopectin, 11, 239 Hydraeine, derivatives, in identification of uronic acids, I, 339 Hydrazine, 1,2-bis(a-methylbenryl-)-, 111, 40 -, a,@-diacetylphenyl-,111, 30 Hydraeones, anhydrides of, 111, 31 benzylphenol-, 111, 28 benzyl-p-tolyl-, 111, 28 butylphenyl-, 111, 28 p-chlorobenzylphenyl-, 111, 28 dibenzyl-, 111, 28 diphenyl-, 111, 28

367

ethyl phenyl-, 111, 28 optical properties of, 111, 27 phenyl-8-phenylethyl-, 111, 28 structure and reactivity of, 111, 23-44 Hydrocarbons, halogenated, as solvents for acetylation of cellulose, I, 313 Hydrocellulose, 111, 206; IV, 162 Hydrochloric acid, rearrangement of orthoesters by, I, 121, 122 Hydrocinnamic acid, 8-hydroxy-, effect on conductivity of boric acid, IV, 195 Hydrocinnamyl alcohol, IV, 91, 92 Hydrofuroin, IV, 90 Hydrogen bonds, between carbohydrates and hydrophilic groupings of proteins of enzymes, V, 55 Hydrogen bromide, hydrolysis of polysaccharides with, 11, 231 Hydrogen cyanide, reaction with osones, 11, 80 cyanohydrin syntheses, I, 1-36,38 Hydrogen ion concentration, effect on halogen oxidation, 111, 170 Hydrogen peroxide, 111, 149 reaction with peroxidase, V, 53 Hydrogen sulfide, IV, 95-97, 106 Hydrogenation, of 5-keto-kgalactonic acid, I, 70 of osazones, 111, 39 of ribosylpyrimidines, I, 208 Hydrogenolysis, of carbon-sulfur bond, v, 1 Hydrolysis, enzymatic, of sugars, 11, 34 of orthoesters, I, 98-107 of polysaccharides with HBr, 11, 231 of polyuronides, I, 335, 337, 340 of starch fractions, I, 268 Hydroquinone, effect on conductivity of boric acid, IV, 191 Hydroxy acids, effect on conductivity of boric acid, IV, 193 Hydroxyl groups, tritylation of, 111, 88 Hydroxylamine, m-nitrophenyl-, IV, 99 5-Hydroxymethylfurfural (HMF), production and removal in manufacture of dextrose, V, 141 Hypobromites, 111, 138, 163 Hypobromous acid, 111, 135, 138, 140. 151, 171 Hypochlorites, 111, 134

368

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Hypochlorous acid, 111, 134, 150 Hypoglycemia, 11, 126 Hypohalites, 111, 133, 134, 156 Hypohalous acids, 111, 134, 135 Hypoiodites, 111, 133, 139, 157, 183 Hypoiodous acid, 111, 136 Hypoxanthine, from desoxyribosenucleic acid, I, 237, 238 from desoxyribose nucleoside, I, 238 from inosinic acid (muscle), I, 210 Hypoxanthine, 9’-(3-phospho-D-ribofuranosy1)-. Bee Inosinic acid (from ribosenucleic acid), Hypoxanthine, 9’-(5-phospho-D-ribofuranosy1)-. Bee Inosinic acid (muscle) Hypoxanthine, ribosyl-. Bee Inosine.

L-Idofuranose, 1,2:3,5-diisopropylidene6-desoxy-6-nitro-, 111, 54 -, 1,2-isopropylidene-&desoxy-&nitro-, 111, 54 D-Idonic acid, 2-amino-2-desoxy-, 11, 62 D-Idonic lactone, reduction of, IV, 365 L-Idopyranose, 1,4anhydro-2,3,6-trimethyl-, 11, 69 0-D-Idopyranoside, methyl 4methyl-, 11, 51 D-Idosaccharic acid, 2,5-anhydro-, 11, 62, 74 D,L-Idosaccharic acid, 111, 50, 51, 66 -, tetraacetyl-, diethyl ester, 111, 51 L-Idosaccharic acid, IV, 227 -, 2,4:3,5-dimethylene-, IV, 299; V, 217 Idose, historical change of D and L symbols of configuration, 111, 14 I D-Idose, I, 4; 11, 67 L-Idose, I, 17; IV, 215, 216 Iditols, I, 5 ~-1dito1,I, 181; IV, 216, 219 -, 3,&anhydro-, 11, 77 -, hexaacetyl-, IV, 240 -, 3,&anhydro-l,2-isopropylidene-, 11, D,L-IditOl, Iv, 219 77 L-Iditol, I, 16, 181; IV, 212, 215, 219, -, 1,4anhydrotrimethyl-, 11, 66 -, 6-desoxy-&nitro-, 111,54, 55 227 -, 2,5-anhydro-, V, 205,206, 226 -, 2,3,6-trimethyl-, 11, 55 -, 2,5-anhydro-l,6-didesoxy-l,6-diiodo-, a-D-Idopyranoside, methyl 4,6-benzylidene-2-methylthio-, V, 20, 28 V, 226 -, 2,5-anhydro-l,&di-p-tosyl-, V, 206, 8-D-Idopyranoside, methyl 4,6-benzylidene-3-desoxy-, V, 21,28 226 -, 2,5-anhydro-l,3,4,64etraacetyl-, V, -, methyl 4,6-benzylidene-3-desoxy-2methyl-, V, 28 226 -, 2,5-anhydro-l-p-tosyl-, V, 206, 226 -, methyl 3-desoxy-, V, 21 -, l,&diacetyl-2,4: 3,6aimethylene-, IV, -, methyl 4,&ben~ylidene-2-methyl-3239 methylthio-, V, 28 -, 1,4:2,&dianhydro-(?), V, 206 -, methyl 4,6-benrylidene-3-methylthio-,V, 21, 28 -, 1,4: 3,&dianhydro-, (Isoidide), 111, xx; V, 195,213,216-217 8-L-Idothiofuranoside,ethyl 2-acetamido2,6-didesoxy-6-nitro-, 111, 384 -, 1,4: 3,&dianhydro-2,5-ditsyl-,V, 216 Imidarole, methyl-, 111, 117 -, 1,4:5,6-dianhydro-, V, 195 -, l,&dibenroyl-2,4: 3,5-dimethylene-, Immunological properties of dextrans, 11, IV, 239 214 of levans, 11, 230 -, dibensylidene-, IV, 239 -, 2,4: 3,&dimethylene-, IV, 239 Indane-l,2-diol, cis- and tram-, effect on -, 2,4: 3,6-dimethylene-l,&ditosyl-, IV, conductivity of boric acid, IV, 192 239 Inhibition, of phosphorylation and suc-, hexaacetyl-, IV, 239 rose synthesis by iodoacetate, V, 33 -, hexaallyl-, IV, 239 Inorganic compounds, biochemical re-, tribeneylidens, IV, 239 duction of, IV, 95

.

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

369

Inosine, I, 199 Intermediate compound theory of enspectrum and structure of, I, 202 zymatic action, V, 51 Inosine, 6-iodoisopropylidene-, I, 206,207 identification of intermediate comInosine, isopropylidene-, I, 206, 207 pound, V, 53 Inosine, isopropylidenetosyl-, I, 206, 207 Intermediates, cellulose ethers as, 11, Inosinic acid, muscle, I, 197, 207, 210, 294 212 Inulase, 11, 256 from ribosenucleic acid, I, 217 Inulin, 11, 226, 254-259, 273, 274 Inositol, from firmly bound lipids of M. molecular weight of, 11, 257 tuberculosis, 111, 329 solubility of, 11, 255 from hexose derivatives, 111, 53 structure of, 11, 258 from M. tuberculosis polysaccharides, -, triacetyl-, 11, 257, 258; IV, 28 111, 317, 318, 333 -, trimethyl-, 11, 257, 258 from phosphatide fraction of M. luber- Inversion, of sucrose, IV, 18 culosis lipids, 111, 326 Invertase (aynonyms, 8-D-fructofuranquercitols from, 111, 67 osidase, aaccharase), 11, 256; IV, 7, racemic, and hexaacetate and hexa18, 22-24, 30, 31; V, 38, 39, 41, 56, benzoate, 111, 57, 58 67-69 structure of, 111, 48 Iodates, 111, 138, 157, 178 from tuberculin polysaccharides, 111, Iodic acid, as oxidant, 111, 178 323 Iodine, adsorption by starch, I, 256 from waxes of M. tuberculosis lipids, colors of products formed from starch 111, 328 by amylases, V, 261 -, dibromodidesoxy-, 111, 58 as oxidant, 111, 151, 169 -, monochlorodesoxy-, 111, 58 solubility of, 111, 136 -, mononitromonodesoxy-, 111,54 Iodine starch complex, dichroism of flow -, tetraacetyl-, 111, 60 of, I, 266 -, tetrachlorotetradesoxy-, 111,58 Iodoacetate, inhibitor of phosphorylado-Inositol, 111, 47, 58-60 tion and sucrose synthesis, V, 33 Iodoform, 111, 139 deztro-Inositol, 111, 47, 56 epi-Inositol, 111, 47, 61-63 Iretol, 111, 64 iao-Inositol, and hexaacetate and hexa- Irisin, 11, 260, 264, 267, 273 Iron, removal in manufacture of dexbenzoate, 111, 57, 58 leuo-Inositol, 111, 47, 56 trose, V, 139 meso-Inositol, 111, 46, 47 Isoagglutination, IV, 37, 40 configuration of, 111, 48 Isoagglutination test, 11, 186 halogenation of, 111, 57 Isoamyl alcohol, IV, 106 periodate oxidation of, 111, 348 as starch precipitant, I, 259 relation to D-glucose, 111, 53 Isoamyl mercaptan, IV, 95 -, 4,bisopropylidene-, 111, 51 Isoandrostanediol, IV, 93 -, 5,6-isopropylidene-, 111, 51 Iso-D-araboascorbic acid, 2,3-dimethyl-, -, 6-C-methyl-, 111, 76 11, 98, 100 muco-Inositol, 111, 47, 58-60 Isoascorbic acid, IV, 331, 332 pseudo-Inositol, 111, 58 Isobutyl alcohol, as starch precipitant, I, Inosose, esters, aromatization of, 111, 64, 259 Isobutyric acid, a-hydroxy-, I, 3 65 -, pentabensoate, 111,64 effect on conductivity of boric acid, IV, epi-mso-Inosose, 111, 61-63 195 acyllo-meso-Inosose, 111, 50, 63, 65, 68, 76 Isocaproaldehyde, phytochemical reduction of, IV, 78 Insulin, 11, 141

370

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Isocitric acid, 111, 238 labelled with isotopic C, 111, 241, 242, 249 Isodynamic law, 11, 153, 159 Iso-D-glucosamine, 111,39 Isoidide, 111, xx. See also ~ I d i t o l , 1,4: 3,6-dianhydro-. Isolated organs, fat conversion by, 11,141 Isoleucine, in blood group substancea, IV, 49 Isomaltose, amylase action on, 111, 289 from corn starch, 111, 297 from starch, 111, 252, 257, 308 Isomannide, 111, xix, xx; IV, 302. Bee also D-Mannitol, 1,4: 3,6-dianhydro-. dinitrate, I, 185; IV, 305 metabolism of, I, 184 Isomytilitol, 111, 76, 77 -, hydroxy-, 111, 77 Isopentane, IV, 324 Isopropyl alcohol, I, 25; IV, 109 Isorhamnonic lactone, 111, 144 Isorhamnose, 111, 101 -, 5-keto-, 111, 103 a-D-Isorhamnopyranoside, methyl, 111, 101 8-D-Isorhamnopyranosidq, methyl, 111, 144 Isorotation, Hudson rules of, 111, 17, 375 Isosaccharic acid, 11, 60, 61, 74 calcium salt, 11, 74 diethyl eater, and its diacetate, 11, 74 Isosaccharic diamide, 11, 74 Isosaccharic dianilide, 11, 74 Isosaocharinose, 111, 364 Isosorbide, 111, xx; IV, 303. See also D-Sorbitol, 1,4: 3,&dianhydro-. dinitrate, IV, 305 Isosucrose, IV, 27, 29; V, 69 octaacetate, IV, 29; V, 30 structure of, IV, 30 -, octamethyl-, IV, 29 Isothiocyanates of sugars, I, 133, 144 Isothiourea, D-glucopyranoside tetraacetate, I, 133 Isothiourea, phenyl-, D-glucopyranoaide tetraacetate, I, 133 Isothioureas, &substituted, desulfuriration with Raney nickel, V, 24

Isotopes, in carbohydrate metabolism studies, 111,229-250 Isotrehslose, octaacetate, IV, 29 Isotrehalose, seleno-, I, 144 Isovaleraldehyde, phytochemicctl reduction of, IV, 106 -, thio-, IV, 95 Itaconic acid, from sucrose, IV, 322, 327 Ivory-nut meal, 111, 143

J “Jeanite” liquid fuel from fermentation of molasses, IV, 32 Jute, xylan percentage in, V, 270 Jute fibers, diffraction pattern, V, 104

K Ketals, of hexitols, IV, 223 Ketene, acetylation of starch with, I, 290 Keto acids, a- and @-, specificity of carboxylase action on, V, 50 a-Keto acids, aromatic, V, 50 @-Ketoacids, oxidation of, 11, 148 a-Ketobutyric acid, V, 50 WKetocaproic acids, V, 50 Ketogenesis, in liver slices, 11, 155 Retolysis, 11, 120, 146, 147, 158 in liver slices, 11, 155 Ketolytic, 11, 146 Ketone, methyl a-chloroethyl, phytochemical reduction of, IV, 81 -, methyl ethyl, phytochemical reduction of, IV, 83 -, methyl hexyl, phytochemical reduction of, IV, 83 -, methyl nonyl, phytochemical reduction of, IV, 83 -, methyl propyl, phytochemical reduction of, IV, 83 Ketone bodies, 11, 120, 131, 145, 150 action of liver slices on, 11, 155 effect of D-ghme on rate of disappearance of, 11, 153 oxidation of, 11, 157 Ketones, phytochemical reduction of, IV, 82-85 oxidation of, 11, 159 reaction with hexitols, IV, 223

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Ketones, di-, phytochemical reduction of, IV, 86 Ketones, poly-, phytochemical reduction of, IV, 89 Ketones, unsaturated, phytochemical reduction of, IV, 92 Ketonuria, 11, 120, 126, 129, 133, 145 effect of D-glucose on, 11, 148, 152, 158 Ketose alkyl orthoesters, I, 120 Ketoses, 111, 11 oxidation of, 111, 130, 149, 181 reaction with sodium hypoiodite, 111, 160

Ketosis, relation to carbohydrate oxidation, 11, 145-159 theory of, 11, 146 a-Ketovaleric acids, V, 50 Konigs-Knorr reaction, I, 79, 114 a-glycoside formation in, I, 84 Kojic acid, 111, 373 from sucrose, IV, 322, 324

L Lactal, 11, 67 D,bLactaldehyde, phytochemical reduction of, IV, 80 Lacquers, cellulose ester, I, 324 Lactic acid, I, 2; 11, 132 effect on conductivity of boric acid, IV, 195

ethyl ester, as solvent in sugar research, I, 24 from glutose, 111, 117 labelled with CI4, 111, 247 labelled with isotopic C, 111, 240, 244 from molasses, IV, 336 from sucrose, IV, 317, 322, 329 from wood sugars, IV, 183 D(1evo)-Lactic acid, 111, 21 effect on ketonuria, 11, 148 optical rotation of, IV, 72 L(dextro)-Lactic acid, configuration, V, 11,12

-, -,

effect on ketonuria, 11, 148 0-methyl-, V, 12 0-methyl-, p-phenylphenacyl ester, V, 12

Lactitol, 1,5anhydro-, V, 18 Lactobionic acid, 111, 145. 152, 154

371

Lactobiononitrile, octaacetyl-, IV, 142, 147

Lactone rule of rotation, I, 18, 19, 160, 163

Lactones, aldonic, I, 22 formation of, 111, 175 of sugar acids, I, 3 Lactonization, of 2-keto-3,4-dihydroxy acids or esters, 11, 83, 87 Lactoprene, IV, 318 8-Lactopyranoside, 2’-naphthyl 1-thio-, V, 18, 27 Lactose, 11, 67; 111, 11; IV, 147 a- and 8-, interaction with boric acid, IV, 205 effect on fat metabolism, 11, 159 effect on ketonuria, 11, 148 oxidation of, 111, 133, 140, 143, 145, 152, 176, 180

Lactose, a-octaacetate, configurational formula, I, 41 Lactose, P-octaacetate, AICl, rearrangement of, I, 46 Lactose, phenylosazone anhydride, 111, 31, 36

Lactose, phenylosotriazole, 111, 38 a-Lactose, acetochloro-, I, 40, 41 Lactyl chloride, acetyl-, 111, 367 Laminarin, IV, 275, 282 Langenbeck’s formulation of enzymatic glycoside hydrolysis, V, 58 Larch, cgalactan of, 11, 249 Larch manna. See Manna. Laurel, California, pentosan content of, V, 271 Lauric acid, as glycogenic agent, 11, 134 starch ester, I, 302 Lauryl alcohol, effect on leaching of starch, I, 263 effect on starch paste, I, 272 as starch precipitant, I, 259 Leaching, aqueous, of starch, I, 251, 261, 276

Lead hydroxide, reaction with sugars, 111, 115, 116

Leather, cellulose eater coatings for, I, 324 Leather industry, lactic acid in, IV, 318

Lecithin, from molasses, IV, 336 Lemon gum, IV, 246

372

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Leprosy, polysaccharide formed by bacillus of, 11, 222 Leucine, effect on ketonuria, 11, 148 Leuconoatoc, dextrans formed by, 11, 190 Leuconostoc agglutinana, 11, 217 Leuconoatoc deztranicum, 11, 217 dextran formation by, 11, 210, 214 methylated dextran from action of organism on sucrose as source of 2,3- dimethyl-D-glucose, V, 70, 161 Leuconoatoc meeenteroidea, 11, 217 dextran formation by, 11, 210, 226; V, 47 methylated dextran as source of 2 , s dimethyl-D-glucose, V, 161 Levan triacetate, 11, 227 Levan, trimethyl-, 11, 227 Levans, 11, 225, 259, 260, 263; IV, 333 bacterial, 11, 190 bacterial and plant, 11, 165 enzymatic synthesis of, 11, 205, 228230 immunological properties of, 11, 230 produced from sucrose or raffinose by bacterial enzymes, V, 47, 48 structure of, 11, 227 Levansucrase, 11, 228 Levoglucosan, I, 51, 52; 11, 38,40, 64, 65, 69; 111, 86 -, 2,4diacetyl-3-tosyl-, 11, 69 -, 2,4-dibenzyl-, 11, 69 -, 2,4dibenzyl-3-tosyl-, 11, 69 -, 2,3,4triacetyl-, 11, 69 -, 2,3,4-tribenzoyl-, 11, 69 -, 2,3,4tribenzyl-, 11, 69 Levulinic acid, 111, 127; IV, 306 esters and salts, IV, 311 from molasses, IV, 336 Levulosans, 11, 259 Levdose. See D-Fructose. Levulosecarboxylic acid, I, 3; 111, 422 Light-scattering measurements, for determination of degree of polymerization of cellulose, 111, 222 Lignin, 111, 187; IV, 160, 177 removal from polyuronjdes, I, 334 removal in purification of xylan, V, 274 Ligno-cellulose, 111, 187; V, 104 Lily bulb starch. See Starch. Linoleic acid, cellulose ester, I, 319

Linseed mucilage, IV, 270 Linters. See Cotton linters. Lipids, polysaccharides of, 111, 326, 328; IV, 116 Lipoaldehydes, 11, 123 Lipositol, 111, 47, 343 Lithium aluminum hydride, for hydrogenation of 1,2-epoxides, V, 22 Lithium chloride, influence upon the activity of pancreatic amylase, V, 237 Lithium hypochlorite, 111, 137 Liver, fat conversion by isolated, 11, 141 ketogenesis in isolated, 11, 155 Lobry de Bruyn-Alberda van Ekenstein transformation, 111, 113 Locust bean mucilage, IV, 267 Lucerne seed, emulsins, V, 63 Lucerne seed, mucilage, IV, 266, 267 Lupinua albus, galactan from seed of, 11, 248 Luteic acid, 11, 165, 191, 224 Luteolin, IV, 63 Luteose, 11, 191, 224 Lysine, in blood group substances, IV, 49 D-Lyxoascorbic acid. See D-Ascorbic acid. D-Lyxomethylitol, tetraacetate, V, 7 L-Lyxomethylitol, tetraacetate, V, 7 D-Lyxomethylose, and pbromophenylosazone and phenylosazone, I, 161, 162 D - L Y X Oacid, ~ ~ C 111, 144 lactone, 111, 144 a-D-Lyxopyranoside, methyl triacetyl-, I, 84 a-D-Lyxopyranoside, phenyl, V, 62, 66 D-LYXOse, IV, 147 oxidation of, 111, 161, 176 D-Lyxose, 5-benzoyl-, IV, 147 -, &desoxy-, IV, 145 D-Lyxose diacetamide, IV, 141, 146, 147, 151 -, B-desoxy-, IV, 145 GLyxose diacetamide, bdesoxy-, IV, 151 D-Lyxose dibenzamide, 5-benzoyl-, IV, 142, 151 -, bbenzoyl-, triacetate, IV, 151 -, tetrabenzoyl-, IV, 151 D-Lyxose dipropionamide, IV, 151 D-Lyxose oxime, IV, 125

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

D-Lyxose, orthoesters of, I, 84 diacetyl-, methyl l,a-orthoacetate, I, 84 t l y x o s e , I, 2 -, 3-C-forrnyl-bdesoxy-, 111, 338 Lyxuronic acid, 111, 165

373

Maltose, heptaacetate, I, 81 a-Maltose, octaacetate, 111, 377 @-Maltose, octaacetate, 111, 377 Maltose, phenylosazone, reaction with KOH,111, 40 a-Maltose, 1-phosphate, V, 71 Maltose, acetyl-1,2-orthoacetyl chloride, M I, 119 Madrone, Pacific, pentosan content, V, Maltose, ditrityl-, 111, 111 271 Maltose, ditritylhexaacetyl-, 111, 111 Magnesium perchlorate, as catalyst in Maltose, hexaacetyl-, methyl 1,a-orthoacetylation of starch, I, 289 acetate, I, 82 Maleic acid,,dihydroxy-, 11, 96; 111, 149 Maltose, methyl 1,2-orthoaoetate, hyMalic acid, 111,238,241; IV, 85 drolysis of, I, 100 labelled with isotopic C, 111, 140, 249 Maltoside, ethyl, heptaacetyl-, I, 81 Malonic acid, 11, 155; 111, 238 0-Maltoside, methyl heptaacetyl-, I, 81, protection of enzyme by, V, 54 82; 111, 377 Maltamylase. See under Amylases. a-Maltosyl bromide, heptaacetyl-, I, 82 Maltase, IV, 25, 30. See also a-Glucosi- Maltosyl chloride, acetyl-, I, 112 dase. Maltosyl chloride, heptaacetyl-, I, 81,119 Maltitol, and nonaacetate, 11, 26 a-Maltosyl chloride, heptaacetyl-, I, 82; -, 1,5anhydro-, V, 18 111, 377 Maltobionic acid, 111, 145, 152, 154 Maltotriose, 111, 254 -, 2-keto-, 111, 148 from arrow-root starch, 111, 274 Maltobiononitrile, octaacetyl-, IV, 148 from a-dextrins, 111, 277 Maltohexaonic acid, 111, 265, 301 from soluble starch, 111, 272 Maltohexaose, 111, 265, 301 from starch, 111, 288, 291, 308 Maltol, I, 89; 111, 357, 372 Mandelic acid, effect on conductivity of Maltose, IV, 148 boric acid, IV, 195 from arrow-root starch, 111, 274 Mandelic acid, hexahydro-, optical rotafrom a-dextrins, 111, 277 tion of, IV, 72 interaction with boric acid, IV, 205 Manna, Alhagi, 11, 4, 10 orthoesters of, I, 80 of ash tree, 11, 3; 111, 145 oxidation of, 111, 148, 176 from Douglas fir, 11, 11 oxidation of, in buffered acid solution, larch, of Briangon 111, 152 Persian, 11, 6, 7 phenylosazone, 11, 25 Turkestan, 11, 5 phenylosazone anhydrides, 111, 31, 37 Manna sugar. See D-Mannitol. phenylosotriazole, 11, 27 Mannan, of yeast, 11, 165, 191, 224 from potato starch, 111, 262, 275 -, presence in alpha cellulose, V, 275 relationship to turanose, 11, 26 8-Mannide, V,209, 217 from soluble starch, 111, 272 metabolism of, I, 184 from starch, 111, 252, 254, 308 Manninositose, 111, 327 from starch by pancreatic amylase, V, Manninotrionic acid, 111, 145 235, 247-250 Manninotriose, 111, 145; V, 66 from starch by amylase of Aspergillus Mannitan. See also D-Mannitol, 1,4oryzae, V, 250-255 anhydro-. from starch by amylase of malted -, metabolism of, I, 184 barley, V, 255-265 Mannitan, monolaurate-ethylene oxide, structure of, 11, 23, 21 I, 187; 111, xviii

-,

374.

CUMWLATWI BUBJECT INDPX FOR VOLS. I-V

Mannitoh, 111, 6, 10 o-Mannitol, I, 16; 111,xvii; IV, 211,212, 214; V, 8, 192,209 acylation of, 111, 91 from Alhagi manna, 11, 10 borates, IV, 220 boric acid complex, IV, 225 effect on conductivity of boric acid, IV, 191 esters, IV, 220 gallate, IV, 302 hexanitrate, I, 185; IV, 220, 302 oxidation of, 111, 150, 348; IV, 226,227 physical properties of, IV, 219 reaction products with boiling hydrochloric acid, V, 210 from sucrose, IV, 299, 301, 322; V, 213 I>-Mannitol, 2(5)-acetyl-1,4: 3,bdianhydro-, V, 227 -, 5-acetyl-1,2 :3,Pdiisopropylidene-6tosyl-, IV, 235 -, 3-allyl-, IV, 234 -, &amino-6-desoxy-1,2 :3,4-diisopropylidene-, V, 2 19 D-Mannitol, l14-anhydro-, (Mannitan) , V, 192, 209, 210, 226 5,&benzylidene-, V, 226 5,6-benzylidene-2,3-dibenaoyl-, V, 226 2,6-(or 3,6) dibenzoyl-, 111, xviii; V, 226 2,3: 5,Bdibenzylidene-, V, 220 2,3,S16-tetraacetyl-, V, 226 D-Mannitol, l,&anhydro-, (Styracitol), V, 15, 16, 27, 198, 200, 218, 226 dibenzylidene-, (a) and (a), V, 226 diisopropylidene-, V, 226 proofs of structure and configuration, V, 198 tetraacetyl-, V, 226 tetrabenzoyl-, V, 226 tetramethanesulfonyl-, V, 226 tetramethyl-, V, 200, 226 tetranitrate, V, 226 transformation to D-fructose, V, 200 u-Mannitol, 5,6-anhydro-l ,2 :3,4dikopropylidene-, V, 219, 226 11-Mannitol, 3,4benzylidene-, I V , 234 --, 3,4henzylidme-l,6-dihenzoyl-,TV, a36

-,

3,4benzylidene-l,&benzoyl-2,6-

methylene-, IV,236 -, 3,~benzylidene-l,2,6,6-tetrabenzoyl-, IV, 235

-, 3,4benzylidene-1,2,6-tribenzoyl-,IV, 235

-, 2-chloro-2-desoxy-1,4 :3,6-dianhydro-

-, -, -, -, -, -, -, -,

-, -, -,

-,

-, -,

-, -,

-, -,

-, -,

-, -, -, -,

-,

bmethanesulfonyl-, V, 228 2-chloro-2-deaoxy-l,4 :3,6-dianhydro5-phenylcarbamyl-, V, 228 1-desoxy-, 111,xx; V, 8, 26 2-desoxy-, pentaacetate, V, 6 3,Pdiacetyl-, IV, 233 . 3,4diacetyl-l,6-dibenzoyl-2,5-dito~yl-,IV, 233 2,5-diacetyl-1,4: 3,6-dianhydro-, V, 225, 227 2,5-diacetyl-1,6-dibenzoyl-3,4ditosyl-, IV, 233 2,bdiacetyl-l,6-dibenaoyl-3,4-isopropylidene-, IV, 235 3,4-diacetyl-1,2 :5,6-diisopropylidene-, IV, 236 1,6-diacetyldibenzoylditosyl-,IV, 233 1,6-diacetyldibenzylidene-,IV, 235 diacetyldimethylene-, IV, 235 1,6-diacetyl-2,4: 3,5-&methylene-, IV, 234 2,5-diacetyl-l,6-ditosyl-3,4-isopropylidene-, IV, 235 2,5-diacetyl-l16-ditrityl-3,4-isopropylidene-, IV, 235 1,6(?)-di(acetylsalicyloyl)-, IV, 233 1,6-diacetyl-2,3,4,btetrabenzoyl-, IV, 233 3,4-diacetyl-l12,5,6-tetrabenzoyl-, IV, 233 1,6-diacrylyl-2,4: 3,5-dimethylene-, IV, 235 3,4-diallyl-, IV, 234 2,5-diallyldianhydro-, IV, 304 3,4-diallyl- 1,2:5,6-diisopropylidcne-, IV, 235 2,5-diamino-2,5-didesoxy-l14: 3,6-dianhydro-, and derivatives, IV, 306; V, 216, 225, 228 I ,6-diaminodimethylene-, IV, 302 1,4: 3,6-dianhydro-, 111, x i x ; V, 206, 210, 213, 215, 228. Bee also Isomannide.

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

-, -,

375

1,2: 5,6-dianhydro-, V, 219 -, 1,6dibenroyltritosyl-, IV, 233 4 2 :S16-dianhydro-3,4ethylidene-, V, -, 1,6-dibensoyldibenrylidene-,IV, 235 219, 220 -, dibenzoyldimethylene-, IV, 235 -, 1,2:5,6-dianhydro-3,4-isopropyli-, 1,6-dibenroylditosyl-, IV, 233 dene-, V, 219 -, 1,6-dibenzoyl-2,5-ditosyl-,IV, 233 -, 1,4 :3,6-dianhydro-al5-dich loro-2,5-di-, 1,6-dibeneoyl-3,4-ditosyl-,IV, 233 desoxy-, V, 227 -, 1,6-dibenzoyl-2,5ditosyl-3,4-isopro- -, 1,4: 3,6-dianhydro-2,5-dicrotyl-, V, pylidene-, IV, 235 228 -, 1,6-dibenzoy1-3,4-isopropylidene-,IV, -, 1,4: 3,6-dianhydro-2,5-didesoxy-2,5235 di-(Ncacetylsulfani1amido)-,V, 228 -, 1,6-dibenzoyl-2,5-methylene-,IV, 235 -, 1,4: 3,6-dianhydro-2,5-didesoxy-2,5- -, dibenzoylmonoisopropylidenemonodiiodo-, V, 228 tosyl-, IV, 235 -, 1,4: 3,6-dianhydro-2,5-didesoxy-2,5- -, 1,6-dibenroylmonomethylene-, IV, di(p-nitrobenzenesu1fonamido)-,V, 235 228 -, 1,6-dibenzoyl-2,3,4,5-tetraacetyl-, IV, -, 1,4: 3,6-dianhydro-2,5-didesoxy-2,5233 disulfanilamido-, V, 228 -, 2,5-dibenzoyl-1,4: 3,6-dianhydro-, V, -, 1,4: 3,6-dianhydro-2,5-didesoxy-2,5209, 228 imino-, V, 215-217 -, 2,3,4,5-dibenzylidene-, IV, 234 -, 1,4: 3,6-dianhydro-2,5-diethyl-,V, 228 -, 2,3,4,5-dibenzylidene-1,6-ditosyl-, IV, --, 1,4: 3,6-dianhydro-2,5-diformyl-, V, 235 227 -, 1,6-dibromo-l,6-didesoxy-,V, 211 -, 1,4:3,6-dianhydro-2,5-dimethacrylyl-, -, 1,6-dichloro-l,6-didesoxy-,111, 69; IV, 304; V, 224 V, 207, 210,218 -, 1,4: 3,6-dianhydro-2,5-dimethanesul- -, 1,6-dichloro-1,6-didesoxy-2,5-difonyl-, V, 210, 228 methyl-, V, 208 -, 1,4: 3,6-dianhydro-2,5-dimethyl-,V, -, 1,6-dichloro-1,6-didesoxy-2,3:4,5-di208 methylene-, 111, 69 -, 1,4: 3,6-dianhydro-2,5-di- (phenylcar- -, 1,6-dichloro-1,6-didesoxy-3,4-isoprobamy1)-, V, 227 pylidene-, V, 208 -, 1,4:3,6-dianhydro-2,5-ditosyl-,V, 228 -, l16-dichlorodimethylene-,IV, 302 -, 1,4:3,6-dianhydro-2,5-ditrityl-, V, -, di(ch1oroethylidene)-, IV, 234 228 -, 1,6-didesoxy-1,6-diiodo-2,3:4,5-di-, 1,4: 3,6-dianhydro-2(5)-methyl-, V, methylene-, 111, 69 228 -, 1,6-didesoxy-1,6-diiodo-2,3,4,5-tetra-, 1,5:3,&dianhydro-, (Neomannide), benzoyl-, 111, 100, 104 V, 217, 228 -, diethyl-, IV, 217 -, 1,5:3,6- dianhydro -2,4 dimethan esu 1- -, 1,2:3,4-diisopropylidene-, IV, 234 fonyl-, V, 228 -, 1,2: 5,6-diisopropylidene-, IV, 234 -, l16-dianisoyl-, IV, 233 -, 1,2:3,4-diisopropylidene-4,5-di-, l16-dibenzoyl-, 111, 89; IV, 222, 233, methyl-,’IV, 235 302 i>-Mannitol, dibenzoyldianhydro-, 111, -, 1,2:5,6-diisopropylidene-3,4-ditosyl-, IV, 235; V, 214 xix -, diisopropylidene-4-methyl-, IV, 235 D-Mannitol, l16-dibenzoyl-2,4:3,5-di-, 1,6-dimethacrylyl-2,4: 3,Bdimethylmethylene-, IV, 234 ene-, IV, 234 -, l,&dibensoy1-2,3,4,5-tetratosyl-, IV, 233 -, l,&dimethyl-, IV, 234 -, 1,6-dibenzoyl-2-tosyl-, V, 205 -, l16-dimethyl-3,4-ethylidene-, IV, 236 ~

-

376

-,

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

1,6-dimethyl-3,4isopropylidene-,IV,

-,

235 -, 5,&dimethyl-, IV, 234 -, -, 1,6-dimethyl-2,4:3,&dimethylene-, IV, 235 -, -, 1,3:4,0 (or 1,3:5,6)-dimethylene-, IV, 234 -, -, 2,4:3,5-dimethylene-,IV, 234,302 -, dimethyleneditosyl-,IV, 235 -, -, 2,4:3,5-dimethylene-l,&ditosyl-, IV, -, 234 -, -, 2,4:3,5-dimethylene-1,6-ditrityl-,IV, 235 -, -, di(p-nitr0benzylidene)-, and isomer, -, IV, 234 -, 1,6(?)-disalicyloyl-,IV, 233 -, -, 2,4ditosyl-,IV, 233 -, 1,6-ditosyl-2,5-methylene-,IV, 235 -, -, 1,6-ditosyl-2,3,4,5-tetraacetyl-, IV, 233 -, -, 3,4ditosyl-1,2,5,6-tetraacetyl-, IV, -, 233

1,2-isopropylidene-3,4,5,6-tetra-

acetyl-,IV, 235 1,2-isopropylidene-3,4,5,0-tetrabenzoyl-,IV, 235 3,4-isopropylidene-l,2,5,6-tetrahcn~oyl-, IV, 222,235 3,4-isopropylidene-l,2,5,0-totramethyl-,IV, 235 1,2-isopropylidene-&trityl-, IV, 235 4-methyl-,IV, 234 Pmethy1-1,2,3,5,6-pentaacetyl-, IV, 235 2,5-methylene-, IV, 234 2,5-rnethylene-l,3,4,&tetraacetyl-,

IV, 235 2,5-methylene-1,3,4,6-tetrabenzoyl-, IV, 235 2,5methylene-l,3,4,&tetratosyl-, IV, 235 2,5-methylene-l-tosyl-, IV, 235 2,5-methylene-&tosyl-l,3,4-triacetyl-, IV, 235 -, l,&ditosyl-2,3,4,5-tetrabenzoyl-, 111, -, monofurfurylidene-,IV, 234 100;IV, 233 -, mono(p-nitrobenzy1idene)-, IV, 234 -, 2,4-ditosyl-l,3,5,&tetrebenzoyl-, IV, -, monosalicyloyl-,IV, 233 233 -, 2,3,4,5,6-pentaacetyl-l-trityl-, 111, -, 3,4-ditosyl-1,2,6,6-tetrabenzoyl-,IV, 110;IV, 235 233 -, 2,3,4,5,&pentamethyl-,IV, 234 -, l,&ditrityl-, 111, 100,110;IV, 234 -, 2,3,4,5-tetraacety1-, IV, 233 -, 1,6-ditrityl-2,3,4,5-tetraacetyl-,111, -, 3,4,5,6-tetraacetyl-, IV, 233 110;IV, 235 -, 1,2,5,6-tetrabenzoyl-, IV, 233 n-kfannitol,3-(cr-~-g~ucopyranosyl)-, 11, -, 2,3,4,5-tetrabenzoyl-, 111, 100; IV, 25 233 nonaacetate,11, 21,23 -, 3,4,5,6-tetrabenzoyl-, IV, 233 -, 1,6-ditrityl-2,3,4,&tetrabensoyl-,111, -, 1,3,5,0-tetrachloro-1,3,5,6-tetra100; IV, 235 desoxy-,V, 208 -, 3,4ethylidene-,IV, 234 -, 1,2,5,6-tetramethyl-, IV, 234 -, hexaacetyl-,IV, 233 -, 2,3,4,6-tetramethyl-, IV, 234 -, hexaallyl-,IV, 234 -, 1,2,6-tribenzoyl-, IV, 222,233 -, hexabensoyl-,IV, 233 -, tribensylidene-,IV, 233 -, hexa-p-bromobenzoyl-,IV, 233 -, tri(m-chlorobenzylidene)-, IV, 234 -, hexacinnamoyl-,IV, 233 -, tri(o-ch1orobenzylidene)-,IV, 234 -, hexagalloyl-,IV, 233 -, tri(p-ch1orobenzylidene)-, IV, 234 -, hexamethyl-,IV, 234 -, tri(p-chloro-rn-nitrobeney1idene)-,IV, -, hexanitrate,I, 185 234 -, tricinnamylidene-,IV, 233 -, hexaphenylcarbamyl-,IV, 233 -, hexa(triacetylgalloy1)-,IV, 233 -, triethylidene-,IV, 233 -, hexa(tribensoylgalloy1)-,IV, 233 -, trifurfurylidene-,IV, 234 -, 1,2-iaopropylidene-,IV, 234 -, 1,2:3,4:5,&triisopropylidene-,IV, 234 -, 3,4iaopropylidene-,IV, 234 -, tri(p-methoxybenry1idene)-,IV, 234

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

-,

tri(p-methy1benzylidene)-, IV, 234 1,3:2,4:5,6-trimethylene-,IV, 233 tri(m-nitr0benzylidene)-,and isomer, IV, 234 -, tri(o-nitr0benzylidene)-, IV, 234 -, tri(p-nitr0benzylidene)-,IV, 234 D-Mannitol group, of carbohydrates, I, 16 D-L,-Mannitol, 11, 109, 112 physical properties of, IV, 219 -, tribenzylidene-, 11, 112 LMannitol, I, 181; IV, 216, 219 -, l12,5,6-diisopropylidene-,IV, 240 -, hexaacetyl-, IV, 240 -, 3,4&opropylidene-, IV, 240 -, 3,4-isopropylidene-l12,5,6-tetramethyl-, IV, 240 -, l12,5,6-tetramethyl-, IV, 240 -, triisopropylidene-, IV, 240 -, trimethylene-, IV, 240 Mannocarolose, 11, 191, 223 Mannocyclitol, tetrahydroxy-, 111, 68 D-Mannofuranose, a- and j3-, IV, 203 -, 2,3: 5,6-diiaopropylidene-, IV, 204 a-D-Mannofuranoside, methyl, 111, 19 a-n-Mannofuranoside, methyl 3,Ganhydro-, 11, 77 D-Manno-D-gala-heptitol (D-Perseitol), 1desoxy-, V, 9, 26 cManno-L-gabheptitol, 7-desoxy-, I, 20; v, 10 -, 7-desoxy-l-trityl-, 111, 111 D-Manno-D-gala-heptononitriie, Iv, 149 -, hexaacetyl-, IV, 126, 147, 149 -, hexabenzoyl-, IV, 126, 130, 147, 149 L-Manno-Irgala-heptononitrile,7-desOXY-, IV, 126 a-D-Manno-D-gala-heptopyranoside, methyl, V, 66, 67 D-Manno-D-gala-heptose, I, 5, 9; Iv, 147 diethyl thioacetal, V, 9, 26 LManno-Irgala-heptose, 7-desoxy-, I , 20 D-Manno-L-gala-nonitol, I, 31 L-Manno-D-gala-nononic acid, 9-desoxy-, I, 29 D-Manno-bgulo-nonitol, I, 31 “~-a-Mannoheptonic’~ acid, I, 23 “~-fi-Mannoheptonicl 1 acid, I, 8 “~-&Mannoheptose,”I, 8 DMannoheptose phenylosotriazole, 111, 38

-, -,

377

D-Mannoheptulose, I, 12 metabolism of, I, 17, 186 D-Manno-L-manno-octitol, I, 18, 35; v, 8 octaacetate, I, 35 D-Manno-bmanno-octonic lactone, I, 6 D-Manno-bmanno-octose, I, 5, 8, 18; v , 10 bManno-D-manno-octose, 8-desoxy-, I, 28; V, 11 D-Mannonamide, 3,4dimethyl-, IV, 290 -, 2,3,6trimethyl-, IV, 290 -, 3,4,6-trimethyl-, IV, 290 D-Mannonic acid, I, 3, 4; 111, 10,143 -, 2,5-anhydro-, (Chitonic acid), 111,145 -, 3,6-anhydro-, 7-lactone and phenylhydrazide, 11, 77 -, 2,3-dimethyl-, phenylhydrazide, IV, 290 -, 2,3,6-trimethyl-, phenylhydrazide, IV, 290 -, 3,4,6-trimethyl-, phenylhydrazide, IV, 290 D,L-Mannonic acid, 111, 143 lactone, 111, 57 bMannonic acid, I, 3, 4; 111, 10 -, 5-keto-, 111, 147 D-MaMOnOnOniC lactone, I, 20 D-Mannonononose, I, 5 D-Mannonolactone, preparation from phenylhydrazide by use of copper sulfate, I, 23 -, 2,3-dimethyl-, IV, 290 -, 3,4dimethyl-, IV, 290 -, 2,3,6-trimethyl-, IV, 290 -, 3,4,6-trimethyl-, IV, 290 D-Mannononitrile, pentaacetyl-, Iv, 146, 149 -, pentabenzoyl-, IV, 126, 130, 146, 149 -, pentapropionyl-, IV, 149 D-Mannopyranose, a- and j3-, Iv, 203 -, tetramethyl-, IV, 266 a-D-Mannopyranose, fermentation by yeast, V, 74, 75 a-D-Mannopyranose, 3,4,6trimethyl-, I, 108 -, l12,3,4-tetraacetyl-6-trityl-,111, 107 8-D-Mannopyranose, fermentation by yeast, V, 74, 75 8-D-Mannopyranose, Pacetyl-l,g-anhydro-2,3-isopropylidene-, 11, 70

378

-,

CUMULATIVE SUBJECT INDBX FOR VOLS. I-V

1,banhydro-, (D-Mannosan <1,6 >&<1,6>), 11, 64, 66,70 -, 1,6-anhydro-2,3-isopropylidene-,11, 67, 70 -, 1,6anhydr0-2,5isopropylidenbP methyl-, 11, 70 -, 1,6anhydro-2,3-isopropylidene-4to~yl-,11, 70 -, 1,6anhydro-2,3,4-triacetyl-,11, 70 -, 1,6anhydro-2,3,4-tribenzoyl-,11, 70 -, l,Banhydr0-2,3,4-trimethyl-,11, 70 -, 1,6anhydro-2,3,4tritosyl-,11, 70 -, 4benzoyl-1 ,banhydro-2,3-isopropylidene-, II,70 -, 4(~-~-glucopyranosyl)-.gee Epimaltose. -, 1,2,3,4tetraaoetyl-t3-trityl-,111, 107 a-D-Mannopyranosidme. See a-Manno-

-,

methyl 2,3-anhydro-4,0-dimethyl-,11, 71 -, methyl 2,3,4,6tetraacetyl-, 111, 381 -, phenyl, V, 66 D-Mannopyranosyl chloride, 4(&~-glucosy1)-, heptaacetate, I, 86 n-Mannosaccharic acid, 111, 146 -, 2,8anhydro-, 11, 60,61, 74 calcium salt, 11, 74 diethyl ester and its diacetate, 11, 74 -, 2,4: 3,Bdimethylene-, V, 217 D-Mannosaccharic diamide, 2,&anhydro-, 11, 74 D-Mannosaccharic dianilide, 2,S-anhydro, 11, 74 n-Mannosaccharic dilactone, 11, 103 D-Mannosacohah 1,4:3,&dilactone, 11, 101,102 &he. D-Mannosaccharic 3,6-lactone, PdesoxyD-Mannopyranoside, methyl, 3,4-di6-keto-, 11, 102 methyl-, 111, 331 D-Mannosaccharic 3,6-lactone, 2,6-dimethyl 3,4,0-trimethyl-, 111, 331 methyl-, methyl ester, 11, 103 -, methyl tetramethyl-, I, 106 6-methyl-, methyl ester, 11, 103 a-DMannopyranoside, ethyl 1-thio, LMannosaccharic dilactone, reduction tetraacetate, 111, 381 of, IV, 216 a-D-Mannopyranoside, methyl, 111, 91 ; L-Mannosaminic acid, N-methyl-, 111, IV, 202 364, 382 -, methyl 3,&anhydro-, 11, 77 -, methyl 2,3-anhydro-4,6benzylidene-, L-Mannosaminic acid nitrile, N-methyl-, 111, 364; IV, 127 11, 71; V, 20 -, pentaacetyl-N-methyl-, 111, 382; IV, -, methyl 4(~-~-glucopyranosyl)-, 126, 149 heptaacetate, I, 86 o-Mannose, 1, 2, 17, 24; 11, 67; 111, 10, -, methyl tetrawetyl-, 111, 381 14, 114, 115; IV, 146 -, methyl 2,3,~~acetyl-6trityl-,111, acylation of, 111, 91 107 alkali action on, 111, 113 -, methyl 6-trityl-, 111, 107 111, 37 -, methyl 4,6-benzylidene-3-dexy- V, anhydrophenylhydrazone, 11, 207 bacterial cellulose from, 20,27 from blood group substances, IV, 46 -, methyl 4,6-benzylidene-3-desoxy-2in damson gum, IV, 62 methyl-, V, 20,27 effect on conductivity of boric acid, IV, -, phenyl, V, 62,66 201 -, phenyl2-desoxy-, V, 66 effect on ketonuria, 11, 148 &D-Mmopyranoside, ethyl l-thio-, ethyl l,2-orthoacetate, I, 84 tetraacetate, V, 16, 27 from h l y bound lipidn of M.tubercu&D-Mannopyranoaide, methyl, IV, 202 lo&, 111, 329 -, methyl 2,3-anhydro-, 11, 71 in gums, IV, 246,246,263, 266 -, methyl 2,&anhydr0-4,6benzylidene-, higher4 sugars from, I, 6 11, 71 methyl l,hrthoacetate, I, 84, 108 in mucilagea, IV, 266,270,276 -, methyl 2,3-anhydrodimethyLJ 11, 49

-,

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

from Mycobaderium tuberculosis polysaccharides, 111, 316-318, 333335 orthoesters of, I, 83 in ovomucoid, IV, 52 oxidation of, 111, 147, 153, 161, 176 from phosphatide fraction of M. tuberculosis lipids, 111, 326 in polyuronides, I, 338 from tuberculin polysaccharides, 111, 322,323 from waxes of M. tuberculosis lipids, 111, 328 in wood, IV, 160 D-Mannose, 2,&&nhydro-. See Chitose. -, 3,6-anhydro-, II,44, 77 benrylphenylhydraronne, 11, 77 -, 2,5-anhydrotribenzoyl-, 11, 73 D-Mannose, 4-(&~-glucopyranosy1)-, I, 85 D-Mannose, 4(&~-glucopyranosyl)-, hexaacetate, I, 85 D-Mannose, 4(fJ-n-ghwopyranosyl)-, heptaacetate, l,fl-orthoacetate, I, 153 D-Mannose, 4-(fJ-D-ghcopyranosyl)-, hexaacetyl-, methyl 1,2-orthoacetate, I, 86 6 - d ~ x y - ,V, 8 -, 2,3-dimethyl-, IV, 267 -, 3,4-dimethyl-, IV, 268 hydrate, IV, 290 -, 2-~-glucuronosyl-, IV, 257 -, 6-methyl-, 111, 96 -, 2,3,4,5-tetraacetyl-6-trityl-, diethyl thioacetal, 111, 107 -, 2,3,4,5-tetrabenzoyl-6-trityl-,diethyl thioacetal, 111, 107 2,3,4,8tetramethyl-, and a- and 8methyl glycosides, IV, 290 D-Mannose, triacetyl-, methyl 1,2-orthoacetate, hydrolysis of, I, 105 -, 2,3,6-trimethyl-, IV, 266, 267 -, 3,4,BtrimethyI-, IV, 247, 290 -, 3,4,6-trimethyl-, methyl 1,a-orthoacetate, I, 108 -, 6-trityl-, 111, 107 fJ-D-Mannose, 6-trityl-, 111, 84 D,L-Mannose, oxidation of, 111, 143 -, phenylhydrazone, 11, 112 -J

379

L-Mannose, I, 3,4 reduction of, IV, 216 D-Mannose anilide, 2,3,4,6-tetramethyl-, IV, 290 -, 2,3,6trimethyl-, IV, 290 -, 3,4,6-trimethyl-, IV, 290 D-Mannose diacetamide, IV, 134, 147, 151 D-Mannose dibenzamide, IV, 130, 134, 135, 147, 151 D-Mannose diethyl thioacetal, V, 7, 26 pentaacetate, V, 7, 26 D-Mannose monobenzamide, IV, 130, 135 D-Mannose oxime, I v , 125 -, hexaacetyl-, IV, 150 a-D-Mannose 1-phosphate, V, 71 a-Mannosidase, V, 61, 66 a-D-Mannoside, ethyl 1-thio-, tetraacetate, 111, 381 -, methyl 6methyl-, 111, 96 @-D-Mannoside, ethyl 1-thio-, tetraacetate, 111, 381 Mannosidostreptomycin, V, 15 D-Manno-D-tag&-heptose, I, 12, 17 D-Manno-D-talo-heptitol. Bee Volemitol. L-Manno-ctalo-heptitol, 7-desoxy-, I, 20 D-Manno-D-tubheptose, I, 9 L-Manno-ctalo-heptose, 7-desoxy-, I, 20 D-Mannuronic acid, 11, 176, 237 D-Mannuronic acid, in polyuronides, I, 338 D-Mannuronic hCtOne, 111, 176 a-D-Mannuronide, methyl, 111, 164 a-D-Mannuronoside, methyl 2,3,4-trimethyl-, 11, 177 Melezitose, 11, 1-36; V, 69, 70 crystallography of, 11, 14 dihydrate, 11, 9, 14, 15 from Douglas fir, 11, 11 enzyme action on, 11, 32, 34 hendecaacetate, 11, 7 history of, 11, 2 in honey, 11, 12 in honeydew, 11, 8 methylation of, 11, 20, 30 monohydrate, 11, 35 oxidation by periodic acid, 11, 30 refractive indices of, 11, 16 specific rotation of, 11, 36 structure of, 11, 6,9, 19, 28

3 80

CUMULhTIVE SUBJECT INDEX FOR VOLS. I-V

of sugar alcohols and their derivatives, Meleritose, hendecamethyl-, 11, 20 I, 175-192 Meleritose honey, 11, 2, 13 of D-volemitol, I, 186 Melibiononitrile, octaacetyl-, IV, 148 -, isotopic tracers in carbohydrate, 111, Melibiose, 111, 95; IV, 148; V , 66, 67 229-250 -, phenylosotriazole, 111, 38 Metasaccharinic acid, 111, 67 -, 1-phosphate, V , 71 Methane, IV, 111 Menthol, as starch precipitant, I, 259 -, bis( 1,3-benzodioxan-6-nitro-S-yl)-, 111, Zevo-Menthol, trityl ether, 111, 86 xvii -, a-D-glucuronide, 111, 164 Mercaptals (see also Thioacetals), forma- -, bromotriphenyl-, 111, 82 tion of, determination of degree of -, chlorotriphenyl-, 111, 79 polymerization of cellulose by, 111, -, dichloro-, as solvent for acetylation of cellulose, I, 313 206 -, nitro-, reaction with aldoses, IV, 217 reductive desulfurization of, V, 5 Methanol, labelled with isotopic C, 111, thioglycosides from, I, 136 233 Mercaptans, IV, 93, 95 metabolism of, I, 176 Mercuric oxides, 111, 145 as solvent in sugar research, I, 24 Mercury salt, of levulinic acid, IV, 31 1 from wood saccharification, IV, 177 Merosinigrin, I, 130 -, triphenyl-, 111, 79, 83 Mesityl oxide, IV, 92 Methanolysis, of orthoesters, I, 123 Mesotartaric acid, 111, 3 Mesoxaldehyde, bis(phenylhydrazone), of sucrose, IV, 25 Methionine, labelled with C**, 111, 233 111, 30 Methoxyl, detection in polyuronides, I, Mesoxalic acid, ethyl ester, 11, 89 337 Mesquite gum, I, 338, 343; IV, 246, Methyl alcohol. See Methanol. 258 Mesylation, 111, 88, 99 Methyl cellosolve, as solvent in sugar reMetabolism, search, I, 24 of carbohydrates, 11, 119-160 Methyl group, oxidation to -CHIOH, 111, of dulcitan, I, 191 147 of dulcitol, I, 191 Methyl iodide, labelled with C", 111, 233 of erythritan, I, 179 Methyl orange, streptomycin salt, 111, of erythritol, I, 178 345, 346 Mcthylated dextrins, not affected by of ethylene glycol, I, 176 of ethylene-oxide-mannitan monolaupancreatic amylase, V, 250 Methylation, effect on optical activity of rate composition, I, 187 sugars, I, 155 of fat, 11, 119-160 of gum arabic, I, 343 of glycerol, I, 177 of glycidol, I, 178 of meleritose, 11, 20, 30 of isomannide, I, 185 of polyuronides, I, 334, 336, 337 of 8-mannide, I, 185 of starch, I, 268, 275, 276 of mannitan, I, 184 of sucrose, IV, 10 LMethylene chloride, as solvent for acetylof D-mannitol, I, 181, 188 ation of cellulose, I, 313 of D-mannoheptulose, 1, 17, 186 0-Methylhydroxylamine hydrochloride, of methanol, I, 176 use in estimation of carbonyl groups, of oleic esters of D-mannitol and manV , 285 nide, I, 186 of polygalitol, I, 191 Methyloses, 111, 101. See aZso w-desoxy of o-sorbitol, I, 183, 187 derivatives of various sugars. Methylpentose, origin of tcrm, 111, 12 of styracitol, I, 186

C U M U L A T I V E S U B J E C T INDEX FOR VOLS. I-V

Microbes, phytochemical reduction by, IV, 106 Microorganisms, carbon dioxide assimilation in, 111, 235 Molasses, glutose and unfermentable reducing substances in cane, 111, 113128 utilization of, IV, 334 -, wood sugar, IV, 186 Molding compositions, I, 322, 326 Molds, polysaccharides of, 11, 165, 223 pectin-esterases in V , 86, 98 Molecular weight, of cellulose esters, I, 316 of desoxyribosenucleic acid, I, 244 of pectins, I, 342 of polyuronides, I, 342 of ribosenucleic acid, I, 234 of starch fractions, I, 276 Molecular weight determination, starch acetate solutions for, I, 295 Molybdic acid, hexitol complexes of, IV, 225 Mucic acid (see also Galactosaccharic acid), I, 7; 111, 5, 49, 57, 58, 66, 146 -, anhydro-, 11, 74 -, 2,3,4-trimethyl-, 11, 176 Mucilages, I, 331, 343 classification of, IV, 265 composition of, IV, 245 neutral, IV, 265 occurrence, function and isolation of, IV, 264 plant, IV, 243-291 seaweed, IV, 275 uronic acid residues in, IV, 269 Mucin, 11, 162 blood group substances from hog, IV, 43, 46 frog spawn, blood group activity of, IV, 50, 52 snail, 11, 165, 191 submaxillary, 11, 198 Muco-cellulose, 111, 187 Mucoids, 11, 162, 196 Mucoitin, sulfate, 11, 164, 183 Mucolipids, 11, 163, 198 classification of, 11, 166 Mucopolysaccharides, 11, 161-201 classification of, 11, 164

381

Mucoproteins, 11, 161-201 classification of, 11, 165 serum, 11, 194 of urine, 11, 198 Mucor javanicus, emulsins of, V, 63 Muscle, ribosylpurine nucleotides of, I, 210 Muscle phosphorylase, V, 35 Mutarotation, of D-altrose, I, 43 of D-fructose, IV, 20; V, 32, 75 of D-ribose and 5-trityl-~-ribose, 111, 85 of turanose, 11, 18, 22 Mutarotation, alpha, of reacting mixtures of pancreatic amylase and starch, V, 236 of amylase of Aspergillus oryzae and starch, V , 251 of alpha amylase of barley malt and starch, V, 257 Mycobacterium tuberculosis, lipid constituents of, 111, 326 polysaccharides of, 11, 166, 201, 222; 111, 311-336 Mycolic acid, 111, 328 Myristic acid, starch ester, I, 302 Myronic acid, I, 129 as glycogenic agent, 11, 134 Myrosin, I, 129, 133 Mytilitol, 111, 75, 77 -, hydroxy-, 111, 77

N Nacconol, for pectin-methylesterase (PM) determination, V , 94 Naphthalene, l,a-dihydroxy-, effect on conductivity of boric acid, IV, 191 -, 2,3-dihydroxy-, effect on conductivity of boric acid, IV, 191 a-Naphthoquinone, phytochemical reduction of, IV, 89 Neohexane, IV, 323 Neolactobionic acid, I, 42 P-Neolactopyranoside, methyl heptaacetyl-, I, 45, 76, 95 a-Neolactopyranosyl chloride, heptaacetyl-, I, 40,41, 43, 76 Neolactose, I, 40-43 phenylosazone, I, 76

382

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Neolactose, hexaacetyl-, methyl 1,2-orthoacetate, I, 45, 46, 76, 95 a-Neolactose, heptaacetyl-, I, 76 -, octaacetyl-, I, 40, 76 8-Neolactose, I, 76 -, heptaacetyl-, I, 76 -, octaacetyl-, I, 40, 76 Neomannide. See D-Mannitol, 1,5:3,6dianhydro-. Nerianthin, I, 148 Nettle stalk, pentosan content, V, 271 Nickel, Raney, reductive desulfurization in the carbohydrate field by, V, 1-28 Nickel-aluminum alloy, for preparation of Raney nickel, V, 3 Nicotine, V, 53 Nitrate, phytochemical reduction of, IV, 101 Nitration, of starch, I, 303 Nitriles, acylated, of sldonic acids, IV, 119-151 from aldoximes, IV, 120 Nitrite, phytochemical reduction of, IV, 101 Nitro compounds, phytochemical reduction of, IV, 97 Nitrocellulose, (see also Cellulose nitrate), degree of polymerization, V, 106 Nitrogen/D-glucose ratio in fat metabolism, 11, 135 Nitrogen compounds, in cane molasses, 111, 124 -, phytochemical reduction of, IV, 97 Nitrogen glycosides, I, 202 Nitropectin, 11, 242 Nomenclature, “aric,” for sugar dibasic acids, I, 29 of bascorbic acid anologs, 11, 82 of carbohydrates, Emil Fischer’s proposals, 111, 9 of carbohydrates, Rosanoff’s modifications, 111, 12 of cyclitols, 111, 46, 66 of pectic enzymes, V, 80, 82, 85, 92 D and L, of perseitol and sorbitol, I, 14 of starch components, I, 250 of sugars, I, 28 of thiosugars, I, 135 Nonitols, configurations of, I, 31 R’ononic lactone, I, 6

Nonose, 111, 11 A20-Norcholenic acid, 21-hydroxy-, lactone glycosides, I, 147 Nori, IV, 281 Nuclease, I, 226 Nucleic acids. See also Desoxyribosenucleic acid and Ribosenucleic acid. Nucleic acids, I, 193-245 from Mycobacterium tuberculosis, 111, 315, 320 the term, I, 194 from tuberculin, 111, 324, 325 Nuclein, I, 194 Nucleinase, I, 226 Nucleoproteins, I, 194 from Mycobacterium tuberculosis, 111, 319 from tuberculin, 111, 325 Nucleosides, 111, 90 of ribosenucleic acid, I, 197, 198 -, desoxyribose, I, 238 Nucleotidase, I, 226, 245 5-Nucleotidase, I, 233 Nucleotides, phosphodesoxyribose, I, 241 of ribosenucleic acid, I, 196, 197 ribosylpurine, of muscle, I, 210-213 ribosylpurine, of ribosenucleic acid, I, 2 14-2 17 ribosylpyrimidine, I, 217-219 0 Oak, pentosan content of tanbark, V, 271 Oat hulls, pentosan content of, V, 271 optical rotation of xylan from, V, 282 Oats, beta amylase of, V, 231 4,6-Octadien-l-o1, IV, 91 1,7-0ctadien-4-yne-3,6diol, 11, 117 4,5-Octanediol, IV, 84 5-Octanone, 4-hydroxy-, phytochemical reduction of, IV, 84 Octasaccharide, from potato starch, 111, 275 2,4,6-0ctatrienic acid, IV, 91 2,4,6-0ctatrien-l-o1, IV, 91 Octose, origin of term, 111, 11 Oidium lactis, IV, 186 Oleandrin, I, 148, 171 Oleandronic acid, I, 172 phenylhydrazide and S-benzylthiuronium salt, I, 168

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Oleandrose, I, 148, 168 and 2,4-dinitrophenylhydrazone, I, 171, 172 Olefins, phytochemical reduction of, IV, 92 Oleic acid, effect on starch paste, I, 272 esters of D-mannitol and mannide, metabolism of, I, 186 as glycogenic agent, 11, 134 as starch precipitant, I, 273 Oligosaccharides, 111, 93 from cellulose, 111, 195, 197, 198 Optical rotation, amide, benzimidazole, and phenylhydrazide rules of, I, 21 lactone rule of, I, 18 of polysaccharides, 11, 231 of starch acetals, I, 296 of sugars and their 2-methyl derivatives, I, 155 Orange, pectin-methylesterases (PM) in Havedo and albedo of, V, 93, 95, 96 Orange gum, IV, 246 Orthoesters, I, 77-127, 138, 153 in altrose series, I, 45 definition and general structure, I, 78 hydrolysis (acid) of, I, 98-104 hydrolysis (alkaline) of, I, 104-107 mechanism of conversion of, I, 121 mechanisms of formation of, I, 113-127 orthoacyl halides and anhydrides, I, 112 preparation and properties, I, 79 structure of, proof, I, 107-112 Osazones, anhydrides of, 111, 31, 33, 36 hydrogenation of, 111, 39 osotriazoles from, I, 25; 111, 37 reaction with bases, 111, 40 reaction with copper sulfate, I, 25;111, 37 spectra of, 111, 29 structure and reactivity of, 111, 23-44 theories of formation of, 111, 41 Osazones, improvements in characterization of, I, 24 Ose, origin of term, 111, 12 Osmotic pressure, of cellulose derivatives, 111, 213 in polyuronide structure study, I, 341 of starch acetate solutions, I, 295

383

Osones, oxidation of, 11, 84;111, 130,131, 148, 155, 164 reaction with hydrogen cyanide, 11, 80 Osotriazoles, sugar, I, 25;111, 37 Ouabain, I, 148 Ovarian cyst fluids, blood group substances from, IV, 44,46 Ovomucoid, 11, 165, 192, 196 blood group A activity of, IV, 52 8-0xa-3-azabicyclo[3,2,l]octane, IV, 316 Oxalacetate 8-carboxylase, 111, 235, 240 Oxalacetic acid, 111, 238, 242, 248 bacterial production of, 111, 235 labelled with isotopic C, 111, 240, 241, 249 oxime, IV, 101 phytochemical reduction of, IV, 85 Oxalcitraconic acid, 111, 242 Oxalic acid, 111, 149 labelled with isotopic C, 111, 231, 232 from sucrose, IV, 297 Oxalosuccinic acid, 111, 243 labelled with isotopic C, 111, 241, 242 Oxidation, of aldonic acids, 11, 85 asymmetric, of sugars, I, 46 of carbohydrates, 11, 145-159 of carbohydrates by animal tissue, 111, 238 of carbohydrates by halogens, 111,129184 of ketone bodies, 11, 157 of ketose sugars, 11, 84 of melezitose, 11, 30 of osones, 11, 84 of streptomycin, 111, 356 Oxidation potentials, of halogen oxidation systems, 111, 132 of halogens, 111, 169 Oximes, ald-, nitriles from, IV, 120 Oximes, aldose, IV, 121, 122

P Pachyra afinie mucilage, IV, 270 Palladium catalyst, 11, 109, 110,113 Palmitaldehyde, 11, 123 Palmitic acid, 11, 125 effect on starch paste, I, 272 D-glucose from, 11, 137 from D-glucose, 11, 121

384

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

starch ester, I, 302 from stearic acid, 11, 123 Palmitoleic acid, 11, 125 Pancreatic amylase. See under Amylases. Paperboard, from sugar cane dry leaves, IV, 295 Para-ascorbic acid, 11, 89 Parsley, glycosides of, IV, 57-74 history of, IV, 60 Peanut, polysaccharides of, 11, 245, 247, 248 Peas, hexose phosphates in, V, 33 Pectase. See Pectin-methylesterase. Pectic acid, 11, 175, 140-145, 150; 111, 146; V, 81 action of depolymerase on, V, 82, 92 methyl ester, 11, 238 of peanut, 11, 247 purification of, I, 334 Pectic enzyme preparations, commercial, V, 86, 101 Pectic substances, I, 331; 11, 235-251 enzymes acting on, V, 79-102 Pectin, 111, 187 calcium D-altronate from, I, 70 characteristics of, 11, 235-238 chemistry and nomenclature, V, 8082 nitrate, 11, 242 structure of, I, 342; 11, 238-241 Pectin gels, 11, 238 Pectinase. See Pectin-polygalacturonase. Pectin-esterase. See Pectin-methylesterase. Pectinic acids, 11,239; V, 81 Pectin-methylesterase (PM), V, 82, 86, 92-101 Pectinol, V, 86, 102 Pectin-polygalacturonase (PG), V, 82, 85-91, 93, 101 Pecto-cellulose, 111, 187; V, 104 Pectolactonic acid, 11, 239 Pectolase. See Pectin-polygalacturonMe. Pectolic acid, 11, 239 Pelargonic acid, glycogen formation from, 11, 128 Penicillin, 111, 342

Penicillium charlesii, carlic acid formation by, 11, 99 polysaccharides formed by, 11,223,224 Penicillium luteum, 11, 165 polysaccharide formed by, 11, 224 Penicillizlm varians, polysaccharide formed by, 11, 223 1,3-Pentadiene. See Piperylene. 1,4-Pentadiene-3-01, 11, 118 Pentaerythritol, tetratrityl-, 111, 85 Pentanal, a-hydroxy-, phytochemical reduction of, IV, 81 Pentane, Pmethyl-, IV, 324 l,a-Pentanediol, 3,4,5-triacetoxy-, 11, 115, 116 1,4Pentanediol, IV, 310 2,3-Pentanediol, IV, 88 2,3-Pentanedione, IV, 88 2,4Pentanedione, IV, 89 lJ2,3,4,5-Pentanepentol,1,2,3-triacetate, 11, 115, 116 2,3,4-Pentanetriol, IV, 89 2,3,4Pentanetrione, phytochemical re, duction of, IV, 89 2-Pentanol, 4methyl-, as starch precipitant, I, 259 3-Pentanol, as starch precipitant, I, 259 Pentasaccharide, from potato starch, 111, 275 Pentasol, I, 276 as starch precipitant, I, 259 1-Pentene, 3,4,5-triacetoxy-, 11, 115, 116 4-Pentene-1,2,3-triol, triacetate, 11, 115, 116 l-Penten-4-yne, 3-hydroxy, 11, 117 1-Penten-4yn-3-01, 11, 117 Pentitol anhydrides, V, 191-228 Pentitols, I, 180; 11, 107, 114-118 Pentopyranosides, tritylation of, 111, 87 Pentosans, amount in various natural products, V, 271 determination of, I, 335 Pentoses, origin of name, 111, 11 from Mycobacterium tuberculosis, 111, 312, 331 tritylation of, 111, 84 from tuberculin, 111,321 1-Pentyne, 5-chloro-3,4dihydroxy-, 11, 115, 116 -, 5-chloro-3,4epoxy-, 11, 115, 116

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

-, -,

4,5-dichloro-3-hydroxy-, 11, 115, 116 3,4,5-triacetoxy-, 11, 115, 116 4-Pentyne-2,3-diol, 1-chloro-, 11, 115, 116 4-Pentyne, 1,2,3-triol, triacetate, 11, 115, 116 1-Pentyn-3-01, 4,5-dichloro-, 11, 115, 116 P-Enzyme, 111, 258 Pepsin, blood group substances from, IV, 43, 46 Peptidase, V, 55 Peptides, in cane juice, 111, 124 Peptone, blood group substances from, IV, 43, 46 Perchloric acid, as catalyst for acetylation of cellulose, I, 312 Periodic acid, oxidation with, 11, 30, 66, 232, 275; 111, 348 Peroxidase, V, 53 Petroselinin, IV, 59, 66, 70, 72 PG. See Pectin-polygalacturonase. Periplocymarin, I, 148 Persea gratissirna, heptulose from, I, 12 Persian manna, 11, 6, 7 D-Perseitol, I, 5, 8, 9, 12, 14-16 and heptaacetate, I, 35 L-Perseitol, I, 9 and heptaacetate, I, 35 D-Perseitol group, of natural carbohydrates, I, 15 D-Perseulose, I, 14 L-Perseulose, I, 12-14, 17 Pharmacology, of erythritol and erythritan, I, 179 of ethylene glycol, I, 176 of glycerol trinitrate, I, 179 of isomannide and 8-mannide, I, 185 of mannitan, I, 184 of D-mannitol, I, 183, 184 of methanol, I, 176 of nitrates of sugar alcohols, I, 185 of selenosugars, I, 145 of D-sorbitol, I, 189 Phenanthrahydroquinone, produced from phenanthraquinone by phytochemical reduction, IV, 89 Phenol, p-amino-, IV, 101 -, 2,4-diacetamido-, and acetate, 111, 350 -, 2,4-diamino-, dihydrochloride, 111, 350

-,

385

p-nitro-, reaction with formaldehyde, 111, xvii -, p-nitroso-, IV, 101 Phenylacetaldehyde, phytochemical reduction of, IV, 80 p-Phenylene diamine, IV, 101 Phenylhydrazide rule of rotation, I, 21, 160 Phenylmercury levulinate, IV, 311 Phlein, 11, 260, 262, 273 -, trimethyl-, 11, 262 Phloroglucinol, effect on conductivity of boric acid, IV, 191 Phosphatase, I, 232, 233; 111, 304, 305 Phosphates, starch, I, 305 transfer in muscle, I, 213 Phosphatides, 111, 326, 330 Phosphoadenosine, I, 217 5-Phosphoadenosine. See Adenylic acid, muscle. Phosphodesoxyribose nucleotides, I, 241 Phospholipids, 111, 326 Phosphopyruvic acid, 111, 245, 246 Phosphoribitol, I, 211 5-Phospho-~-ribofuranose,I, 21 1 3-Phosphoribonic acid, I, 215, 216 5-Phosphoribonic acid, I, 215, 216 and y-lactone, I, 211 3-Phospho-~-ribose,I, 214-216 Phosphoric acid, in starch, 111, 302 Phosphorolysis, 111, 258, 264 definition, V, 34 of sucrose, starch and glycogen, V, 34 Phosphorus, in starch, I, 270 Phosphorylase (see also Transglucosidase), 111, 258; IV, 32, 281, 283; V, 35, 70 Phosphorylation, 11, 205, 217; IV, 105 sucrose formation and, V, 33, 70 Phosphotungstate, of streptomycin, 111, 345 5-Phospho-uridine, I, 218 Photosynthesis, isotopic tracers in, 111, 233 Phthalic acid, cellulose ester, I, 320 Phthiocerol, 111, 328 Physical properties, configuration and, of similar sugars, I, 26 Physiological activity, of ascorbic acid Ltnalogs, 11, 94

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

386

Phytin, 111, 47 Phytochemical reduction, alcoholic fermentation and, IV, 105 of aldehydes, IV, 77-81 of disulfides, IV, 93 of heterocyclic compounds, IV, 90 of ketones, IV, 82-85 by microbes, IV, 106 of nitrogen compounds, IV, 97 the term, IV, 76, 77 of thioaldehydes, IV, 93 by yeast, IV, 101 Phytomonas pruni, levan formed by, 11, 227

Phytomonas prunicola, levan formed by, 11, 227 Phytomonas tumejaciens, polysaccharide formation by, 11, 219 Picein, IV, 66 Pinacol, IV, 323 Pine, pentosan content of ponderosa, V, 271

Pinitol, 111, 56, 58 Piperylene, IV, 310 Plantago mucilage, IV, 270 Plant gums. See Gums. Plant mucilages. See Mucilages. Plastic, amylose trincetate, I, 300 cellulose ester, I, 326 starch acetate, I, 297 Plasticizers, IV, 304, 311, 318, 320, 326, 328

Plastic powder, from wood saccharification residues, IV, 158 PM. See Pectin-methylesterase. Pneumococcus, blood group substances from, IV, 46 -, polysaccharides of, 11, 185, 189 Pneumococcus heterophile, antigens, 11, 166

Pneumococcus Type 111, polysaccharide of, 111, 97 Pneumococcus Type XIV, polysaccharide of, IV, 51 Poan, 11, 260, 263 Polar compounds, adsorption by starch, I, 252, 255 effect on starch paste, I, 272 precipitation of starch by, I, 252

Polyafiity between polar groups of enzyme and substrate, V, 55 Polycarbonyl compounds, phytochemical reduction of, IV, 89 Polydispersity, of cellulose, 111, 224 Polyfructosans, 11, 253-267 Polyfructoses. See Levans. Polygala amara, V, 198 Poly-a-D-galacturonic acids, 11, 239, 243 hydrolysis of, I, 336 of pectins, V, 80 structure of, I, 341 Polygalacturonides, 11, 242 Polygala senega L., V, 15 Polygala tenuifolia, V, 198 Polygala vulgaris, V, 198 Polygalitol, (see also D-Sorbitol, 1,5-anhydro-), I, 135 metabolism of, I, 191 Polyglucose. See Dextrans. Polymerization, degree of, for cellulose, 111, 202, 205, 212; V, 106 for cellulose esters, I, 316; 11, 287, 289, 29 1

for 8-dextrin, 111, 266 of starch and its derivatives, 111, 252, 255

Polysaccharides. (See also Mucopolysaccharides.) of Acetobacter chroococcum, 11, 220 of albumin, 11, 194 of anthrax bacillus, 11, 223 Azotobacter, 11, 165 bacterial, 11, 189, 203-233 of Bacillus krzemieniewski, 11, 220 of Bacterium dysenteriae, 11, 200 of Bacterium typhimurium, 11, 200 of Retabacterium vermiforme, 11, 219 blood group, IV, 37-55 of cholera organism, 11, 222 of Clostridium perfringens, 11, 223 constitution (calculated) of, 111, 259 of Corynebacterium diphtheriae, 11, 223 of Cytophagae, 11, 165 of Eberthella typhosa, 11, 223 of egg, 11, 192 of Friedlander’s bacillus, 11, 165 of globulin, 11, 194 hydrolysis with HBr, 11, 231 of leprosy bacillus, 11, 222

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

of lipids, 111, 326, 328 mold, 11, 165, 223 of Mycobaclerium tuberculosis, 111, 311336 optical rotation of, 11, 231 of pathogenic bacteria, 11, 222 of peanut, 11, 245, 247, 248 periodic oxidation of, 11, 232 of Phylomonas tumefaciens, 11, 219 Pneumococcus, 11, 164, 180, 185, 221 Rhizobia, 11, 165, 220 of Salmonella typhimurium, 11, 223 of seromucoid, 11, 195 of Shigella dysenteriae, 11, 222 of Streptococcus bovis, 11, 219 of Streptococcus salivarius, 11, 219 structure of, 11, 219, 231 trityl ethers of, 111, 85 of tubercle bacillus, 11, 166, 223; 111, 321-326 of tuberculin, 11, 223 of yeasts, 11, 223 Polyuronides, I, 329-344 analysis of, I, 334 definition of, I, 329 detection of, I, 331 hydrolysis of, I, 335, 340 hydrolytic products from, I, 337 identification of units in, I, 337 isolation of, I, 331 pectin class of, V, 79 purification of, I, 333 structure of, I, 340 sugars of, I, 338 uronic acids of, I, 338 Potassium chloride, influence upon the activity of pancreatic amylase, V , 237 Potassium cyanide, labelled with isotopic C,111, 231, 233 Potassium carabonate, 111, 161 Potassium n-galactonate, 111, 161 Potassium D-gluconate, 111, 161 Potassium thiocyanate, as catalyst in acetylation of starch, I, 289 Potato, starchless, 11, 228 Potato, sweet, beta amylase of, V, 231, 234 Potato phosphorylase, V, 35 Potato starch. See Starch.

387

Precipitation, selective, in starch fractionation, I, 252, 255, 258, 263, 276 Precipitin reaction, 111, 330 Primeverose, 111, 94 Prolan, 11, 197 Proline, in blood group substances, IV, 49 -, hydroxy-, in blood group substances, IV, 49 Propane, 2,3-dihydroxy-l-guanidino-, 111. 377 1,2-Propanediol. See Propylene glycol. 1,3-Propanediol. See Trimethylene glycol. 2-Propano1, as solvent in sugar research, I, 24 trityl ether, 111, 86 2-Propanone, 3-hydroxy-%phenyl-, IV,87 Propionaldehyde, reduction of, IV, 108 a,@-dichloro-, 11, 115, 116 Propionic acid, carbohydrate formation from, 11, 128 cellulose esters, I, 310, 317, 322 labelled with CI3, 111, 245 labelled with isotopic C, 111, 231 reduction of, IV, 108 starch ester, I, 301 from sucrose, IV, 322, 324 -, N-acetyl-2-amino-, V , 11 -, a-hydroxy. See Lactic acid. -, 0-hydroxy-, effect on conductivity of boric acid, IV, 195 Propyl alcohol, IV, 108 as starch precipitant, I, 259 l,2-Propylene glycol, IV, 80, 144 from molasses, IV, 336 * phytochemical reduction of, IV, 84 from sucrose, IV, 299, 300 Proteins. See also Mucoproteins. blood, IV, 37 carbohydrate complexes with, 11, 162 Protocatechuic acid, effect on conductivity of boric acid, IV, 191 Protopectin, V, 81, 82, 84 Protopectinase, V , 82, 84 Prunus amygdalus, emulsins, V, 63 Prunus avium, emulsins, V , 63 Pseudo-amylose, 111, 259 Pseudofructose. See n-Psicose. Pseudomonas saccharophilia, V, 32, 33,36, 39, 41, 43, 46, 70

3 88

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Pseudotagatose, 111, 115 D-Psicofuranose, 1,2,3,4diiiopropylidene-, I, 65 L-Psicofuranose, 1,2,3,4diisopropylidene-, I, 64, 65 8-D-Psicopyranose, 5-acetyl-3,4-anhydro1,2-isopropylidene-, 11, 72 -, 3,4-anhydro-5-benzoyl-1,2-isopropylidene-, 11, 72 -, 3,4-anhydro-1,2-isopropylidene, 11, 72 -, 3,4-anhydro-1,2-isopropylidene-5methyl-, 11, 72 -, 3,4-anhydro-l,2-isopropylidene-5tosyl-, 11, 72 D-Psicose, I, 65, 66; 111, 113-115, 123 -, 1-desoxy-, osazone, 111, 44 -, 3,4-anhydro-1,2-isopropylidene-, 11, 48 L-Psicose, I, 64, 65 from allitol, IV, 226 kelo-D-Psicose, pentaacetyl-, I, 66; V, 6 reduction of, IV, 217 -, 1-desoxy-1-diazo-tetraacetyl-,I, 66 -, 1-desoxy-tetraacetyl-, I, 66 Pulegone, IV, 92 Purine, I, 200 Purinenucleosidase, I, 226 Purines, deaoxyribosyl-, I, 238 -, ribosyl-, I, 198-207 Purple plum gum, IV, 246 Pyran, 2,4dibenzamido-l,3,5-trihydroxytetrahydro-, and triacetate, 111, 349 Pyranose, 111, 18 Pyranose ring, detection of, 111, 103 5-Pyrazolone, 1-phenyL4phenylhydrazono-, 111, 30, 32 Pyrazolopyradazine ring, 111, 37 Pyridazine, 3-amino-6-methyl-, IV, 312 -, 3-chloro-6-methyl-, IV, 314 -, 6-methyl-3-sulfanilamido-, IV, 312 3-Pyridazone, 2-amyl-6-methy1, IV, 314 -, 2-butyl-Bmethyl-, IV, 314 -, 2-(diethylaminoethyl)-6-methyl-, IV, 314 -, 2,6-dimethyl-, IV, 313 -, Bmethyl, and dihydro deriv., IV, 312

Pyridine, as catalyst for acetylation of starch, I, 284 sorbitol compound with, IV, 213 tritylation of carbohydrates in, 111, 80

Pyridine, 5-amino-2-butoxy-, V, 223 Pyridinium compounds, (6-trityl-~-glucosyl) - chloride, 111, 107 Pyrimidine-2,4-dione, 1,2,3,4tetrahydro1-(5-trityl-~-ribofuranosyl)-, 111, 89 Pyrimidinenucleosidase, I, 226 Pyrimidines, desoxyribosyl-, I, 240 -, diphosphodesoxyribosyl-, I, 241 -, ribosyl-, I, 207-210 Pyrogallol, effect on conductivity of boric acid, IV, 191 a-Pyrone, 5,6-dihydro-Bmethyl-, 11, 89 y-Pyrone, 3-hydroxy-2-methyl-, 11, 89 Pyrrole, IV, 298 Pyruvic acid, 11, 123 bacterial production of, 111, 235 effect on ketonuria, 11, 148 labelled with 0 8 , 111, 237 labelled with isotopic C, 111, 231, 232, 240, 245, 247 reduction of, IV, 108 yeast carboxylase action on, V, 50 -, benzylidene, phytochemical reduction of, IV, 91 -, dimethyl-, V, 50 -, mercapto-, IV, 97 -, oximino-, IV, 101 -, sorbylidene-, phytochemical reduction of, IV, 91 Pyruvic aldehyde, hydroxy-, 111, 52

Q Q-Enzyme, 111, 258 Quebrachitol, 111, 56 Quercinitol, 111, 60 deztro-Quercinitol, 111, 66, 67 Quercitols, 111, 51, 66, 67 Quince seed mucilage, IV, 269 Quinic acid, 111, 70, 72, 73, 75 Quinic amide, 3-acetyl-4,5-methylene-, 111, 73, 75 Quinidine. See also Camphor. catalyst for synthesis of optically active mandelonitrile, V, 53

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Quinine. See also Camphor. catalyst for synthesis of optically active mandelonitrile, V, 53 salts with uronic acids, I, 339 Quinizarin, IV, 90 Quinone, oxime, IV, 101 o-Quinone, tetrabromo-, IV, 89 Quinones, phytochemical reduction of, IV, 89

389

of orthoesters, I, 82, 100, 121 of sugar acetates by AIClr, I , 44, 46 Reductic acid, 11, 96 Reduction. See aEso Phytochemical reduction. biochemical, at expense of sugars, IV, 75-117 ofrcarbonyl compounds, 111, 355 enzymatic, IV, 79 by Raney nickel, I, 24; V, 1-26 R of sugars to alcohols, I, 24 of trityl ethers, 111, 82 Raffinose, 11, 29 Reductone, 11, 95, 96; 111, 127 constitution as 6-[a-~-galactopyrano- Relractive index, of meleaitose, 11, 16 syll-a-~-glucopyranosyl p-D-frucReineckate, of dihydrostreptomycin, 111, tofuranoside, V, 68 355 enzymatic hydrolysis of, 11, 34 of streptomycin, 111, 345 hydrolysis by yeast p-D-fructofuranosiof streptomycin B, 111, 380 dase, V, 68, 69 Residual affinity, in theory of enzyme -, tritrityl-, 111, 111 action, V, 54 -, tritrityloctaacetyl-, 111, 111 Resinous materials, IV, 304, 318, 322, Ramie, V, 104, 107, 116, 122-124, 271 326, 328, 330 crystallinity of, V, 116 from bagasse, IV, 296 non-crystalline cellulose of, V, 107 from molasses, IV, 335 rate of acetylation, V, 122 Resonance, in orthoester formation, I, Raney nickel (see aZso Nickel), in reduc117 tion of sugars, I, 24; V, 1-26 in osazone formation, 111, 43 Rayon, I, 322; V, 107,113-116,119, 121 Resorcinol, effect on conductivity of boric acid, IV, 191 Rayons, accessibility of cellulose of, V, Resorcinol, 5-nitro-, diacetate, 111, 55 114, 115, 121 Respiratory quotient, 11, 121, 151 -, degree of crystallinity, V, 116 in fat metabolism, 11, 137 -, yarn properties, V, 116, 119 Reaction velocity, of hydrolysis of of isolated organs, 11, 142 oligosaccharides of cellulose, 111, 197 Retrogradation, of starch, I, 247, 250, of oxidation of aldoses by sodium 251, 264, 273, 276 hypoiodite, 111, 159 Rhamninose, oxidation of, 111, 145 of oxidation by halogens, 111, 170, 172, Rhamninotrionic acid, 111, 145 D-Rhamnitol, 111, xx; V, 7 175 L-Rhamnitol, 111, xx of tritylation, 111, 86 Reactivity of hydrazones and osazones, L-Rhamnoascorbic acid, 11, 83, 95 111,23-44 L-Rhamnofuranose, 2,3-isopropylidene-5Rearrangement, acyl migration, acidic tosyl-, 11, 55 Rhamnoheptose, I, 7 orthoester formation during, I, 109 acyl migration, 111, 91 “Rhamnoheptose” of Fischer and Piloty, acyl migration, in glycosides, I, 113 v, 10 Amadori, 111, 42, 43 L-Rhamnoheptose, I, 28 through anhydrides of ethylene-oxide La-Rhamnohexitol, 1-trityl-, 111, 111 type, I, 55;II,41-56; V, 218 Rhamnohexitols, I, 20 of anomers by TiClr, I, 53 “ a-Rhamnohexonic acid,” I, 7 of a-hydroxy aldehydes, 111, 374 “8-Rhamnohexonic acid,’’ I, 7

390

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

“8-Rhamnohexonic” lactone, I, 7 -, dimethyl-, methyl 1,2-orthoacetate, I, “ a-Rhamnohexose,” of Fischer and 105 -, 3,4-dimethyl-, IV, 272, 274, 286 Piloty, V, 10 Rhamnohexoses, I, 7, 18, 19 methyl 1,2-orthoacetate, I, 99, 107 L-Rhamno-L-manno-heptononitrile,IV, -, 2-methyl-, specific rotation of, I, 155 149 synthesis of, I, 151, 153 -, pentaacetyl-, IV, 149 -, 4-methyl-, IV, 274 L-Rhamnonamide, 3,4-dimethyl-, IV, 286 and phenylosazone, IV, 286 L-Rhamnonic acid, 111, 144 -, trimethyl-, methyl l,a-orthoacetate, 2,3,4-trimethyl-, phenylhydrazide, IV, I, 105 286 -, 2,3,4trimethyl-, IV, 251 keto-, 111, 150 L-Rhamnose anilide, 2,3,4trimethyl-, IV, L-Rhamnonic lactone, 111, 142, 143, 147 286 L-Rhamnononitrile, tetraacetyl-, IV, 145, L-Rhamnose oxime, IV, 125 149 -, hexapropionyl-, IV, 125 -, tetrabeneoyl-, IV, 126, 130, 146, 149 -, pentapropionyl-, IV, 150 -, tetrapropionyl-, IV, 149 L-Rhamnoside, 7-methyl-, monoacetate, L-Rhamnonononic acid, I, 28 I, 80 LRhamnooctose, I, 28 -, 7-methyl-, triacetate, I, 79 a-L-Rhamnopyranose, IV, 204 j3-L-Rhamnoside, methyl, triacetate, I, LRhamnopyranose, 3,4diacetyl-, methyl 79 Rhesus factor (Rh), IV, 39 1,2-orthoacetate, I, 153 L-Rhamnopyranoside, methyl 2-methyl-, Rhizobia, polysaccharides of, 11, 165, 189 3,4-diacetate, I, 108, 154 Rhizobium radicicolum, methylated cap-, methyl 2,3,4-trimethyl-, 111, 331 sular polysaccharide of, as source of j3-L-Rhamnopyranoside, methyl, triace2,3-dimethyl-~-glucose, V, 160 tate, I, 108, 154 polysaccharide formation by, 11, 220 Rhodeose. See n-Fucose. -, methyl, trimethyl-, I, 105 Rhodizonic acid, 111, 48 -, methyl 2,3,4-trimethyl-, I, 107 n-Rhamnose, 11, 237; v , 8 Ribitol, 11, 86, 115, 117 L-Rhamnose, I, 28; 111, 12; IV, 145 1,5-anhydro-, V, 14, 15, 221, 222, 225 1,5-ditrityl-, 111, 111 in cardiac glycosides, I, 148 configuration of, I, 19 phospho-, I, 211 in gums, IV, 245, 246, 250 2,3,4-triacetyl-, V, 225 higher-C sugars from, I, 7 2,3,4-tribenzoyl-, V, 27, 225 interaction with boric acid, IV, 204 Riboflavin, IV, 101, 107 methyl 1,2-0rthoacetate, I, 98, 105, 107 acylation of, 111, 91 in mucilage, IV, 268, 270, 274 bphosphate, 111, 92 in Mycobaclerium tuberculosis polysac- n-Ribofuranose, 1,5-anhydro-2,3-dicharides, 111, 333, 334 acetyl-, 11, 66; 111, 102 orthoesters of, I, 79 -, 5-phospho-, I, 211 oxidation of, 111, 143, 147, 161, 176 -, trimethyl-, I, 203, 204 -, 5-trityl-1,2,3-triacetyl-,11, 66; 111, phenylosotriazole from, 111, 38 in polyuronides, I, 338 102 specific rotation of, I, 155 D-Ribofuranoside, methyl 2,&isopropyliL-Rhamnose, diacetyl-, methyl 1,l-orthodene-, I, 212 -, methyl 2,3-isopropylidene-5-phosacetate, spectrum of, I, 107 pho-, I, 212 -, 3,4diacetyl-, I, 154 methyl l,a-orthoacetate, structure of, D-Ribohexulose. See D-Psicose. I, 10s D-Ribomethylose, I, 161-163

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

D-Ribonate, ethyl thiol-, tetraacetate, V, 22, 28 D-Ribonic acid, I, 199, 207 -, 3-phosph0-, I, 215, 216 -, 5-phosph0-, I, 211, 215, 216 L-Ribonic acid, 2-keto-, 11, 86 y-D-Ribonic lactone, 5-phospho-, I, 211 -, trimethyl-, I, 209 6-D-Ribonic lactone, trimethyl-, I, 203, 204 D-Ribononitrile, tetraacetyl-, IV, 126, 129, 149 Ribonuclease, I, 227, 231 Ribonucleic acid, desoxy-, 111, 321, 324, 331 D-Ribonyl chloride, tetraacetyl-, V , 22 D-Ribopyranose, 1,4-anhydro-2,3-diacetyl-, 11, 69 -, 2,3,4trimethyl-, I, 203 D-Ribopyranoside, methyl, 111, 90 j3-D-Ribopyranoside, 2‘-naphthyl 1-thio-, tribenzoate, V , 15, 27, 222 8-tRibopyranoside, methyl 2,3-anhydro-, V, 22 Ribose, 3‘-hydroxyacetonyl 1,a-orthoacetate, I, 87 1,2-orthoacetic acid, I, 87 D-Ribose, I, 2, 39 cyanohydrin synthesis with, I, 37, 38 from cytidine and uridine, I, 207 mutarotation of, 111, 85 from nucleic acid, I, 195 orthoesters of, I, 86 oxidation of, 111, 144, 176 from ribosenucleic acid, I, 198 synthesis of, I, 199 D-Ribose, 2-desoxy-, from nucleic acid, I, 195 from thymus nucleic acid, I, 239 -, diacetyl-, methyl 1,2-orthoacetate, I, 87 -, 3,4-diacetyl-, 3’-acetoxyacetonyl 1,2orthoacetate, I, 87 -, 2,3-diacetyl-1,5-ditrityl-,111, 109 -, 1,5-ditrityl-, 111, 109 -, 3-phospho-, I, 214-216 -, 1,2,3-triacetyl-5-trityl-,111, 109 -, 5-trityl-, 111, 85, 109 aldehydo-D-Ribose tetraacetate, V, 22, 28

391

L-Ribose, I, 42 orthoesters, I, 86 oxidation of, 111, 176 synthesis of, I, 10, 199 L-Ribose, 2-desoxy-, I, 239 -, 3,4-diacetyl-. 3’-acetoxyacetonyl 1,2orthoacetate, I, 87 -, 5-desoxy-3-C-formyl-, 111, 338 Ribosenucleic acid, desoxy-, I, 195, 236245 Ribosenucleic acid, from tobacco mosaic virus, I, 235 8-L-Riboside, methyl 3-desoxy-, V , 22 Ribosylpurine nucleotides, of muscle, I, 2 10-2 13 of ribosenucleic acid, I, 214-217 Ribosylpurines, I, 198-207 Ribosylpyrimidines, I, 207-210 Ribosyltheophylline, I, 200, 201 Ribosylpyrimidine nucleotides, I, 217219 Rice, beta amylase of, V, 231 Rice starch. See Starch. Ring formation, in anhydro sugars, 11, 41-47, 56 Ring scission, in anhydro sugars, 11, 47, 49 Rosa canina, emulsins, V, 63, 64 Rosanoff’s modification of sugar nomenclature, 111, 12 Rousta, 11, 7 Rubber, synthetic, IV, 311, 318 Rye straw, pentosan content of, V, 271 S

Saccharase. See j3-D-Fructof uranosidasc. Saccharic acid, dimethyl-, IV, 10 Saccharic acids, 111, 7, 131, 146, 148, 155 from hexitols, IV, 226 Saccharification, 111, 271, 307; V , 229266 of amylose, 111, 263, 264 of a-dextrins, 111, 276, 277 of potato starch, 111, 262 of wood, IV, 153-188 Saccharogenic amylase, 111, 261 Saccharomyces cerevisiae, 11, 217 dextran formed by, 11, 226 polysaccharide formed by, 11, 225

392

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Saccharomyces fragilis, source of galactokinase, V, 49 emulsin of, V, 63 Saccharose D, IV, 29 Salicylaldehyde, phytochemical reduction of, IV, 79 Salicylic acid, boric acid complex, IV, 194 effect on conductivity of boric acid, IV, 195 Saliva, blood group substances from, IV, 45, 46 Salivary amylase (see also Amylases, salivary), V, 265 Salmonella typhimurium, polysaccharide formed by, 11, 223 Salt effect, on viscosity of cellulose esters, I, 317 on action of pancreatic amylase, V, 237 SJrcina iuentricuZi,-cellulose formation by, ,II, 206 Sarmentocymarin, I, 148, 172 Sarmentonic acid, phenylhydrazide and S-benzylthiuronium salt, I, 168 Sarmentose, I, 148, 168, 172 Schardinger dextrins, 111, 305; V, 266 Scillaren A, I, 148 ' Scyllitol, 111, 47, 571 60, 61 -, C-methyl-, 111, 76 Seaweed mucilages, IV, 275 Secalin, 11, 260, 263, 273 Sedative, calcium lactobionate-calcium bromide as, 111, 155 Sedimentation, in polyuronide structure study, I, 341 a-Sedoheptitol, identity with volemitol, I, 47 &Sedoheptitol, I, 12, 13, 16, 47-49 Sedoheptulosan, I, 48-50, 52 -, tetramethyl-, I, 48-50 Sedoheptulose, I, 11-13, 17, 47-49 Sedum spectabile, sugar from, I, 12 Selenoisotrehalose,I, 144 Selenosugars, I, 144 Selenoxide, of methyl 8-D-glucoside triacetate, I, 145 Semicarbazide, 4-~4(p-chlorophenylazo)1-naphthyll-, streptomycin derivative, 111, 380 Sequoitol, 111, 46

Serine, 11, 149 in blood group substances, IV, 49 Seroglycoid, 11, 165, 195 Seromucoid, 11, 165, 195 Serum mucoproteins, 11, 194 Shigella dysenteriae, polysaccharide formed by, 11, 222 Shikimic acid, 111, 70, 73, 75 -, dihydro-, 111, 73 -, 4,5-methylene-, 111, 75 Shikimic nitrile, 3-acetyl-4,5-methylene-, 111, 75 Sierra juniper, pentosan content of, V, 271 Silage, molasses addition to, IV, 335 Sinalbin, I, 129, 131 Sinapin, I, 129, 131 Sinapinic acid, I, 131 Sinigrin, I, 129 Sinistrin, 11, 191, 260, 261, 273 Sionin, I, 187 Sisal, xylan percentage in, V, 270 Sizes, textile, starch xanthates m, I, 307 Slow rates of change in amylase actions, V, 241,253,267,268 Snail mucin, 11, 165, 191 Soaps, phenylmercury levulinate in germicidal, IV, 312 Sodium acetate, as catalyst for acetylation of starch, I, 288 Sodium bicarbonate, effect on ketonuria, 11, 155 Sodium chloride, addition compound with D-glucose, V, 132 Sodium cupri-cellulose, 11, 286 Sodium cyanide, in preparation of aldonic acids with Ca or Ba salt, I, 23 Sodium hypochlorite, 111, 139 Sodium hypoiodite, 111, 160 Sodium salts, influence upon the activity of pancreatic amylase, V, 237 Sodium thiocyanate, as catalyst for acetylation of starch, I, 289 Sodium thiosulfate, phytochemical reduction of, IV, 106 Solvents, for acetylation of cellulose, I, 313 for reductive desulfurizations, V, 2 in sugar researches, I, 24

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Sorbic aldehyde, phytochemical reduction of, IV, 91 Sorbitan, IV, 303 D-Sorbitol (synonym, D-Glucitol), I, 14, 16, 181; 111, xvii, 5; IV, 212, 213, 218; V, 5, 15 boric acid complex, IV, 225 effect on conductivity of boric acid, IV, 191 esters, IV, 220 gallate, IV, 302 metabolism of, I, 183, 187 oxidation of, 111, 150; IV, 226, 227 physical properties of, IV, 219 from sucrose, IV, 299, 301 D-Sorbitol, 5-acetyl-1,3: 2,4-dibenzylidene-6-trityl-, IV, 231 -, 5-acetyl-1,3: 2,4-diethylidene-6tosyl-, IV, 231 -, 5,6-acrylidene-1,3: 2,4.-dimethylene-, IV, 229 -, 6-amino-6-desoxy-1,3: 2,4-diethylidene-, V, 219 -, 2-amino-1,2-didesoxy-, pentaacetate,

393

proofs of structure and configuration, V, 194 tetraacetate, V, 5, 23, 26, 28, 202, 226 tetramethyl-, V, 200 -, 1,5-anhydro-4-(P-~-galactopyranoSyl)-, V, 18, 27 -, 1,5-anhydr0-4 (a-~-glucopyranosyl)-, V, 16-18, 27 heptaacetate, V, 27 -, 1,5-anhydro-4(~-~-g~ucopyranosyl)-, V, 16, 17, 27 heptaacetate, V, 27 -, 1,5-anhydro-6-(P-~-glucopyranosyl)-, V, 27 heptaacetate, V, 27 -, 2,5-anhydro-, V, 226 -, 2,5-anhydro-l,6-dibenzoyl-,V, 226 -, 2,5-anhydro-l,6-dibenzoyl-3,4-ditosyl-, V, 226 -, 3,6-anhydro-, V, 194, 197, 226 -, 3,6-anhydro-2,5-dimethyl-, V, 226 -, 5,6anhydro-, V, 226 -, 5,6anhydro-2,4-bensylidene-l-tosyl-, v. 11 V, 226 -, 1,4anhydro- (synonyms, Arlitan, -, 5,6-anhydro-1,3 :2,4diethylidene-, V, Sorbitan), IV, 303 219,226 -, 1,4-anhydro-benzylidene-(a), V, 226, -, 5-benzoyl-l,3 :2,4diethylidene-, IV, (b), V, 226 231 -1,4-anhydro-3,5-benzylidene-, V, 196, -, 6-benzoyl-1,3: 2,4-diethylidene-, IV, 226 226 -, 1,4-anhydro-3,5-benzylidene-6-iodo--, 5-benzoyl-1,3: 2,4diethylidene-66-desoxy-, V, 226 trityl-, IV, 231 -, 1,4-anhydr0-3,5-benzylidene-6-tosyl-, -, 6-beneoyl-1,3: 2,4dimethylene-, IV, V, 226 230 -1,4-anhydro-6-chloro-6-desoxy-, V, -, 2,4benzylidene-, 111, 90; IV, 229 195,226 -, 1,4-anhydro-6-chloro-6-desoxy-3,5- -, 2,4-bensylidene-l,bdibenzoyl-5,6-isopropylidene-, IV, 231 benzylidene-, V, 196, 226 -, 1,4-anhydro-6-chloro-6-desoxy-2,3,5--, 2,4-benzylidene-5,6-isopropylidene-, IV, 229 triacetyl-, V, 226 -, 1,4-anhydro-2,3,5,6-tetramethane- -, 2,4-benzylidene-3,5-diacetyl-l,6-ditrityl-, IV, 231 sulfonyl-, V, 226 -, l14-anhydro-2,3,5,6-tetramethyl-,V, -, 2,4benzylidene-1,3 :5,6-diisopropylidene-, IV, 229 194, 226 -, 2,4-benzylidene-1,6-ditosyl-,IV, 231 ; -, 1,4-anhydro-5-tosyl-, V, 195 V, 205 -, l,Panhydro-6-tosyl-, V, 226 -, l,Panhydr0-2,3,5-tribenzoyl-,V, 226 -, 2,4-benzylidene-1,6-ditrityl-,IV, 231 -, 1,5-anhydro- (synonym, Polygalitol), -, 2,4-benzylidene-6-methyl-l-tosyl-, IV, 231 V, 6, 15, 27, 198, 226

394 -

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

, 2,4-benzylidene-1,3,5,6-tetraacetyl-, -, 1,4: 3,6-dianhydro-2,5-dimethanesul-

IV, 231 2,4-benzylidene-l-tosyl-, V, 206 -, -, 3,5-benzylidene-2,4-diacetyl-l,6-di-, trityl-, 111, 110 -, 3,5-bensylidene-l,6-ditrityl-,111, 110 -, 5(?)-chloro-5-desoxy-1,4:3,6-dianhy- -, dro-, V, 227 -, -, 1-desoxy-, pentaacetate, V, 26 -, l-desoxy-2-methyl-, V, 11 -, tetraacetate, V, 26 -, 2-desoxy-, pentaacetate, V, 26 -, -, 2,5-diacetyl-1,4: 3,6-dianhydro, V, -, 224, 225, 227 -, -, 5,6-diacetyl-l13:2,4dibenaylidene-, IV, 231 -, 1,6-diacetyl-2,4: 3,5-dimethylene-, IV, -, 230 -, 3,5-diacetyl-l,6-ditosyl-2,4-methyl- -, -, ene-, IV, 230 -, 5,6-diacetyl-1,3: 2,4dimethylene-, IV, -, 230 -, 2,5-diacrylyl-1,4: 3,6-dianhydro-, IV, -, 304; V, 224, 227 -, 2,5-diallyl-1,4: 3,6-dianhydro-, V, 224, -, 227 -, 2,5-diallyldianhydro-, IV, 304 -, 2,5-diamino-2,5-didesoxy-l,4:3,6-di- -, anhydro-, IV, 306; V, 216, 225,227 dimethylene D-ghcosaccharate, V, 227 -, hydrochloride, V, 227 -, oxalate, V, 227 -, picrate, V, 227 sulfate, V, 227 -, 1,4: 3,6-dianhydro-, (Isosorbide), V, -, 195, 197, 211, 227 -, differing stabilities of rings, V, 212 -, production from sucrose, V, 213 -, 1,4: 3,6-dianhydro-2,5-dibenzoyl-,V, -, 227 -, 1,4 :3,6-dianhydro-2,5-dichloro-2,5- -, didesoxy-, V, 227 -, -, 1,4: 3,6-dianhydro-2,5-di-(N4-acetylsu1famide)-, V, 227 -, -, 1,4: 3,6-dianhydro-2,5-diethyl-, V, .227 . ~ -, 1,4 :3,6-dianhydro-2,5-dimethacrylyl-, -, V, 227 -, 1,4: 3,6-dianhydro-2,5-dimethallyl-,V, -, 227 -,

-,

fonyl-, V, 227 1,4: 3,6-dianhydro-2,5-dimethyl-,V, 217, 227 1,4: 3,6-dianhydro-2,5-dinitro-(?), V, 227 1,4 :3,6-dianhydro-2,5-di-(p-nitrobenaenesu1fonamido)-, V, 227 1,4: 3,6-dianhydro-2,5-diamino-2,5didesoxy-disalicylidene-, V, 227 1,4 :3,6-dianhydro-2,5-disulfanilamido-2,5-didesoxy-, V, 227 1,4: 3,6-dianhydro-2,5-ditosyl-, V, 227 1,4: 3,6-dianhydro-2,5-ditrityl-, V, 227 1,4 :3,6-dianhydro-x-iodo-x-desoxy-x'tosyl-, V, 227 1,5-diazoyl-2,3,4,6-tetramethyl-,IV, 231 1,6-dibenzoyl-, IV, 222, 229 1,6-dibeneoyl-2,4 :3,5-dibenrylidene-, IV, 231 1,6-dibenzoyl-2,4 :3,5-dimethylene-, IV, 230 5,6-dibeneoyl-l,3:2,4dibenzylidene-, IV, 231 5,6-dibenzoyl-1,3 :2,4-diethylidene-, IV, 231 5,6-dibenzoyl-1,3: 2,4dimethylene-, IV, 230 5,6-dibenzoyl-l,2,3,4tetraacetyl-, IV, 229 1,3:2,4-dibenzylidene-, IV, 229 1,3:2,4-dibenzylidene-5,6-ditosyl-,IV, 231 1,3:2,4dibeneylidene-6-trityl-, IV, 231 2,4: 3,5-dibenzylidene-, IV, 229 2,4: 3,5-dibenzylidene-l16-dimethacrylyl-, IV, 231 2,4: 3,5-dibenzylidene-l,6-ditosyl-, IV, 231 1,3:2,4-diethylidene-, IV, 229 1,3:2,4-diethylidene-5,6-dimethyl-, IV, 231 1,3:2,4-diethylidene-5,6-ditosyl-,IV, 231 1,3:2,4-diethylidene-&methyl-, IV, 231; V, 219 1,3:2,4diethylidene-6-tosyl-, IV, 231 1,3:2,4-diethylidene-6-trityl-, IV, 231

CUMULATIVE SUBJECT I N D E X FOR VOLS. I-V

-, 2,4: 5,6-difurfurylidene-, IV, 229 -, 1,6-dimethacrylyl-2,4 :3,5-dimethylene-, IV, 230 2,3-dimethyl-, IV, 230 -, 2,3-dimethyl-1,4,5,6-tetraazoyl-,IV, 231 -, 1,6-dimethyl-2,4 :3,5-dimethylene-, IV, 230 -, 5,6-dimethyl-1,3: 2,4-dimethylene-, IV, 230 -, dimethylene-3-methyl, IV, 230 -, 1,3:2,4-dimethylene-, IV, 229 -, 1,3: 2,4dimethylene-6-tosyl-, IV, 230 -, 1,3:2,4dimethylene-6-trityl-, 111, 110; IV, 230 -, 2,4: 3,5-dimethylene-, IV, 229 -, 2,4 :3,5-dimethylene-1,6-ditosyl-,IV, 230 -, 2,4: 3,5-dimethylene-1 ,&ditrityl-, IV, 230 -, di(m-nitrobenay1idene)-,IV, 229 -, di(p-nitrobenzy1idene)-, IV, 229 -, 1,6-ditosyl-2,4methylene-, IV, 230 -, l,g-ditrityl-, 111, 110; IV, 230 -, 1,6-ditrityl-2,4-furfurylidene-, IV, 231 -, 1,6-ditrityl-2,4-methylene-,111, 110; IV, 230 -, ditrityl monobenaylidene-, 111, 90 -, 2,4furfurylidene-, IV, 229 -, 3-(a-~-glucopyranosyl)-,11, 25 nonaacetate, 11, 21, 23 -, hexaacetyl-, IV, 229 -, hexaallyl-, IV, 230 -, hexabutyryl-, IV, 229 -, hexamethyl-, IV, 230 -, hexapropionyl-, IV, 229 -, 3-methyl-, IV, 230 -, 6-methyl-, IV, 230 -, 6-methyl-l,2,3,4,5-pentaacetyl-,IV, 231 -, 2,4methylene-, IV, 229 -, 2,4-rnethylene-lJ3,5,6-tetraacetyl-, IV, 230 -, 2,4-methylene-triben&oyl-,IV, 230 -, mono(o-chlorobenzy1idene)-, IV, 230 -, mono(2,6-dichlorobenaylidene)-, IV, 230 -, mono(o-nitrobenay1idene)-,IV, 229 -, mono(m-nitr0benaylidene)-, IV, 230 -, mono(p-nitrobenzy1idene)-,IV, 230

-,

-,

395

mono(2-nitro-5-chlorobeneylidene)-, IV, 230 -, l-(a-naphthylcarbamyl)-2,3,4,5,6pentamethyl-, IV, 231 -, 1,2,3,5,6-~entamethyl-,IV, 230 -, 2,3,4,5,6-~entamethyl-,IV, 230 -, 2,3,4,6-tetramethyl-, IV, 230 -, 2,3,5,6-tetramethyl-, IV, 230 -, l12,5-triaaoyl-3,4,6-trimethyl-, IV, 231 -, 1,3,5-triazoyl-2,4,6-trimethyl-,IV, 231 -, 1,4,5-triazoyl-2,3,6-trimethyl-,IV, 231 -, 1,5,6-triaaoyl-2,3,4-trimethyl-, IV, 231 -, 1,2,6-tribenzoyl-, IV, 222, 229 -, 1,3:2,4: 5,6-tribenaylidene-, IV, 229 -, tri(o-chlorobenzy1idene)-, IV, 229 -, triethylidene-, IV, 229 -, 1,3:2,4: 5,6-trifurfurylidene-, IV, 229 -, triisopropylidene-, IV, 229 -, 2,3,4-trimethyl-, IV, 230 -, 2,3,6-trimethyl-, IV, 230 -, 2,4,6-trimethyl-, IV, 230 -, 3,4,6-trimethyl-, IV, 230 -, 1,3:2,4:5,6-trimethylene-, IV, 229 -, tri(m-nitrobeney1idene)-, IV, 229 -, tri(o-nitrobeney1idene)-, IV, 229 L-Sorbofuranose, 3,4-diacetyl-lJ2,6-tritrityl-, 111, 108 -, 2,3 :4,6-diisopropylidene-l-trityl-,111, 108 a-L-Sorbofuranose, configurational formula, V, 42 8-L-Sorbofuranose, configurational formula, V, 42 a-L-Sorbofuranoside, a-D-glucopyranosyl, IV, 34; V, 42, 57, 70, 71 Sorbose, historical change of D and L symbols for, 111, 14 D-Sorbose, 111, 53, 113 reduction of, IV, 216 L-Sorbose, I , 16; V, 41, 43, 47, 57 effect on conductivity of boric acid, IV, 207 L-iditol preparation from, IV, 216 orthoesters of, I, 93 oxidation of, 11, 84, 86; 111, 141, 149

396

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

phenylosotriazole from, 111, 38 from D-sorbitol, 111, 150;IV, 226 -, 6-desoxy-2,3-isopropylidene-, 11, 93 -, 6-desoxy-2,3-isopropylidene-l-tosyl-, 11, 93 -, 2,3:4,6-diisopropylidene-,111, 87,164 -, 2,3:4,6-diisopropylidene-l-trityl-,111, 87 -, 1,6-ditosyl-2,3-isoprpylidene-,11,192 -, 6-iodo-6-desoxy-2,3-isopropylidene-1tosyl-, 11, 92 -, 2,3-isopropylidene-, 11, 92 -, triacetyl-, ethyl and methyl orthoacetals, I, 93 keto-rcsorbose, 1-benzoyl-3,5:4,Gdiethylidene-, IV, 226 Sorbyl alcohol, IV, 91, 92 Sorghum starch. See Starch. Soy beans, beta amylase of, V, 231 Specificity, of enzymes in the domain of carbohydrates, V, 49-78 Spectra, of 1-, 3-, 7- and 9-methylxanthines and xanthosine, I, 201 -, structure a d , of orthoesters, I, 107 -, of osazones, 111, 29 Spinner’s fluff, accessible cellulose of, V, 116 -, definition, V, 115 Spruae, pentosan content of white, V, 271 Stachyose, V, 68,69 Staling of bread, I, 273 Starch, V, 105 A and B fractions, I, 247,250,259,260, 262, 263-271 acetolysis of, I, 287 adsorption by, I, 252,255 aldehyde content of, I, 276 alkali lability of, I, 253,267 alkali number of, I, 254 amylase action on, I, 276;111, 301 6-amylase action on, I, 269;111, 268 arrow-root, limit dextrins from, 111, 292,293,298,300 arrow-root, malt a-amylase action on, 111, 274, 280 arrow-root, phosphoric acid in, 111, 303 arrow-root, salivary amylase action on, 111, 299 arrow-root, taka-amylase action on, 111, 298

banana, I, 296 barley, dextrinization of, 111, 282 barley, limit dextrins from, 111, 292, 293 barley, malt a-amylase action on, 111, 281 barley, taka-diastase action on, 111, 298 botanical aspects of, I, 275 canna, I, 271, 296 and cellulose, comparison of chajfl structure, V, 105 commercial acid hydrolysis of, V, 128143 constitution of, 111, 252 corn, I, 255, 267, 268, 270-272, 275, 282, 296; 111, 279, 290, 295; V, 229-267 corn, amylose from, 111, 256 corn, electrophoresis of, I, 251 corn, limit dextrins from, 111, 290,295 corn, malt amylase action on, 111, 289 corn malt a-amylase action on, 111, 279,282 corn, taka-amylase action on, 111, 295 defatting of, I, 256 degradation of, I, 254 dichroism of flow of iodine complex, I, 266 electrophoresis of, I, 251 enzymatic conversion of, I, 269, 270; 111, 261-308; V, 22S267 enzymatic fractionation and hydrolysis of, I, 252 enzymatic synthesis of, 111, 258 fractionation of, I, 247-277 gelatinization of, I, 275 gelation of, I, 264, 272 glycerol degradation product, 0-amylase action on, 111, 267 granule structure of, I, 253 hydrolysis of, I, 268 hydrolysis by acid, 111, 308, 309; V, 128-143 hydrolysis by amylases, V, 229-268 hydrolysis rate of, by @amylase, salivary amylase, and malt a-amylase, 111, 278 iodine adsorption by, I, 256 leaching (aqueous) of, I, 251, 261, 276

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

397

from lily bulbs, I, 261 soluble, malt a-amylase action on, 111, Lintner, ,?-amylase action on, 111, 267 272 Lintner, action of a-amylases on, V, sorghum (waxy), I, 261 233, 239, 243, 244, 251-254, 257 structure of, I, 253, 275 malt *amylase action on, 111, 271 synthesis of, I, 270; IV, 34 malt amylase action on, 111, 287 tapioca, I, 261, 263, 267, 268, 271, 272, methylation of, I, 268, 275, 276 296 nomenclature of components of, I, 250 ultracentrifuge studies of, I, 267 oxidation of, I, 274; 111, 153 viscosity of solutions of, I, 266 paste, I, 255, 271 wheat, I, 255, 272, 294, 296 paste, viscosity of, I, 249, 253 wheat, acetylation of, I, 289 phosphoric acid in, 111, 302 wheat, p-dextrin of, 111, 266 phosphorolysis of, V, 34 wheat, limit dextrins from, 111, 292, potato, I, 261, 263, 267, 268, 270-272, 293 292, 294, 296; 111, 251-310; V, wheat, phosphoric acid in, 111, 302 229-267 wheat, pretreatment of, I, 287 potato, acetylation of, I, 286, 289 X-ray diffraction of, I, 265 potato, ,?-amylase action on, 111, 267 Zulkowski, @-amylase action on, 111, potato, amylose from, 111, 256 267 potato, ,?-dextrin from, 111, 266 Starch, 2,3-ditosyl-3-iodo-3-desoxy-, I, potato, electrophoresis of, I, 251 302 potato, limit dextrins from, 111, 293, Starch acetate, I, 281 294, 297, 300 banana, optical rotation of, I, 296 potato, malt a-amylase action on, 111, canna, optical rotation of, I, 296 270,274 corn, optical rotation of, I, 296 potato, maltose from, 111, 262 determination of acetyl value of, I, 290 potato, pancreatic amylase action on, diffusion constants for, I, 295 111, 254, 298 film-forming properties of, I, 297 potato, phosphate, I, 305 fusion temperatures of, I, 297 potato, phosphoric acid in, 111, 303 molecular weight determinations, I, potato, taka-amylase action on, 111, 295 297 optical rotation of, I, 296 precipitation (selective) of, I, 258, 263, osmotic pressure of solutions of, I, 295 276 potato, optical rotation of, I, 296 precipitation with polar organic subpotato, solubility of, I, 292 stances, I, 252 potato, viscosity of, I, 294 pretreatment for esterification, I, 282 preparation of, I, 284, 289 problems, I, 275 properties and characteristics of, I, 290 products of enzymatic degradation of, properties of solutions of, I, 292 111, 251-310; V, 229-268 rice, optical rotation of, I, 296 retrogradation of, I, 247, 250, 251, 264, solubility of, I, 291 273, 276 tapioca, optical rotation of, I, 296 rice, I, 256, 271, 296 viscosity of solutions of, I, 293 rice, limit dextrins from, 111, 292, 293, waxy corn (maize), optical rotation of, 297 I, 296 rice, nitration of, I, 304 waxy corn, solubility of, I, 292 rice, taka-amylase action on, 111, 298 wheat, optical rotation of, I, 296 sol, I, 265 wheat, viscosity of, I, 294 soluble (see also Starch, Lintner), Starch benzoate, I, 303 @-amylaseaction on, 111, 267 Starch butyrate, I, 301

398

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Starch Starch Starch Starch

chloroacetate, I,301 cinnamate, I,303 dichloroacetate, I,301 3,4-dichlorobenzenefulfonate, I,

heptabenzoyldesoxy-, 111,378

-, iodoheptabenzoyl-, 111,378 -, mesylheptabenzoyl-, 111,378

-,

303

octaacetyl-, 111,347 Streptobiosamic acid monolactone, 111,

279-307

-,

Starch esters, prepn. and properties of, I,

~

-,

Starch formate, I,300 Starch laurate, I,302 Starch laurate benzoate, I,302 Starch myristate, I, 302 Starch nitrate, I,281, 303 Starch palmitate, I,302 Starch phosphate, I,305 Starch propionate, I,301 Starch stearate, I,302 Starch sulfate, I,306 Starch p-toluenesulfonate, I,302 Starch trichloroacetate, I,301 Starch trityl ether, 111,96, 111 Starch xanthate, I,307 Starchless potato, 11,228 Stearaldehyde, 11,123 Stearic acid, conversion to palmitic acid,

11,123

starch ester, I, 302 Stereoformulas, Emil Fischer’s fundamental conventions for, 111,1-22 Stereoisomerism, cis-trans, in orthoester formation, I,118 theory of orthoester formation, I,114 Sterols, phytochemical reduction of, IV,

92

Stilbene, V,4 Straw, as source of D-xylose, V,279 Streptamine, 111,350,384 aromatization of, 111,350 isomers, IIJ,351 and salts, 111,348 -, N,N’-diacetyl-, 111,348, 349 -, N,N’-dibenzoyl-, 111,348, 349,378 -, N,N’-dibenzoyldesoxy-, 111,378 -, hexaacetyl-, 111,348,350 -, hexabenzoyl-, 111,348 Streptidine, 111,53, 338,357, 359 configuration of, 111,384 oxidation of, 111,349,376 and salts, 111,346 structure of, 111,347 --, heptabeneoyl-, 111,377

363

pentaacetyl-, 111,363 and methyl ester, 111,361 L-Streptobiosamic acid monolactone, pentaacetyl-, and methyl ester, 111,383 Streptobiosamine, 111,347, 351,359 -, N-acetyldidesoxydihydro-, 111, 356,

-, -, -, -, -, -,

360

didesoxydihydro-, 111,358, 360 dihydro-, 111,365,368 hexaacetyldihydro-, 111,378 pentaacetyldesoxydihydro-, 111,358 tetraacetyl-, 111,361 tetraacetyldidesoxydihydro-, 111,356,

358,360,361;V, 19,26

L-Streptobiosamine, pentaacetyldesoxydihydro-, 111,383 -, pentaacetyltetrahydroanhydro-, hydrochloride, 111,383 -, tetraacetyl-, 111,383 -, tetraacetyldidesoxydihydro-, 111,376,

383

a-LStreptobiosamine, hexaacetyldihydro-, 111,383 -, pentaacetyldihydro-, 111,383 @-L-Streptobiosamine; hexaacetyldihydro-, 111,383 y-Streptobiosamine, hexaacetyldihydro-,

111,383 Streptobiosaminide, ethyl N-acetyldihydrothio-, 111,357 -, ethyl dihydrothio-, 111,357 -, ethyl pentaacetyldihydrothio-, 111,357 -, ethyl tetraacetyl-, diethyl thioacetal,

-,

111,357

ethyl tetraacetylthio-, 111,361 diethyl thioacetal, 111,355,356,359 -, ethyl thio-, diethyl thioacetal, 111,

355,365;V, 12

hydrochloride, V, 12 tetraacetate, V, 26,27 -, methyl, dimethyl acetal, 111,346,351,

352,355, 357, 365

hydrochloride, 111,346;V, 13 tetraacetate, 111,347, 359

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

-,

methyl N-acetyl-, dimethyl acetal, 111,365, 366 -, methyl N-acetyldihydro-, 111, 365, 366 -, methyl dihydro-, 111,357,365 .-, methyl pentaacetyldihydro-, 111,357, 360;V, 19 a-L-Streptobiosaminide, ethyl pentaacetyldihydro-, 111,383 -, ethyl tetraacetylthio-, diethyl thioacetal, 111,383 -, methyl pentaacetyldihydro-, 111,378, 383 -, methyl tetraacetyl-, dimethyl acetal, 111,383 8-L-Streptobiosaminide, ethyl tetraacetylthio-, diethyl thioacetal, 111,383 -, methyl pentaacetyldihydro-, 111,378, 383 -, methyl tetraacetyl-, dimethyl acetal, 111,383 Streptobiosaminidic acid, methyl, methyl ester, 111,356 tetraacetate, 111,356 LStreptobiosaminidic acid, methyl tetraacetyl-, methyl ester, 111,383 Streptobiosaminidic acid amide, methyl tetraacetyl-, 111,357 Streptobiose, desoxy-, tetraacetate, V, 27 Streptococcus bovis, levan formed by, 11, 228 polysaccharide formation by, 11,219 Streptococcus salivarius, levan formed by, 11,228, 230 polysaccharide formation by, 11,219 Streptomyces griseus, 111,339, 340 Streptomyces lavendulae, 111,339 Streptomycin, 111,53,337-384 antibiotic activity of, 111,342 assay of, 111,341,379 (p-chlorophenazo-) -1 -naphthyl]4-[4semicarbazone, 111,380 degradation to maltol, 111,374 discovery of, 111,339 formula for, 111,358, 359 glycosidic bonds in, 111,375 hydrazone with 9-hydrezinoacridine, 111,379 hydrogenation of, 111, 354 inactivation of, 111,351,352

399

isolation of, 111,343 mercaptolysis of, V, 12 oxidation of, 111,356 production of, 111,340 purification of, 111,344 reaction with NaOH, 111,357 salts, 111,344, 346 stability of, 111,342 structure of, 111,338,345, 366 Streptomycin, dihydro-, 111,357,367 and salts, 111,355 -, dihydro-, methanolysis, V, 19 -, dodecaacetyldihydro-, 111,378 Streptomycin, mannosido, V, 15 Streptomycin B,and reineckate, 111,380 -, dihydro-, 111,380 Streptomycinic acid, 111,356 Streptonose, 111,338 Streptose, 111,338,354,358,359 structure of, 111,360,364,367 -, didesoxydihydro-, 111,360,383 LStreptose, didesoxydihydro-, 111,383 -, di-p-nitrobenzoyldidesoxydihydro-, 111,383 Streptosonic acid, 111,362 Streptosonic acid diamide, 111,362 L-Streptosonic acid diamide, 111,383 Streptosonic acid monolactone, 111,367 -, diacetyl-, 111,361,363 LStreptosonic acid monolactone, 111,361, 383 -, diacetyl-, 111, 383 Streptothricin, 111,339, 342 Strepturea, 111,348, 350 Strontium 1,2-kopropylidene-~-xyluronate, 111,153 Strontium L-rhamnonate, 111,144 Strontium zylo-trihydroxyglutarate, 111, 153 Strophanthin, I, 148 k-Strophanthin-p, I, 173 Strophanthobiose, I, 173 Structure, of desoxyribosenucleic acid, I, 242 of orthoesters, proof of, 107-112 of polyuronides, I, 340 of ribosenucleic acid, I, 219 of starch, I, 253 of starch A and B fractions, I,263,264 of starch granule, I,275

400

CUMULATIVE SUBJECT I N D E X FOR VOLS. I-V

Styracitol (see also n-hlannitol, 1,5-anhydro-), metabolism of, I, 186 “Styracitol, 1,4glucosido,” V, 16 “Styracitol, 1,6-glucosido,” V, 16 Styras obassia, V, 15, 198 Subniaxillary mucin, 11, 165, 198 Succinamide, dimethoxy-, D-threo, IV, 14 L-threo-, IV, 11 -, dimethoxy-N,N’-dimethyl-, n-threo-, IV, 14 Succinic acid, 11, 130; 111, 238, 241 bacterial production of, 111, 235 cellulose ester, I, 320 labelled with (311, 111,238 labelled with C1a, 111,236, 240 labelled with isotopic C, 111, 231, 248, 249 protection oE enzyme by, V, 54 Succinic acid, dimethoxy-, D-threo, and dimethyl ester, IV, 14 -, dimethoxy-, cthreo, and dimethyl ester, IV, 11 -, meso-dimethoxy-, I, 203, 204, 209 -, D ( -)-dimethoxy-, V, 202 -, L(+)-dimethoxy-, V, 199, 202 -, i-dimethoxy-, IV, 15 -, iodo-, 111, 151 Succinic dehydrogenase, V, 54 Sucrose, 111, 11; IV, 1-35; V, 29-39, 67-71 acid transformation products, IV, 306 from Alhagi manna, 11, 10 alkali degradation products, IV, 317 in cement mortars, IV, 321 configuration and structure of, IV, 1-35 diagram of posulated union with saccharase, V, 56 effect on conductivity of boric acid, IV, 198 electrical constants, IV, 16 enzymatic hydrolysis of, 11, 34 fermentation processes for conversion of, IV, 322 j3-D-fructofuranosyl ring in, IV, 12, 21 a-D-glucopyranosyl ring in, IV, 9, 17 heat of combustion of, IV, 16 history of, 11, 2; IV, 1 hydrolysis by acids, 11, 274; IV, 8 inversion of, IV, 7, 18 -invert sugar relationship, IV, 3

melting point, IV, 2 methanolysis of, IV, 25 methylation of, IV, 25 molecular weight, IV, 5, 16 octaacetate, IV, 2, 7, 27, 28, 318 octabutyrate, IV, 320 octanitrate, IV, 7, 320 octapropionate, IV, 10, 320 optical constants, IV, 16 oxidation of, 111, 141, 165; IV, 17 oxidation products of, IV, 297 phosphoric acid complex,hV, 33 producing countries for, IV, 294 reaction with sodium hypoiodite, 111, 160 reduction products of, IV, 299 refractive index of, 11, 17 synthesis of, IV, 2, 27, 31; V, 29-46 utilization of, IV, 293-336 wood treatment with, IV, 321 Sucrose, dibenzyl-, IV, 320 -, heptaallyl-, IV, 320 -, heptamethyl-, IV, 10, 320 -, octamethyl-, IV, 10, 320 -, pentabenzyl-, IV, 320 -, tritrityl-, 111, 111;IV, 16 -, tritritylpentaacetyl-, 111, 111 Sucrose phosphorylase (synonym,Transglucosidase), V, 31-36, 47, 48, 59, 70-73 Sucrose series, biochemical synthesis in, IV, 31 Sugar, ropy, 11, 190 Sugar alcohols, oxidation of, 111, 150, 166 tritylation of, 111, 85 Sugar anhydrides, 11, 37-77; 111, 101 classification of, 11, 40 of ethylene oxide type, 11, 47-56 of glycosan type, 11, 64-66 of hydrofuranol type, IV, 5G64 as intermediates in interconversion of configurational isomers, 11, 51 in synthesis, 11, 67 Sugar beet pulp, IV, 297 Sugar cane, IV, 295 Sugar Research Foundation, Inc., IV, 293 Sugars, amino, 11, 49, 167, 221 in polysaccharides of M . tuberculosis, 111, 333, 334 desoxy, 111, 101 ~~~

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

dicaTbony1, 111, 103 interconversion of isomers, 11, 51 interconversion in nature, 11, 53 ketose, oxidation of, 11, 84 methylated, bromine oxidation of, 111, 145 Sugars, biochemical reductions a t expense of, IV, 75-117 Sugars, of cardiac glycosides, I, 147-173 configuration and physical and chemical properties of similar, I, 26 2-desoxy, I, 148 Fischer cyanohydrin synthesis and configuration of, I, 1-36 nomenclature of, I, 28 in polyuronides, identification of, I, 338 reduction of, to alcohols, I, 24 seleno-. See Selenosugars. similar, I, 26 solvents for, I, 24 thio-. See Thiosugars. Sugar acetates, rearrangements with MCII, I, 44,46 Sugar alcohols. See Alcohols. Sulfanilamide, N’-[5-(carboxymethyl)-P methyl-2-thiazolyl]-, and ethyl eater, IV, 312 -, N’-(6-methyl-3-pyridazy1)-,IV, 312 Sulfatase, IV, 281 Sulfates, starch, I, 306 Sulfides, sugar, I, 136, 144 Sulfite process, wood hydrolysis in, IV, 186 Sulfite waste liquor, alcohol and yeast from, IV, 187 Sulfones, sugar, I, 136 Sulfonic acids, cellulose esters, I, 321 Sulfosinapisin, I, 129 Sulfur dioxide, as catalyst in acetylation of starch, I, 289 liquid, as solvent for acetylation of cellulose, I, 313 as catalyst for acetylation of starch, I, 286 Sulfur trioxide, as catalyst in acetylation of starch, I, 289 Sulfuric acid, as catalyst for acetylation of cellulose, I, 312 Sulfuryl chloride, as catalyst in acetylation of starch, I, 289

401

Sweet potato, beta amylase of, V, 231, 234 Synthesis, Fischer cyanohydrin, I, 1-36, 37, 38 of starch, I, 270 of sucrose, V, 29-46

T D-Tagatopyranose, phenylosazone, III,29 fi-D-Tagatopyranose,3,4-anhydro-, 11, 72 -, 3,4anhydro-5-acetyl-1,2-isopropylidene-, 11, 72

-,

3,4-anhydro-l,2-isopropylidene-5-pnaphthosulfonyl-, 11, 72 -, 3,4-anhydro-l,2-isopropylidene-5tosyl-, 11, 72 D-Tagatose, I, 68, 69; 111, 113 -, 3,Panhydro-1,2-isopropylidene-, 11, 50 diisopropylidene-, I, 68, 69 D-Tagaturonic acid, I, 69, 70 -, diisopropylidene-, I, 68, 69 Taka-amylase. See under Amylases. Taka-diastase, V, 250 Talitol, 111, 5 D-Talitol, I, 181; Iv, 212,217,219 -, 1,5-anhydro-, V, 17, 203, 204, 226 tetraacetate, V, 226 -, l,&diacetyldimethylene-, IV, 241 -, 2,5-diacetyl-1,3:4,6-dimethylene-, IV, 241 -, 1,6-dibenzoyldimethylene-,IV, 241 -, 1,3: 4,6-dimethylene-, IV, 241 -, 1,3: 4,6-dimethylene-2,5-ditosyl-,IV, 241 -, 2,3,4,5-dimethylene-, IV, 241 -, dimethylene-1,6-ditosyl-, IV, 241 -, hexaallyl-, IV, 241 -, 2,4methylene-, IV, 241 -, 2,Pmethylene-1,3,5,6-tetraacetyl-, IV, 241 - , 2,4-methy lene-1,3,5,6-tetrabenzoyl-, IV, 241 -, tribenzylidene-, IV, 241 -, 1,3:2,4: 5,6-trimethylene-, IV, 241 cTalitol, I, 181; 111,xvii; IV, 217, 219 D,L-Talitol, physical properties of, I v , 219 tTaloheptulose, I, 48

-,

402

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Talomucic acid, 2,banhydro-, and calcium salt, 11, 74 D-Talomucic acid, I, 10, 38, 39, 67, 68 D,tTalomucic acid, 111, 49, 50, 63 D-Talomucic 1,4-lactone, I, 67, 68 D-Talomucic 3,6-lactone, I, 67, 68 D-Talonic acid, I, 39, 67, 68 and brucine salt, 111, 143 D-Talonic acid, 2,5anhydro-, and brucine salt, 11, 73 D-Talonic lactone, reduction of, IV, 217 8-D-Talopyranose,3,4: 1,6dianhydro-, 11, 67, 70 -, 3,4I 1,6-dianhydro-2-tosyl-, 11, 70 a-D-Talopyranoside, phenyl, V, 66 Talosan, 3,4-anhydro-, 11, 70 -, 3,banhydro-2-tosyl-, 11, 70 D-Talose, oxidation of, 111, 176 reduction of, IV, 217 -, 2,5-anhydro-, 11, 73 -, 1,2-0rthobenzoic acid, I, 93, 111 orthoesters of, I, 92 -, triacetyl-, methyl l,2-orthoacetate, I, 92 Tapioca starch. See Starch. Taranjbin, 11, 4 Tartaric acid, configuration of, 111, 7 oxidation of, 111, 149 from sucrose, IV, 297 D-Tartaric acid, 111, 15 L-Tartaric acid, 111, 15; IV, 332 Tartrimide, N-ethyl, effect on conductivity of boric acid, IV, 192 Tartrimide, N-methyl, effect on conductivity of boric acid, 111, 52 Tartronic dialdehyde, 111, 52 Terenjabine, 11, 7 Terpene series, phytochemical reduction in, IV, 89 a-Terpineol, aa starch precipitant, I, 259 Testosterone, labelled with CI4, 111, 233 AtTestosterone, IV, 93 Tetramethylenesulfone-2,3-diol, cis- and trans-, effect on conductivity of boric acid, IV, 192 -, 1,4-dimethyl-, Cis- and trans-, effect onconductivity of boric acid, IV, 192 -, 2-methyl-, cis- and trans-, effect on conductivity of boric acid, IV, 192

Tetrasaccharides, from corn starch, 111, 290 from potato starch, 111, 276 Tetrazolium chloride, 2,3,btriphenyl-, IV, 100 Tetritols, metabolism of, I, 178 Tetronic acid, hydroxy-, 11, 91 Tetrose, origin of name, 111, 11 Textile weaving, starch use in, I, 273 Thallous ethylate, use in methylation of cellulose, V, 123 Theophylline, D-glucopyranosyl-, 111, 90 -, ribosyl-, I, 200, 201 -, 7'-(6-trityl-p-~-glucopyranosyl)-, 111, 90, 106 -, 7'-(6-trityl-2,3,4-triacetyl-p-~-glucopyranosy1)-, 111, 106 Thevetin, I, 148 Thialdine, IV, 93 Thiamine, in fat formation, 11, 124 Thiamine pyropLosphate, 11, 124 5-Thiazoleaceticacid, 2-amino-4methyl-, IV, 312 -, bmethyl-, IV, 312 -, 4-methyl-2-sulfanilamido-, and ethyl ester, IV, 312 Thioacetaldehyde, phytochemical reduction of, IV, 93 Thioacetals, I, 140 thioglycosides from, I, 136 reductive desulfurization of, V, 5 Thioalcohols, IV, 93, 95 Thioaldehydes, phytochemical reduction of, IV, 93 Thioaldoses, I, 134, 141 Thiobutyraldehyde, IV, 95 Thiocellobiose. See Cellobiose, thio-. Thiocyanate, of aceto-D-glucose, I, 133 Thiocyanates, reductive desulfurization of, V, 24 Thioethers, formation and hydrogenolysis, V, 19 Thio-D-fructoside, ethyl. See D-Fructoside, ethyl thio-. Thiogalactose. See Galactose, thio-. 1-Thio-D-glucose. See D-Ghcose, 1-thio-. Thio-D-glucoside. See D-Glucoside, thio-. Thioglycoses, I, 135 Thioglycosides, from thioacetals, I, 136 natural, I, 129

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

reductive desulfurization of, V, 1, 14 synthetic, I, 132 Thioisovaleraldehyde, IV, 95 Thiolesters, hydrogenolysis, V, 22 2-Thiophenealdehyde, phytochemical reduction of, IV, 91 2-Thiophenecarbinol, IV, 91 Thiosugars, I, 129-144 Thiosulfate, phytochemical reduction of, IV, 95, 106 D-Threaric acid, dimethyl-. See Succinic acid, D( -)-dimethoxy-. LThrearic acid, dimethyl-. See Succinic acid, L( +)-dimethoxy-. D-Threitol, I, 180 LThreitol, I, 180 L-Threonamide, 3,4dimethyl-, 111, 165 LThreonic acid, 3,4-isopropylidene-, 11, 93 Threonine, in blood group substances, IV, 49 LThreonyl chloride, 2-acetyl-3,4-isopropylidene-, 11, 93 D-Threopentulose, l-N-piperidyl-1desoxy-5-trityl-, and hydrochloride, 111, 109 Threose, historical reversal of D and L symbols, 111, 14 D-Threose, 11, 90; I v , 145 L-Threose, IV, 145 -, 3-C-hydroxymethyl-, illustrative formula, 111, 21 D-Threose diacetamide, IV, 142-145, 151 -, benzylidene-, IV, 151 -, triacetyl-, IV, 151 -, tribenzoyl-, IV, 151 L-Threose diacetamide, IV, 145, 151 -, benzylidene-, IV, 151 -, triacetyl-, IV, 151 -, tribenzoyl-, IV, 151 LThreuronic acid, 11, 104 -, bmethyl-, 11, 104 Thymidine, I, 240, 243 -, diphospho-, I, 242 -, btosyl-5-trityl-, I, 241 -, 5-trityl-, I, 240 Thymine, from desoxyribosenucleic acid, I, 237 desoxyribose nucleoside, I, 238, 240

403

from nucleic acids, I, 195 phosphodesoxyribosylnucleotide,I, 241 Thymine, 3'-desoxyribosyl-, I, 240 Thymoquinone, phytochemical reduction of, IV, 89 Thymus nucleic acid. See Desoxyribosenucleic acid. Titanium tetrachloride, reaction with ' orthoesters, I, 86 reaction with triacetylfructose methyl orthoacetate, I, 91 in rearrangement of methyl tetraacetyl-8-D-altroside, I, 53 rearrangement of orthoesters by, I, 122 Tobacco, pectin-esterases of, V, 93, 95 Tobacco mosaic virus, ribosenucleic acid from, I, 235 Toluene, 2-amino-4,6-dinitro-, IV, 100 -, 4-amino-2,6-dinitro-, IV, 100 -, 2,4-diamino-6-nitro-, IV, 100 -, 2,6-dinitro-Phydroxylamino-,IV, 100 -, 2,4,6-trinitro-, bioreduction of, IV, 99 p-Toluenesulfonic acid, cellulose esters, I, 321 starch ester, I, 302 Tomato, pectin-esterases of, V, 85, 93-97 Torula monosa, for fermentation of only monosaccharides, V, 38 Torula ulilis, IV, 101, 181, 185 Tosylation, 111, 88, 98 Tragacanth gum, IV, 246, 251 Tragacanthic acid, IV, 246, 262 Transfer reactions between one enzyme and two species of substrate, V, 57 Transglucosidase (sucrosephosphorylase), V, 49, 58, 59, 70-73 Transition temperature in dextrose manufacture, V, 135 Transphosphorylation, V, 49, 59, 70-73 Tree bark, pentosan content, V, 271 Trehalose, acylation of, 111, 91 from acetone-soluble fats of M. tuberculosis lipids, 111, 327 unaffected by sucrose phosphorylase, V, 72 Trehalose, 6,6'-diiodo-6,6'-didesoxy-2,3,4,2',3',4'-hexaacetyl-, 111, 99, 104 -, ditrityl-, 111, 104 -, 6,6'-ditrityl-, 111, 84, 111 -, 6,6'-ditritylhexaacetyl-, 111, 111

404

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Trehalosedieen, hexaacetyl-, 111, 104 Triacetin, 11,127 2,1,3-TriazoleJ 2-phenyl-4-formyl-, II1,38 -, 2-phenyl-P(~-arabo-tetrahydroxybuty1)-, and tetraacetate and tetrabenzoate, 111, 38 Tributyrin, 11, 127 -, deuterio-, 11, 162 Tricaproin, 11, 127 Tricaprylin, 11, 127 Tricarballylic acid, 111,73,74 Tricarboxylic acid cycle, in carbohydrate oxidation, 111, 238 Triheptanoin, glycoside formation from, 11, 128 Trihexosan Pringsheim, @-amylaseaction on, 111, 267 Trimethylene glycol, IV, 114 Triolein, D-glucose from, 11, 137 Triose, origin of name, 111, 11 Triphenylmethyl ethers. gee Trityl ethers. Tripropionin, 11, 128 Trisaccharides, from corn starch, 111, 290 oxidation of, 111, 146 from potato starch, 111, 264, 276 Tris (1,2-isopropylidene-~ttyl-n-glucofuranosyl)-3-phosphateJ111, 107 Tritanol, 111, 79, 83 Trithiodigalaatose, I, 138 Triticin, 11, 260, 263, 273 Triticonucleic acid, I, 196 Tritylation, of carbohydrates, 111, 80 of pentosea, 111, 84 of sucrose, IV, 16 of sugar alcohols, 111, 86 velocity of, 111, 88 Trityl bromide, 111, 82 nitJrl chloride, I, 204; 111, 79 Trityl ethers, alcoholysia of, 111, 81 analysis of, 111, 82 of carbohydrates, 111, 79-111 cleavage of, 111, 81 properties of, 111, 80 purification of, 111, 80 reaction with alkalies, 111, 84 eolubility of, 111, 86 (anityl-D-glucosyl)pyridinium chloride, 111, 107

(6-Trityl-D-glucose) trimethylammonium bromide, 111, 107 Trityl group, 111, 79, 83 Trityl intermediates, in synthesis of carbohydrates, 111, 90 Trivalerin, glycogen formation from, 11, 128 Tryptophane, in blood group substances, IV, 49 Tuberculin, polysaccharides of, 11, 223; 111, 321-326 Tuberoulinic acid, 111, 315, 316, 320 Tuberculin reaction, 111, 329 Tuberculin protein, 111, 824 Tuberculosis, 111, 339 Tularemia, 111, 339 Turanjabine, 11, 4, 10 a-Turanofuranose, octaacetate, 11, 21 p-Turanofuranose, octaacetate, 11, 21 a-Turanopyranose, octaacetate, 11, 21 8-Turanopyranose, heptaacetate, I, 89; 11, 21 -, methyl l,2-orthoacetateJ I, 89, 100; 11, 21 -, octaacetate, 11, 21 -, hexaacetyl-, methyl lJ2-orthoacetate, I, 99;11, 21 8-Turanopyranoside, methyl, and heptaacetate, 11, 21 8-Turanopyranosyl bromide, heptaacetyl-, 11, 21 8-Turanopyranosyl chloride, heptaacetyl-, 11, 21 8-Turanopyranosyl iodide, heptaacetyl-, 11, 21 Turanose, 11, 1-36 crystabation of, 11, 17 enzymatic hydrolysis of, 11, 33 history of, 11, 6 mutarotation of, 11, 18, 22 octaacetates, 11, 19 orthoesters of, I, 89 phenylosazone, 11, 9, 25, 27 phenylosotriazole from, 11, 27, 28; 111, 38 . photograph of crystals of, 11, 18 relationship to maltose, 11, 26 structure of,. 11,. 9,. 19,. 22-24 keto-Turanose, octaacetate, 11, 21

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

Turanose, heptaacetate, I, 89 methyl 1,2-orthoacetate, I, 89, 100 -, pentaacetyltritrityl-, 111, 111 -, tritrityl-, 111, 111 Turanoside, methyl, heptaacetate, I, 89 Turkestan manna, 11, 5 “Tween 80,” favoring growth of tubercle bacilli, V, 223 Typhoid fever, 111, 339 Tyrosine, in blood group substanoes, IV, 49 labelled with CI4,111, 233

U Ulmus fulva mucilage, IV, 270 Ultracentrifuge, in polyuronide structure study, I, 341, 342 in starch research, I, 267 Ultracentrifuge measurements, for determination of degree of polymerization of cellulose, 111, 222 with polysaccharide from tuberculin, 111, 320, 326 Ultraviolet light, as catalyst in oxidation, 111, 162, 177 Undecylic acid, carbohydrate formation from, 11, 128 Unsaturated carbohydrates, 111, 102 Uracil, from nucleic acids, I, 195 from ribosenucleic acid, I, 198 -, l’-(ditrityl-D-ribofuranosyl)-,111, 109 -, 1’-(2,gdimethyl-&trityl-~-ribofuranosy1)-methyl-, 111, 110 -, lf-(2,3-ditosyl-5-trityl-~-ribofuranosy1)-, 111, 109 -, &methyl-. See Thymine. -, 3’-~-ribofuranosyl-. See Uridine. -, 1’-(5-trityl-~-ribofuranosy~)-, 111, 109 Uridine, I, 207-210 -, 5’-bromo-, I, 208 -, dihydro-, I, 208 -, 2,bdimethyl-, I, 209 -, 2,3-dimethyl-5-tosyl-, I, 210 -, 4’,5’-diphenylhydrazino-,I, 208 -, 2,3-ditosyl-, I, 209 -, 2,4ditosyl-5-trityl-, I, 209 -, ditrityl-, I, 209 -, iodoisopropylidene-, I, 210 -, 2,3-isopropylidene-, I, 210, 218

405

-, -, -, -, -, -, -,

isopropylidenetosyl-, I, 210 N(1’)-methyl-, I, 208 monotrityl-, 111, 89 5’-nitro-, I, 208 5-phospho-, I, 218 5-phosphoisopropylidene-,I, 218 5-trityl-, I, 209 Uridylic acid, I, 196, 217 guanine-, I, 223-226 nucleotidase action on, I, 226 Urine, blood group substances from, IV, 42, 46 mucoproteins of, 11, 198 Uronic acids, 11, 221 determination of, I, 335 oxidation of, 111, 130, 131, 146 of polyuronides, I, 338 Uronides, hydrolysis and oxidation of, 111, 146 Uzarin, I, 148

V Valeraldehyde, phytochemical reduction of, IV, 78, 106 Valeric acid, carbohydrate formation from, 11, 128 -, 7-hydroxy-, effect on conductivity of boric acid, IV, 195 Valeric ylactone, IV, 310 Valine, in blood group substances, IV, 49 Vanillin p-D-glucopyranoside, v, 64, 65 Van’t Hoff-LeBel theory, I, 2, 4, 18; 111, 2 Varianose, 11, 223 Vernine, I, 198 Vibris perimastrix, action on cellulose, V, 122 Vicianobionic acid, calcium salt, 111, 154 Vicianose, 111, 95, 154 Vinyl acetate, reaction with Br, 111, 168 Viscose, V, 107, 113, 114, 116, 119 Viscosity, of cellulose esters, I, 315 of cellulose ethers, 11, 287 in polyuronide structure study, I, 341, 342 of starch acetate solutions, I, 293 of starch paste, I, 249, 253 of starch solutions, I, 266

406

CUMULATIVE SUBJECT INDEX FOR VOLS.

Viscosity measurements, for determination of degree of polymerization of cellulose, V, 222 Vitamin C (see also L-Ascorbic acid), I, 71 Vitamin Bs,from cane molasses, IV, 336 D-Volemitol, I, 8,9,11-13, 15,16; 111,166 identity with orsedoheptitol, I, 47 metabolism of, I, 186 and heptaacetate, I, 34, 35 synthetic, I, 32 Volemose, I, 32, 71 Volemulose, I, 13, 32, 71

I-v

Scholler process, IV, 166 utilization of sugars from, IV, 178 Wood waste, sugar from, IV, 154

X

Xanthate, ethyl tetraacetyl-8-D-glucopyranosyl-, V, 23, 28 -, ethyl triacetyl-n-arabinopyranosyl-, V, 23 Xanthates, S-glycosyl-, reductive desulfurization to anhydrides of sugar alcohols, V, 23 Xanthates, starch, I, 307 W Xanthine, 1-, 3-, 7- and 9-methyl-, spectra of, I, 201 Walden inversion, I, 54, 57, 115, 124; 11, -, 9’-(3-phospho-~-ribofuranosyl)-.See 45, 61, 63 Xanthylic acid. Wassermann antigens, 11, 166 Xanthorhamnin, 111, 145 Wassermann substance, 11, 198 Xanthosine, I, 199, 201 Wax, sugar-cane, IV, 296 Xanthylic acid, I, 214, 216 Waxes, from lipids from M. tuberculosis, X-ray diffraction, of starch, I, 265 111, 326, 327 X-ray diffraction measurements, for deWheat, beta amylase of, V, 231 termination of degfee of polymerizaWheat starch. See Starch. tion of cellulose, 111, 223 Wheat straw, Garabinose in xylan of, V, X-ray diffraction studies, of crystallites in 279 cellulose, V, 104, 106-108 -, pentosan content, V, 271 D-Xylal, 2-hydroxy-, triacetate, V, 221 -, xylan of, V, 282 Xylan, V, 269-290 Whey, Saccharomyces fragilis grown on, biological decomposition, V, 288 v, 49 composition and structure, 11, 240; V, White mustard seed, mucilage, IV, 270 278-284, 289 Wohl degradation, of aldononitriles, IV, furfural from, V, 288 129 nitric acid oxidation, V, 285 Wood fibers, diffraction pattern, V, 104 optical rotation, V, 282 Wood pulp, 11,281,282; V, 106,113,115, periodate oxidation, V, 284 121 Xylan, crystalline, from birchwood, V, as cellulose source, I, 311 278 Wood saccharification, IV, 153-188 -, dimethyl-, V, 281 Bergius-Willsttitter process, IV, 159 -, esparto, yield of crystalline n-xylose by-products of, IV, 177 from, V, 278 concentrated-acid processes, IV, 159 -, holocellulose as source of, V, 274 dilute-acid processes, IV, 155 -, straw, V, 288 history of, IV, 154 yield of crystalline D-xylose from, V, Madison wood sugar process, IV, 175 278 material for, IV, 169 Xylan esters, benzoyl ester, V, 287 pilot plant experiments, IV, 166 diacetate, V, 286 procedure for hydrolysis, IV, 171 dinitrate, V, 287 Prodor process, IV, 160 oleoyl ester, V, 287 Rheinan process, IV, 160 stearoyl ester, V, 287

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

sulfate, V, 287 xanthate, V, 287 Xylanase, enzyme from Aspergillus niger, V, 288 Xylitol, I, 180 effect on conductivity of boric acid, IV, 191 oxidation of, 111, 166 -, 1,4:2,5-dianhydro-, V, 220, 221 -, l+ditrityl-, 111, 111 -, lI5-ditrity1-1,2,3-triacetyl-, I1I , 111 D,L-Xylitol, 1-desoxy-2,4:3,5-dimethylene-, V, 25, 28 -, 1-desoxy-1-thiocyano-2,4:3,5-dimethylene-, V, 24, 25, 28 -, 2,4: 3,5-dimethylene-l-tosyl-, V, 24 D-Xyloascorbic acid. See D-Ascorbic acid. Xylobiose, from partial acid-hydrolysis of xylan, V, 280 crystalline hexaacetate, V, 280 Xylobioside, methyl, V, 280 crystalline pentaacetate, P,280 -, methyl pentamethyl-, V, 280 D-Xylofuranose, 3,5-anhydro-l,2-isopropylidene-, 11, 66, 73; V, 207 -, 1,2-isopropylidene-5-tosyl-,11, 66 p-Xylohydroquinone, IV, 89, 106 Xyloidine, I, 303 8-D-Xyloketofuranoside, a-D-glucopyranosyl, IV, 34; V, 35, 39, 69, 71 D-Xyloketose, 111, 177; v, 39, 46 D-Xylomethylose, I, 161 D-Xylonamide, 2,3-dimethyl-, IV, 285 D-Xylonic acid, 111, 154 -, 2,3-dimethyl-, p-bromophenylhydraBide and phenylhydrazide, IV, 285 -, 2,3,4trimethyl-, phenylhydrazide, IV, 285 D-Xylonic &lactone, 3,4dimethyl-, IV, 285 -, 2,3,4trimethyl-, 111, 146; IV, 285 r)-Xylonic r-lactone, 2,3,5-trimethyl-, V, 282 D-Xylononitrile, tetraacetyl-, 11, 90; IV, 144, 145, 149 bxylononitrile, tetraacetyl-, IV, 145,149 a-D-Xylopyranose, IV, 205 8-D-Xylopyranose1 configurational formula, 11, 240

407

D-Xylopyranoside, methyl 2,3-dimet hyl-, V, 281, 289 -, methyl 2-methyl-, V, 289 -, methyl monomethyl-, V, 282 -, methyl 2,3,4trimethyl-, V, 289 8-D-Xylopyranoside, methyl diacetyltrityl-, 111, 109 - , methyl ditrityl-, 111, 87, 109 -, methyl tritrityl-, 111, 87 -, phenyl-, V, 62, 65 -, phenyl 1-thio-, triacetate, V, 14, 27, 22 1 p-Xyloquinone, phytochemical reduction of, IV, 89, 106 Xylose, historical reversal of D and L symbols, 111, 14 D-Xylose, 11, 62, 236, 240; 111, 12, 14, 16; IV, 144; V, 279 in damson gum, IV, 52 in gums, IV, 245, 246, 253, 256, 258, 26 1 interaction with boric acid, IV, 205 in mucilages, IV, 270, 274 oxidation of, 111, 144, 147, 161, 176 phenylosazone anhydride, 111, 31 phenylosotriazole, 111, 38 in polyuronides, I, 338 preparative methods, V, 279 specific rotation of, I, 155 from wood, IV, 160 D-Xylose, 2-desoxy-, I, 239 -, 5-desoxy-, I, 30 -, 2,3-dibenzoyl-l,5-ditrityl-,111, 109 -, 2,3-dibenzoyl-5-tosyl-l-trityl-, 111, 109 -, 2,3-dibenzoyl-l-trityl-,111, 109 -, diisopropylidene-, IV, 205 -, dimethyl-, V, 284 -, 2,3-dimethyl-, V, 282-284 -, 2,4dimethyl-, IV, 284 -, 3,4dimethyl-, IV, 262, 274 -, ditrityl-, 111, 84 -, l,&ditrityl-, 111, 109 -, $-methyl-, IV, 274, 284; V, 283 specific rotation of, I, 155 -, monomethyl-, V, 284 -, 5-thioethyl-, I, 143, 144 -, 5-thiomethyl-, I, 141, 143 -, 2,3,4trimethyl-, IV, 254, 262, 274, 284; V, 282, 284

408

CUMULATIVE SUBJECT INDEX FOR VOLS. I-V

-, 2,3,4triacetyI-&trityl-, diethyl thioacetal, 111, 109 -, trityl-, 111, 85 -,

1-trityl-, 111, 109 a-D-Xylose, 1-phosphate, V, 71 D-Xylose anilide, 2,3-dimethyl-, IV, 284 -, 2,4-dimethyl-, IV, 284 Xyloside, methyl, 111, 16 D-Xyloside, methyl 2,3-dimethyl-, 111, 146 p-GXyloside, methyl 3-desoxy-, V, 22, 28 -, methyl Smethylthio-, V, 22, 28 D-Xylosone, 11, 83 D-Xyluronk acid, 1,2-isopropylidene-, 11, 57; V, 197 strontium salt, 111, 153 (sy2o)Trihydroxyglutaric acid, from oxidation of xylan, V, 285

Y Yantak sugar, 11, 7 Yarns, accessibility of regenerated cellulose of, 11, 114, 116 Yeast, brewer’s, cr-galact.osidase from, V, 66

effect on dextran formation, 11, 217 from molasses, IV, 336 phytochemical reduction by, IV, 101 polysaccharides formed by, 11,223 from sucrose, IV, 333 from sulfite waste liquor, IV, 187 from wood sugars, IV, 184 Yeast carboxylase, V, 50 Yeast a-galactosidme, V, 66 Yeast a-glucosidase, 111, 98 Yeast hexokinase, V, 73 Yeast mannan, 11, 165, 191, 224 Yeast nucleic acid. See Ribosenucleic acid. Yew, Pacific, pentosan content of, V, 271 Z

Zemplh degradation, of aldononitriles, IV, 138 Zinc chloride, acetonation catalyst with acetic acid, 111, 51 as catalyst for acetylation of cellulose, I, 312 as catalyst for acetylation of starch, I, 288 Zinc D-gluconate, 111, 142

Author Index* for Volume VI A

Barbier, A., 297 Barker, H. A., 34, 37, 38, 72 (42, 43), 73 (40),74 (26), 78 (39), 137, 143 Acree, S. F., 89 Adams, R.,103 (9,10, ll), 145, 146, 148, 159 (89), Adelson, D.E., 249 163 (89), 173, 174, 183, 187, 198 (21a),199 (21a,21c), 309 Agens, M. C.,249 Aichner, F. X.,66, 139 Barrett, Elliott P.,209, 210 (4),211, 213 Albaum, H.G.,158 (4),218, 220 (4), 221 (41,223 (4), Alder, K.,105 227 Alexander, B. H.,13,21 (12a),23 (12a) Barry, V. C., 120 Allen, B. B., 247 Bass, L. W.,136 Allen, H. V., Jr., 211 Bates, F. J., 116, 137 Ambler, J. A., 233, 234 (37),236, 237, Bauer, L. N.,280 239, 240,242, 243 (72,80,82), 244, Bauerlein, K.,50, 66 (117),80 (117) Baup, S.,232 245, 247 Ames, S. R.,191 Baxter, R. A., 148, 151 (95) Andersen, C.C.,49,67 (115,214),69,76 Beath, 0.A., 232 Bbchert, P., 46,67 (100) (115,214) Becker, B., 139,203 Anderson, C. N., 248 Becker, Johanna, 67 (218),69,77 (218) Andreae, E., 85,89 (8) Anschutz, R.,245 Beckley, V. A., 86 Beevers, C. A., 127 Arlt, F. von, 253 Armstrong, E. F.,36, 51 (28) Behr, A., 232 Beilstein, E.K.,28 Arnold, H.W., 59,70 (153) Bell, D.J., 12,13 (7, 9),14 (7,9),15 (7), Aronoff, S.,309 16 (7,9,27), 17 (7,9),18 (7),19,20 Aso, K.,97, 102, 106 Astbury, W.T.,127 (7,9, 27, 28, 30, 32, 33), 22, 23 (9), 25 (49,50), 115, 121 (24),200 (49), Auk, R. G.,13, 115 203 Austin, W.C.,139, 141 (37) Bellis, M. P., 48 B Benedict, S. R.,137 Benson, A., 309 Backendorf, K. H., 105 Benz, F., 139,203 Bacon, J. S. D., 13, 18, 19,20 (32,33) Berger, Eva, 138, 142, 148, 170, 173, 174 Berger, L., 138, 139 (28),149 (29),161, Baddiley, J., 165 Baer, E., 59, 67 (196,197),68 163 (28,141, 142) Balch, R. T.,233, 234 (37),236,240 (37) Bergmann, M., 45, 55, 56, 57, 62, 66, 74 Baldwin, E.,16 (27),17, 20 (27,28), 25 (140),78 (135,139),316 Berlin, H., 32 (49),200 (49),203 Bamberger, C.,295 Bernhard, K.,137, 143 (13) Bar, F.,188, 190, 200 (30) Bertram, W.,245

* The numbers in parentheses are reference numbers. 409

410

AUTHOR INDEX FOR VOLUME VI

Bevan, E. J., 59 Binkley, W. W., 34, 65, '67 (201), 68, 74 (21) Birkofer, L., 106, 163 Bistrzycki, A., 189, 198 (31), 202 (31) Bjerrum, J., 109 Blair, C. M., Jr., 249 Bland, N., 245 Blanksma, J. J., 85, 89, 95, 97, 98, 99 (7a), 101 (28), 136, 138 (7), 139 (7), 141 (33), 143 (7), 308 Blell, Ingrid, 264, 266 (38), 268 (38), 287 (38), 288 (38), 289 (38) Block, S. S., 87 Boeseken, J., 108, 247 BognAr, R., 71 (229), 81 Bohm, E., 28 Bonner, W. A., 45, 254, 255, 257, 258, 260, 271, 275, 276, 277, 278 (55), 279 (55), 282 (55), 284 (21, 24, 25, 52, 55, 56, 58), 285 (45, 52), 286 (21, 23, 25), 287 (23) Boord, C. E., 276 Bott, H. G., 91 Bourne, E. J., 11 Bourquelot, E., 32, 36 (13) Braconnot, H., 231 Braun, G., 45 Braun, J. von, 136, 143 (8) Brauns, D. H., 58, 66, 78 (151), 253 Brauns, F., 274, 282 (46) Bredereck, H., 46, 47, 50, 66 (117), 67 (202), 68, 71 (93), 73 (93), 75 (202), 80 (50), 102, 138, 142, 147, 148, 170, 173, 174, 253 Bridel, M., 36 Brigl, P., 40, 42, 50, 67 (198, 199, 209), 68 (222), 69, 75 (199, 235), 77 (199), 254, 303 * Brink, N. G., 148, 167 (93) Broeg, C. B., 233, 234 (37), 236, 240 (37) Brown, D. M., 172 Brown, Ena L., 184, 198 (23c) Brown, E. V., 149, 163 Brown, J. M., 209, 210 (4), 211, 213 (4), 218, 220 (4), 221 (4), 223 (4), 227 Brown, R. L., 292 Browne, C. A., 143 Bruce, W. F., 234, 235 (42), 245 (42) Bruckner, Z.,46, 49, 77 (99), 79 (97)

Bubl, E. C., 191 Buchanan, J. M., 309 Buchstab, 246 Burtner, R. R., 105 Byall, S., 239, 240, 243 (72) Bywater, R. A. S., 122 C

Cagianut, B., 90 Cahill, J. J., 148, 167 (93) Calloway, N. O., 105 Calvin, M., 309 Cameron, A., 12, 25 (la) Campbell, N., 184, 198 (230) Cantor, S. M., 87, 94 (18), 98 (18), 142, 207, 208 (3), 238, 253 Carter, C. E., 155 Cason, J., 280 Casparis, P., 46, 67 (100) Cavalieri, Doris K., 86 Cavalieri, Liebe F., 86, 94 (16c, 16d), 98 (16~) Chaikoff, I. J., 309 Challino:, 5. W., 21, 23 (35) Chandler, L. B., 255 Charlton, W., 24 (44), 61 Charney, J., 138 Cherbuliez, E., 137, 143 (13) Claisen, L., 235 Clark, E. P., 137, 161 (19) Clocker, E. T., 248 Cobenzl, A., 90 Cochran, W., 127 Cohen, S. S., 137 Cohn, W. E., 155 Coirre, J., 32, 36 (13) Coleman, G. H., 48,71 (226), 75 (113), 81 Colley, A., 41 Collier, D. W., 243 Compton, J., 117, 118 (34), 146 Conley, Maryalice, 193 Conrad, M., 235 Consden, R., 144 Cook, H. A., 233 Cooke, Kathleen R., 137, 143 (lo), 183, 199 (21c) Cooper, W. F., 99, 100 (60) Costa, D., 274, 275 Cotter, S. E., 207 Cotton, R. H., 233

AUTHOR INDEX FOR VOLUME VI

Cox, E. G., 127

411

Crpig, J. M., 277, 278 (551, 279 (55), 282 (55), 284 (55, 58) Cramer, F., 120, 145 Crasso, G. L., 231, 247 (5) Crofts, J. M., 59 Cross, C. F., 59 Csiiros, Z., 67 (216), 69 Curl, A. L., 247 Curten, T., 248

Dollman, S. C., 249 Dore, W. H., 38, 73 (40), 78 (39) Doudoroff, M., 34, 37, 38 (34b), 72 (42, 43), 73 (40), 74 (26), 78 (39) Drake, N. L., 137, 141 (14), 143 (14), 148 (14) Drew, H. D. K., 25 (51) Diill, G., 84 Dunstan, W. R., 294 Diirr, W., 45 Dymond, T. S., 294

D

E

D’Alelio, G. F., 249 Dambergis, C., 268, 287 (39), 288 (39) Dangschat, Gerda, 235 Daraens, G., 317 Dauben, H. J., Jr., 56, 74 (234), 78 (138), 81 Davies, M. M., 127 Davis, Alice R., 137 Davis, D. J., 252 Davis, H. A., 13 DavoU, J., 151, 165 (114) Day, A. R., 198 (44), 202 Dean, G. R., 32, 87, 94 (18), 98 (IS), 207, 208 (3) Debowska-Kurnicka, H., 40, 73 (49), 75 (49), 80 (49) Degering, E. F., 296 Deitz, V. R., 206, 207 Dellbruck, K., 33, 39 (15), 45, 48 (15), 75 (15) Deriaz, R. E., 99 Dessaignes, V., 235, 247 (50) Deuel, H., 110 Devlin, J. A., 238 Dewar, E. T., 18, 20 (29) Diehl, H. W., 60 Diels, O., 105 Dienes, M. T., 115, 116 (26) Dimler, R. J., 13, 21 (12a), 23 (12a), 143, 145 (53), 183, 185, 186, 187 (22), 188, 189, 190, 191, 194 (22), 195, 198 (22, 41, 45), 199 (22, 26), 202 (22, 28) Dinelli, D., 103, 105 (73) Dittmer, K., 151, 164 (112) Dodge, A. A., 232

Easterfield, T. H., 235, 245 (46) Edgar, Rachel H., 94 Edwards, J. W., 190 Eggleston, L. V., 239, 245 Egmond, G., 97 Eich, H., 67, 69, 77 (212) Ekenstein, W. Alberda van, 32, 54, 84, 85, 93, 98, 136, 138 (7), 139 (7), 141, 143 (7), 279, 308 Elek, A., 190 El Heweihi, Z., 143, 168 (57) Ellinghaus, J., 142 Elsner, H., 28 English, J. E., Jr., 270, 271, 285 (43, 44), 286 (43) Erdmann, E., 85 Ericks, W. P., 246, 246, 248 (98) Erickssn, F. J., 87 Euler, H. v., 137 Evans, L. K., 94 Evans, T. W., 249 Evans, W. L., 44,47,48,49, 56,59, 62, 66 (79, 105, 112), 69, 70 (105, 112, 153), 72 (168), 74 (234), 77 (107), 78 (107, 138, 225), 79 (79, 105, 238), 80 (225, 238, 239), 81, 94, 159

Cox,F. W., 249

F Fabian, F. W., 87 Fairhead, E. C. F., 121 Farrar, Kathleen R., 137, 143 (ll), 183, 187, 198 (21a), 199 (21a) Fawcett, E. W., 248 Feldmann, L., 67 (196), 68 Feller, D. D., 309

412

AUTHOR INDEX FOR VOLUME VI

Fellers, C. R., 87 Felton, G. E., 62, 63 Fenton, H. J. H., 59, 87, 88, 99 (24b), 100 (24a, 24b), 101 (24a), 102 (19, 24b), 297 Fieser, L. F., 42 Fieser, Mary, 42 Filrtchione, E. M., 62, 63 Fischer, E., 31, 32 (lla), 33, 35 (6), 36, 39 (15), 45, 48 (15), 51 (28), 62, 66, 67 (206), 68, 85, 88, 89 (8), 90, 100 (25), 101 (25), 102 (25), 135, 136, 138 (l), 139, 143, 145, 176, 177, 261, 275,276 (28), 292,297,303,307,308, 315 (25), 316 (25) Fischer, H. 0. L., 59, 67 (196, 197), 68, 146, 235, 298, 299, 302, 303, 306, 308,310,311,312 (53), 313,314 (54), 316 (54) Flaschentriiger, B., 90 Flesch, H., 67 (205), 68, 71 (205), 81 Fletcher, H. G., Jr., 42, 45, 60, 150, 151, 152 (109, 110, lll), 154 ( l l l ) , 155, 159, 193 Flexser, L. A., 145 Fokin, S., 247 Folkere, K., 148, 167 (93) Forsyth, W. G. C., 99 Fowler, R. E., 252 Fox, H. H., 149 Frahm, H., 31, 35 (7) Frei, P., 139, 203 Freudenberg, K., 14, 46, 49, 62, 63, 66, 67 (88a, 115,204), 68 (208,212,214), 69, 73 (230), 75 (88a, 230), 76 (115, 208, 214, 236), 77 (208, 212), 79 (230), 80 (230), 81, 120, 122, 193, 253, 274, 282 (46) Fried, S., 103 Friedrich, K., 49, 67 (116), 76 (115) Friese, P., 294 Fromhertz, K., 102 Frtischl, N., 261, 276 (29), 246 Frosch, C. J., 249 Frush, Harriet L., 43, 44, 139 Fiihrer, K., 275 Funcke, F., 179 Fume, R. J., 241 Furth, O., 239

G

Gakhokidze, A. M., 40, 62, 63, 64, 66 (173, 174, 175), 67 (51), 68 (50), 70 (181, 182), 71 (51, 173, 181, 183), 72 (50, 51, 173, 174, 175, 176), 76 (50, 51), 269, 289 (40) Gardner, J. H., 86, 94 (17), 98 (17) Gtitzi, K., 269, 286 (42), 292 Gayle, F. L., 244 Gehrke, M., 66, 139 Georg, A., 68 (221), 69 Georges, L. W., 32, 53, 77 (130) Gerecs, A., 34, 45, 46, 49, 66 (98), 67 (205), 68 (98), 71 (205, 227), 77 (98), 79 (97, 98), 80 (240), 81 Gerorgescu, M., 180, 198 (14), 202 (14) Gest, H., 310 Gibbs, M., 309 Giedroyc, M., 245, 246 Gilbert, R., 42 Gilbert, Violet E., 29, 31, 51, 74 (4), 76 (41, 78 (4) Gillam, A. E., 94 Gilman, H., 105 Go, Y., 49, 67 (1151, 76 (115) Godchaux, L., II., 241 Goepp, R. M., Jr., 42, 193 Goggins, W. C., 249 Goodman, I., 151, 164 (112) Goodson, J. A., 232, 235 (16) Goodwin, T.H., 127 Goodyear, E. H., 25 (51) Gootz, R., 42, 47, 66, 80 (102) Gordon, A. H., 144 Gorski, I. M., 294, 317 Gostling, Mildred, 87, 88, 100 (24a), 101 (24a), 102 (19) Gottfried, J. B., 32 Gottschalk, A., 108 Goulding, E., 294 Graf, L., 67 (200), 68, 75 (200) Grant, J. K., 202 (54), 203 Gray, H. F., Jr., 249 Green, F. O., 253 Green, S. W., 23 Greenleef, C. A., 233 Greville, G. D., 20 Griess, P., 176, 177, 178, 179, 198 (lo), 200 (3, lo), 202 (3, 10)

AUTHOR INDEX FOR VOLUME VI

Griswold, P. H., Jr., 270, 271, 285 (43, 44), 286 (43) Grosheintz, J. M., 310, 311 Grote, A. von, 84 Griiner, H., 67 (209), 69, 303 Gulland, J. N., 137, 143 (9, 10, 11), 170, 172, 183, 187, 198 (21a), 199 (21a, 21c) Guttag, A., 146 Guyot, Olga, 106 Gyr, M., 14

H Habu, T., 248 Hadhcsy, I., 45 Hale, W. J., 90, 98 (36), 105 (36) Halenda, P. P., 223 Hall, Claude M., Jr., 218 Hammett, L. P., 43 Hammond, W. A., 47 Hardy, H. F., 233 Hann, R. M., 12, 13, 34, 35 (24), 49, 57, 66 (25), 68 (24), 73 (25), 74 (25), 76 (25), 78 (144), 113, 115, 173, 181, 201 (18, 52), 203 Hanson, A. W., 249 Hardegger, E., 40, 51, 143, 168 (57) Harris, S. A., 156, 157 Harrow, G., 176, 177, 178;179, 198 (lo), 200 (3, lo), 202 (3, 10) Hart, M. C., 232 Harwood, H. J., 184 Haskins, W. T., 34, 49, 57, 66 (25), 73 (251, 74 (25), 76 (251, 78 (144, 115, 180, 181, 187 (15), 188, 194, 195 (15), 199 (15), 200 (15), 201 (15) Hass, H. B., 293, 294, 295, 296, 315 (10) Hgssel, O., 129 Haaselbring, H., 232 Hassid, W. Z., 34, 37, 38 (34b), 72 (42, 43), 73 (40), 74 (26), 78 (391, 121, 309 Hastings, A. B., 309 Haworth, W. N., 12, 13, 21, 22 (37, 38, 39), 23 (35, 38, 391, 24 (lb, 41a, 43, 44a, 46), 25 (lb, 41a, 43, 44% 51), 51, 56, 61, 74 (232), 75 (1201, 78 (139, 142, 237), 81, 85, 88 (ll), 91 (21), 93, 96, 98 (ll), 102 (11, 211, 103 (21), 104 (79), 106 (79), 115, 122

413

Haynes, L. J., 166, 172 Hecht, O., 264, 265 (37), 266 (37), 287 (37), 288 (37) Helferich, B., 12,28,33,34,37,42,45,46, 47, 49 (16b), 50, 66, 67 (23, 202, 217, 218), 68 (220, 224), 69, 71 (93, 228), 73 (93, 94, 95), 75 (202), 77 (218), 78 (23), 79 (103), 80 (102, 103, 117), 81, 148, 253, 298 Hendricks, Sterling B., 218, 221 (8) Henry, H. C., 239, 240, 243 (72), 244 Henry, L., 293 Hentschel, W., 235 Henee, H. R., 247 Hhrissey, H., 32, 36 (13) Hermann, H., 239 Hess, K., 117, 118 (35), 119 (45), 121, 122, 261, 276 (28) Heuser, E., 85 Heyl, F. W., 232 Hibbert, H., 88, 106, 121 Hickinbottom, W. J., 24 (441, 40,43, 46, 50, 51, 75 (120) Hielscher, Marianne, 178 Hilbert, G. E., 13, 32, 148, 164 Hill, A., 249 Hill, A. C., 32, 36 Hill, H. B., 104, 105 Hill, H. S., 88 Hill, William L., 218, 221 (8) Hiller, L. A., Jr., 95 Hinsberg, O., 177, 179 Hirschberger, J., 292 Hirst, E. L., 13, 14, 16 (23), 17, 21, 22 (39), 23 (23, 35, 391, 24 (41% 461, 25 (41a, 46, 52), 56, 61, 74 (2321, 78 (139, 142, 237), 81, 88, 91 (21)) 102 (21), 103 (21), 115, 122, 145 Hixon, R. M., 67 (204), 68 Hlasiwetz, H., 232 Hochstetter, H. v., 45 Hockett, R. C., 60, 115, 116 (25,26), 139, 140, 146, 161, 191, 193, 255, 275 (18) Hodge, E. B., 293 Hodgson, R., 121 Hoepfner, Eva, 148 Hoff, G. P., 94 Holden, It. F., 279 Holly, F. W., 148, 167 (93)

414

AUTHOR INDEX FOR VOLUME VI

Iselin, B., 311, 312 (53) Holm, G.L., 233 Holysz, R.P.,42,276,277,279,280,284 Iwadare, K., 311 hard, E.F.,248 (54,64,65),285 (54),289 (65) Honeyman, J., 163, 174 Horecker, B. L.,137 J Hori, E.,235 Jackson, E. L., 24 (42),43, 158, 173 Horne, W.D.,218 Hornstein, F.,261, 262, 263, 276 (27), Jackson, H., 297 Jacobs, W. A,, 135, 136,141 (2),143 (2), 286 (27,32) 145 (3),155, 292 Horrocks, R. H.,144 James, S. P.,115 Horton, P. M.,218, 220 Houben, J., 262,275 Jeanloz, R.,150,151,152 (109,110),159, 174 Hough, L.,20, 144, 145 Howard, G. A., 148, 149, 151 (96,loo), Jelgasin, S. A., 279 Jennings, W.L.,104,105 161 (107),162, 163,164, 166 (100) Hudson, C. S., 12, 13, 24 (42), 34, 35 Jeremias, C.G.,262,277 (30),282 (24),39,42,43,45,49,54,56,57,58, Jermstad, A., 232 60,66 (25,40), 68 (24),73 (25,134, Jerzmanowska, Z., 245,246 147, 148, 231), 74 (25, 149, 150), Johnson, J. M.,66, 73 (231),81,253 76 (25),78 (144), 81, 92, 108, 113, Johnson, J. R.,89, 103 115, 130, 139, 140, 143, 146, 150, Johnson, K., 296 151, 152 (109,110), 154 (lll),155, Jones, D.I., 24 (41a),25 (41a) 158, 159, 161, 173, 180, 181, 186, Jones, J. K. N., 14, 16 (23),17, 23 (23), 24 (45),144, 145 187 (15), 188, 194, 195 (15), 196, 198 (42,46,47), 199 (42),199 (15), Jones, W.G. M., 85,88 (ll), 91,93,96, 98 (ll),102 (ll), 103, 104 (79),106 200 (15, 42, 47,50),201 (15,18,42, 46, 50, 51, 52), 202 (46), 203, 253, (79) Jowett, H. A. D., 232,235 (11) 254,255, 275,276,282 (63),291 Huebner, C. F., 183, 187 (22), 188, 189, Joyner, L. G.,223 190,191,193,194 (22),198 (22),199 Jiinger, A., 12, 33,34 (16) Jung, H., 315 (22,36),202 (22) Jung, J. R., 113 Hughes, Elizabeth E., 89 Humoller, F. L.,139, 141 (37) K Humphreys, R. W.,25 (52) Hunter, M.J., 121 Hurd, C. D.,42, 62, 63, 253, 255, 257, Kahlenberg, L., 252 258,260,275,276,277,279,280,282,Kalckar, H. M.,155 284 (21,24,25, 52,54, 64,65),285 Kaplin, N.,37 (52,54), 286 (21,23, 25), 287 (23), Karabinos, J. V., 149 Karashima, J., 99,102 289 (65) Karrer, P.,137, 139,203 Kaszuba, F.J., 249 I Kaufmann, W. E.,103 Keenan, G.L.,240,242, 243 (80) Ingold, C. K., 246 Keenan, G. T., 142 Ionescu, C. N.,37 Irvine, J. C., 12, 25 (la, 481, 33, 34, 35, Kenner, G. W.,147, 148, 149, 161 (107), 162,163,164,165,166,168 (90,153) 03,68 (223),69,74 (233),81 Isbell, H. S., 43, 44, 93, 139, 142, 143, Kent, P. W.,144, 174 Kiermayer, J., 84,96,102 (4) 186,303 Kinsoher, M.,263,286 (34),289 (34) Iseki, T.,97,102 (51)

AUTHOR INDEX FOR VOLUME VI

Kizyk, A., 37 Kleene, R. D.,103 Klein, W., 34,47, 67 (23,217),68 (220), 69, 78 (23) Kleker, C., 235 Klemperer, F. W.,309 Klimek, R.,173 Klimenko, 246 Klingensmith, C. W.,48, 66 (112), 70 (112),159 Knauf, A. E.,34, 35 (24), 57, 68 (24), 113, 173 Knoevenagel, Claudia, 67,69, 77 (212) Knopf, E.,45, 67 (88a>, 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<., 90, 98 (36), 105 (36) Phillips, M. A,, 182, 184, 198 (19) Pictet, A., 33, 34, 297 Pigman, W. W., 42, 142 Piloty, Oscar, 135, 136, 138 (I), 139, 143, 303, 308 Plant, Millicent M. T., 56, 74 (232), 81 Plevako, E. A., 87 Podwissotaky, W. V., 145 Pomilio, V., 247 Pool, W. O., 184 Potter, A. L., 38, 72 (43), 121 Pratt, J. W., 198 (46), 201 (46), 202 (46) Prinsen-Geerligs, H. C., 233 Prochownick, Vilma, 149 Prout, F. S., 280 Pryde, J., 25 (52) Praeworski, G., 189, 198 (31), 202 (31) Pucher, G. W., 239 Pummerer, R., 106 Purdie, T., 33, 35 Purves, C. B., 37 Putnam, E. W., 38, 121, 309

0

Oelwerke, N., 248 Ohle, H., 12, 67 (207), 69, 177, 178, 188 (7), 198 (7), 199 (7), 264, 265 (37), 266 (37, 38), 268 (38), 287 (37, 38, 39), 288 (37, 38, 39), 289 (38) Oldham, J. W. H., 12, 13 (7), 14 (7), 15 (71, 16 (71, 17 (71, 18 (7), 20 (71, 33, 67 (215, 219), 69, 74 (233), 81 Oleck, S. O., 209, 210 (4), 211, 213 (4), 218, 220 (4), 221 (4), 223 (4),227 Oliver, J. H., 246 Ollendorff, G., 32, 72 (11) Orlow, N., 232 Orton, K. J. P., 245 Ottar, B., 129 Overend, W. G., 170, 172, 316

AUTHOR INDEX FOR VOLUME VI

418

Putnoky, N. von, 315 Pyle, R. E.,48, 75 (113)

R Rabe, A., 66 Raistrick, H.,21, 22 (37,38), 23 (38) Ralston, A. W., 184 Ramsden, H.E.,115, 116 (26) Rauch, H.,46, 71 (228),73 (94),81 Raymond, A. L.,56, 67 (211),69,92 Reber, F., 14, 15 (19),16 (19) Reeder, W.H.,191 Reeves, H.F.,Jr., 244 Reeves, R. E.,109, 110 (6),111 (6),112, 113 (6),114 (10, 19, 23), 115, 116 (11, 19, 23, 27, 28), 117 (29), 118 (29), 119 (29, 44), 120 (29), 121 (29), 122 (lo), 125 (28), 127 (28), 128 (23),129 (10,19, 23), 130, 131 (19,28), 134 (6) Regnault, V., 231 Reichstein, T., 14, 15 (18,19), 16 (19), 98, 100, 102 (63),103 (63),130,269, 285 (42),292 Reinemund, K., 139, 141 (39) Remick, A. E.,153 Rennert, E.,56, 57, 74 (140) Reynolds, D.D.,44, 47,48, 49, 66 (79), 68 (225),69,77 (107),78 (107,225), 79 (79),80 (225) Reynolds, R. J. W., 56, 73 (232), 78 (1421,81 Rich, F. V., 67 (203),68 Richtmyer, N. K.,12, 49, 58, 67 (115), 73 (148), 74 (150), 76 (115), 130, 140, 143, 146, 173, 193, 196, 198 (42,46, 47), 199 (42), 200 (42, 47, 50), 201 (42,46, 50, 51), 202 (46), 203, 255, 275 (17,20) Riker, A. J., 120, 121 Riley, Elizabeth F.,293,296, 315 (10) Rinkes, I. J., 102 Rist, C. E.,148, 164 Ritchie, G.G.,16 Ritchie, P.D.,269 Roberts, E. J., 236, 237, 239, 240, 243 (82),244, 245, 247 Robertson, G . J., 13, 16 (16),17 (16), 20 (la), 67 (213),69

Robinson, F., 88, 99 (24b), 100 (24b), 101 (24b) Rodda, H.J., 166, 168 (153) Rogerson, H.,245 Rorabaugh, G.,233 Rosenfeld, D.A., 198 (46),201 (46,51), 202 (46), 203 Rosenqvist, Ulla, 178 Rothe, G., 138 Rothrock, H.S.,249 Fbxas,

M.L.,86

Ruell, D. A., 12,24 (lb), 25 (lb) Ruff, O.,32, 59, 72 (ll),140 Ruhemann, S.,245 Rund, Charlotte, 67 (206),68 Runde, M.M.,89 Rust, E.,295 Rutenberg, A., 74 (234),81 Rutz, G.,296, 313 S

Salomon, H., 139, 203 Sandstrom, W.M.,292 Sartori, L.,235, 237 Scallet, B. L.,86, 94 (17),98 (17) Schaefer, C., 85 Schafer, W., 47, 50, 66 (117), 67 (217), 69,79 (103),80 (103,117) Schaffer, R., 306,313 Scheindlin, S.,232,235 (17) Schetelig, W.,48,75 (111) Schilling, B.,179, 188,202 (11) Schinle, R., 67 (198),68 Schlenk, F.,137 Schlubach, H.H.,25 (47),35,40, 42,43, 46,47, 48, 75 (lll),149 Schltkhterer, E., 121 Schmidt, E.,110,296,313 Schmidt, H.,90 Schmidt, J. M.,232 Schmidt, 0.Th., 115 Schopp, K., 139, 203 Schotte, H.,55, 56, 57, 62, 74 (140),78 (135,139), 316 Schreier, E.,143, 168 (57) Schroter, G.A., 46, 47 Schuetz, R. D.,86, 94 (16c, 16d), 98 ( W Schwaer, L.,237

419

AUTHOR INDEX FOR VOLUME VI

Schweizer, E., 117 Scott, D.B. McNair, 137 Scott, E. W.,89, 103 Seibert, A. H.,233, 234 (34),235 (34), 236 Seka, R.,184 Sell, W.J., 235, 245 (46) Semerano, G., 235,237 Sengsen, P. T., 220 Sharp, Violet E.,42, 48 (59a),52 (59a), 66 (59a),73 (59a),75 (59a) Shilling, W. L., 67 (201),68 Shoji, K.,237 Shriner, R.L., 184 Shunk, C.H.,148,167 (93) Siebert, H.,237 Siegel, H.,274,282 (46) Simms, H.S.,156 Simons, H.,110 Singh, B., 87,94 (18),98 (18) Singh, Bhagat, 207,208 (3) Skinner, A. F.,33,68 (223),69,74 (233), 81 Skolnik, H., 198 (44),202 Skraup, Z.H.,57,253 Slomin, G.W.,132 Smeykal, K.,14 Smith, C.,59 Smith, F.,12,14,15 (20),16 (20),17, 19 (2), 20 (2),21, 23 (2, 20, 36), 24 (45),29,31, 51,74 (41,76 (41,78 (4), 115 Smith, H., 172 Smith, J. A. B., 24 (46),25 (46) Smith, M. E.,146 Smith, R. A., 257 Smyrniotis, Pauline Z.,137 Sobotka, H.,164, 190 Soff, K.,76 (236),81,253 Sohst, O.,90 Solmesen, U.V., 138, 149 (29),151 (29), 161, 163 (141) Solomon, A. K., 309 Solteberg, S., 193 Somerville, J. C.,20, 22 (34),23 (34) Sorkin, E.,14, 130 Sowden, J. C.,106, 141, 143 (43),146, 298, 299, 300, 301, 302, 303, 305, 306,308.309, 310, 313,314 (30,541, 315,316

Spiith, E., 279 Sparmberg, G., 46, 73 (95) Spencer, Guilford L.,221 Sperber, N., 292 Spies, J. R.,137, 141 (14),143 (14), 148 (14) Sprenger, G. E., 248 Spring, F.S.,148, 149,151 (95,loo), 165 (100) Stacey, M., 21, 22 (37,38, 39), 23 (38, 39),29,31,42,48(59a),51,52 (59a), 66 (59a),73 (59a),74 (4),75 @a), 76 (4),78 (4),99, 115, 121,174,316 Staudinger, H., 117 Steiger, Marguerite, 138, 139 Steinkopf, W.,294 Stiller, E. T., 34, 63, 146, 147, 156, 158, 168, 172 (88) Stohmann, F., 235 Streight, H.R.L., 56,78 (139,237),81 Strobele, R.,139, 161 Stross, M.J., 48 Struyk, C., 249 Sttiber, O.,293,309 (9) Sumiki, T., 89 Summerbell, R. K.,280 Surmatis, J. D.,195 Swallen, L. C.,276 Swarts, T., 247 Synge, R. L. M., 65, 144

T Talley, E. A., 44, 48,66 (79),79 (79),80 (239),81 Tanaka, C., 86,96 (13) Tarkow, L.,87 Tatchell, A. R.,163 Taube, C.,59 Tausz, J., 315 Tawney, P. O.,249 Taylor, C.S.,232,239 Taylor, C. W.,147, 148, 168 (90) Teece, Ethel G., 99 Teunissen, H. P., 98, 105 (53) Thiele, H.,12 Thomas, C. A., 252 Thomas, H.A., 56,78 (139,237),81 Thompson, H.J., 118, 119 (44) Thorpe, Jocelyn F.,245, 246

420

AUTHOR INDEX FOR VOLUME VI

Tipson, R.S.,56, 113, 136,143,146,148 (56), 151 (56), 158, 159, 160 (4), 170, 172 (51) Tissot, G., 246 Todd, A. R., 136, 147, 148,149 (96),151 (96, loo), 156, 160 (4), 161 (107), 162, 163, 164, 165 (100,114), 166, 168 (90,153), 170 (127), 172 (127), 174 Toepffer, H., 67 (208,214), 69, 76 (208, 214), 77 (208) Tollens, B.,28, 84,90 Topper, Y.J., 309 Trister, S. M., 14, 16 (22a),17 (22a),20 (224,23 Tschitschibabin, A. E.,279 Turer, J., 240, 242,243 (80)

Watters, A. J., 56, 57 Weakley, F. B.,32 Webb, J. I., 56,78 (139,237), 81 Wedemeyer, K.F.,47 Wegscheider, R.,235 Weidenhagen, R.,185 Weissborn, F.W., Jr., 240, 244 (81) Weltzien, W., 118 Wenis, E., 138, 149 (29),151 (29),161 Wernicke, E.,115 West, E.S., 279 West, R. M.,233 Westgarth, G. C., 12,24 (lb), 25 (lb) Westheimer, F.H., 309 Westphal, w., 67,69,77 (212) Weygand, F.,139,141 (39) Wheeler, A. S.,104 Wiche, W., 232 U Wichehaus, H., 247 Widmaier, O.,67 (199),68,75 (199,235), 77 (199) Umbreit, W. W., 158 Wiedenkoff, E., 263, 286 (33) Upson, R. W., 184 Wiggers, H.A. L., 39 Usteri, E., 137 Wiggins, L. F.,86, 88, 94 (12),97, 99, V 100 (22), 101 (22), 103, 104 (791, 106 (79),115, 174,316 Wiley, H. W., 233 Vanderbilt, B. M., 293,294 Willaman, J. J., 233 Van der Lane, G., 248 Williams, E.G.,248 Van Der Weide, B., 247 Williams, R. T., 65 Vanlerenberghe, J., 190 Vargha, L.v., 67 (207),69,302 Williamson, S., 12, 13 (9),14 (9),16 (9), Vennesland, B.,309 17 (9),20 (9),22,23 (9) Ventre, E. K.,233, 239, 240, 241, 243 Wilson, E. J., Jr., 67 (200),68,75 (200) (72),244 Winkler, S.,28 Verkade, P. E.,245 Wiselogle, F. Y.,190 Vickery, H.B.,239 Withrow, J. R.,47 Vintilescu, I., 37 Wohl, A., 60 Visser, D.W., 151, 164 (112) Wolf, A., 66,73 (230),75 (202),79 (2301, Vogel, H., 33,40,73 (49),75 (49),80 (49) 80 (230),81 VotoEek, E.,89, 90,101 (31b), 103 Wolff, W., 248 Wolfrom, M. L., 32, 34, 43, 44, 47, 53, W 54,65,67(201),68,74(21),77 (130), 86, 92, 94 (160,16d), 98 (16c),103 Wadman, W. H., 144 (42),149, 156, 292 Wagstaff, A. I., 127 Wolochow, H., 38 Waisbrot, 8. w., 292 Wood, H.G.,309 Walden, P., 235,245 (48) Wren, H.,269 Walker, J., 235 Wurster, C.,295 Wallace, E. G.,92,103 (42) Wyatt, B. W., 247 Waaowicz, D.,232

AUTHOR INDEX

Y Yoder, P. A., 90, 232, 236 Yundt, A. P., 121 Yusem, M., 193

Z Zaheer, S. H., 67 (208), 69, 73 (230), 75 (230), 76 (208), 77 (208), 79 (230), 80 (230), 81 Zahn, K., 264, 286 (36) Zak, H., 261, 276 (29) Zanon, B., 231, 232 Zaugg, H. E., 292

FOR VOLUME VI

421

Zelinsky, N., 302 Zellner, J., 261, 276 (29) ZemplBn, G., 34, 43,45, 46, 49, 60, 61, 62, 66 (98), 67 (205, 216), 68 (98), 69, 70 (165), 71 (205, 227, 229), 72 (161, 165, 166), 77 (98, 99), 79 (97, 98), 80 (240), 81 Zerban, F. W., 143, 215, 232 Zervas, L., 67, 69, 298, 300, 303, 316 (28) Zilversmit, D. B., 309 Zimmerman, G. B., 48 Zinner, H., 143, 149, 151 (98), 168 (58, 102) Zissis, E., 200 (50), 201 (50), 203 Zschokke, H., 100, 102 (63), 103 (63)

Subject Index, Volume VI A

hardness, 211 resistance to fluid flow, 211 Acetophenone, 259 D-galacto-Aldopenhse, 6-C-acetylAchillea acid. See Aconitic acid. 1,2:3,4-diisopropylidene, 268, 287 Achillea millefolium, 232 -, 1,2:3,4-isopropylidene-&C-proAconitase, 239 pionyl-, 287 Aconitate (cis), monomethyl anhydro-, Allolactoee, 73 246 B-octaacetate, 73 Aconitates (cis and tram), monomethyl, DAltronic acid, 254 six isomers, 246 Ca salt, 140 Aconitic acid, 231-249 a-D-Altropyranose, 4-(@-~-galactoanalytical estimation, 236-239 pyranosy1)-, octaacetate, 73 cis and trans isomers, 244, 245 8-D-Altropyranose, 4-(p-~galactodecarboxylation, 247 pyranosy1)-, octaecetate, 73 insoluble aconitate salts, 242-244 a-D-Altropyranose, 4-(8-~-glucooccurrence in plants, 232-234 pyranosy1)-, monohydrate (Celtrophysical properties, 234, 235 biose), 74 recovery in sugar manufacture, 239a-octaacetate, 74 2p4 B-octaacetate, 74 -, &-anhydride, 245, 246 fl-D-Altropyranose,4-(tetraacetyl-@-nAconitic esters, 246 galactopyranosy1)-2,3,6-triacetyl-, Aconitum napellus, 232 73 Aconitum paniculatum, 232 a-D- Altropyranoside, methyl, 130 Activated carbon, in refining sucrose and fl-D-Altropyranoside,methyl, 130 dextrose, 208, 219, 220, 226, 227 a-n-Altropyranoside, methyl 2,6Acylal function, chlorination of, 252-254 anhydro-, 112, 116 Adenine, 138 -, methyl 4,6-benzylidene-, 112, 130 cuprous salt, 138 8-D-Altropyranoside, methyl 4,tLbenzyli-, 9-&D-ribopyranoeyl-, 165 dene-, 130 Adenosine, 137, 138, 146, 168 a-D-Altropyranosyl chloride, ~-(,T-D5-phosphate, 172 galactopyranosy1)-, heptaacetate, 73 synthesis of, 165, 166 -, 4- (@-D-glucopyranosyl)-,hepta-, 2,3-isopropylidene-, 170 acetate, 74 Adenylic acid, 157 ~-Altrosan(1,5)~( 1,6), 129 Adonis vernalis, 232 D-Altrose, 255 ribitol in, 145 -, 4-(B-~-galactopyranosyl)-,(NeoAdonitol. See Ribitol. lactose), 73 Adaorbents, granular, for sugar refining, Amine glycosides, mechanism of iso205-230 merization of, 163 bulk density ,209 Amylopectin, 8, 9 depurative powers, 207-209, 214-218, Amylose, 8 220 Angles, in ring conformations, 111 422

SUBJECT INDEX, VOLUME VI

423

Arabinal, 139 -, 1,l-C-di-p-tolyl-, 263, 286 n-Arabinofuranose, 5-(j3-~-glucoa-IrAraboketofuranoside, a-no-glucopyranosy1)-, 62 pyranosyl-, 38, 72 heptaacetate A, 72 D-Arabonaldehyde, 2,3 :4,5-diisoproheptaacetate B, 72 pylidene-, 270, 271 thabinopyranose, 3-(a-~-glucoL-Arabonic acid, 135 pyranosy1)-, 38, 72 n-habonk acid, 2,3,5-trimethyl-, 7 D-habinopyranose, 3-(tetraacetyl-p-~- IrArabonic lactone, triacetyl-, 263 glucopyranosyl)-2,4diacetyl-,72 Ascorbic acid, synthesis of, 8 p-n-Arabinopyranoside, methyl, 116 Aspergillus species, production of 5-hyj3-D-Arabinopyranosyl bromide, tridroxymethylfuroic acid by, 89 acetyl-, 66 j3-tArabinopyranosy1 bromide, triB acetyl-, 66 u-D-Arabinopyranosyldihydroxyacetone, Bauxite, calcined, as adsorbent, 212, 221 tetraacetyl-, 70 Benzene, 3,4dibromo-l-(tetraacetyl-j3-~a - t Arabinopyranosyldihydroxyacetone, glucopyranosy1)-, 278, 284 tetraacetyl-, 70 -, p-D-galactopyranosyl-, 260 u - D , t ArabinopyranosyIdihydroxy ace-, j3-gentiobiosyl-, heptaacetate, 284 tone, tetraacetyl-, 70 -, a-D-glucopyranosyl-, 284 3-a-~r Arabinop yranos ylgl yceraldeh ydetetraacetate, 276, 277, 282, 284 dibenzylcycloacetal, triacetyl-, 70 tetramethyl ether, 284 D-Arabinose, 59, 136, 305, 314, 316, 317 -, j3-wglucopyranosyl-, 284 tkabinose, 305-307 tetraacetate, 256, 275, 276, 280, 282, condensation with 2-nitro-4,5284 dimethylaniline, 161 tetrabenzoate, 284 n-Arabktose, 2,4diacetyl-, 3-(tetraacetyltetramethyl ether, 284 8-D-galactopyranosy1)-,71 tetrapropionate, 284 -, 2,4diacetyl-, 3-(tetraacetyl-a-~trimethyl ether, 284 -, glycosylation of, 256 glucopyranosyl), 72 -, diacetyl-, 2-(tetraacetyl-a(?)-~-gluco- -, j3-lactosyl-, heptaacetate, 284 pyranosy1)-, 72 -, j3-maltosyl-, heptaacetate, 284 -, 3-(j3-~-galactopyranosyl)-,32, 60, 72 -, u-D-mannopyranosyl-, tetraacetate, -, 3-(wD-glucopyranosyl)-, 72 280, 284 -, 3-(fl-n-glucopyranosyl)-, 61, 72 -, 8-D-mannopyranosyl-, tetraacetate, heptaacetate A, 72 284 heptaacetate B, 72 -, j3-wxylopyranosyl-, 257, 282, 284 heptaacetate C, 72 triacetate, 200, 284 -, 2-(~-glucopyranosyl)-, heptaacetate, Benzimidazole, 179, 189 -, %(D-gZycero-l,2-dihydroxyethyl)-, 198 72 D-Arabinoside, j3+glucopyranosyl-, -, 5,&dimethyl-l-(~-ribofuranosyl)-,167 heptaacetate, 72 -, 5,&dimethyl-l-(a-~-ribofuranosyl)-, D-habitol, 3,5-benzylidene-1-desoxy-1148 nitro-, 141 -, 2-formyl-, 190 -, 1-desoxy-1-nitro-, 300, 305 dinitrophenylhydrazone, 190 tetraacetate, 313 oxime, 190 Irhabitol, 1,l-C-dibenzyl-, 286 -, 2 - ( 2 - f ~ ~ l )192 -, -, 1,l-Gdiphenyl-, 263, 286 -, 2-[~-gZuco-3-(~~-galactopyranosyl)2,3,4,5tetrabenzoate, 263, 286 1,2,4,5-tetrahydroxypentyI~,4-car-,1,4-anhydro-l, 1-C-diphenyl-, 263, 286 boxylic acid, 202

424

-,

SUBJECT INDEX, VOLUME VI

hydrochloride, 200 picrate, 200 1,2,4,5-tetrahydroxypentyl]-, 4-car-, 2- (ega2acto-ll2,3,4,5-pentahydroxyboxylic acid, 202 -, 2 ( ~ - g a b c g u ~ o - o c t o - ~ , ~ , ~ , ~ , ~ , 6 , 6 , 7 - penty1)-, 200 heptahydroxyhepty1)-, 201 -, 2-(~,cgalado-1,2,3,4,5-pentahydroxy-, ~ ( ~ - g ~ u c o - c g a ~ a - o c t o - ~ , ~ , ~ , ~ , ~penty1)-, , 6 , ~ - 200 -, 2-(~-g2ueo-1,2,3,4,5-pentahydroxyheptahydroxyhepty1)-, 201 penty1)-, 200 -, 2-(D-g~UC~L-kclo-0~0~,2,3,4,6,6,7hydrochloride, 200 heptahydroxyhepty1)-, 201 -, 2-(~-altro-~-gluco-hepto-l,2,3,4,5,6- N-benzyl derivative, 200 picrate, 200 hexahydroxyhexy1)-, 201 -, 2-(~-altro-D-mnno-hepto-1,2,3,4,5,6--, 2-(~-gZuco-1,2,3,4,5-pentahydroxypenty1)-, 200 hexahydroxyhexy1)-, 201 -, 2-(~-gu2o-1,2,3,4,5-pentahydroxy-, 2-(~-ga~a-cg~uco-hepto-~,~,~,~,6,6penty1)-, 200 hexahydroxyhexy1)-, 201 -, 2-(~-gabcmanno-hepto-~,~,~,~,5,6-, 2-(o-ido-ll2,3,4,5-pentahydroxypenty1)-, 200 ' hexahydroxyhexy1)-, 201 -, ~ ( D - g ~ U ~ D - g U ~ ~ h e P t ~ l , 26, 3 , 4 , 5 , -, 2-(~-manno-1,2,3,4,5-pentahydroxypenty1)-, 200 hexahydroxyhexy1)-, 201 hydrochloride (hydrated), 200 o-tartrate, dihydrate, 201 ' picrate, 200 -, 2-(~-gluco-~-ido-hepto-1,2,3,4,5,6-, 2-(~-talo-1,2,3,4,5,-p~ntahydroxyhexahydroxyhexy1)-, 201 penty1)-, 200 -, 2- (D-?nan?w-o-gah-hepb1,2,3,4,5,6-, 2-(~-ga~to-~,2,3,4,5-pentahydroxyhexahydroxyhexy1)-,201 penty1)-, Ccarboxylic acid, 202 -, 2-(~-glycero-l-hydroxyethyl)-,198 -, 2-(~-g~uw-l,2,3,4,5-pentahydroxyhydrochloride, 198 penty1)-, Ccarboxylic acid, 202 -, 2-(cglyce~o-l-hydroxyethyl)-,198 -, 2-(~-g~u~~,2,3,4,5-pentahydroxyhydrochloride, 198 pentyl)-&methyl-, 202 -, 2-(D,cgl~c~o-1-hydroxyethyl)-, 198 -, 2-(~-arabo-1,2,3,4-tetrahydroxyhydrochloride, 198 butyl)-, 198 picrate, 198 hydrochloride, 198 -, 2-(Dlcglycero-1-hydroxyethyl)-5picrate, 198 methyl-, 202 l14-anhydro-, 198 -, 2-hydroxymethyl-, 189, 198 1,4-anhydro-2,3,-iaopropylidene-,198 acetylderivative, 198 -, 2-(ca~abo-l,2,3,Ctetrahydroxypicrate, 198 butyl)-, 198 -, 2-hydroxymethyl-5-methyl-, 202 hydrochloride, 198 acetyl derivative, 202 picrate, 198 -, 2- (cgala-D-gluco-hept+l12,3,4, 5tetraacetyl derivative, 198 pentahydroxyhexy1)-, 200 -, ~~~-~~~112,3,4-tetrahydroxybuty1)-. -, 2-(egala-~-mnno-hepb1,2,3,4,5199 pentahydroxyhexy1)-, 201 hydrochloride, 199 -, 2-(cmanno-cgala-hepto-l,2,3,4,5picrate, 199 pentahydroxyhexy1)-, 201 1,4anhydro-, 199 -, ~(D-altTo-~,2,3,4,5-pentahydroxyIl4-anhydro-, picrate, 199 penty1)-, 200 -, 2-~~-~bo-l,2,3,4-tetrahydroxybutyl)-, -, 2-(~-ga2acto-l,2,3,4,5-pentahydroxy143, 199 penty1)-, 200 hydrochloride, 199 hexaacetvl derivative. 200 picrate, 199 2-[D-glUCO-3-(~D-~UCOp~anOsyl)-

SUBJECT INDEX, VOLUME VI

425

1,kanhydro-, dihydrate, 199 tables of properties, 198-203 1,4anhydro-, picrate, 199 ultraviolet absorption spectra, 190 -, Z(~-zyl0-1,2,3,4-tetrahydroxybutyl)-, from uronic acids, 186 199 Benzimidazoles, anhydro-, 190-194 hydrochloride, 199 Benzoic acid, p-benzoyl-, 260 picrate, 199 Benzophenone, 256,263 1,4anhydro-, 199 Bone char, for sugar refining, 205-230 1,4anhydro-, N-benzyl derivative, 199 as alkaline buffer, 208 1,kanhydro-, hydrochloride, 199 consumption, 207 +anhydro-, picrate, 199 “Brenzcitronsaure.” See Aconitic acid. -, 2-(~-zyZo-1,2,3,4-tetrahydroxybutyl)-, “Brigl’s anhydride,” 50 199 Butane, 1-(tetracetyl-a-D-glucopyrano1,4anhydro-, 199 Syl)-, 284 1,4-anhydro-, picrate, 199 Butanol-2, 125 -, 2-(1rarabo-l,2,3,4-tetrahydroxybuty1)-, 4-carboxylic acid, 202 C -, 2-(1.-arabc-l,2,3,4-tetrahydroxybuty1)-&methyl-, 202 Cellobial, 8 -, 2-(~-guZucto-l,2,3,4tetrahydroxyCellobiose, 7, 34, 49, ‘51, 64, 76, 88, 140 penty1)-, 199 p-octaacetate, 76 hydrochloride, 199 structure, 7 picrate, 199 synthesis, 51 -, 2-(~-gluco-1,2,3,4-tetrahydroxy- -, octamethyl-, 6 penty1)-, 199 a-Cellobiosyl bromide, heptaacetyl-, 66 -, 2- (cmanno-l,2,3,4-tetrahydroxya-Cellobiosyl chloride, heptaacetyl-, 255 penty1)-, 199 Cellulose, 8, 49, 85, 88, 112 hydrochloride, 199 cuprammonium complexes, 117, 118 picrate, 199 specific rotation, 119 -, 2-(~-ribo-2,3,4trihydroxypentyl)-, Celtrobiose, 58, 74, 255 199 a-octaacetate, 74 picrate, 199 p-octaacetate, 74 -, 2-(~-erythr0-1,2,3-trihydroxypropyl)-, a-Celtrobiosyl chloride, heptaacetyl-, 255 198 Chitaric acid, 85 -, 2- ( h e rythro- 1,2,3-trihydroxyChitonic acid, 85 propy1)-, 198 Chitose, 85, 86, 96 Benzimidazole carboxylic acid, 179, 189 Chloroplatinic acid, as catalyst, 55 Benzimidazole dicarboxylic acid, 180 Chromatography, partition, 99, 144, 145 Benzimidazole nucleus, numbering of, Citraconic acid, 247 176 Citridinsaure.” See Aconitic acid. Benzimidazole rule of rotation, 196-197 Condensing agents, in glycoside synBenzimidazoles, from aldonic acids, 175theses, 46, 47 203 Conductivity in cuprammonium solufrom aldoses, 176-180 tions, measurement of, 134 from aric acids, 186 Conformations, predicted normal, of copper salts, 183 aldopentoses and aldohexoses, 124 from glycosides, 186, 187 Cozymase, 167 oxidation, 188 Croton tiglium L, 137 pharmacological properties, 190 “Cupra,” the term, 110 preparation, 181-187 “Cupre A,” preparation of, 131 silver salts, 196 “Cupra B,”preparation of, 131

426

SUBJECT INDEX, VOLUME VI

Cuprammonium complexes, 116-131 compensating, 127 Cuprammonium-glycol reaction, 109 correlation with other reactions, 113116 Cytidine, synthesis of, 165 -, 2,3-isopropylidene-, 170

D

2,3’-Difurfurylethane-6,5‘-dialdehyde, 101 Digitoxose, benzimidazole from, 185, 197 Diglycolamide, ~-S-phenyl-,283 L-enantiomorph, 283 Dihydroxyacetone, @-cellobiosyl-, octaacetate, 79 -, @-gentiobiosyl-,octaacetate, 79 -, monoacetate, 67 6-(1,2 :3,4-Diisopropylidenea-~-galactose) 3-(1,2: 5,6-diisopropylidenea-D-glucose) ether, 74 Di-D-ribose anhydride, tetramethyl-, 146 Diribosylamine, 161 Dische reaction, for 2-desoxypentoses,99 Dumont’s sugar refining by granular bone char, 205

Degradation, by oxidation of glycals, 62 “Dehydromucic acid,” 90 Delphinium, 232 2-Desoxyaldose synthesia, 315 2-Desoxy-~-glucose. See ~-arabo-2Desoxyhexose. ~-arabo-2-Desoxyhexose,316 benzylphenylhydrazone, 316 E ~-e).ythro-2-Desoxypentose, 315, 316 bensylphenylhydrazone, 315 Emulsin, 36, 37, 138 milide, 316 End-group method, 8 2-Desoxypentoses, Dische test for, 99 Dessicants, in glycoside synthesis, 47, 48 Epicellobiose, 8, 56-58 Epigentiobiose, 12-(@-~-mannopyranoDextran, 9 syl)-, 78 Dextrose refining, 208, 221, 226 8-hendecaacetate, 80 3,4-Diacetyl-~-ribopyranose 1,2-(3’Epilactose, 8, 56, 74 acetoxyacetonyl) orthoacetate, 70 a-anomer, 74 3,4-Diacetyl L-ribopyranose 1,2-(3’panomer, 74 acetoxyacetonyl) orthoacetate, 70 rroctmcetate, 74 3,4-Diacetyl-~,~-ribopyranose 1,2-(3’Epimaltose, 8, 78 acetoxyacetonyl) orthoacetate, 70 octmcetate, 78 Diazomethane syntheses, 292 Equisetic acid. See Aconitic acid. Dibenrimidazole, from galactaric acid, Equisetum, 232 202 Erythraric acid, dimethyl-, 146 dihydrochloride, 202 Erythritol anhydride, 112, 116 dipicrate, 202 D-Erythrose, 305, 314 -, from D-glucaric acid, 202 -, 2,4benzylidene-, 141, 300, 305 dihydrochloride tetrahydrate, 202 -, 2-(@-~-galactopyranosyl)-,70 dipicrate trihydrate, 202 hexaacetate, 70 -, from D-mannaric acid, 202 -, 2-(cu-~-glucopyranosyl)-,70 dihydrochloride, 202 hexaacetate, 71 dipicrate, 202 -, 2-(@-~-glucopyranosyl)-,71 hexaacetyl derivative, 202 hexaacetate, 71 -, from L-threaric acid, 202 n-Erythroside, a (1)D-glucopyranosyl-, dihydrochloride dihydrate, 202 hexaacetate, 71 Dibenzylchlorophosphonate, 156 Ether, 6-(1,2 :3,4diisopropyliden4a-~5,5’-Diformyl-l, 1’-furylmethyl ether, 97, galactose) 3-(1,2: 5,bdiisopropyli102 dene-a-D-glucose), 74 Difruotose anhydrides, 86 Ethyl glyoxylate, 297

SUBJECT INDEX, VOLUME VI

F

-,

427

l,l-C-dibenzyl-4,5-isopropylidene-, 288 Fanning’s friction factor, 211 -, 1,l-C-dibutyl-2,3: 4,5-diisopropylidene-, 288 Flavazole, l-phenyl-3-(~-eryMro-trihydroxypropy1)-, 178 -, 1,l-C-diethyl-2,3 :4,bdiisopropyliFormic acid, 84 dene-, 288 Friction factor, Fanning’s, the term, 211 -, l,l-C-diisobutyl-2,3 :4,bdiisopropylidene-, 288 Friedel-Crafts process in carbohydrate -, 1,l-C-diisopropyl-2,3:4,bdiisopropyseries, 251-289 lidene-, 288 a-mhctofuranoside, &D-glucopyranofJ-D-Fructose, 2,3 :4,5diisopropylidenesyl (Isosucrose), 74 1,l-C-dimethyl-, 265, 287 octaacetate, 74 n-Fructose, 2,3 :4,5-diisopropylidene-l, 1&D-Fructofuranoside, a-D-glucopyranoC-diphenyl-, 266, 289 syl, (Sucrose), 74 -, 2,3:4,bdiisopropylidene-111-Coctaacetate, 74 dipropyl-, 288 D-Fructofuranose, 1,l-C-dimethyl-, 265, -, 1,1-C-dimethyl-, phenylhydrazone, 287 287 -, l,l-C-diphenyl-2,3-isopropylidene-, -, l1l-C-dimethyl-4,6-isopropylidene-, 267, 288 265 -, 1,3,4,6-tetramethyl-, 6, 7 -, 1,l-Gdiphenyl-, 267 D-Fructopyranose, x-benzoyl-1 ,1-chydrate, 288 diethyl-2,3-isopropylidene-, 288 tetraacetate, 288 -, l,l-C-diben~yl-2,3-isopropylidene-, a-D-Fructose, 4-(8-D-galactopyranosyl)-, 288 (Lactulose), 73 -, 2,3 :4,bdibenzylidene-, 67 keto-D-Fructose, l-(j3-D-glucopyranosy1)-, -, 2,3 :4,bdibenzylidene-1- (8-mglucodihydrate, 76 pyranosy1)-, 75 D-Fructose, l-(b-D-glucopyranosyl)-, tetraacetate, 75 octaacetate, 75 -, 1,l-C-diethyl-2,3-isopropylidene-,287 keto-D-Fructose, 3,4,5,6tetraacetyl-, 67 -, 2,3 :4,5diisopropylidene-, 67 a-D-Fructosyl chloride, tetraacetyl-, 253 -, 2,3 :4,5diisopropylidene-l-(~-~-gluco-a-I,-Fucopyranoside, methyl, 114 pyranosy1)-, 75 -, methyl 3,4-isopropylidene-, 114 tetraacetate, 75 Fuller’s earth, 212 @-D-hctopyranose, 1,l-C-dimethyl-2,3Fumaric acid, 108 isopropylidene-, 265, 287 2-Furaldehyde, 83, 84, 87, 98, 102 D-Fructopyranose, l,l-Gdiphenyl-2,3anti- and sywoximes, 102 isopropylidene-, 267, 288 color reactions, 98 -, 1,l-C-dipropyl-2,3-isopropylidene-, as inhibitor of fermentation, 87 288 -, bacetoxymethyl-, 99, 100, 102 D-Fructose, 88. See also D-Fructopyra- -, bbenzoxymethyl-, 99, 100 nose, D-Fructofuranose and keto-D- -, bbenzyl-, 100 Fructose. anti- and syn-oximes, 102 D-Fructose, 1,2-anhydro-l,l-C-dimethyl- -, 5-bromomethyl-, 87, 100 4,&isopropylidene-, 265, 287 -, 5-chloromethyl-, 87,99, 100 -, x,x-anhydro-1,l-Gdiphenyl-,288 -, 5-ethoxymethyl-, 100 -, 1,l-C-dibenzyl-, 288 -, bhydroxymethyl-, 83-87 tetraacetate, 288 anti- and syn-oximes, 102 -, l,l-C-dibenzyl-2,3 :4,5diisopropylicolor reactions, 98 dene-, 208, 288 condensation with hydantoin, 102

428

SUBJECT INDEX, VOLUME VI

condensation with malonic ester, 102 conversion to pyridine derivatives, 106 an ether from, 97, 102 as inhibitor of fermentation, 87 preparation, 96 properties, 97, 98 reactions of furan ring, 103 reactions of hydroxymethyl group, 99 in sterilized media, 87 -, Bmethoxymethyl-, 100 -, Bmethyl-, 88, 98, 100, 102 anti- and 8yn-oxime5, 102 color reactions, 98 -, 5-p-tolylmethyl-, 100 Furan, 5-acetoxymethyl-, 2-acrylic acid, 102 -, 2,Bdihydroxymethyl-, 101 -, cis-2,3-dihydroxytetrahydro-. See Erythritol anhydride. -, 2,5-dimethyl-, 103 addition of maleic anhydride, 105 addition of acetylene dicarboxylic acid, 105 -, 2,5-dihydroxymethyltetrahydro-,103 -, Bhydroxymethyltetrahydro-, %carboxylic acid, 103 -, tetrahydro-, 2,6-dicarboxylic acid, 104 Furan compounds, from hexoses, 83-106 from hexose acids, 89 mechanisms of formation, 91 Furan 2,Bdialdehyde, 99 condensation with malonic ester, 102 Furan 2,Bdicarboxylic acid, 90, 99, 104 reduction to dihydro deriv., 104 Furanose, origin of term, 8 Furfural. See 2-Furaldehyde. Furfurylalcohol, 101 2-Furoic acid, 101 benzimidaeole from, 192 -, Bformyl-, 99 cyanhydrin, 101 methyl eater, 89 -, 5-hydroxymethyl-, 89, 101-103 acetyl derivative, 89 metabolic product from Aspergillus, 89 Furoin, 101 G

n-Galactal, 2,4-dimethyl-, 15 Galactark acid, 90

-,

dibenzimidaeole from, 202 dihydrochloride, 202 dipicrate, 202 D-Galactaric acid, 2,4dimethyI-, 17 -, 2,3,4-trimethyl-, 21 D-Galactitol, 1,4-anhydro-l,l-C-diphenyl-, 264, 286 -, 1-deaoxy-1,1-diphenyl-, 260, 286 -, 1,l-C-dibeneyl-, 286 -, 1,l-C-diphenyl-, 263, 264, 268 dibenzoate, 286 pentaacetate, 286 -, 1,1-C-di-p-tolyl-, 286 a-D-Gdactofuranose, 1,Banhydro-, 13,21 D-Galactofuranose, 2,3,5,Btetramethyl-, 12 -, 2,3,&trimethyl-, 12 D-Galactonio acid, 89 -, 2,4-dimethyl-, 20 amide, 17, 20 lactone, 17, 20 phenylhydraeide, 20 -, 2,Bdimethyl-, amide, 20 lactone, 20 phenylhydraeide, 20 -, 3,Pdimethyl-, amide, 18, 20 lactone, 20 -, 2-methyl-, amide, 16 lactone, 16 -, Bmethyl-, lactone, 16 -, 2,3,4,Btetramethyl-, amide, 25 b-lactone, 25 phenylhydraeide, 25 -, 2,3,5,&tetramethyl-, y-lactone, 25 -, 2,3,4trimethyl-, lactone, 23 phenylhydraeide, 23 -, 2,3,6trimethyl-, amide, 23 lactone, 23 phenylhydraeide, 23 -, 2,3,&trimethyl-, lactone, 23 phenylhydraeide, 23 -, 2,4,&trimethyl-, amide, 23 lactone, 23 -, 3,4,&trimethyl-, lactone, 23 PGalactonic lactone, tetraacetyl-, 264 fl-D-Gdaotopyranose, l,&anhydro-, 12, 19, 114, 129 -, l,Banhydro-3,4-impropylidene-, 14, 15, 114 -, 1,Banhydro-%methyl-, 15, 114, 129

SUBJECT INDEX, VOLUME VI

-,

429

1,6-anhydr0-2-methyl-3,4-isopropyli- -, methyl 6-(P-~-rhamnopyranosyl)-, dene, 114 hexaacetate, 71 -, 1,6-anhydro-2,3,4-trimethyl-,19 -, methyl 2-tosyl-, 13 a-D-Galactopyranose, 1,2 :3,4-diisoproD-Galactopyranoside (a and p ) , methyl pylidene, 14, 67 3-t0syl-, 14 -, 1,2:3,4-diisopropylidene-6-(tetraa-D-Galactopyranoside, methyl 6-tosyl-, acetyl-fl-D-galactopyranosyl)-,73 12 -, 1,2:3,4-dii~opropylidene-6-(2’,3~,-, methyl 6-trityl-, 12, 19 5’,6’-diisopropylidene-&~-manno8-D-Galactopyranoside, methyl 6-trityl-, furanosy1)-, 79 12 -, 1,2 :3,4-diisopropylidene-6-(p-~-gluco- a-D-Galactopyranosyl bromide, tetrapyranosy1)-, 75 acetyl-, 66 tetraacetate, 75 a-D-Galactopyranosyl chloride, 6 - ( 8 - ~ -, 1,2:3,4-diisopropylidene-6-(heptarhamnopyranosy1)-, hexaacetate, 71 acetyl-p-cellobiosy1)-, 79 -, tetraacetyl-, 253 -, 1,2:3,4-diisopropylidene-6-~-lactosyl-, -, 2,3,4-triacetyl-, 67 hydrate, 80 D-Galactosan < 1,5 > p <1,6 >. 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

SUBJECT INDEX, VOLUME VI

-, 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 <1,4 >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

SUBJECT INDEX, VOLUME VI

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 <1,5>@<1,6>, 3-methyl-, 129 d d o s e , 6-desoxy-6-nitro-, 311 nitrodesoxyinositola from, 311 Inosine, 155 &phosphate, 170 -, 2,%isopropylidene-, 170

434

SUBJECT INDEX, VOLUME VI

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

SUBJECT INDEX, VOLUME VI

-,

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 <1,5>@<1,6>. 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

SUBJECT INDEX, VOLUME VI

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

SUBJECT INDEX, VOLUME VI

-,

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

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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

1

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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