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Industrial Chemical Cresols and Downstream Derivatives

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CHEMICAL INDUSTRIES A Series of Reference Books and Textbooks

Consulting Editor HEINZ HEINEMANN

Berkeley, California

Fluid Catalytic Cracking with Zeolite Catalysts, Paul B. Venuto and E. Thomas Habib, Jr. 2. Ethylene: Keystone to the Petrochemical Industry, Ludwig Kniel, Olaf Winter, and Karl Stork 3. The Chemistry and Technology of Petroleum, James G. Speight The Desulfurization of Heavy Oils and Residua, 4. James G. Speight 5. Catalysis of Organic Reactions, edited by William R. Moser Acetylene-Based Chemicals from Coal and Other 6. Natural Resources, Robert J. Tedeschi 7. Chemically Resistant Masonry, Walter Lee Sheppard, Jr. 8. Compressors and Expanders: Selection and Application for the Process Industry, Heinz P. Bloch, Joseph A. Cameron, Frank M. Danowski, Jr., Ralph James, Jr., Judson S. Swearingen, and Marilyn E. Weightman Metering Pumps: Selection and Application, 9. James P. Poynton 10. Hydrocarbons from Methanol, Clarence D. Chang 1.

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11. Form Flotation: Theory and Applications, Ann N. Clarke and David J. Wilson 12. The Chemistry and Technology of Coal, James G. Speight 13. Pneumatic and Hydraulic Conveying of Solids, O. A. Williams 14. Catalyst Manufacture: Laboratory and Commercial Preparations, Alvin B. Stiles 15. Characterization of Heterogeneous Catalysts, edited by Francis Delannay 16. BASIC Programs for Chemical Engineering Design, James H. Weber 17. Catalyst Poisoning, L. Louis Hegedus and Robert W. McCabe 18. Catalysis of Organic Reactions, edited by John R. Kosak 19. Adsorption Technology: A Step-by-Step Approach to Process Evaluation and Application, edited by Frank L. Slejko 20. Deactivation and Poisoning of Catalysts, edited by Jacques Oudar and Henry Wise 21. Catalysis and Surface Science: Developments in Chemicals from Methanol, Hydrotreating of Hydrocarbons, Catalyst Preparation, Monomers and Polymers, Photocatalysis and Photovoltaics, edited by Heinz Heinemann and Gabor A. Somorjai 22. Catalysis of Organic Reactions, edited by Robert L. Augustine 23. Modern Control Techniques for the Processing Industries, T. H. Tsai, J. W. Lane, and C. S. Lin 24. Temperature-Programmed Reduction for Solid Materials Characterization, Alan Jones and Brian McNichol 25. Catalytic Cracking: Catalysts, Chemistry, and Kinetics, Bohdan W. Wojciechowski and Avelino Corma 26. Chemical Reaction and Reactor Engineering, edited by J. J. Carberry and A. Varma 27. Filtration: Principles and Practices: Second Edition, edited by Michael J. Matteson and Clyde Orr 28. Corrosion Mechanisms, edited by Florian Mansfeld 29. Catalysis and Surface Properties of Liquid Metals and Alloys, Yoshisada Ogino

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30. Catalyst Deactivation, edited by Eugene E. Petersen and Alexis T. Bell 31. Hydrogen Effects in Catalysis: Fundamentals and Practical Applications, edited by Zoltán Paál and P. G. Menon 32. Flow Management for Engineers and Scientists, Nicholas P. Cheremisinoff and Paul N. Cheremisinoff 33. Catalysis of Organic Reactions, edited by Paul N. Rylander, Harold Greenfield, and Robert L. Augustine 34. Powder and Bulk Solids Handling Processes: Instrumentation and Control, Koichi Iinoya, Hiroaki Masuda, and Kinnosuke Watanabe 35. Reverse Osmosis Technology: Applications for High-Purity-Water Production, edited by Bipin S. Parekh 36. Shape Selective Catalysis in Industrial Applications, N. Y. Chen, William E. Garwood, and Frank G. Dwyer 37. Alpha Olefins Applications Handbook, edited by George R. Lappin and Joseph L. Sauer 38. Process Modeling and Control in Chemical Industries, edited by Kaddour Najim 39. Clathrate Hydrates of Natural Gases, E. Dendy Sloan, Jr. 40. Catalysis of Organic Reactions, edited by Dale W. Blackburn 41. Fuel Science and Technology Handbook, edited by James G. Speight 42. Octane-Enhancing Zeolitic FCC Catalysts, Julius Scherzer 43. Oxygen in Catalysis, Adam Bielanski and Jerzy Haber 44. The Chemistry and Technology of Petroleum: Second Edition, Revised and Expanded, James G. Speight 45. Industrial Drying Equipment: Selection and Application, C. M. van’t Land 46. Novel Production Methods for Ethylene, Light Hydrocarbons, and Aromatics, edited by Lyle F. Albright, Billy L. Crynes, and Siegfried Nowak 47. Catalysis of Organic Reactions, edited by William E. Pascoe

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48. Synthetic Lubricants and High-Performance Functional Fluids, edited by Ronald L. Shubkin 49. Acetic Acid and Its Derivatives, edited by Victor H. Agreda and Joseph R. Zoeller 50. Properties and Applications of Perovskite-Type Oxides, edited by L. G. Tejuca and J. L. G. Fierro 51. Computer-Aided Design of Catalysts, edited by E. Robert Becker and Carmo J. Pereira 52. Models for Thermodynamic and Phase Equilibria Calculations, edited by Stanley I. Sandler 53. Catalysis of Organic Reactions, edited by John R. Kosak and Thomas A. Johnson 54. Composition and Analysis of Heavy Petroleum Fractions, Klaus H. Altgelt and Mieczyslaw M. Boduszynski 55. NMR Techniques in Catalysis, edited by Alexis T. Bell and Alexander Pines 56. Upgrading Petroleum Residues and Heavy Oils, Murray R. Gray 57. Methanol Production and Use, edited by Wu-Hsun Cheng and Harold H. Kung 58. Catalytic Hydroprocessing of Petroleum and Distillates, edited by Michael C. Oballah and Stuart S. Shih 59. The Chemistry and Technology of Coal: Second Edition, Revised and Expanded, James G. Speight 60. Lubricant Base Oil and Wax Processing, Avilino Sequeira, Jr. 61. Catalytic Naphtha Reforming: Science and Technology, edited by George J. Antos, Abdullah M. Aitani, and José M. Parera 62. Catalysis of Organic Reactions, edited by Mike G. Scaros and Michael L. Prunier 63. Catalyst Manufacture, Alvin B. Stiles and Theodore A. Koch 64. Handbook of Grignard Reagents, edited by Gary S. Silverman and Philip E. Rakita 65. Shape Selective Catalysis in Industrial Applications: Second Edition, Revised and Expanded, N. Y. Chen, William E. Garwood, and Francis G. Dwyer

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66. Hydrocracking Science and Technology, Julius Scherzer and A. J. Gruia 67. Hydrotreating Technology for Pollution Control: Catalysts, Catalysis, and Processes, edited by Mario L. Occelli and Russell Chianelli 68. Catalysis of Organic Reactions, edited by Russell E. Malz, Jr. 69. Synthesis of Porous Materials: Zeolites, Clays, and Nanostructures, edited by Mario L. Occelli and Henri Kessler 70. Methane and Its Derivatives, Sunggyu Lee 71. Structured Catalysts and Reactors, edited by Andrzej Cybulski and Jacob A. Moulijn 72. Industrial Gases in Petrochemical Processing, Harold Gunardson 73. Clathrate Hydrates of Natural Gases: Second Edition, Revised and Expanded, E. Dendy Sloan, Jr. 74. Fluid Cracking Catalysts, edited by Mario L. Occelli and Paul O’Connor 75. Catalysis of Organic Reactions, edited by Frank E. Herkes 76. The Chemistry and Technology of Petroleum: Third Edition, Revised and Expanded, James G. Speight 77. Synthetic Lubricants and High-Performance Functional Fluids: Second Edition, Revised and Expanded, Leslie R. Rudnick and Ronald L. Shubkin 78. The Desulfurization of Heavy Oils and Residua, Second Edition, Revised and Expanded, James G. Speight 79. Reaction Kinetics and Reactor Design: Second Edition, Revised and Expanded, John B. Butt 80. Regulatory Chemicals Handbook, Jennifer M. Spero, Bella Devito, and Louis Theodore 81. Applied Parameter Estimation for Chemical Engineers, Peter Englezos and Nicolas Kalogerakis 82. Catalysis of Organic Reactions, edited by Michael E. Ford 83. The Chemical Process Industries Infrastructure: Function and Economics, James R. Couper, O. Thomas Beasley, and W. Roy Penney

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84. Transport Phenomena Fundamentals, Joel L. Plawsky 85. Petroleum Refining Processes, James G. Speight and Baki Özüm 86. Health, Safety, and Accident Management in the Chemical Process Industries, Ann Marie Flynn and Louis Theodore 87. Plantwide Dynamic Simulators in Chemical Processing and Control, William L. Luyben 88. Chemicial Reactor Design, Peter Harriott 89. Catalysis of Organic Reactions, edited by Dennis G. Morrell 90. Lubricant Additives: Chemistry and Applications, edited by Leslie R. Rudnick 91. Handbook of Fluidization and Fluid-Particle Systems, edited by Wen-Ching Yang 92. Conservation Equations and Modeling of Chemical and Biochemical Processes, Said S. E. H. Elnashaie and Parag Garhyan 93. Batch Fermentation: Modeling, Monitoring, and Control, Ali Çinar, Gülnur Birol, Satish J. Parulekar, and Cenk Ündey 94. Industrial Solvents Handbook, Second Edition, Nicholas P. Cheremisinoff 95. Petroleum and Gas Field Processing, H. K. Abdel-Aal, Mohamed Aggour, and M. Fahim 96. Chemical Process Engineering: Design and Economics, Harry Silla 97. Process Engineering Economics, James R. Couper 98. Re-Engineering the Chemical Processing Plant: Process Intensification, edited by Andrzej Stankiewicz and Jacob A. Moulijn 99. Thermodynamic Cycles: Computer-Aided Design and Optimization, Chih Wu 100. Catalytic Naptha Reforming: Second Edition, Revised and Expanded, edited by George T. Antos and Abdullah M. Aitani 101. Handbook of MTBE and Other Gasoline Oxygenates, edited by S. Halim Hamid and Mohammad Ashraf Ali 102. Industrial Chemical Cresols and Downstream Derivatives, Asim Kumar Mukhopadhyay

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103. Polymer Processing Instabilities: Control and Understanding, edited by Savvas Hatzikiriakos and Kalman B . Migler 104. Catalysis of Organic Reactions, John Sowa 105. Gasification Technologies: A Primer for Engineers and Scientists, edited by John Rezaiyan and Nicholas P. Cheremisinoff

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Industrial Chemical Cresols and Downstream Derivatives Asim Kumar Mukhopadhyay Consultant to Chemical Industries Mumbai, India

Marcel Dekker

New York

Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book. The material contained herein is not intended to provide specific advice or recommendations for any specific situation. Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress. ISBN: 0-8247-5954-0 This book is printed on acid-free paper. Headquarters Marcel Dekker, 270 Madison Avenue, New York, NY 10016, U.S.A. tel: 212-696-9000; fax: 212-685-4540 Distribution and Customer Service Marcel Dekker, Cimarron Road, Monticello, New York 12701, U.S.A. tel: 800-228-1160; fax: 845-796-1772 World Wide Web http:==www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales=Professional Marketing at the headquarters address above. Copyright # 2005 by Marcel Dekker. All Rights Reserved. Neither this book nor any part may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, microfilming, and recording, or by any information storage and retrieval system, without permission in writing from the publisher. Current printing (last digit): 10

9 8 7 6 5 4 3 2 1

PRINTED IN THE UNITED STATES OF AMERICA

Dedicated to my Parents Whose Continued Support and Counseling Helped me to Become a Citizen of the World

Preface

After having held several top management positions in various organizations, I took up a challenging assignment in a sick chemical company in Gujarat State, India as the Chief Executive Officer in November 1987. The company had been incurring perpetual losses since its inception. My good friends, also not-so-good friends, thought that this was the end of my professional career as my failure was guaranteed. The Company, Gujarat Aromatics Limited, was making synthetic cresols from toluene but since the finished product, mixed cresols (cresylic acid) did not have sufficient market, more often than not the company’s manufacturing facilities at Ankleshwar, Gujarat had to be shut down. The company was soon amalgamated with Atul Limited, a big multiproduct Chemical giant of Gujarat, and, was reconstituted as the Aromatics Division of Atul. The division was considered a step child, an untouchable at Atul as it was not at all contributing to the bottomline of Atul. In fact, the aromatics division was eating away a chunk of Atul’s profit. Not surprisingly, everybody thought that my days were numbered. v

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But it was not to be. With an open mind I took up the rehabilitation and revival of aromatics division in right earnest. A detailed SWOT analysis enabled me to identify the strengths and inherent weakness of the division. It also helped me to visualize the opportunities that were to be made toward the division’s turnaround. When there is a will there is a way. With full financial and moral support of management, I decided to diversify the product mix by adding new high value products (such as pure p-cresol) having both domestic and overseas market. After achieving turnaround of the division within a reasonable period it was considered prudent to further widen the product base by incorporating downstream derivatives of p-cresol. Gradually, Atul’s aromatics division turned out to be one of the most diversified and integrated cresols complexes in the world. Atul’s aromatics division since has been operating the largest p-anisic aldehyde plant in the world. It also started manufacturing and marketing, for the first time in India, such fine chemicals as p-anisic alcohol, p-anisic acid, etc., p-Cresidine, a (speciality dye intermediate) plant using captive p-cresol also has become the largest in the world. It is no exaggeration that the aromatics division became a jewel in the crown of Atul. I also had the opportunity of interacting with virtually every manufacturer of cresols, natural and synthetic, and also with players in the field of individual cresol derivatives in the world. While busy on the development of global business in the field of cresols and allied products, I felt that authentic and necessary information and data pertaining to various allied products in the domain of cresols network was not easily available, and there was a long standing demand for a comprehensive book dealing with all aspects of alkyl phenols and downstream derivatives. And hence this book. I sincerely believe that this book will benefit both students and teachers, professional managers, and management

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interested in diversification or expansion of related business. This book will be a standard reference book or a handbook for practicing chemists, engineers, and R&D Scientists. They will definitely benefit in more ways than one. Asim Kumar Mukhopadhyay

About the Author

Dr. Asim Kumar Mukhopadhyay, a highly qualified technocommercial manager of high competence, had his earlier education in the district town of Bankura, West Bengal, India. He graduated in Chemical Engineering from Jadavpur University, Calcutta and earned his Master’s degree in Chemical Engineering from Indian Institute of Technology, Kharagpur. He received his Ph.D. in Chemical Technology from Moscow Institute of Petrochemicals and Gas Industries, Moscow, then a part of USSR. After completion of his studies Dr. Mukhopadhyay joined the industry and became a multidisciplinary Professional Manager by handling different Portfolios encompassing Process and Project Management, R&D Management, Financial Management, etc. Dr. Mukhopadhyay held top management positions in organizations of repute. He was the first Managing Director of WEBCON, a Multi-functional development Consultancy Organization Promoted by Industrial Development Bank of India (IDBI) and other financial and promotional institutions and Banks. ix

x

About the Author

He was whole time Director of IVP Ltd. Bombay for four years and helped in the development of the company. For ten and half years he was the chief executive officer of Gujarat Aromatics Ltd., later rechristened as the Aromatics Division of Atul Products Ltd., Valsad, Gujarat State and was instrumental in converting this single product sick unit to a highly profitable multiproduct establishment and a leader in the field of cresols and downstream products. Since his early retirement from Atul, Dr. Mukhopadhyay has been working as a national and international consultant and helping in the development of the fine chemicals industry. Dr. Mukhopadhyay is a widely traveled person, a versatile writer having authored several technical articles, short stories, poems and a book, and is truly a multifaceted personality.

Acknowledgment

I express my deep sense of gratitude to my wife, Mamata, for her inspiration, positive support and help that catalyzed me to write this book. My sincere thanks to my daughter, Anasuya, for her assistance in the preparation of some of the figures. I also take this opportunity to express my deep sense of appreciation to the Chief Librarians of Harris County Public Library at Katy near Houston, Texas, USA and the Indian Institute of Technology, Mumbai, India for using their Library facilities. My sincere thanks are due to the authors and publishers of various books, periodicals and technical articles in the allied fields. I had the privilege of exchanging views and interacting with a few experienced and knowledgeable officials of such global companies as Sumitomo Corporation Japan, Sumitomo Chemicals Co. Ltd., Japan, Osaka Godo, Japan, Rhone-Poulenc, USA and France, Merisol Co., USA and South Africa, Inspec Ltd., UK, SRI Consulting Engineers, Switzerland, UOP, USA, etc., in the field of cresols and their derivatives. I express my sincere appreciation and gratitude to these people who helped me in my global market research on cresols related business. xi

Contents

Preface . . . . v About the Author . . . . ix Acknowledgment . . . . xi Introduction . . . . xvii 1. Phenol, Cresols and Other Alkyl Phenols . . . . . 1.1. General . . . . 1 1.2. Monohydroxy Benzenes . . . . 3 1.3. Dihydroxy Benzenes . . . . 4 1.4. Trihydroxy Benzenes . . . . 4 1.5. Alkyl Phenols . . . . 5 1.6. Production of Phenol and Higher Homologues–— Global Scenario . . . . 14 1.7. Indian Scenario . . . . 16

1

2. Production of Synthetic Cresols . . . . . . . . . . . . 2.1. General . . . . 19 2.2. Sulfonation of Toluene . . . . 23 2.3. Alkylation of Toluene . . . . 30 2.4. Chlorination of Toluene [1,6] . . . . 36

19

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Contents

3. Production of Individual Cresols . . . . . . . . . . . 3.1. Crystallization and Centrifuging . . . . 39 3.2. Separation of Meta-, Para-Cresols via Alkylation with Isobutylene . . . . 42 3.3. Other Processes for Production of Pure Paraand Meta-Cresols . . . . 46 3.4. Production of Ortho-Cresol . . . . 48 3.5. Production of Meta-Cresol . . . . 49 3.6. Separation of Meta and Para-Cresol from a Mixture—A Review of Other Processes . . . . 52 3.7. Summary . . . . 57

39

4. Cresols and Their Derivatives . . . . . . . . . . . . . . 4.1. General . . . . 59 4.2. Derivatives of Cresols . . . . 59

59

5. Derivatives of Para-Cresol . . . . . . . . . . . . . . . . . 63 5.1. BHT . . . . 63 5.2. p-Anisic Aldehyde . . . . 66 5.3. Vanillin . . . . 77 5.4. 3,4,5-Trimethoxy-Benzaldehyde (TMBA) . . . . 81 5.5. Para-Hydroxy Benzaldehyde . . . . 83 5.6. Raspberry Ketone . . . . 86 5.7. 2-Nitro-p-Cresol [45] . . . . 88 5.8. Ethers and Esters . . . . 90 5.9. 3,4-Dimethoxy Toluene [2] . . . . 94 5.10. Creosol [45] . . . . 95 6. Derivatives of Meta-Cresol . . . . . . . . . . . . . . . . . 97 6.1. Para-Chloro Meta-Cresol [1,33] . . . . 97 6.2. Thymol [1,30] . . . . 99 6.3. 2,3,6-Trimethyl Phenol (2,3,6-TMP) [1] . . . . 103 6.4. 4-Nitro-m-Cresol [45] . . . . 104 6.5. Meta-Phenoxy Toluene and Meta-Phenoxy Benzaldehyde [45] . . . . 104 6.6. Musk Ambrette [30] . . . . 107 6.7. m-Anisic Aldehyde [46] . . . . 108 6.8. m-Anisyl Alcohol [45] . . . . 109

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6.9. m-Cresyl Acetate . . . . 109 6.10. m-Anisic acid [2,45] . . . . 110 7. Derivatives of Ortho-Cresol . . . . . . . . . . . . . . . . 113 7.1. Coumarin . . . . 113 7.2. Epoxy-Cresol–Novolac (ECN) Resins . . . . 115 7.3. Other Products . . . . 117 7.4. O-Anisic Aldehyde [2,45,46] . . . . 119 7.5. O-Anisyl Alcohol [46] . . . . 120 7.6. O-Anisic Acid [46] . . . . 121 7.7. O-Cresyl Acetate [46] . . . . 122 8. Cresol Derivatives—Building Blocks for Agrochemicals . . . . . . . . . . . . . . . . . . . . . . . . 123 8.1. General . . . . 123 8.2. Fenitrothion [14,26] . . . . 129 8.3. Acifluorfen-Sodium [26] . . . . 131 8.4. Tolclofos-Methyl [26] . . . . 132 8.5. DNOC [26,35] . . . . 133 8.6. Bromoxylin [26,35] . . . . 134 8.7. Ioxynil [26,35] . . . . 136 8.8. Mecoprop (MCPP) [26,35] . . . . 138 8.9. MCPA [26,35] . . . . 139 8.10. Other Herbicide=Insecticides from m-Cresol [14] . . . . 139 9. Cresol Derivatives—Building Blocks for Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . 141 9.1. General . . . . 141 9.2. Dilitiazem Hydrochloride [36,37] . . . . 142 9.3. Trimethoprim [36,37] . . . . 144 9.4. Nadifloxacin [44] . . . . 146 9.5. Vitamin E . . . . 147 9.6. Pentazocine [44] . . . . 149 10. Flavors, Fragrances, and Food Additives from Cresol Derivatives . . . . . . . . . . . . . . . . . . . . . . . 151 10.1. General . . . . 151 10.2. Essential Oils . . . . 152

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10.3. Global Scenario [42] . . . . 164 10.4. Indian Scenario . . . . 166 10.5. Industrial Cresols as Components of Aroma Chemicals and Food Products . . . . 167 11. Waste Minimization Through Recovery of Inorganic By-Products in a Cresols Complex . . . . . . . . . . . . . . . . . . . . . . . . 173 11.0. Backdrop . . . . 173 11.1. Sodium Sulfite and Sodium Sulfate . . . . 175 11.2. Calcium Sulfate . . . . 178 11.3. Manganese Sulfate . . . . 179 11.4. Cobalt Acetate and Manganese Acetate . . . . 182 11.5. Summary . . . . 184 12. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . 187 12.1. Current Scenario . . . . 187 12.2. Future Possibilities . . . . 192 References . . . . 195 Index . . . . 201

Introduction

Phenol, also known as carbolic acid, the mother compound of the homologous series of monohydroxy benzenes, is among the most well-known organic chemicals having multiplicity of uses. A typical phenol plant today has a capacity of 300 tpd or 100,000 tpa, and that makes it among the top highest volume bulk chemicals in the world. Other higher hydroxy benzenes such as cresols, xylenols, resorcinol, naphthols, or alkyl phenols, etc., have less uses for organic chemical synthesis. Mixed cresols, also known as cresylic acids, the lowest among the alkyl phenols, were primarily produced as by-products from coal carbonization plants or recovered from the petroleum refinery caustic washes. These cresols obtained from natural sources were known to the chemical industry for the last 75 years and had limited uses. Production of synthetic cresols from toluene opened up new avenues for these products Isolation of pure p-cresol and later on m-cresol from an isomeric mixture of m-, p-, and o-cresols was a master problem in organic chemical synthesis. Whereas o-cresol could xvii

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be separated from this mixture through fractionation without much difficulty because of a reasonable difference in boiling points of o-cresol and other isomers, meta and para isomers could not be easily separated as they had virtually identical boiling points. Other methods of separation of p- and m-cresols were soon found out and that led to synthesis of a host of downstream derivatives. For many years butylated hydroxy toluene (BHT), universally accepted as the most popular antioxidant, was the single largest volume outlet of p-cresol, which was the most widely used individual cresol. Soon p-anisic aldehyde produced from p-cresol through the process of methylation of the hydroxy group and subsequent oxidation of the methyl group, turned out to be a very important organic chemical and an attractive outlet of p-cresol. p-Anisic aldehyde is effectively used for making octyl methoxy cinnamate (an UV-B sunscreen chemical) and dilitiazem (an antihypertension drug). Subsequently, a series of downstream derivatives of p-cresol have been synthesized and commercially produced. Isolation of pure m-cresol from a mixture of m-, p-, cresols soon became a reality and commercially viable during manufacture of BHT from a mixture of m-, p-, cresols through the process of butylation, and dealkylation of butylated m-cresol. A number of companies are now producing BHT from mixed cresols and obtaining pure m-cresol as a co-product. m-Cresol is also commercially produced from isophorone. As in the case of pure p-cresol, a number of important organic chemicals are now synthesized from m-cresol. For instance, synthetic pyrethroids from m-phenoxy benzaldehyde obtained from m-cresol are already produced by Sumitomo Chemical Co. of Japan. Similarly 2,3,6-trimethyl phenol (TMP), a vital raw material for manufacture of synthetic Vitamin-E, the fastest growing vitamin, is now made from m-cresol by a number of companies. Slowly, but steadily, m-cresol network is expanding.

Introduction

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Last, but not the least important is pure o-cresol, which is obtained as a co-product during p-cresol production based on sulfonation of toluene. Pure o-cresol is also produced from phenol through a methylation process. o-Cresol has been conveniently used for manufacture of Coumarin, a vital fine chemical, and also epoxy resins and ECN resins. o-Cresol is also being used as a building block of agrochemicals. In a nutshell, cresols network is expanding very quickly. Much has been achieved but much more will have to be done. This will call for intensive R&D work in the field of cresols and their derivatives. It is true that because of significant R&D work in various laboratories in different countries in recent times it has been possible to identify and establish technologies for a number of new products in the domain of cresols. However, there are still a number of cresols derivatives which could not be produced on a commercial scale because of nonavailability of proven technologies. For some of the products it will be necessary to search for clean technologies or green chemistry keeping in mind protection of the environment. Various issues will be discussed at appropriate places. For most of the cresols related products, Chemical Abstracts Services [CAS] registry numbers have been provided for easier identification. However, in spite of best efforts, CAS registry numbers of a few products could not be located. It is needless to emphasize that collectively cresol isomers and their downstream derivatives have proved to be as important as phenol and related products for organic chemical synthesis. While for most of the products relevant references have been mentioned in the book, in some cases no reference has been mentioned as data and information have been based on my own market research and discussions with knowledgeable people in the field.

5954-0 Mukhopadhyay Ch01 R2 080304

1 Phenol, Cresols and Other Alkyl Phenols

1.1. GENERAL Phenol, monohydrobenzene, or carbolic acid discovered in 1834 by F. Runge is the parent compound of a homologous series of compounds with the hydroxy (–OH) group attached to the benzene ring. Cresols are an isomeric mixture of the simplest of alkyl phenols, i.e., monomethyl phenol or monohydroxy-toluenes. Similarly xylenols are the next higher homologues of cresols and are known as dimethyl phenols or hydroxy xylenes. Sometimes phenols where a hydroxy group replaces one or more of the hydrogen atoms has been compared with alcohols, where the –OH group is attached to a paraffinic carbon atom, whereas in case of phenols, the (–OH) group is attached to a carbon atom in an aromatic system. The simplest member of the group, phenol, has no isomer, whereas cresols exist in three isomers namely ortho, meta, and para. Xylenols have six different isomers. Some 1

5954-0 Mukhopadhyay Ch01 R2 080304

2

Chapter 1

of the important properties of phenol, isomers of cresols, isomers of xylenols are as follows [1,2]: CAS No. [108-95-2] Crystallizes in colorless prisms Pungent odor m.p.: 41 C MW: 94.11 b.p.: 184.75 C nD40: 1.5418 d440: 1.071 Molecular formula ¼ C6H6O CAS No. [95-48-7] m.p.: 31 C b.p.: 191 C

MW: 108

Molecular formula ¼ C7H8O CAS No. [103-39-4] m.p.: 12 C b.p.: 202 C

MW: 108

Molecular formula ¼ C7H8O

CAS No. [106-44-5] m.p.: 34 C b.p.: 201 C

MW: 108

Molecular formula ¼ C7H8O

CAS No. [526-53-0] m.p.: 72.5 C b.p.: 217 C

MW: 122

Molecular formula ¼ C8H10O

CAS No. [105-67-9] m.p.: 24.5 C b.p.: 211 C

MW: 122

Molecular formula ¼ C8H10O

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CAS No. [105-67-9] m.p.: 74.8 C b.p.: 211 C

MW: 122

Molecular formula ¼ C8H10O

CAS No. [576-26-1] m.p.: 45.6 C b.p.: 201 C

MW: 122

Molecular formula ¼ C8H10O CAS No. [95-65-8] MW: 122 m.p.: 62.11 C b.p.: 227 C

CAS No. [108-68-9] MW: 122 m.p.: 63.27 C b.p.: 221 C

1.2. MONOHYDROXY BENZENES Higher homologues of phenol include thymol (2-isopropyl-5methyl phenol) and its isomer carvacrol (5-isopropyl-2methyl-phenol) CAS No. [89-83-8] MW: 150.22 m.p.: 51 C b.p.: 232.5 C 20 d4 : 0.9756 nD20: 1.5227

CAS No. [499-75-2] MW: 150.22 m.p.: 0 C b.p.: 237 C 20 d4 : 0.976 nD20: 1.523

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1.3. DIHYDROXY BENZENES The three isomeric dihydric phenols or di-hydroxy benzenes are catechol, resorcinol, and hydroquinone having the following properties [2–5]:

CAS No. [120-80-9] m.p. 104 C

CAS No. [108-46-3] m.p. 110 C d20 4 1:272

CAS No. [123-31-9] m.p. 172 C, b.p. 285–287 C d10 4 1:112

Colorless needless, A crystalline compound Colorless crystalline subsoluble in alcohol, readily soluble in water stance, readily soluble in ether water, ethanol and ether A strong reducing Strong reducing agent Used as a dyeagent, used as a intermediate in developer in rubber as an additive, photography for making resorcinol– formaldehyde resins, etc.

Two important derivatives of catechol are guaicol and veratrole prepared by reaction of catechol and dimethyl sulfate:

CAS No.[90-05-1] [91-16-7] m.p. 27.9 C b.p. 205 C Aromatic odor Faintly yellowish

m.p. 21-22 C b.p. 206-207 C Colorless crystals

1.4. TRIHYDROXY BENZENES There are three isomeric trihydric phenols or trihydroxy benzenes or benzenetriols, namely pyrogallol, phloroglucinol, and

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hydroxyquinone having the following properties [5]:

1,2,3 trihydroxy benzene CAS No. [87-66-1] M.W.: 126.11 m.p.: 133–134 C b.p.: 309 C

A crystalline powder. Dissolves readily in water. In alkaline solution is a strong reducing agent used as a photographic developer, intermediate for dyes and drugs, antioxidant in lubricating oils, reducing agent, etc.

1,3,5 trihydroxy benzene CAS No. [108-73-6] M.W.: 126.11 m.p. (anhydrous): 218–220 C m.p.: 116–117 C (dihydrate) Soluble in diethyl ether Crystallizes out from water with two molecules of water of crystallization. Anhydrous form melts at 218 C used for testing of lignins in wood, decalcifying agent for bones, pharmaceutical, and dye intermediate, textile dyeing and printing, etc.

1,2,4 trihydroxy benzene CAS No. [533-73-3] M.W.: 126.11 m.p.: 140.5–141 C

Soluble in water, and polar solvents Used as stabilizer, antioxidant and polymerization inhibitor

1.5. ALKYL PHENOLS Alkyl phenols as mentioned earlier are phenol derivatives wherein one or more of the benzene ring hydrogens are substituted by an alkyl group. Cresols are monosubstituted methyl phenols, xylenols are dialkyl phenols with two methyl groups. Similarly other alkyl groups such as butyl phenols, butyl cresols are also examples of alkyl phenols. Some of them

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are shown below:

2.6-di-tert-butylphenol CAS No. [128-39-2] m.p.: 37 C M.W.: 124.14 d420: 0.9144 Molecular formula ¼ C7H8O2

2,6-di-tert-butyl-pcresol CAS No. [128-37-0] m.p.: 70 C M.W.: 136.20 d420: 1.048 nD75: 1.4859 Molecular formula ¼ C9H12O

Mesitol (2.4.6-trimethylphenol) CAS No. [527-60-6] m.p.: 69 C M.W.: 136.20 b.p.: 220 C Molecular formula ¼ C9H12O

Alkyl phenols have been synthesized by several approaches, including alkylation (CH3–, C2H5–, C3H7–, C4H9–) of a phenol, hydroxylation of an alkyl benzene, dehydrogenation of an alkyl cyclohexanol etc. 1.5.1. Xylenols Xylenols or di-methyl phenols, also known as C8 phenols, are alkyl phenols in the homologous series of phenol, cresols, and xylenols. Traditionally, phenol is produced from benzene, cresols from toluene and xylenols from xylenes. There are three isomers of xylenes, namely, p-xylene, o-xylene, and m-xylenes. Accordingly, there are six isomers of xylenols which have been mentioned earlier vide 1.1. Some of the properties of various xylenols have also been mentioned. Commercially, xylenols have assumed great significance. In some cases, xylenols can be used as substitutes of cresols. However, some of the individual xylenol isomers have importance in organic chemical synthesis. Xylenols which are clear crystalline compounds soluble in alcohol, acetone, and many organic solvents, are present in various essential oils and also in tea, tobacco, roasted coffee, and in various smoked foods. In some cases xylenols contribute to the flavor of these products [1]. Xylenols also known as dimethyl phenol, hydroxy dimethyl benzene, or dimethyl hydroxy benzene have the

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following properties [2]: CAS No. [1300-71-6] Formula C6 H3 ðCH3 Þ2 OH White crystalline solid D15 4

1:021:03

m:p: 2076 C b:p:

203225 C

They are toxic by ingestion and skin absorption. Xylenols are used in chemical organic synthesis and also as solvents. Their uses have been shown vide Fig. 1.2 1.5.1.1. Xylenols production from xylenes Though traditionally obtained from coal tar or from fractions during secondary refining processes of petroleum, they are also obtained as mixed xylenols from a mixture of xylenes CAS no. [1330-20-7] or as pure isomers from individual xylems i.e., m-xylene, o-xylene, or p-xylene. Process chemistry for production of xylenols from xylenes is similar to that of cresols from toluene (see Chapter 2), i.e., sulfonation of the respective aromatic hydrocarbons, followed by neutralization of the sulfonic acids, caustic fusion and acidification of the sodium=potassium salts and purification via distillation. Summary of principal properties of xylene isomers has been shown vide Table 1.1. Among the xylene isomers p-xylene is commercially the most important and highest volume chemical because pxylene is the critical feed stock for production of purified terephthalic acid or dimethyl terephthalate which is converted to synthetic fibers. O-xylene is the next important isomer which is used for manufacture of phthalic anhydride. M-xylene is commercially the least important isomer and more often than not it is not separated as a pure product and is sold as a component of mixed xylenes along with ethyl benzene as a solvent or as a thinning agent in the paint industry.

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Chapter 1

Summary of Principal Properties of Xylenes [2,8]

Product and properties CAS no. Formula Formula wt. Density D20 4 m.p. b.p. ( C) at 760 mm Pres. Z20D

m-Xylene

o-Xylene

p-Xylene

[108-38-3] C6H4(CH3)2 106.088 0.8641 47.87 139.103 1.4972

[95-47-6] C6H4(CH3)2 106.088 0.8802 25.182 144.411 1.5054

[106-42-3] C6H4(CH3)2 106.088 0.8610 þ13.26 138.351 1.4958

However, production of xylenols from isomeric xylene mixtures or individual isomers via propylene alkylation has not been attempted so far, neither established commercially nor even been tried in a laboratory or pilot plant. As in benzene and toluene alkylation processes it has been reported that Mitsubishi Gas Chemical Co., Japan obtained 3,5 xylenol by oxidation of 3,5-dimethyl cumene by alkylation of m-xylene with propylene to 3,5-dimethyl cumene hydroperoxide and thereafter its cleavage to 3,5-xylenol. Economics of the process did not justify its commercialization [1,38]. Methylation of phenol with methanol to produce o-cresol and 2,6-xylenol, and 2,4-xylene from p-cresol and 2,3-xylenol and 2,5-xylenol from m-cresol has been reported [1,47,48]. Sulfonation of toluene with 98–102% H2SO4 to produce toluene sulfonic acids has been discussed in detail in Chapter 2. The process can be extended to xylene for production of xylene sulfonic acid. Thus sulfonation of m-xylene with 95% sulfuric acid or chlorosulfonic acid yields a product consisting predominately of 2,4-dimethylbenze sulfonic acid which on caustic fusion at 320 C produces 2,4-xylene with 79% yield [1]. On heating the sulfonation mixture to approx. 220 C the more stable 3,5-dimethyl sulfonic acid which on fusion with excess alkali gives 3,5-xylenol [1,50]. 2,4-=3,5-dimethyl benzene sulfonic acid mixture on being heated with water (steam) to 140–160 C, is selectively hydrolyzed in the following alkali fusion process and gradually 2,4-xylenol and 3,5-xylenols are produced with a yield of 70% based in m-xylene.

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Similarly, 2,5-xylenol is produced starting with p-xylene and 3,4-xylenol from o-xylene [1,5,52]. As in case of cresols, separation of individual isomers of xylenols had been a critical problem in organic chemistry. In case of cresols there are only three isomers whereas there are six isomers of xylenols and that makes it more difficult to isolate them as pure individual isomers. Separation of cresols into pure isomers as ortho-, meta- and para has been discussed in details in a subsequent chapter. While separating xylenols somewhat similar procedure is adopted making use of boiling points differences, and for those isomers with almost identical boiling points using their differences in melting points (solidification points) (see Table 1.2). The process of separation is done in multiple stages. The crude xylenol fraction is rectified in a tall fractionation column into fractions of a narrow boiling temperature range and then further purified via crystallization and centrifuging. This multiple stage purification will be economically justified only if pure isomers have reasonable demand at an attractive price. Otherwise lower purity materials (say upto 90% purity) will be offered for sale. In any commercial plant demand in bulk volume and price will ultimately dictate the viability of such a multistage separation process. As in case of mixed cresols, mixed xylenols have been used for manufacture of carbolic soaps, disinfectants, wire enamels, and fire-retardant plasticizers. However, 2,4xylenol, 2,6-xylenol, and 3,5-xylenols have been used for organic chemical synthesis. 2,6-Xylenol is a precursor for an engineering plastic polyphenylene oxide also known as polyphenylene ether. Table 1.2

Xylenol Isomers and Their Melting and Boiling Points

Properties Melting point C Boiling point C at atmospheric pressure

2,32,42,52,63,4 to 3,5Xylenol Xylenol xylenol Xylenol Xylenol Xylenol 72.57 216.87

24.54 210.93

74.85 211.13

45.62 201.03

65.11 226.95

63.27 221.69

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2,4-Xylenol on butylation with isobutylene produces 2,4-dimethyl-6-t-butyl phenol, a hindered phenol antioxidant. Similarly, 2,6-xylenol along with m-cresol has been used for manufacture of 2,3,6-trimethyl phenol, a precursor for di-alpha-tocopherol, popularly known as vitamin-E. On chlorination 3,5-xylenol is converted to 4-chloro-3,5-xylenol — an antifungal medication and some pesticides [1,6]. In sum, some quantities of individual xylenols are used in organic chemical synthesis. However compared to cresols derivatives, downstream derivatives of xylenol isomers are relatively still not very significant. 1.5.2. Other Hydroxy Aromatics Resorcinol, dihydroxy benzene, and naphthols both a and b, are the most important hydroxy-aromatics having wide applications and are produced from benzene and naphthalene, respectively, using similar technologies as in production of synthetic phenol from benzene or cresols from toluene. It may be relevant to discuss briefly about these products. 1.5.2.1. Resorcinol Briefly discussed under Sec. 1.3, resorcinol is a vital organic intermediate for special resins, dyes, and organic chemical synthesis. M-dihydroxybenzene or resorcinol forms white crystals, which become pink on exposure to light. It has a m.p. of 110 C and a b.p. of 276.5 C. Being a skin irritant, when absorbed through skin may cause toxic effects. It is chemically very reactive due to the reinforcing influence of the two hydroxyl groups—this explains many reactions such as easy ammination with aqueous ammonia at 200 C to m-amino phenol and with ammoniacal ammonium sulfite solution to m-phenylenediamine C6 H4 ðOHÞ2 C6 H4 ðOHÞ2

aq:H3 C6 H4 NH2 OH; 200 C NH4 ðNH3 Þ2

! C6 H4 ðNH2 Þ2

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Caustic fusion of resorcinol has been used for the manufacture of trihydroxy benzene, phloroglucinol. Resorcinol has been made commercially using the same process of sulfonation of benzene followed by neutralization of disulfonic acid, caustic fusion, and separation. Since two sulphonic acid groups (–SO3H) are introduced to the benzene ring, sulfonation is done twice. Firstly, using 98–102% sulfuric acid and, secondly, using 65% oleum. Other unit processes are similar to cresols except that recorcinol is always obtained as a powdered solid material or as flakes [1,7]. Other more prominent process for production of resorcinol is through alkylation of benzene using propylene in such as a way that alkylation is done carefully to introduce isopropyl in 1 and 3 position, i.e., diisopropyl benzene which is then converted to resorcinol using a similar process of phenol from isopropyl benzene or cresols from iosopropyl toluene. For most resorcinol plants, sulfonation=caustic fusion is the common route, however, in Japan Sumitomo Chemicals are operating the world’s largest resorcinol plant based on alkylation of benzene with propylene using anhydrous AlCl3 as the catalyst. Some companies even today use solid phosphoric acid (SPA) as the catalyst for alkylation. Other downstream processes, i.e., oxidation of diisopropy benzene and its clevage to resorcinol are more or less similar to phenol and cresols processes. Because of environment consideration and keeping ‘‘clean’’ technology in mind quite a few resorcinol plants using the sulfonation–caustic fusion technology have been already closed down. Sumitomo Chemicals and one or two Japanese companies will continue to play major roles in supply of resorcinol to the world market. More than 20,000 tPA are now supplied by the Japanese companies and global demand is estimated to the tune of 30,000 tpa. 1.5.2.2. Naphthols Both a-naphthol and b-naphthols are important organic intermediates particularly for pesticides and dyes manufacturing. Traditionally, both are made from naphthalene, a two-ringed

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aromatic hydrocarbon, mostly available as solid powder or flakes. Being of great commercial importance and an allied hydroxy-aromatic, the process of manufacture is same for the more conventional sulfonation–caustic fusion technology using solid naphthalene as the feedstock. The two most important processes for production of naphthols are as follows: 1. 2.

alkali fusion of naphthalene sulfonic acids; hydroperoxixation of 2-isopropyl naphthalene to form 2-naphthol and acetone (not applicable to 1-naphthol or a-naphthols).

Naphthols resemble phenols in their chemical properties but their hydroxyl groups are more reactive. Properties of naphthols are briefly examined vide Table 1.3. 1-naphthol or a-naphthol has found uses in dyes industry and synthetic perfumes. A widely known pesticide sold earlier as ‘‘sevin’’ by Union Carbide is based on 1-naphthyl methyl carbamate and also more well-known is carbaryl based on 1-naphthyl chloroformate and methylamine or by reaction of 1-naphthol and methyl isocyanate (MIC). This last named compound has been discussed in greater details in many publications related to the worst gas tragedy in Bhopal, India, in December 1984. Table 1.3 Sr. no. 1 2 3 4 5 6 7

Properties of Naphthols

Properties CAS No. Formula m.p, C b.p. C at atm.pres. d20 4 Dissociation constant Physical form

a-Naphthol

b-Naphthol

[90-15-3] C10H8O 96 280

[135-19-3] C10H8O 123 295

1.224 1.4 1010 (20 C)

1.217 1.4 1010 (20 C)

Forms colorless plates Colorless prisms upon sublimation, which which darken on darken on expoure to air exposure to air or or light nonvolatile in light, steam volatile steam and sublimable

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2-naphthol or b-naphthol is more versatile, produced in bulk quantities and is a key intermediate in the dyestuff industry. The sulfonated and carboxylated derivatives are widely known. Using the conventional technology, China has already become the largest supplier of b-naphthol in the world. The simple ether derivatives, 2-methoxy-naphthalene [CAS no. 93-04-9], nerolin, and 2-ethoxy-naphthalene [CAS no. 93-18-5] now are made easily by methylation (using dimethyl sulfate) or ethylation (using di-ethylsulfate) for use in perfume formulation and more recently as drugs intermediates. Reaction of b-naphthol with chloroacetic acid in aqueous alkaline solution gives 2-naphthoxyacetic acid which is used as a growth promoter for fruits. The largest single use of b-naphthol has been reported for synthetic rubber industry as an antioxidant. Several companies in India and China make b-naphthol using sulfonation–caustic fusion technologies. Many Indian companies were forced to close down as the Chinese material was found to be much cheaper. a-Naphthol is mostly recovered as a co-product during b-naphthol manufacture. Also the Union Carbide technology after its Bhopal plant disaster and subsequent closure has been used by one or two companies in a pirated form. Using the conventional technology, China has already became the largest supplier of b-naphthol in the world. However, from economic and environmental point of view both USA and Japan use the propylene alkylation route, as this method of manufacture is more amenable to continuous operations with recycle stream. The alkylation with propylene and isomerization are carried out upto 240 C with traditional solid phosphoric acid (SPA) catalyst and more recently with anhydrous AlCl3 catalyst. Final catalytic oxidation at 90–110 C gives the hydroperoxide, as in cumene and cymene processes, which on cleavage with dilute sulfuric acid gives 2-naphthol in high overall yield. [53] Both Kellog and UOP and some Japanese companies do have excellent technologies and would be interested in

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licensing their technologies. Plant capacities should be in the range of 10,000–20,000 tPA and a good and steady supply of naphthalene has to be guaranteed. Both coal-based naphthalene and petroleum-based (produced by hydrodealkylation of side chains of two fused benzene rings) would be ideal.

1.6. PRODUCTION OF PHENOL AND HIGHER HOMOLOGUES–—GLOBAL SCENARIO Presently most of phenol is obtained synthetically from benzene; however, till World War I, phenol was obtained primarily from coal tar. In the 1990s, more than 99% of phenol was obtained via synthetic processes. Worldwide production of phenol has been estimated at 5.5 million metric tones per annum. More than 60% of cresols are now obtained by synthetic processes based on toluene. Most of the xylenols and some quantities of cresols are isolated from coal tar and petroleum refinery spent caustics. Currently, more than 1,50,000 tonnes of cresols, both mixed and as pure individual isomers and approximately 100,000 tonnes of xylenols are produced annually. Cresylic acids or tar acids are other names under which mixed cresols containing all the isomers of cresols, some quantities of phenol and mixed xylenols and even some higher alkylated phenols are available in the market. Traditionally, cresylic acids or mixed cresols have been obtained from coal tar isolated during production of metallurgical coke (semi or smokeless) via high or low temperature carbonization of coal, primarily bituminous. On an average high-temperature coke oven tar contains 0.4–0.6% phenol, 0.8–1% cresols, 0.2–0.5% xylenols. In the United Kingdom, cresols have been traditionally produced from low-temperature coal tars obtained in the production of smokeless fuels. The key player has been Coalite Chemicals. Similarly, in Germany Ru¨tgers VFT AG has developed excellence in coal tar chemistry and has been producing cresylic acids and 3,5-xylenols for years. CdF Chimie in

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France and Nippon Steel Chemical Co. of Japan have been also producing some coal tar-based cresols. The most prominent player in the field of cresols from coal tar had been SASOL of South Africa that has been operating coal chemical plants using pressure gasification of bituminous coals based on Lurgi process. In these plants, initially phenol and ortho-cresol are separated from the cresylic acid mixture using fractionation, and a mixture rich in cresols (upto 94%) containing some xylenols is produced and the product is marketed as mixed cresols (primarily para cresol, meta cresol, and small percentage of mixed xylenols and a very little quantity of unrecovered phenol). It has been reported that for select customers, SASOL can supply upto 99% pure cresols (metal þ para cresols). In the USA, natural cresols and xylenols have been historically made from the naphtha fractions of catalytic, thermal cracking or even coking processes in the petroleum industry. These products contain to the tune of 1% C6–C8 phenols [1,8]. Sulfur compounds such as alkyl and aryl thiols are treated with concentrated alkaline solutions in a process known as ‘‘sweetening’’ and cresols and xylenols are recovered from spent caustic washes, producing sodium cresolates= xylenolates. The composition of spent caustic cresolates varies in the range of 20–25% of C6–C8 phenols and 10–15% sulfur compounds. The caustic washes are collected by the cresols producing companies, most prominent among them being Merichem of Houston, TX, USA. Other companies such as Northwest Petrochemical and Productol are understood to have closed down because of inadequate feedstocks and environmental reasons. Production of cresols and xylenols from spent caustic washes of the petroleum refineries has been confined mostly to the Untied States since cresolates feedstocks have been inadequate in other countries. Besides as a result of use of UOP’s Merox process of sweetening which does not use NaOH solution, or of hydrotreating process, less and less cresols

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and xylenols are recovered from the refinery secondary streams. Bituminous coal or even lignite tars have been used in Germany, Czech Republic, Russia, Ukraine, and India for recovery of mixed cresols and xylenols. However, many of these plants, particularly in Germany, are being closed down since coal carbonization processes are considered as noneco-friendly. By the end of 1997 and beginning of 1998, SASOL of South Africa and Merichem of USA who have been leading cresols players decided to amalgamate their phenolics business. Accordingly, a new company known as Merisol was formed as a joint venture taking over the phenolics (including phenol, cresols, and xylenols) business of these two companies. Merisol is headquartered in United Kingdom and has operating plants in Sasolburg, Johannesburg, South Africa, and Greens Bayou, Houston in USA. Consequently, Merisol has become the largest manufacturer of all types of cresols and xylenols, both natural and synthetic in the world. The spectrum of cresylic acid resources of Merisol has been further broadened by taking over a part of high-purity synthetic m,p-cresols from Sumitomo Chemicals Japan via a new JV Company Sumika-Merichem K.K. (SMKK). Needless to emphasize that Merisol is now the most versatile and largest cresols player in the world. Merisol has since then diversified into downstream cresols derivatives which will be discussed in the succeeding chapters.

1.7. INDIAN SCENARIO Mixed cresols are available in India both from coal and lignite carbonization plants and are also produced synthetically, particularly p-cresol, using toluene as the critical feedstock. Synthetic cresols production from toluene feedstock will be discussed in some details in a subsequent chapter. A brief review of cresols or cresylic acid production from coal=lignite is presented here.

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Figure 1.1

17

Derivatives of phenol.

M=s Neyvelli Lignite Corporation Limited, Tamilnadu produce approximately 400–425 tpa mixed cresols via carbonization of lignite. Cresols produced are coproducts along with a number of key carbonization products such as gas, phenol,

Figure 1.2

Applications of xylenols.

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Figure 1.3

Chapter 1

Applications of mixed cresols.

xylenols, other distillate products such as bitumen and coke. Cresols recovered from the carbonization products consist of 40–42% meta-cresol, 50–52% para-cresol, and the rest unrecovered phenol, ortho-cresol, and mixed xylenols (particularly those isomers having overlapping boiling points with cresols). Mixed cresols or cresylic acids produced have been ideally used in production of wire-enamels, disinfectants, carbolic soap, etc. Mixed xylenols to the tune of 200 tPA are also produced. Steel Authority India Ltd. (SAIL) has been producing approximately 100–125 tpa mixed cresols in their coke oven plant at Rourkela, Orissa State. Similarly, Dankuni Coal Complex (near Calcutta) of Coal India Ltd. (CIL) have been producing mixed cresols and xylenols to the tune of 200 tpa. Quality of cresols produced by SAIL and CIL is more or less similar to that produced by Neyvelli Lignite. In the following chapters monomethyl phenols or cresols and their downstream derivatives will be discussed. Uses of the mother compound in the group of hydroxybenzenes i.e., phenol and also C8 phenols i.e., xylenols and mixed cresols have been shown in Figures 1.1–1.3. Some relevant higher alkyl phenols will be examined at appropriate places.

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2 Production of Synthetic Cresols

2.1. GENERAL Along with the olefins, particularly ethylene and propylene, aromatic hydrocarbons, more specifically benzene, toluene, para- and ortho-xylenes, for long had been the key building blocks for synthesis into a number of critical organic chemicals and intermediates. Among aromatic hydrocarbons benzene, toluene, and xylenes (BTX), toluene was earlier considered commercially the least important, and a number of processes were developed for conversion of surplus toluene into more lucrative benzene and C8 aromatics. More recently, demand of toluene has started picking up partly for augmenting octane number of gasoline, and more importantly, as a critical feedstock for a few important chemicals as shown in Fig. 2.1. Earlier hydrodealkylation of toluene into benzene, disproportionation of toluene into benzene and xylenes and transalkylation of toluene and C9 aromatics into xylenes were developed and commercialized to strike a right balance in desired aromatic 19

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Figure 2.1

Derivatives=uses of toluene.

hydrocarbons. Commercially three processes, namely the xylenes þ process of the Atlantic Richfield Co., Tatoray process licensed by UOP and Mobil’s Disproportionation process have been in operation. These are summarized as follows [1,6]: a.

Hydrodealkylation:

b.

Xylenes Plus

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c.

21

Disproportionation

Wherever the situation warranted either one or all of the processes were used to maximize benzene and xylenes production in lieu of toluene which used to be produced in surplus quantities in a catalytic reforming unit of a petroleum refinery. Commercial processes for conversion of toluenes and in pure fractions to benzene and other aromatic hydrocarbons are shown in Table 2.1 [9]. During the last two and half decades or so the picture has dramatically changed, and, toluene is no longer considered a ‘‘stepchild’’ in the family of aromatic hydrocarbons. Properties of toluene, both commercial grade, and nitration grade are as follows [1,2]: Commercial grade: CAS No. [108–88-3] A colorless, flammable liquid of low viscosity m.w. m.p. BP d25 4 Z20 D

92.13 94.99 C 110.625 C 0.8631 1.49693

Good solvent for fats, oils, tars, resins, etc. completely miscible with alcohols, ethers, ketones, phenols, esters, etc. slightly soluble in water. Nitration grade: ASTM d204 Color (Hazen) Boiling range Sulfur content

D 841 0.8690–0.8730 20 110–111 C no H2S=SO2

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Table 2.1

Chapter 2

Commercial Processes for Conversion of Toluene [9]

Process 1. Hydeal

Licensor

Process charge

Toluene, xylenes and other alkyl benzenes heavy reformate, from rerun catalytic reformate, light cycle oil from cat. Cracking 2. Detol Houndry Process Toluene=xylenes, and Chemical Co. heavy catalytic cycle oil, aromatics from petroleum coking, steam cracking 3. Unidak Union Oil Co. of Catalytic reformate California bottoms, aromatic fractions from severe thermal cracking liquid feedstocks 4. THD Gulf Oil Toluene, xylenes Corporation and other alkyl benzene fractions 5. – Sun Oil Co. Nitration toluene, reformates 6. HAD Atlantic Richfeld Heavy reformate Co., Hydrocarbon light cycle oil, Research Inc., cracked gas oils from coke ovens 7. Litol Houdry Process and Typically any cut Chemical Co. boiling in the range of 60–150 C 8. ‘‘Xylenes Atlantic Richfield Co. Toluene or higher plus’’ aromatics 9. Pyrotol

UOP

Houdry Process and Chemical Co.

Pyrolysis gasoline impure BTx fractions

Application A catalytic process for making benzene and naphthalene

A process for production of benzene and naphthalene

Benzene and xylenes

Benzene and naphthalene Benzene and napthalane Benzene, naphthalene and selected aromatics High-purity benzene and xylenes High-purity benzene and xylenes High-purity benzene

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It is absolutely necessary that toluene being used as the critical feedstock for organic chemical synthesis including production of cresols must be very pure, i.e., nitration grade. It should be free from benzene and other C6 hydrocarbons and C8 aromatics-based products will be present as contaminants in the finished product based on toluene. Indeed the toluene chemistry has made very significant progress. Toluene is now considered as an important building block for organic chemical synthesis. benzaldehyde, TDI, nitrotoluenes, chlorotoluenes, etc. are some of the key products being produced from toluene. Fig. 2.1 shows various applications=uses of toluene. Among the toluene derivatives cresols have been occupying a pride of place. Significant R&D work has led to development of a number of important derivatives from cresols, and more predominantly, from para-cresol, and to some extent from meta-cresol and to a lesser extent also from ortho-cresol. Processes that have been commercialized for production of cresols from toluene have been mostly an adaptation and extension of those used for manufacture of phenol, from benzene. As in the case of phenol the three most important processes for manufacture of cresols from toluene (nitrate grade) are based on i. sulfonation of toluene; ii. alkylation of toluene with propylene; iii. chlorination of toluene. These processes are briefly discussed here.

2.2. SULFONATION OF TOLUENE Sulfonation of toluene has been carried out using 98% H2SO4, 65% oleum, SO3, or even chlorosulfonic acid. As a result of sulfonation, a mixture of all the three isomers of toluene sulfonic acids are formed. However, the distribution of sulfonic acid isomers would follow the sequence: maximum p-toluene sulfonic acid followed by o-toluene sulfonic acid and minimum of m-toluene sulfonic acid. In order to produce more m-toluene

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sulfonic acid, the mixed sulfonic acids are isomerized using conc. H2SO4 as the catalyst. More m-toluene sulfonic acid is formed at the expense of para- and ortho-sulfonic acids. Similarly, at higher temperature say at 100 C more para-isomer is formed at the cost of ortho-isomer. Content of meta-isomer remains more or less same and varies between 3% and 5%. It has been reported that at lower temperatures say, between 0 C–10 C formation of meta-isomer is minimal, and in some cases is not more than 1% of the mixed toluene sulfonic acids. Some amounts of tolyl sulfones (about 1%) cannot be avoided in the sulfonation process. Reactions proceed as follows:

The properties of toluene sulfonic acids isomers are presented in Table 2.2 [7]. Table 2.2 Component

Isomers of Toluene Sulfonic Acids Usual form and molecular wt.

Melting points

o-Toluene Hygroscopic plates associated 57 C changes to p-isomer sulfonic acid with two molecules of on heating at 140–150 C water of crystallization MW 208 m-Toluene Oily MW 172 Freezing pt. 117 C sulfonic acid 106–107 C (anhydrous) p-Toluene Hygroscopic plates sulfonic acid associated with one molecule of water of crystallization, MW 190

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Para-toluene sulfonic acid (pTSA) can be separated from a mixture of toluene sulfonic acids by crystallization and centrifuging. Para-toluene sulfonic acid is a versatile catalyst being as effective as sulfuric acid. In fact being solid it is less likely to affect the reactants in a process and is sometimes preferred to sulfuric acid. pTSA has been used extensively in the preparation of alkyl resins, in foundry chemicals, etc. pTSA can be directly converted to pure para-cresol (98–99%) and the mother liquor after separation of pTSA can be conveniently converted to mixed cresols. 2.2.1. Neutralization of Toluene Sulfonic Acids Sulfonation of toluene produces along with sulfonic acids some water which is usually entrained with excess toluene and is removed azeotropically and the reaction mass is thereafter neutralized with soda ash (Na2CO3) or sodium sulfite (Na2SO3) which is recovered as a by-product in the cresols plant.

Generated CO2 or SO2 is used in the postcaustic fusion reaction to convert sodium cresolates to cresols. Commercially, sulfonic acids are neutralized by sodium sulfite by PMC specialities group, a division of PMC Inc. USA, the sole producer of para-cresol in the states, Konan Chemicals Co. of Japan and Inspec (Now Laporte) of UK. Atul Limited the sole producer of para-cresol in India has been traditionally using CaCO3 and soda ash for neutralization of toluene sulfonic acids. Generated CO2 gas is used for past fusion conversion of cresolates to cresols. However, this produces a low-grade, low-value gypsum which more often than not creates a disposal problem.

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2.2.2. Caustic Fusion After neutralization sodium salt of toluene, sulfonic acids is heated with caustic soda (70%) at 330–350 C for several hours to produce cresolates as follows:

Cresolates react with CO2 or SO2 or even H2SO4 to produce cresols in crude form which can be distilled to get pure cresols.

The cooled fusion melt is leached with minimum amount of water to dissolve out the sodium cresolates and the resultant slurry is centrifuged to recover the sodium sulfite which is always associated with small quantities of sodium carbonate and sodium sulfate. Sodium carbonate is formed mainly by reaction between the molten alkali and atmospheric CO2. Sodium sulfate is produced from the sulfuric acids derived by hydrolysis of the sulfonic acids by the superheated steam produced during the reaction. For caustic fusion of the sulfonic acids salts it has been observed that if para-isomer is predominant (for producing para-cresol) the viscosity of the molten mass is too high and it poses problems during agitation of the mass. It has been found that 4–5% of caustic potash (KOH) if added to caustic soda, maintains proper fluidity throughout the reaction. Most companies have been operating sulfonators and caustic fusion vessels batchwise. Continuous alkali fusion, particularly in conjunction with continuous sulfonation has obvious advantages. The difficulty is, the viscosity of the melt in the beginning and at the end of the reaction creates problems in pumping the reaction mixture. Inspec (Now Laporte) of UK has presumably sorted out this problem and they have

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been producing cresols using continuous sulfonation and fusion systems. A block diagram of a conventional p-cresol plant is shown in Fig. 2.2. It is necessary to mention here that the process of sulfonation and the neutralization of toluene sulfonic acids adopted in this process is very inefficient and certainly a lot more can be done to improve upon it. Ballestra S.P.A., Italy has suggested that the process of making sodium toluene sulfonate can be improved by removing water formed from the sulfonation reactors by azeotropic distillation of water–toluene mixture along with excess of toluene required (necessary to form the proper mole ratio of water=toluene). Toluene along with water is condensed as an azeotrope from the distillation column and then recovered toluene is recycled back to the sulfonators. By using this process, less of toluene and H2SO4 will be required for the process of sulfonation.

Figure 2.2 plant.

Block diagram for p-cresol production (conventional)

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Figure 2.3

Chapter 2

Process block diagram for STS production plant.

Neutralization of toluene sulfonic acids can however be done either by NaOH as shown or a cheaper material like Na2SO3 which is obtained as a by-product from the plant during post caustic fusim process. Figure 2.3 shows the flow scheme as proposed by Ballestra. 2.2.3. Commercial Plants While mixed cresols (m-p-cresols) are mostly recovered from natural feedstocks as discussed above, para-cresol and coproduct ortho-cresol are produced via sulfonation of toluene. Meta-cresol is commercially produced as a co-product during manufacture of BHT from meta–para-cresols mixture. This is discussed in some details in the next chapter. Under controlled (mild) sulfonation conditions and relatively mild caustic fusion, it is possible to produce cresols mixture with very small (less than 1%) meta-cresol content. It has been reported that sulfonation with chlorosulfonic acid at 33–45 C gives a product free from meta-cresol.

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In other words ortho- and para-toluene sulphonyl chlorides are formed, which on high temperature hydrolysis produces ortho- and para-toluene sulfonic acids. This mixture on neutralization, caustic fusion, and acidification produces a mixture of ortho- and para-cresols. The resultant product contains approximately 85% p-cresol and 15% o-cresol from which pure para-cresol (99%þ) and pure ortho-cresol (99%þ) can easily be obtained. Similarly, sulfonation of toluene with SO3–SO2 mixture at relatively low temperature of 25–50 C leads to a toluene sulfonic acid mixture practically free from metaisomer. PMC, USA, and Synthetic Chemicals, UK (sold to Inspec, UK and later on to Laporte, UK) are presumably using the above sulfonation processes and producing pure p-cresol and co-product o-cresol. Konan Chemicals, Japan are also producing a very pure grade p-cresol (99%þ). In China, there are a number p-cresol plants where purity varies from 96% to 99%. In India Atul Limited, Valsad, Gujarat State is the sole manufacturer of para-cresol. Atul’s technology was developed by the company’s R&D department at its Ankleshwar plant, Gujarat State. Strictly speaking, the technology was an adaptation of the process licensed by Honshu Chemicals Japan for production of mixed cresols (38–40% meta, 45–50% para and 5–10% ortho-cresol, phenol, and xylenols). In the first phase, Atul introduced 95–96% pure para- cresol and then gradually 98–99% pure para-cresol. In Atul’s process of production of para-cresol, toluene is sulfonated with 98–102% H2SO4 to produce a mixture of isomeric toluene sulfonic acids. The acid mixture is neutralized with CaCO3=Na2CO3 and then fused with caustic soda lye (70% NaOH) with 3–5% KOH to maintain the fluidity of the molten mass. By heating the mixture around 330 C for

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several hours, the fusion mass (cresolates) reacts with CO2 (generated captively during neutralization of sulfonic acids) to produce a mixture of cresols (p-cresol 84–85%, o-cresol 10–12%, m-cresol 2–3% phenol and xylenols <1%). On distillation of the above mixture in a distillation column, a bottom fraction containing 95–96% p-cresol, 4–5% m-cresol, 1% o-cresol and other alkyl phenols is produced. O-cresol and phenol mixture from the top of the column are further separated into o-cresol (98–99%) and phenol. Further enrichment of p-cresol to 98–99% is done through the process of crystallization and centrifuging. This is discussed in some details in the next chapter. PMC, USA, Laporte, UK, Konan Chemicals, Japan, and Atul Limited, India are the key manufacturers of para-cresol and all of them use nitration grade toluene as the critical feedstock and produce para-cresol via sulfonation, neutralization, caustic fusion, acidification, and distillation. Name plate capacities of these major producers are: PMC 15,000–16,000 tpa, Laporte 15,000–16,000 tpa, Konan approx. 4000 tpa and Atul 5500–6000 tpa.

2.3. ALKYLATION OF TOLUENE Production of cymenes or isopropyl toluene from toluene and propylene is an adaptation of cumene process from benzene and propylene. Through hydroperoxidation of cumene and cleavage of the resultant molecule, phenol and acetone are produced. There are a large number of phenol plants operating throughout the world based on alkylation of benzene. The alkylation and oxidation reactions are as follows:

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For nearly 50 years, alkylation of benzene to produce cumene was based on solid phosphoric acid (SPA) or aluminum chloride (AlCl3) anhydrous catalysts. Recently, UOP’s Q-maxTM Cumene Technology has been based on new zeolitic catalyst. The Q-max process provides excellent cumene product quality 99.97 wt% purity) and unprecedented yield (>99.7 wt%). The zeolitic catalyst used in the Q-max process is completely regenerable, and significant catalyst disposal problems associated with SPA or AlCl3 are eliminated. This is also an eco-friendly process and augurs well with the concept of green chemistry [10]. Similarly, DOW-Kellog cumene process which is offered to the industry is based on DOW’s unique, shape-selective 3 First, Q-max phenol unit has been established at JLM Chemicals, Blue Island, IL, USA.

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DDM zeolite catalyst. It is claimed that the process is characterized by its low capital cost, superior product yield, high-purity product, corrosion fee environment, low operating cost, etc. Oxidation of cumene to cumene hydroperoxide and its cleavage to phenol and acetone were first published by H. Hock and S. Lang in 1944. This was commercialized shortly after World War II by the Distillers Co., Ukand Hercules Powder Co. in the USA. UOP is offering the technology for conversion of cumene to phenol and acetone based on UOP=Allied (Now Mobil) phenol process. Similarly, Kellog is offering the technology of Hercules and lately Dow-Mousanto Process. Production of cresols based on alkylation of toluene, oxidation of cymenes, or isopropyl toluenes and cleavage into cresols and acetone is a direct extension of phenol process from benzene. The process is, however, more complex since three isomeric cymenes and cresols are involved. The chemistry of the process is as follows: i.

ii. Isomerization p-cymene

of

o-cymene

to

m-cymene

and

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iii. Cymenes oxidation to cymenes hydroperoxide

The properties of cumene and the three cymenes are presented in Table 2.3 [1].

Table 2.3

Properties of Cumene and Three Cymenes

Cumene C6H5CH(CH3)2 CAS No.[98-82-8] For wt: 120.2 C m.p.: 96.9 C

m-Cymene

o-Cymene

p-Cymene

CH3C6H4CH (CH3)2 CH3C6H4CH (CH3)2 CH3C6H4CH (CH3)2 [535-77-3] [527-84-4] [99-87-6] 134.2 C 134.2 C 134.2 C <25 C 73.5 C 68.9 C to 73.5 C BP 152–153 C at 175.7 C at 175–176 C at 176–177 C at 760 mm 760 mm 760 mm 760 mm pressure pressure pressure pressure d25 0.8696 0.8760 0.8750 4 0.8600 Z20 1.4939 1.5021 1.4947 D 1.4913 Insoluble in Insoluble in Insoluble in Insoluble in water, water, soluble water, soluble water, very soluble in ether, in ether, in ether, soluble in alcohol etc. alcohol, benzene alcohol and other alcohol, benzene organic used in organic used in organic mobile pleasant synthesis synthesis metal synthesis metal odor used in agreeable odor polishes polishes, etc organic synthesis

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As in the case of cumene and phenol process starting with benzene, UOP is offering UOP zeolitic cymene process for production of cymenes from toluene using zeolytic catalyst and also isomerization and conversion into m-cymene and p-cymene. m- and p-cymenes are separated into pure meta-cymene and pure para-cymene in UOP cymexTM process. UOP zeolytic cymene process represents a new generation of cymene technology based on a highly selective and stable zeolytic catalyst. As in case of cumene based on benzene, cymenes or isopropyl toluenes are produced by alkylation of toluene using traditional solid phosphoric acid (SPA) or anhydrous AlCl3. However, UOP’zeolitic catalysts have proved to be much superior. Even by-products production is much less by using a zeolytic catalyst. It is expected that new cresol complexes based on alkylation of toluene will use zeolitic catalyst system. Similarly, some of the existing cresol plants will switch over to the new catalysts. The UOP CymexTM process is based on UOP’s general SorbexTM system and separates pcymene and m-cymene isomers. Production of high purity (99%þ) meta and p-cymenes is achieved in block operations. During 1997, the process was satisfactorily demonstrated to a team of professionals of Atul Limited at their experimental pilot plant facilities at Des plaines, IL. Until 1972, the Hercules Powder Co. operated a plant at Gibbstown in USA for production of para-cresol from para-cymene obtained from natural terpenes from pine trees. Kellog is offering Hercules technology through a licence agreement for conversion of para- and meta-cymenes to the respective cresols. UOP-Kellog cymenes and cresols production starting with toluene (nitration grade) and propylene is shown in Fig. 2.4. It has been recently announced that technology for separation of para- and meta-cymenes is offered by Chiyoda Corporation in Yokohama, Japan through Kellog. As in the case of phenol from benzene via cumene, acetone is obtained as a co-product during production of cresols from toluene via cymenes.

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Figure 2.4 Overall flow diagram for cresols complex based on recent technology.

Acetone has the following properties: Structural CAS No. MW BP m.p. d204 Z20D

CH3COCH3 [67-64-1] 58 56.2 C 94.7 c 0.7908 1.3587

Acetone is a colorless, flammable liquid with a mildly pungent and aromatic odor. It is miscible with water and organic solvents, such as ether, methanol, ethyl alcohol, and esters. Acetone is used as a solvent for cellulose acetate, nitrocellulose and acetylene as a raw material for the chemical synthesis of such products as ketones, acetic anhydride, methyl methacrylate, bisphenol-A, diacetone alcohol, methyl isobutyl ketone, isophorone, etc.

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2.3.1. Commercial Plants Mitsui Petrochemical Industries Limited and Sumitomo Chemical Co. Ltd., Japan have been operating two 20,000 tpa plants wherein they produce mixed cresols (60% m-cresol and 40% p-cresol mixture) for the last many years. However, they do not separate the mixture of meta- and para-cymenes but convert the cymenes mixture to meta–para-cresols. M=s. Yanshen Petrochemicals, China near Beijing have been operating a similar 20,000 tpa meta–para-cresols plant based on alkylation of toluene. Both the Japanese and Chinese plants have been producing pure meta-cresol and BHT. Through a recent agreement, Sumitomo Chemicals sell 10,000 tpa cresols mixture to Merisol and the remaining 10,000 tpa m–p-cresols are converted pure meta-cresol and BHT. From environmental point of view, cresol plants based on alkylation of toluene are much cleaner and more eco-friendly than those based on sulfonation of toluene. The process is continuous, very low in operating costs. Catalyst is regenerable. However, such plants are much more capital intensive and will call for much higher cresols production. These plants will be attractive only if a few downstream derivatives based on pure meta-cresol and para-cresol (if cresols are separated) apart from BHT are integrated with the mother plant. 2.4. CHLORINATION OF TOLUENE [1,6] Again production of cresols via chlorination of toluene is an extension of the process for production of phenol from benzene. The process popularly known as Raschig–Hooker process was first developed by Dr. F. Raschig G.M.b.H. in 1923–31. In 1937, the Durez plastic Division of Hooker Chemical Corporation acquired the US rights and built the first plant in 1940. The Hooker Corporation improved the technology and overcame the disadvantages over the original process, in particular by modifying the oxychlorination reactor and developing effective catalysts for the vapor phase hydrolysis stage.

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Vapor phase hydrolysis of chlorotoluenes appears to be accompanied by a much smaller degree of isomerization than liquid phase hydrolysis, and accordingly, the Hooker–Raschig process is considered more attractive than the original Dow process. The process, however, is much less attractive than the sulfonation and alkylation processes. The chemistry of the process is as follows:

The only commercial plant in the world is operated by BAYER AG in Germany. Easy availability of chlorine at a low price might have made Bayer’s plant still attractive. It is to be specifically mentioned that chlorination reaction has to be very carefully controlled so as to avoid chlorination of the methyl group, otherwise a large number of unwanted and commercially unattractive by-products will be formed which will affect the yield and quality of cresols. Under controlled conditions para- and ortho-chlorotoluenes will be produced in significant amounts and meta-isomer will be minimal.

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3 Production of Individual Cresols

The isolation of individual cresol isomers, more particularly, meta- and para-cresols from a mixture of isomeric cresol mixture had been a master problem in organic chemical synthesis. While ortho-cresol could be more easily separated because of somewhat lower boiling point (approx. 191 C at atmospheric pressure) meta- and para-cresols could not be separated by distillation because of almost identical boiling points (202 C and 201–202 C at atmospheric pressure, respectively). Various processes have been established in the laboratory but only a few have been commercialized. Some of the commercial processes are discussed here in some detail. 3.1. CRYSTALLIZATION AND CENTRIFUGING In a typical p-cresol plant after separation of ortho-cresol, p-cresol feedstock would have the following composition: p-cresol 95–96%, meta-cresol 4–5%, o-cresol and xylenols not more than 1%. Though meta- and para-cresols are close 39

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boiling isomers, their melting points (freezing points) meta— 12 C approx. para—34 C approx.) have an appreciable difference indicating that crystallization can be used for separation of the isomers. But there is a restriction on recovery of pure individual isomeric compounds by crystallization because of formation of eutectics at two different temperatures [13]. In a batch process, meta–para cresol mixture is passed through a jacketted crystallizer equipped with good agitation system and heating and cooling devices, and after p-cresol crystals are adequately formed, the solid–liquid mixture is fed to a centrifuge from where pure p-cresol 98–99% is recovered after the mother liquor (approx. 65–70% p-cresol, 25–30% m-cresol, 1–2% o-cresol and xylenols) is drained out. It may be mentioned that using a very good fractionation system, it is possible to get o-cresol and almost xylenols free feedstock and that would ensure a better purity of p-cresol. Mother liquor will be predominantly meta- and para-cresol mixture. This entire process has been illustrated in Figs. 3.1–3.3. Needless to say that a continuous system is much more efficient and p-cresol output is better both qualitatively and

Figure 3.1

Binary eutectic of m-cresol and p-cresol.

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Figure 3.2 Block diagram showing enrichment of lean p-cresol to pure p-cresol.

quantitatively. It may also be added that if the feedstock is more or less free from ortho-cresol, a very good quality of both p-cresol (99% pure) and mother liquor (m–p-cresol) will be obtained. Meta–para-cresol mixture, i.e., the mother liquor having approximately a composition of 65–75% p-cresol and 30–35% m-cresol with not more than 1% o-cresol and xylenols, is an ideal feedstock for making butylated hydroxy toluene (BHT). Traditionally this mixture is being sold to carbolic

Figure 3.3

Block diagram: one stage slurry recycle crystallizer.

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soap manufacturers in India. The block diagram of a plant combining distillation and crystallization is in Fig. 3.4. Static crystallization and scraped surface crystallization systems are supplied by Sulzer-Chemtech, Buchs, Switzerland. Matching Centrifugation Systems are also supplied by Sulzer. Scraped surface crystallizers are also supplied by M=s Armstrong Engineers, Pennsylvania, USA and their sister organization Chemtec B.V., Scotland and Singapore. Atul has been operating scrapped surface crystallizers (10 TPD and 6 TPD) supplied by Chemtec B.V., Scotland for enrichment of p-cresol from 95–96% to 98–99%, last few years. Performance of the crystallization system has been satisfactory though output of pure p-cresol obtained has been much less than the name plate capacities. Some Chinese and Japanese companies have been operating p-cresol plants wherein they produce 99% pure p-cresol from a relatively lean meta–para cresols (p-cresol 95% or less). In Japan, Kobe Steel has sometime ago developed a high pressure crystallization technique known as Fine Cry Process in which m-, p-cresol mixture is introduced into a high pressure vessel of the piston-cylinder type and is crystallized adiabatically at 200 MPa. After draining off the mother liquor the system is decompressed and p-cresol emerges as the pure crystalline product [1]. 3.2. SEPARATION OF META-, PARA-CRESOLS VIA ALKYLATION WITH ISOBUTYLENE Butylated hydroxy toluene or BHT is a universally popular antioxidant which used to be made traditionally from pure para-cresol. Last few years, the trend has been to produce BHT by butylation of a mixture of meta–para-cresols. There are two distinct advantages: a. b.

The feedstock m–p cresol is cheaper than pure paracresol. More importantly by alkylating a mixture of m–p cresols, a mixture of butylated meta-cresol and

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butylated para-cresols is produced. By the process of dealkylation of either one or both of these products, it is possible to get pure meta-cresol and pure para-cresol or BHT and pure meta-cresol. Process chemistry is summarized below [1,6]:

In the alkylation process, apart from butylated cresols isobutylated homopolymers diisobutylene and triisobutylene are also formed.

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Figure 3.4 Flow diagram for combined distillation and crystallization of a cresol mixture.

Figure 3.5 shows the flow scheme of a typical BHT plant operating in India. In the above process, usually 2 mol of isobutylene react with each mole of cresol in the presence of acidic catalyst. Dilute H2SO4 is the most popular catalyst for both alkylation and dealkylation process. Some of the plants use p-toluene sulfonic acid or even a mixture of sulfuric acid and p-toluene sulfonic acid. It is reliably learnt that at least one plant has been using some quantities of a very strong Friedel Crafts alkylation catalyst—Triflic acid or trifluoromethane

for very fast alkylation reaction. The process being reversible, dealkylation of butylated cresols particularly butylated metacresols produces desired meta-cresol which is otherwise very

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Figure 3.5 Block diagram and material balance for 1.7 MT BHT from 1 MT PC (95%).

difficult to obtain as a pure product. Butylated meta- and para-cresols have the following boiling points [7]:

Component DBPC MBMC MBMC MBPC

Boiling point, at 2.67 KPa or 20 mm Hg pressure 147 C 167 C 124–129 C

In the commercial process, monobutylated cresols are usually recycled to the alkylators and are converted back to dibutylated cresols which are separated into BHT and dibutylated meta-cresol which on dealkylation produces pure metacresol and isobutylene, which is recycled to the alkylators. Sumitomo Chemical Co. Ltd. and Mitsui are operating such plants in Japan and are producing BHT and meta-cresol as co-products. M=s. Yanshen Petrochemicals, near Beijing, China, are also producing BHT and meta-cresol. BAYER AG have been also producing BHT and meta-cresol in a plant in Germany. Rhone-Poulence used to produce BHT, MBMC

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and meta-cresol in their plant at Oil City in Pennsylvania, USA. Subsequently Rhone-Poulence sold out their plant to Merisol in 1997. Merisol has the versatility of feedstocks and are producing BHT, m-cresol, MBMC, etc. as and when the market demands. Usually di-tert-butyl cresols are dealkylated at around 200 C in presence of acid catalysts mentioned earlier and produce meta-cresol, para-cresol, and isobutylene. Individual cresols are purified by distillation. Such processes produce 99% þ pure individual cresols. As of now, the companies mentioned above produce BHT and m-cresol based on alkylation of m–p-cresols. However, as of now, no company is making pure p-cresol. But theoretically very pure p-cresol can be obtained by dealkylation of BHT. 3.3. OTHER PROCESSES FOR PRODUCTION OF PURE PARA- AND META-CRESOLS Only one commercial plant based on UOP’s proprietary CresexTM Process is operated by Merichem (Now Merisol) at Houston, TX, USA. Cresex is an extension of UOP’s wellknown Sorbex process based on adsorption and desorption. The process is based on the fact that alkali metalmodified or alkaline earth modified zeolites of type X, A, L or ZMS-5 and also titanium dioxide, adsorb p-cresol more strongly than m-cresol. Thus m-=p-cresol mixtures can be separated in an adsorption column and can be dissolved again with a suitable desorbing liquid such as an aliphatic alcohol and ketone. The separating efficiency depends both on adsorption and desorption. Adsorption technology as provided by the SORBEX processes can separate complex feed mixtures by class or by specific isomer. Unlike conventional processes which only rely on differences in physical properties, adsorption can be customized to achieve a precise separation. Commercial Sorbex processes include: i.

‘‘Molex’’ for separation of normal paraffins from iso-paraffins and cyclic hydrocarbons.

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ii. ‘‘Olex’’ process for separation of olefins from a mixture of olefins and paraffins. iii. ‘‘Parex’’ process for separation of para-xylene from other C8-aromatics. iv. ‘‘Cymex’’ process for recovery of individual cymenes isomers, more particularly p-cymene, from a mixture of para- and meta-cymenes. v. ‘‘Cresex’’ process for separation of pure para-cresol and meta-cresol from a mixture of m–p-cresols. Essentially all Sorbex process units consist of an adsorption chamber, a Rotary Valve and an extract and a Raffinate Column. Process flow scheme is as shown in Fig. 3.6 [11,12]. Needless to emphasize that UOP’s Cresex process—an adaptation and extension of its generalized Sorbex processes—provides a unique opportunity for separation of m–p-cresols into pure p-cresol (99%) and pure m-cresol (99%). Quite surprisingly UOP has till now licensed cresex technology

Figure 3.6

Block diagram of UOP SORBEX flow scheme.

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to only one company, i.e. Merichem at Houston (now Merisol). Discussions with Merisol representatives revealed that a lot of modifications have been made in their cresex plant. Recently Chiyoda Corporation, Japan, has announced that the company through a licensing agreement with Kellog is in a position to offer a suitable technology for separation of meta and para-cresol from an isomeric mixture of cresols. Though not much is known about Chiyoda’s process, it is learnt that the same is not very different from UOP’s Cresex process.

3.4. PRODUCTION OF ORTHO-CRESOL Because of somewhat lower boiling point compared to mcresol and p-cresol, o-cresol is obtained as a co-product during fractionation of cresols from coal tar acids or during production of para-cresol based on sulfonation of toluene. Most of the p-cresol manufacturers such as PMC, INSPEC (now Laporte), Atul and others are producing o-cresol in the range of 600–1500 tpa depending on p-cresol production. Merisol has been producing approximately 3–5000 tpa of very pure o-cresol (>99%). Some o-cresol is also produced by other coal or lignite processing units. However, there is still a substantial demand–supply gap, and a few end users are producing their own o-cresol by other methods. One of the most popular methods of manufacturing ocresol is via methylation of phenol in the presence of a catalyst (currently most popular is zeolite catalyst). Some quantity of 2,6-xylenol is produced as a co-product

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Subsequently o-cresol and 2,6-xylenol are separated by fractionation. By selection of a suitable catalyst, it might be possible to obtain some quantities of p-cresol. Methylation of phenol is carried out either in vapor phase or liquid phase. Catalysts employed have been magnesium oxide, mixtures of magnesium oxide and oxides of manganese, copper, titanium, etc. Temperatures have varied from 390 C to 420 C and pressures atmospheric or somewhat higher pressure. Of late, zeolite catalysts have proved to be more effective and eco-friendly. General Electric of USA have been producing 10,000 tpa o-cresol and 70,000 tpa 2,6-xylenols, in USA, and in Holland further, 4000 tpa o-cresol and 16,000 tpa 2,6-xylenols. Synthetic Chemicals, UK (later on taken over by Inspec and now Laporte) have been producing 8000 tpa o-cresol and 2,6-xylenols in UK. There has been production of o-cresol and 2,6-xylenols in Japan, Russia, and Czech Republic [1,6].

3.5. PRODUCTION OF META-CRESOL Since meta-cresol and para-cresol have more or less identical boiling points, it has not been possible as yet to recover meta-cresol from a mixture of m–p-cresols. It has already been discussed in detail that only commercial method so far employed has been to convert a mixture of m–p-cresols to BHT and pure meta-cresol by alkylating the mixture with isobutylene and thereafter dealkylating butylated meta-cresol to pure meta-cresol. This remains even today the most attractive commercial method for production of pure meta-cresol. However, the disadvantage is that this process produces pure BHT as the main product and therefore commercial feasibility of production of the co-product meta-cresol would be dictated by the demand of BHT. One popular commercial process for production of meta-cresol has been via partial demethanization of isophorone, which is briefly discussed here.

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Isophorone (3,5,5-trimethyl-2-cyclohexene-1-one or 1,1,3trimethyl-cyclohexene-3-one-5) has the following properties: Structural CAS No. [78-59-1] Formula wt. Freezing point Boiling point ZD20 20 d20

138.21 8.1 C to 12 C 215.3 C at 760 mm Hg 1.4775 0.9229

It has a light yellow color and a disagreeable camphoraceous odor. It is completely miscible with organic solvent and is only sparingly soluble in water. Isophorone usually contains 2–5% of the isomer b-isophorone CAS No. [471-01-2] also known as 3,5,5trimethyl-3-cyclohexene-1-one. The term a-isophorone is sometimes used in referring to the a,b-unsaturated ketone, whereas b-isophorone connotes the unconjugated derivatives [1,2]. Isophorone is produced by aldol condensation (trimerization) of acetone under alkaline conditions. Severe reaction conditions effect the condensation and partial dehydration of three molecules of acetone. Both liquid and vapor phase continuous technologies are practiced

Traditionally demethanization (pyrolysis) of isophorone at high temperature produces 3,5-xylenol. However, controlled demethanization would produce meta-cresol as follows:

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It is absolutely necessary to control the hydrogenation process in order to avoid production of phenol or a mixture of hydroxybenzenes with or without an alkyl group. It has been reported that 2,3,5-trimethyl phenol is also obtained during aromatization of isophorone [1,7]:

Isolation of meta-cresol from the products of high temperature pyrolysis=aromatization of isophorone has been commercially successful, and both meta-cresol and 3,5-xylenol are being produced by a number of companies, pioneered by Shell Chemicals, UK. In USA, Union Carbide used to be the sole producer of isophorone. However, Hu¨ls Germany has been by far the largest isophorone producer in the world. They have reportedly a capacity of 45,000 tpa. Atochem, France, SPA-SISAS, Italy and British Petroleum, England collectively produce 25,000 tpa of isophorone. Union Carbide used to produce isophorone at their Institute, W. Virginia plant. Dow Chemicals have since taken over the facilities of Union Carbide. Isophorone would continue to be an attractive and alternative feedstock for production of meta-cresol and 3,5-xylenol since acetone availability would not pose any problem.

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3.6. SEPARATION OF META AND PARACRESOL FROM A MIXTURE—A REVIEW OF OTHER PROCESSES Considering the importance of separation of pure para-cresol from a mixture of meta–para-cresols, a number of alternative processes were tried out in various academic and research institutions. These processes were mostly studied in laboratories but for various reasons could not be commercialized. Both neutral and synthetic cresols were examined. After removal of o-cresol and phenol from mixed cresols or cresylic acid, a binary mixture of varying composition (meta content 40–60%, para content 60–40%) is obtained. Processes for separation of pure components are briefly outlined here. 3.6.1. Azeotropic Distillation Rectification of two components of a binary mixture such as meta–para-cresol having almost similar boiling points will require very high reflux ratios, large number of trays, longer cross-section towers and correspondingly high heat requirements. Even then proper separation will be very difficult and yield will be low. In these cases, in order to get pure products, a third component, sometimes called an entrainer, can be added to the binary mixture to form a new boiling azeotrope with one of the components. The volatility of this low boiling azeotrope is such that they can be easily separated by distillation. In case of the binary mixture of meta and para-cresols, the entrainer used has been benzyl alcohol (CAS no. [10051-6], C6H5CH2OH, FCC grade, b.p. 206 C, d25 4 1.040–1.050, 1.5385–1.5405) and for separation of the azeotrope, a n20 D vacuum of 5–100 mm mercury has been used in the distillation column [1,13]. Results had been still inconclusive, the purity reportedly was low and the recovery or yield unsatisfactory. More R&D work will be required to establish the commercial viability [14].

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3.6.2. Adductive Crystallization In such a crystallization process, an extraneous agent is added which leads to creation of a solid phase even before the binary eutectic temperature of the feed components is reached. Here the extraneous agent selectively forms an adduct or an addition compound with one of the two components to be separated. The adduct can be easily separated from the other components and thus both components can be separated in relatively pure forms. 3.6.2.1. Urea Adduct Method Urea (CAS no. (57-13-6), CO(NH2)2, white crystalline substance m.p. 132.7 C), one of the highest volume bulk chemicals in the chemical industry has been commonly used to form an adduct with meta-cresol. The adduct urea–metacresol is in solid form and is easily separated by filtration or centrifuging. The added is usually dissolved in hot water (70–80 C) and separated from meta-cresol. The other component p-cresol remains in the mother liquor and both relatively pure grades of meta- and para-cresols are obtained [15]. The drawback with this method is that temperature involved to form the adduct is low (10 C to –20 C) and recovery is poor. However, stage wise adduct formation and separation would improve the yield as was established in experiments conducted in Atul’s laboratory. 3.6.2.2. Tertiary-butyl Alcohol Method A separation method involving use of t-butyl alcohol (CAS no. [75-65-0](CH3)3COH, colorless liquid, b.p. 82.9 C, freezing point 25.5 C using 60% meta- and 40% p-cresol) has been also reported. Mixed cresols are added to 55.7% t-butyl alcohol which forms an adduct having 70% p-cresol and 30% m-cresol. On progressive crystallization at 0 C and 10 C, the composition of 90% p-cresol, 10% m-cresol and also 95.5% p-cresol and 4.5% m-cresol is obtained. The t-butyl alcohol is separated from p-cresol by distillation [15]. Here also more experimental work will be necessary to establish the commercial feasibility and economics of the process.

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3.6.2.3. Benzidiene Adduct Method Benzidiene (CAS no. [92-87-5], NH2(C6H4)2NH2, a grayish-yellow, white or reddish-gray crystalline powder, m.p. 127 C, b.p. 400 C) was found to selectively form an adduct with p-cresol when 60–40 mixture of meta–para-cresol was mixed with 100 g of benzidine at 110 C. The p-cresol–benzidiene compound would be formed as a precipitate, leaving m-cresol in the liquid state. After a few stages of separation involving filtration, crystallization and recycling of the mother liquor metacresol almost 99% pure and 98% p-cresol were produced [16]. One major drawback of this method is that benzidiene is a very costly material not easily available. Unless benzidiene losses are minimized and is recycled to the feed system almost quantitatively, the process would not be economically viable. Carcinogenic properties of benzidiene apart from other considerations preclude this process. A more suitable and practical process is one in which benzylamine (C6H5CH2NH2, CAS no. [100-46-9], a light 20 amber liquid, d20 4 0.9813, b.p, 184.5 C, ZD 1.540, soluble in alcohol, ether, water, combustible), an auxiliary substance forms with m-cresol a 1:1 adduct, which has a melting point of 39.5 C. After separation from the p-cresol mixture mother liquor the centrifuged m-cresol benzylamine adduct in solid phase is separated and fractionated into a top product benzylamine for recycle and pure m-cresol is usually recovered also as a top product in the second column. The mother liquor on distillation in the same way separates p-cresol after crystallization in a much purer form and benzylamine is recycled [1,17]. It has been also attempted to take advantage of adduct formation between cresols and certain other phenols with the objective of separating cresols. For example, m-cresol forms an adduct with phenol with a melting point of 25.9 C while p-cresol forms an adduct with bisphenol A [1,19,20]. m-Cresol can also be precipitated as an addition compound with anhydrous sodium acetate (CAS no. [127-09-3], CH3COONa, colorless crystals, odorless efflorescent, d20 4 1.528, m.p. 324 C, soluble in water) from m–p-cresol mixtures

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(in the ratio of 65:35) in an organic solvent (such as benzene or toluene) at 20–40 C. The precipitate on removal from the mother liquor is decomposed in the same solvent by heating to 80–95 C and sodium acetate is filtered, m-cresol is obtained from the organic solvent as a technically pure product, 96–99%, yield 70% [1,20]. Higher yields (approx. 75%) and improved m-cresol purity (99.5%) are said to have occurred if the adduct is decomposed at room temperature with a polar solvent such as acetone [21]. 3.6.3. Extractive Crystallization In the process of extractive crystallization, a solvent, say, acetic acid (CAS no. 64-19-7, CH3COOH, clear colorless liquid, m.p. 16.63, b.p. 118 C), helps in extracting the desired component, say m-cresol from a binary eutectic system. The solvent helps to achieve a higher recovery of the pure component from the eutectic mixture than otherwise what would have been possible. Unfortunately acetic acid has not been proved to have much effect on both the binary and ternary system as there is an overlapping of both p-cresol–acetic acid and m-cresol– acetic acid binary systems. Also the phase behavior of both the cresols with acetic acid is very similar, particularly in acetic acid rich regions wherein the freezing temperatures of various binary mixtures of m–p-cresols with varying compositions are almost identical. Conclusions derived from a few extractive crystallization experiments using acetic acid as the solvent for separation of cresols are that acetic acid is not a suitable solvent. In order to make this method more effective and commercially attractive more effective solvents other than acetic acid should be used [13,22]. 3.6.4. Dissociation Extraction In the process of dissociation, a single compound splits into two or smaller products, which may be capable of recombining to form the reactant, where dissociation is incomplete a

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chemical equilibrium exists between the compound and its dissociation products. Dissociation constant defines the numerical value of the extent of incomplete dissociation. In the process of dissociation extraction, the difference in the dissociation constants of the components of a mixture is used to achieve separation. Its use in particular is felt in the case of closely boiling isomers as in the case of metaand para-cresols. It is a two-phase process for the separation of organic acids or bases. In a single stage dissociation extraction process, the feedstock containing two acidic components (such as weak m-cresol and p-cresol acids) in an organic solvent like benzene or chloroform is contacted with an aqueous phase containing a strong base, say, NaOH, with a much stoichiometric quantity. In such a case, the strong acid, i.e., m-cresol, will react preferentially with the strong base, say, caustic soda, and form sodium salt of meta-cresol leaving relatively unreactive p-cresol in the organic phase. Extending this principle to a multi-stage operation (countercurrent), the products of high purity meta- and para-isomers after neutralization with a mineral acid like sulfuric acid [23]. The dissociation constants of meta- and para-cresols are 9.8 1044, and 6.7 1044, respectively. Accordingly, m-cresol will selectively react with caustic soda forming the salt in the aqueous phase and para-cresol being less reactive remains in the organic phase. Separation should therefore be possible using available techniques [24]. 3.6.5. Dissociation Extractive Crystallization Separation of relatively pure para-cresol from mixed cresols using an organic solvent and thereafter formation of a solid crystalline complex with the solvent has been reported. Piperazine and DABCO (diazabicyclo-octane) have been found to be very effective as extracting agents in this process of separation. There is very little effect of m-cresol in this process. The values of separation factor approach infinity as 100% p-cresol-base complex is crystallized. The yield of p-cresol was impressive with some aliphatic polar solvents, but

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Table 3.1

Separation of m-Cresol (A) and para-Cresol (B) Feed concentration (mol=L)

Solvent Diisoproyl ether Diisopropyl ether þ n-heptane (1:1) Diisopropyl ether Diisopropyl ether Toluene

57

Composition Recovery of solid Extracting Temperaof agent ture ( C) A B B (%)

A

B

0.92

0.92

DABCO

10

–

100

85

0.92

0.92

DABCO

0

0.8

99.2

78

1.05

1.05

PIP

20

–

100

70

1.05

0.97

PIP

20

–

100

91

2.41

1.33

PIP

20

–

100

32

DABCO: diazabicyclo octne; PIP-piperazine.

relatively lower temperatures were required to increase the yield. In aromatic solvents like toluene the yield decreased drastically even at lower temperatures. In absence of a proper solvent, the highly polar nature of m-cresol can reduce the recovery of p-cresol-base complex and can also affect the selectivity. The organic bases can be recovered from precipitated complex by thermal treatment. Table 3.1 shows the summary of results [25]. 3.7. SUMMARY Various academic and industrial research centers have tried to establish a viable process for separation of para-cresol from a mixture of meta–para-cresols after low boiling ortho-cresol and phenol have been removed from a cresol mix. This is true not only for synthetic cresols made from toluene but also from natural mixtures. However, as emphasized earlier, only the processes of solidification, crystallization and centrifuging, alkylation via

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isobutylene method or the proprietary ‘‘sorbex’’ (cresex) method of UOP had been found commercially applicable. Other methods mentioned under Sec. 3.6 have been tried out in the laboratories or bench scale systems. None of the processes has been found commercially attractive as yet. More R&D work will be necessary to establish commercially the viability of one process or the other.

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4 Cresols and Their Derivatives

4.1. GENERAL Phenol, the lowest of the monohydroxybenzenes, is the parent compound of a homologous series of chemicals encompassing cresols, xylenols, and other alkyl phenols. Phenol is a versatile high volume organic chemical and is a major building block for a number of finished products of great importance. Xylenols, both mixed and individual isomeric compounds, have also found some uses in making of industrial finished products. Uses of phenol and xylenols have been earlier demonstrated in Figs. 1.1 and 1.2. 4.2. DERIVATIVES OF CRESOLS While phenol downstream chemistry has been well known and gradually developed during the last hundred years, cresols have been relatively unknown even some 50 years ago. Mixed cresols, also known popularly as cresylic acids, derived from coal carbonization plants and also from the spent washes 59

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in a petroleum refinery had some limited applications in production of special soaps (carbolic acid) particularly by Lever Brothers (Hindustan Lever Limited has been producing ‘Lifebuoy’ carbolic acid soap, very popular in the countries of Indian subcontinent and the adjoining countries of South-East Asia such as Vietnam, Thailand, Malaysia, The Philippines, etc.). Cresol mixture was also used as solvent in the wire enamel industry and for some household applications and as fire retardant plasticizers, namely, tricresylphosphate, disinfectants, metal cleaning compounds, oil additives, etc. Things, however, changed for the better after technologies for separation of individual cresols were successfully developed and commercialized. Pure para-cresol isolated from isomeric cresols mixture occupied a pride of place among all cresols including o-cresol and meta-cresol. The highest volume derivative from p-cresol was undoubtedly Butylated hydroxy toluene or di-tert-butyl para-cresol popularly known as BHT which proved to be the most effective antioxidant for petroleum products, polymers, rubber, etc. Establishment of a number of petroleum refineries and petrochemicals plants particularly in USA, Canada, Europe, and Japan proved a boon for BHT and for para-cresol. Globally till early 1990s, 60,000–70,000 tpa of BHT were consumed by various end users. Being the cheapest and most easily available antioxidant, use of BHT was extremely popular and widely accepted. It is only in recent years that other more effective antioxidants have been developed and manufactured commercially. This will be discussed in some detail in the next chapter. So far some very important aroma chemicals better known as flavor and fragrance chemicals used to be isolated and extracted from natural products such as essential oils, resinoids, extracts, etc. Solvent extraction, steam distillation or, more recently, supercritical fluid extraction using high pressure CO2 have been some of the important methods for isolation of the important flavor and fragrance chemicals. There is a wide range of aromatic chemicals both from natural sources or made by organic chemical synthesis which have been introduced in various finished products. They are never used in very pure form but are further formulated for specific

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fragrances and flavors. They are used in soaps, cosmetics, confectionaries, alcoholic and non-alcoholic beverages, perfumes, ice creams, aerosol, sprays, syrups, pharmaceutical preparations, etc. They are also used in industrial products, like paints, polishes, adhesives, dry cleaning, leather and rubber articles, printing inks, veterinary products, insecticides, etc. Today many aroma chemicals are being synthesized and used in quite a few countries including India. Such chemicals include thymol, menthol, camphor, terpineol, phenyl ether, alcohols, esters, etc. just to name a few. It may be very relevant to mention that p-cresol and in some cases m-cresol and to a lesser degree o-cresol are being used as the critical feedstock for making some of these aroma chemicals. Indeed substantial R&D work has paved the way for use of individual cresols for a number of aromatic products, dye, and drug intermediates. It has opened a new vista for use of isomeric cresol as the building blocks for organic chemical synthesis. For instance, p-cresol has been used as the starting material for manufacture of p-anisaldehyde (a vital raw material for UV-B Sunscreen Chemicals and anti-hypertension drug, namely Dilitiazem), Synthetic Vanilin, 3,4,5-trimethoxy benzaldehyde (a starting material for Trimethoprim), perfumery products such as p-cresyl acetate, p-cresyl phenyl acetate, and a host of other products. Pure meta-cresol has been used for manufacture of synthetic musk—musk ambrette, used as a fixative to perfumes, for manufacture of synthetic Thymol and Menthol and also leather preservative p-chloro-meta-cresol, synthetic pyrethroids, and lastly for manufacture of 2,3,6-trimethylphenol—an intermediate for vitamin E. o-Cresol has been used for manufacture of Coumarin and some derivatives which are employed in perfumery as fixative. o-Cresol has also been used for making Novolac and epoxy resins and also for the herbicides based on di-nitro-ortho-cresol, etc. In sum, individual cresols have been very successfully converted to important intermediates in the organic chemical synthesis. It is expected that further development work will lead to synthesis of many more organic chemicals of vital importance. While new chemicals using individual cresols are in the pipeline

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some of the well-known and established finished products need to reviewed and reexamined. For instance, p-cresol based BHT as an antioxidant will continue to dominate the demand pattern of p-cresol; however, two recent developments have put this in doubt. The Food and Drug administration of USA has removed BHT from its GRAS (Generally Regarded As SAFE) list of foodstuff additives on the grounds of suspected carcinogenic properties. This has caused diminished demand of 15% of BHT in USA [8]. Additionally there is some competition from a new antioxidant based on p-cresol namely 2-cyclopentyl-pcresol=dicyclopentadiene p-cresol which is claimed to be as effective at 1=5th of the concentration of BHT [8,14]. There is, however, a silverlining that demand of p-cresol based para-anisic aldehyde that is used in preparation of OMC, the sunscreen (UV-B) agent, should grow because of the concerns over the increasing incidence of melanoma, particularly in Europe (France, Italy, and Spain) and the USA and Australia. Even Japan of late is witnessing some moderate growth. Currently OMC is the only safe UV-B sunscreen agent. There had been, however, some concerns over use of OMC since doubts have been raised regarding its stability with other ingredients used in the formulation or OMC based sunscreen agents. It has been reported that one formulator in Germany has decided to make sunscreens minus OMC. So there is a question mark regarding global growth of OMC [14]. In case of m-cresol derivatives, an official process literature has reported that m-cresol is a possible intermediate for production of antiarrythmic toliprotol which is reportedly produced by Bochringer Ingelheim KG Germany [14]. Uses of individual cresols, i.e. p-cresol, m-cresol and o-cresol, have been illustrated vide Figs. 5, 6 and 7. A number of downstream derivatives based on individual cresols have been examined in some detail. Properties, technologies, and marketability of these products along with brief details about the existing manufacturers have been highlighted in Chapters 5–7.

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Different derivatives of para-cresol are illustrated in Fig. 5.1, which are discussed in detail in the following sections. 5.1. BHT 2,6-Di-tert-butyl-p-cresol, 2,6-di-tert-butyl-4-methyl-phenol CAS No: [128-37-0] MW : 220.34 m.p.: 69 C b.p.: 220 C d420: 1.048 nD75: 1.4859 White crystals Soluble in alcohol Mol. formula: C15H24O d4 20

1:048

ZD 75

1:4859

A number of antioxidants have been produced based on individual cresol isomers. However, p-cresol occupies a pride 63

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Figure 5.1

Derivatives of para-cresol.

of place for manufacture of antioxidants. Butylated hydroxy toluene (BHT) also known as 2,6-di-t-butyl-p-cresol (DBPC) is the most widely used antioxidant derived from any cresol. Some of the salient features of BHT are as follows: – BHT is the largest single volume antioxidant used in plastics and rubbers; especially for poly-olefins, such as, PE and PP. It is also used in lubricating oils. – The volatility of BHT is relatively high and hence it is predominantly used in products with lower processing temperatures. – BHT being available at a relatively low price is the preferred antioxidant for various end uses. BHT had a phenomenal growth in the 1960s, 1970s, and 1980s in USA, W. Europe and Japan because of significant growth of petroleum refining and petrochemical industries. Currently the demand of BHT is somewhat stagnant in these regions and the growth will be minimal. In other Asian countries, particularly in China and India, the demand is growing because of growth of petroleum refining and petrochemical

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industries. Similarly growth is expected in other developing countries in Asia and Africa. Ciba’s IrganoxÕ 1010 is the preferred product in automotive applications due to better heat resistance. Its growth will exceed that of BHT. IrganoxÕ 1010 patents have expired and new producers are expected to enter this market. Ciba is also expected to introduce new blends of antioxidants. A few antioxidants are under development. These products may, however, use less p-cresol. 2-tert-Butyl-p-cresol, another low volume antioxidant, has a smaller outlet for p-cresol. It is used as a precursor of antioxidant 2246 and one type of Tinuvin. There is a range of other antioxidants manufactured from p-cresol. An important example is p-cresol dicyclopentadiene. Production of BHT from pure para-cresol=m–p-cresol has been discussed in some detail in Chapter 3. Global production facilities are discussed subsequently. There are currently three US producers of BHT, namely, PMC, Uniroyal and Merisol. These companies produce both feedgrade (limited use) and technical grade BHT. Shell chemical ceased domestic production of BHT in 1982. Rhone-Poulenc Inc. sold their BHT facilities at Oil City, Pennsylvania to Merisol by end 1997. There are large BHT manufacturers in Japan, Europe, Table 5.1

World Wide BHT Production Facilities

Company PMC, USA Merisol, USA Uniroyal, USA Laporte, UK Bayer AG, Germany Sumitomo, Japan Toshitomi, Japan Mitsui, Japan Yan shen, China Other manufacturers Russia Mexico Brazil, etc.

Raw material

Capacity (tpa)

Captive pc Captive mpc=pc Purchased pc Captive pc Captive mpc Captive mpc Purchased pc Captive mpc Captive mpc Pc=mpc=phenol

4500 5500 2500 5000 7500 10,000 3500 5000 5000 15,000–20,000

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and China. Most of the Indian BHT manufacturers in the small scale have virtually closed down since imported BHT from Japan has become more attractive. World wide BHT production facilities are shown in Table 5.1 [6,14]. Considering the use and growth pattern of BHT, there will be no demand–supply gap of BHT till 2005 and there will be hardly any scope for new manufacturers unless one or two plants are closed down because of some reasons or other.

5.2. p-ANISIC ALDEHYDE CAS No: [123-11-5] m.p.: 0 C b.p.: 248 C d420: 1.119–1.122 nD20: 1.570–1.572 Mol. formula: C8H8O2 Mo. Wt: 136 A clear colorless liquid with hawthorn odor Soluble in five volumes of 50% alcohol, insoluble in water

Next only to BHT, p-anisic aldehyde, also known as p-anisaldehyde, 4-methoxy benzaldehyde, or Aubepine is the second largest volume organic chemical made from p-cresol. Currently a few important world producers are manufacturing this product having multiple end uses. The major manufacturers are BASF (Germany), Nippon Shokubai (Japan), Atul (India). Koffolk Chemicals (Israel) and Laporte (USA) used to be the two important players but because of a number of reasons they have since then stopped production of p-anisic aldehyde. A few Indian companies apart from Atul have also started manufacture of this material. This compound is used as a raw material for a few important outlets such as: – p-Anisyl alcohol, an intermediate for nadifloxacin used for treatment of acne.

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– octyl methoxy cinnamate, a popular sun screen (UV-B) agent. – Dilitiazem, a calcium blocker antihypertension drug. – Flavors and fragrances. – Metal plating. Uses of p-anisic aldehyde have been shown vide Fig. 5.2. From organic synthesis point of view, two steps are involved in the production of p-anisic aldehyde from p-cresol, namely, methylation of p-cresol to PCME and oxidation of PCME to p-anisic aldehyde

While the same process of methylation is adopted by the manufacturers, the oxidation process differs. BASF uses a

Figure 5.2

Derivatives of p-anisic aldehyde.

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very clean process of electrochemical oxidation of PCME; Nippon Shokubai uses vapor phase oxidation of PCME using a closely guarded catalyst; other manufacturers have been making use of the traditional catalyst namely MnO2 (81–82% battery grade) and sulfuric acid (80%) in the liquid phase: (i) BASF process is an electro-oxidation of p-substituted toluenes (PCME) as follows [5]:

(ii) Vilsmeir-Haack synthesis

N-methyl formamide or N-N-dimethyl formamide can be used instead of N-methyl formanilide. (iii) Gattermann–Koch aldehyde synthesis [3]

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Table 5.2 Major Producers of Para-Anisic Aldehyde with Name Plate Capacities Atul Limited, India Nippon Shokubai, Japan BASF, Germany

Approximately 3000 tpa Approximately 1200 tpa Not revealed but estimated at 2500 tpa Approximately 1800 tpa

Other Indian manufacturers (Metro Chem, Universal Chemicals, Nandolia Chemicals)

This is a special use of Friedel–Crafts reaction. However, except the BASF electro-process, the other two processes have not been commercialized. Production of p-anisic aldehyde used for pharmaceuticals (Dilitiazem) requires much pure p-cresol (99%þ). For sun screen agents (OMC) theoretically a lower quality (98–99%) p-cresol may be possibly used. Also, in metal plating, a lower quality p-anisic aldehyde (approx. 98% pure) is normally used. Total current world demand of p-anisic aldehyde has been estimated at 7000 tpa. Major producers with their nameplate capacities are shown in Table 5.2. Needless to mention that production facilities established will more than meet the current demand. In fact there will be no demand–supply gap till 2005. Current worldwide consumption of PAA by end-use and projected growth rate is summarized in Table 5.3. Table 5.3 Worldwide Consumption of Para-Anisic Aldehyde and Projected Growth Rate Application Sun screen (UV-B) octyl methoxy cinnamate Dilitiazem Anisyl alcohol Flavors and fragrances Electroplating

Quantity (tpa)

Anticipated growth rate (%)

3350

10

2000 1000 450 150

10 5 7 5

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5.2.1. p-Anisic Alcohol CAS No: [105-13-5] MW: 138.17 m.p.: 24–25 C solidifies at room temperature b.p.: 259 C d1515: 1.113 nD20: 1.541–1.545 Mol. formula: C6H10O2

(synonyms: anisyl alcohol, anise alcohol, p-methoxy benzyl alcohol) There are two well-established processes for production of p-anisic alcohol from p-anisic aldehyde. i.

Technical grade p-anisic aldehyde reacts with pure hydrogen gas in presence of a Raney-Nickel Catalyst at 50–60 C and 3–5 kg=cm2 pressure in presence of methanol=isopropanol. The resultant product is thereafter distilled to produce 99.5% pure p-anisyl alcohol. ii. p-Anisic aldehyde reacts with formaldehyde via crossed Cannizzaro reaction to produce p-anisyl alcohol which is subsequently purified by distillation. Both are proven processes. However, all major manufacturers use the first process only. Isolated material from natural sources (anise seed) is also available in the market. Worldwide p-anisyl alcohol from p-anisic aldehyde is estimated at 1200 tpa. Major producers are: BASF Koffolks Penta manufacturing Co., USA Atul; & Associated Companies (India)

600–750 tpa 150 tpa 300 tpa 200 tpa

Para-anisyl alcohol is used primarily in flavor and fragrance chemicals applications. It is also used as an intermediate for production of anisyl acetate and anisyl formate. Both products are small volume products. One new application is production of nadifloxacin, an anti-acne drug. The

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Indian company Ranbaxy laboratory has been making a veterinary drug Pentozocine from p-anisyl alcohol for quite some time. In India, Atul was earlier supplying 100–125 tpa of p-anisic aldehyde for toll manufacturing of p-anisyl alcohol. M=s Sanmer Chemicals, Tamilnadu were also equipped with facilities for conversion of p-anisic aldehyde to p-anisic alcohol. Atul has now established its own hydrogenation facilities and is in a position to captively consume p-anisic aldehyde for conversion into panisyl alcohol. Atul has been exporting approximately 100 tpa to Japan and has been supplying approximately 50 tpa to the Indian market. Continued small growth of p-anisyl alcohol is expected during the next decade in India and other countries. 5.2.1.1. p-Anisyl Acetate [30] CAS no.: [104-21-2] d420: 1.1084 nD20: 1.514–1.516 MW: 180.20 Mol. formula: C10H12O3

Synonym: p-methoxy benzyl acetate Colorless liquid, lilac odor. Insoluble in water, soluble in four volumes of 60% alcohol combustible. Manufactured by reaction of p-anisyl alcohol and sodium salt of acetic acid or acetic anhydride, preferably in the presence of sulfocamphoric acid as catalyst.

Two grades are available commercially, namely, technical grade and FCC grade. p-Anisyl acetate has been found in berries. It has a fruity slightly balsamic blossom odor and is sometimes used in sweet-flowery compositions or in flavor

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compositions for fruity notes. It is a low volume fine chemical and global demand would not exceed 50–60 tpa. 5.2.1.2. p-Anisyl Formate (also known as p-methoxybenzyl formate) d420: 1.139–1.141 nD20: 1.514–1.516 MW: 166.12 Mol. formula: C9H10O3

Colorless liquid, lilac odor Insoluble in water, soluble in 5.5 volumes of 70% alchol Combustible This chemical compound is manufactured by reaction of p-anisyl alcohol and formic acid in an alkaline medium

Para-anisyl formate has been used mostly in perfumery formulations and also as a component of flavoring agent. Being a low volume product global demand would not exceed 50 tpa. 5.2.2. p-Anisic Acid (p-Methoxybenzoic Acid) CAS No: [100-09-4] m.p.: 184 C b.p.: 275–280 C d420: 1.385 nD40 Solid at ambient temperature soluble in alcohol and ether Mol formula: C8H8O3 Mol. Wt: 152.15

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p-Anisic acid is a very low volume compound produced via oxidation of p-cresyl-methyl ether

Small quantities of p-anisic acid are also obtained during controlled oxidation of PCME to p-anisic aldehyde. Koffoks of Israel has been separating p-anisic acid (upto 1%) from p-anisic aldehyde. An easier method of production of p-anisic acid is methylation of p-hydroxy benzoic acid obtained as a co-product during manufacture of o-hydroxy benzoic acid (salicylic acid) via Kolbe reaction of phenol and CO2

Global demand of p-anisic acid is estimated to be not more than 150 tpa. The compound is used mostly as a photographic chemical and also as a dye intermediate. Atul has been supplying p-anisic acid approximately 50 tpa to Fuji, Japan. Atul has been now manufacturing this product from p-hydroxy benzoic acid supplied by Gujarat Organics Ltd., Ankleshwar, Gujarat state. p-Anisic acid has been used also as a local antiseptic, antirheumatic agent as a repellent and ovicide. Continued small growth is expected for this product. 5.2.3. Sunscreen Chemicals Consequent upon depletion of ozone layer, primarily as a result of over consumption of flurochlorocarbons (Freon,

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CF4, chloroform, etc.), it has become absolutely necessary to use sun screen agents to prevent penetration of both ultraviolet-A and ultraviolet-B into the screen. Direct penetration of sunrays without the use of sunscreen agents in the body would cause both sunburn and suntan. Sunburn is an acute cutaneous inflammatory reaction in the skin and suntan is a kind of skin disease in which melanin pigments accumulate in the skin and might cause skin cancer in the long run. Both natural and synthetic UV-A and UV-B Sunscreen agents have been used in various cosmetic formulations, lotions, soap, etc. Butyl methoxy dibenzoyl methane is the most popular UV-A Sunscreen. This is a pale yellow to white powder, having weak aromatic odor, with a minimum assay of 95%, mp 81–86 C with only traces of metallic impurities. Butyl methoxy dibenzoyl methane is now manufactured in India, Europe, and USA. Global demand has been estimated at 200 tpa. In India, the FMCG major Hindustan Lever Ltd. (HLL) is the largest manufacturer and user of the material. Their brand name is Hysol. Another chemical company known as Chemspec Chemicals Pvt. Ltd. also manufactures this product for merchant sale. Based on the discussions with officials of HLL and Chemspec, it was learnt that 60–75 tpa is the total Indian requirement. Some quantities are exported to Europe and USA. It is, however, UV-B Sunscreen agent which is more critical from skin protection point of view. Several UV-B Sunscreen agents have been introduced having various degrees of sun protection factor and effectiveness to the skin: Following are some of the common UV-B Sunscreen agents [32]: Chemical Sunscreens Aminobenzoic acid and derivatives PABA Benzophenones Dioxybenzone Oxybenzone

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Cinnamates Octyl methoxycinnamate Salicylates=Anthranilates Methyl salicylate Menthyl salicylate Menthyl anthranilate Octyl salicylate Physical Sunscreens Titanium oxide (Micro) Zinc oxide Among all these UV-B Sunscreen agents octyl methoxy cinnamate accounts for almost 90% of all the Sunscreen agents and has been occupying a pride of place. Besides, octyl methoxy cinnamate (OMC) also known as 2-ethyl-hexyl cinnamate is produced from p-cresol via p-anisic aldehyde and will be discussed here in some detail. 5.2.3.1. Octyl Methoxy Cinnamate (OMC) CAS No: [83834-59-7] m.p.: 184 C b.p.: 275–280 C d420: 1.1008–1.013 nD20: 1.5420–1.5480 Colorless to pale yellow liquid, odorless to mild odor Soluble in ethanol, isopropanol

Manufacture of OMC from p-anisic aldehyde involves two steps [21]: 1.

Ethyl p-methoxy cinnamate from p-anisic aldehyde and ethyl acetate

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2. OMC (octyl methoxy cinnamate or 2-ethyl-hexyl p-methoxy cinnamate) from ethyl p-methoxy cinnamate and 2-ethyl hexanol

Because strict regulations apply in the registration of UV filters, the introduction of new substances is time consuming and none is likely during the next five years. Accordingly, the growth rate of OMC sunscreen agent application is estimated at high rates, probably to exceed 7–8% p.a., till 2004. Thereafter the demand increase is expected to slow down. Currently the key players of OMC are: – ISP, Vandyke, USA (since closed) – Hoffman-La Roche (previously Givaudan Roure, Switzerland) – BASF, Germany – Haarman & Reimer, Germany (reported to have closed down) Collectively they can produce approximately 2500 tpa and their total installed capacity is estimated at 3000 tpa. There is one manufacturer in Taiwan, apparently with a built in capacity of 300 tpa. In Japan, there is either zero or negligible production since OMC is still not popular in Japan; however, it is reliably learnt that OMC-based sunscreen is now used in some cosmetic formulations. In India, OMC sunscreen agent is gradually penetrating into the market. The largest user of OMC is Hindustan Lever Ltd. (HLL). Approximately, 100 tpa of OMC are used by HLL and its group companies for various product formulations. Other Indian companies such as Cadilla, Torrent, Ranbaxy,

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etc. are also using some quantities. An optimistic market demand in India is projected at 150 tpa by end of the year 2003. Technology for production of OMC is not unknown in India. A number of companies including HLL have been working on production of OMC from para-anisic aldehyde. Most of the companies in this field have perfected the technology. HLL, however, has decided to procure the material from other supplies. M=s Chemspec, Bombay, and Gallaxy, Thane Belapur Road, Maharashtra, do produce some quantities and supply to HLL. However, even now almost 50% of OMC is imported into India.

5.3. VANILLIN CAS No: [121-33-5] m.p.: 82 C b.p.: 285 C d420: 1.056 Mol. formula: C8H8O3 Mol. Wt: 152

White crystalline needles sweetish smell Soluble in 125 parts water, in 20 parts glycerol and 2 parts 95% ethanol soluble in chloroform and ether Vanillin, also known as 3-methoxy-4-hydroxy-benzaldehyde, is a natural product, can be found as a glucoside (glucovanillin) in vanilla beans at concentration of approximately 2%. It can be extracted with water, alcohol, or other organic solvents. The best known source of vanillin is the vanilla plant, vanilla platifolia A, which belongs to the Orchid family. It is cultivated mainly in Mexico, Madagascar, Reunion, Java, and Tahiti. The demand for this universally popular flavoring agent cannot be satisfied by vanilla beans alone. For economic reasons, the consumption of naturally occurring vanilla has

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gradually given way to synthetic vanillin, which is identical with natural vanillin, but differs in smell and flavor from natural vanillin as a result of various compounds in the natural extracts that do not exist in artificial vanillin. Vanillin can be produced synthetically as follows [19]: 1. From Eugenol (oil of cloves)

2. Via Reimer–Tiemann reaction of guaiacol

2-Hydroxy-3-methoxy-benzaldehyde can be separated by virtue of its greater volatility with steam. Most of commercial vanillin is synthesized from guaiacol, the remainder is obtained by processing waste sulfite liquors from paper units. The later route is, however, not environment friendly. Commercially, a more viable solution has been found by synthesizing vanillin from p-cresol; p-cresol is brominated, methoxylated, and oxidized to give vanillin as follows:

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It may be logical to assume that most of synthetic vanillin will be produced from p-cresol in future either in isolation or along with other important derivatives such as verataldehyde and 3,4,5-trimethoxy benzaldehyde. Following are the major uses of vanillin. – In flavor formulations, as a sweetener or as a flavor enhancer. – In butter, chocolate and all types of fruit flavors, root beer, cream soda, etc. – In baking. – In chemical synthesis, Rhone-Poulenc, the French multinational, is the largest manufacturer of pure grade vanillin and their brand name is Rhonavil. There are other producers of vanillin from guaiacol, in Japan (UBE Industries) China, and Norway, for example. But Rhone-Poulenc is the only company with a broad range of vanillin grades. While it is difficult to guess the exact world demand of vanillin, unofficial discussions with Rhone-Poulenc and others have revealed that the total market would be more than 1000 tpa. In India, there is no source of natural vanillin. It is either imported from China and Mexico or partly made from sulfite liquor wastes. The technology for synthesis from p-cresol has been developed by one or two companies, such as Zora Pharma, Ahmedabad. Indian market is estimated to the tune of 100 tpa. 5.3.1. Veratraldehyde CAS No: [120-14-9] m.p.: 42–45 C b.p.: 281 C Mol. mol. formula: C9H10O3 Crystalline solid

Veratraldehyde, also known as 3,4 dimethoxy-benzaldehyde, with a woody, vanilla like aroma has been primarily manufactured from vanillin:

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However, technology for manufacture from p-cresol either directly or via vanillin made from p-cresol has now been established.

Veratraldehyde crystallizes as needles from ether, petroleum ether, toluene, or CCl4. It is freely soluble in alcohol and ether. It is learnt that DSP, Andino, Holland is a major player in veratraldehyde and uses it for organic chemical synthesis and as an intermediate for a finished drug. Reportedly, they have been consuming to the tune of 150–175 tpa. In Europe, Borregaard, one of the largest producers world wide, is manufacturing this compound from vanillin. In the USA, Givaudan and Penta Manufacturing Co. are suppliers of this compound. One or two Japanese companies (Midori Kagaku is producing this compound from m-cresol) have been also producing from vanillin (imported from China or synthetically made from p-cresol). Otsuka Chemicals, Japan, is a key player. In India, one or two companies has established the technology from both vanillin and p-cresol.

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5.4. 3,4,5-TRIMETHOXY-BENZALDEHYDE (TMBA)

3,4,5-TMBA, a drug intermediate widely used for an antibiotic Trimethoprim, has been traditionally made from gallic acid (3,4,5-trihydroxy benzoic acid) or vanillin imported from China where they extract it from a particular bark of a tree. However, during the last decade or so, it has been more economically made from p-cresol

Following are the steps for synthesis of 3,4,5-TMBA from p-cresol [21]: Step I: Bromination

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Step II: Methoxylation

Step III: Methylation

Step IV: Oxidation

According to one Indian manufacturer 3,5-dimethoxy p-cresol is initially oxidized to 3,5-dimethoxy-4-hydroxybenzaldehyde (syringe aldehyde) which is then methylated to 3,4,5-TMBA

Syringe aldehyde [CAS No. [134 – 96 – 3] m.p. 110–113 C, b.p. 192–193 C=14 mm Hg

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China has been producing 3,4,5-TMBA from gallic acid and vanillin which used to be extracted from the bark of a tree. However, China has also recently switched over to p-cresol and most of 3,4,5-TMBA is now made from p-cresol. Japan has introduced the technology for synthesis of 3,4,5-TMBA from p-cresol almost two decades ago. Otsuka Chemical is a key player producing approximately 300 tpa of TMBA. DSM, Andino, Holland, one of the largest manufacturers of Trimethoprim, has been mostly importing TMBA from China, Japan, and India. Sulmetozin, an ulcustherapenticum, is a small volume application of 3,4,5-TMBA. This compound was introduced back in 1970 and has apparently reached the top of its life cycle. No growth in demand is expected during the next decade. Total global demand of 3,4,5-TMBA is estimated at 2000 tpa. Five percent annual growth is projected [14,34]. In India, both synthesis of 3,4,5-TMBA and its conversion into Trimethoprim have been carried out during the last two decades. M=s. Inventaa, Hyderabad produce almost 50 tpm or 600 tpa of 3,4,5-TMBA. Zora Pharma, Ahmedabad used to produce 25 tpm or 300 tpa of the material. Both Inventaa and Zora 3,4,5-TMBA production were based on p-cresol. One Bombay based drug co., namely, Alpha Drugs, produces TMBA from gallic acid imported from China. Indian production of 3,4,5-TMBA is estimated to the tune of 1200 tpa. Most of this quantity is captively consumed to make trimethoprim. However, some quantities of TMBA (300–400 tpa) are exported mostly to W. Europe. 5.5. PARA-HYDROXY BENZALDEHYDE CAS No: [123-08-0] m.p.: 116 C (sublimes) Colorless needles, d420 1.129 Soluble in alcohol, ether and hot water Mol. formula C6H4OHCHO Mol wt. 122

Traditionally para-hydroxy benzaldehyde has been produced as a co-product during production of ortho-hydroxy

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benzaldehyde (salicyl aldehyde) from phenol via Reimer– Tiemann reaction

Direct oxidation of p-cresol to p-hydroxy benzaldehyde is a difficult reaction. However, experimental investigations conducted in various industrial R&D centers and research and educational institutions revealed that unlike the other two isomers, p-cresol can be directly oxidized to p-hydroxy benzaldehyde by selecting a proper catalyst

Significant work has been done in Japan on liquid and vapor phase oxidation of p-cresol. Similarly Professors Sheldon and Jihad Dakka of Delft University of Technology, Holland have reported use of metal alumino-phosphate sieves (MeAPos) more particularly, CoAPO, for selective oxidation to p-hydroxy benzaldehyde with molecular oxygen in alkaline methanolic solution at 50 C [33].

Indeed direct oxidation of p-cresol to p-hydroxy benzaldehyde with reasonable yield had posed some problems to

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various research workers throughout the world. Significant work has been since carried out by Sumitomo Chemicals, Japan and Dow Chemicals, USA. European Patent No. 12939 granted to Sumitomo on December, 1979 and subsequently US Patent No. Dow (no. 4471, 140 on September 11, 1984) have revealed very useful and pertinent information regarding oxidation of substituted aromatic hydrocarbons. Based on these patent information work carried out in Indian laboratories led to the following conclusion [28]: A methyl substituted aromatic compound such as pcresol can be best converted to the corresponding aldehyde such as p-hydroxy benzaldehyde by reacting a methanolic alkaline p-cresol in presence of a mixed co-acetate-Mn-acetate catalyst at a pressure of 8–10 kg=cm2 and temperature of 75–100 C in presence of air and a solvent such as piperidine or an amine (ammonia, triethylamine, etc.) that would yield approximately 80–90% of the aldehyde in about 16–18 hr. Para-hydroxy benzaldehyde is an important building block for a number of key organic compounds including panisic aldehyde, 3,4,5-trimethoxy benzaldehyde veratraldehyde, bromoxylin and others. Important uses have been shown in Fig. 5.3. In India, a lot of work has been initiated for establishing the technology for p-hydroxy benzaldehyde from p-cresol. However, there is no producer of the material in India. The material is mostly imported from China, where some companies have been producing the material as a co-product during production of salicylaldehyde. Production of p-hydroxy benzaldehyde from p-cresol and its derivatives hold a lot of promise. One important reaction which is important from analytical chemistry point of view is Komarowsky reaction which is between certain alcohols and p-hydroxybenzaldehyde in dilute sulfuric acid solutions to give soluble colored complexes, 1,2-propylene glycol, for instance, gives a colored product while ethylene glycol does not. The reaction has also been used to determine cyclohexanol in cyclohexanone [2].

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Figure 5.3

Chapter 5

Derivatives of para-hydroxy benzaldehyde.

5.6. RASPBERRY KETONE CAS No: [5471-51-2] m.p.: 82–83 C b.p.: 200 C at 760 mm MW: 164.2 Mol. formula: C10H12O2

– Highly characteristic component of raspberry. – Forms colorless crystals (mp 82–83 C) with a sweet-fruity odor strongly reminiscent of raspberries. – Prepared by alkali catalyzed condensation of the alkali salt of p-hydroxybenzaldehyde and acetone followed by selective hydrogenation of the double bond of 4-hydroxy benzal acetone. While a large number of volatile compounds contribute to the flavor of raspberries, most are present at less than 10 ppm.

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Compounds include alcohols, acids, esters, carbonyls, ketones, and other hydrocarbons. However, a particular ketone 1-(4-hydroxy phenyl)-3-butanone has an odor very much like raspberry [7,30]. This particular ketone, i.e., raspberry ketone, is sold under trade names Frambinon (Dragoco) and Oxyphenylon (IFF). In Hawai, the acetate of raspberry ketone is used under the trade name of Cue-Lure CAS No. [3572-06-3] to attract the harmful melon-fly, Dacus Curcurbitae. It may not be out of place to mention that ketones are partly or wholly responsible for the odor of many natural products such as camphor, raspberries, coffee, musk, caraway, butter, rue, and jasmine. The study of the structures of these odoriferous ketones has enabled organic chemists to prepare new and useful compounds for food and drink additives. Raspberry ketone is very slightly soluble in water, but it is soluble in ethyl alcohol, propylene glycol perfumery uses: Babe, Blackberry, Blase´, Blueberry natural occurrence: Beef, Pineapple, Raspberry, Strawberry [46]. Synthetic raspberry ketone is a very high value but low volume product. The product is very popular in Europe, particularly, UK, and Germany and also in North America. Global demand is estimated at 50 tpa. Traditionally raspberry ketone has been produced by reaction of phenol with methyl vinyl ketone in the presence of a Friedel–Crafts catalyst in an inert solvent at a temperature between 5 C and þ5 C and in the absence of an acid alkylation catalyst. UK patents 876684 and 876685 granted to Dragoco describe the process in detail. Some modifications and new developments have also been mentioned in the said patents [29]. Phenol route was the chosen one since p-hydroxy-benzaldehyde so far was expensive. The only source of obtaining p-hydroxy benzaldehyde was as a by-product during production of salicylaldehyde. Since p-hydroxybenzaldehyde now can be easily made from p-cresol by direct oxidation, the product will be relatively cheaper and should prove to be an ideal feedstock for making raspberry ketone.

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5.6.1. Raspberry Ketone Methyl Ether [46] CAS No: [104-20-1] m.p.: 8 C=760 mm b.p.: 276–278 C MW: 178.23 Mol. formula: C11H14O2

Synonyms: anisyl acetone methyl ether 4-(para-methoxy phenyl)-2-butanone methyl ether Odor description: sweet dried Raspberry rose, Cherry fruity Cassic Absolute Density d254 1.045 Z20D 1.517–1.52 Insoluble in water, but soluble in ethyl alcohol Perfumery uses: Aloe, Cassia, Cheery, Jasmin Natural: Anise Seed, Aloc wood Process of manufacturer: methylation of OH-group to – OCH3 by reaction of raspberry ketone and di-methyl sulfate (CH3)2SO4 Process of synthesis being very recent, it is very difficult to estimate the global demand, gradually it will be a popular flavor and fragrance material 5.7. 2-NITRO-p-CRESOL [45] CAS No: [119-33-5] m.p.: 32–35 C b.p.: 234 C MW: 153.14 Mol. formula: C7H7O3N d4 38 : 1.24

Synonym: 4-methyl-2-nitrophenol Yellow crystals, slightly soluble in water, soluble in alcohol and ether Combustible Toxic by ingestion, inhalation and skin absorption Irritant

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Uses: mostly as an intermediate in the dyestuff industry Manufacturers: There are a number of manufactures including a few Chinese companies, Sumitomo Chemical Co., Japan, Bayer AG, Atul. Most of them consume the product captively. 5.7.1. Para-cresidine [1,2] CAS No: [120-71-8] m.p.: 51.5 C b.p.: 235 C MW: 164.2 Mol. formula: C8H11NO White crystals and soluble in organic solvent, insoluble in H2O

p-Cresidine, a food colorant and a dye intermediate, is made from p-cresol via, nitration, methylation, and reduction as follows:

Till a few years ago, p-cresidine used to be a very important dye intermediate. However, this was one of the products with an amino (–NH2) group and was in the banned list of 22 azo compounds, by Germany. Though this was not an azo dye intermediate, however, being in the banned category, demand was restricted in Germany and elsewhere. Currently PMC, USA is a key manufacturer (approx. 600 tpa). Japan used to manufacture this item. However, currently, Japan is importing the material mostly as p-cresidineortho-sulfonic acid from both China and India. Two or three Chinese companies are producing the material and they offer very low price. p-Cresidine is also sold as p-cresidine vinyl sulfones (pCVS). World demand is estimated at around 1800 tpa.

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In India, Atul is currently the only manufacturer of p-cresidine, Atul offers this material to the Indian manufactures of vinyl sulfones. Atul has a name plate capacity of 720 tpa. Atul has been exporting this material as pCOSA and pCVS to USA and Japan. Atul also exports some quantities as p-cresidine (to a company in Germany). However, because of restrictions in the use of p-cresidine as discussed above, p-cresidine market is not likely to grow. In fact, Atul has witnessed decrease in sales of p-cresidine during last two years. It appears that this trend would continue. 5.8. ETHERS AND ESTERS Vanillin and veratraldehyde are two fine examples of flavor and fragrance chemicals which have been successfully synthesized from p-cresol. A number of low volume synthetic perfume materials based on p-cresol esters and ethers have also been introduced. Following are some of the important products. 5.8.1. Para-cresyl Methyl Ether (PCME) CAS No: [104-93-8] b.p.: 177 C MW: 122 nn 20 : 1.5123 d4 20 : 0.978 Mol. formula: C8H10O

PCME made by methylation of p-cresol using (CH3)2SO4 or CH3Cl in presence of NaOH has a well-defined odor of wall flowers with a definite suggestion of Ylang–Ylang. The compound is more known as an intermediate for manufacture of p-anisic aldehyde. Most of the PCME produced in the world is converted to p-anisic aldehyde. However, approximately 300 tpa are sold in the world market as a perfumery chemical.

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It is a colorless liquid with a Pungent odor. Dilute solution has a flower like fragrance. 5.8.2. Para-cresyl Phenyl Ether [30] Para-phenoxy toluene CAS No: [101-53-1] m.p.: 84 C MW: 184 n20 n : 1.5025 d20 4 : 1.5720 Mol. formula: C13H12O

This is another low volume perfume chemical made from pcresol where the –OH group has been replaced by a –OC6H5 group. It has a very powerful odor of the hyacinth rose type. Also used as a germicide. World demand is not more than 50 tpa. However, it has been reliably learned that Sumitomo Chemical Co., Japan, has developed a catalyst to convert p-phenoxy toluene to p-phenoxy benzaldehyde for a new type of agrochemical. 5.8.2.1. p-Phenoxy Benzaldehyde or 4-Phenoxy Benzaldehyde [45] CAS No: [67-36-7] m.p.: 24–25 C b.p.: 185=14 mm C MW: 198.22 Mol. formula: C13H10O2 d15 4 : 1.132 n20 D : 1.611

This is used as an intermediate in flavor and fragrance and pharmaceutical industry. Also is used as a pesticide=herbicide herbicide intermediate.

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5.8.3. p-Cresyl Acetate or p-Tolyl Acetate [30] CAS No. [140-39-6] Mol. formula: C9H10O2 Mol. wt.: 150.18 bp: 209 C Colorless liquid, floral odor, soluble in 2.5 volumes of 70% alcohol and in most fixed oils d20 4 1.055 Z20 4 1.5025

This is made by acetylation of p-cresol as follows:

This is a synthetic perfume having a definite penetrating odor of narcissus and is used in many perfumes of the lily, lilac, and honey suckle type. Global demand is estimated at 300 tpa. In India, approximately 50 tpa is consumed by aroma chemicals companies such as S.H. Kelkar, manufacturers of Agarbatti (incense stick), mostly in and around Mysore, Karnataka state. 5.8.4. Para-Cresyl Phenyl Acetate [30] CAS No [101-94-0] Mol. formula C15H14O2 MW 226.27 C Narcissus odor and a honey note

Preparation: prepared by esterification of p-cresol with phenyl acetic acid.

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Used in blossom compositions with a slight animal note, not found in nature. C6H5CH2COOC7H7 is used to a considerable extent as a narcissus perfume. This is a crystalline substance having a melting point of 75 C. Global demand is to the tune of 300 tpa in India, approximately 30–40 tpa is consumed by various companies. 5.8.5. Para-cresyl Isobutyrate [2,45] Synonyms: 4-Methyl phenyl 2-methyl propanoate p-Tolyl isobutyrate CAS No: [103-93-5] m.p.: 24–25 C b.p.: 185=14 mm C MW: 178.1 Mol. formula: C11H14O2

Appearance: colorless to pale yellow liquid Odor: animalic, warm, floral, fruity Purity: minimum 98% d20 4 0.989–0.997 20 Z4 1.484–1.489 Uses: a modifier in floral bouquets where a narcisse jasmine effect is needed. This compound is best prepared by esterification of paracresol either with isobutyric acid; CAS No. [79-31-2], (CH3)2 CHCOOH or with isobutyric anhydride: CAS No. [97-72-3], [(CH3)2CHCO]2 O. p-Cresyl isobutyrate has been used both as a perfumery chemical and also in flavor formulations. Globally the product is made by BASF, H&R, Givaudan, IFF, etc. Some quantities are also made in India mostly for export. It has been estimated that the global demand is to the tune of 75–100 tpa.

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5.9. 3,4-DIMETHOXY TOLUENE [2] CAS No: [494-99-5] b.p.: 220–222 C=760 mm 83 C=6 mm MW: 152.19 Mol. formula: C9H12O2

(4-methyl veratrole-4-methyl-1,2-dimethoxybenzene) Appearance: clear liquid Sparingly soluble in water, acids and alkalies, soluble in org. solvents. Following are the steps in manufacture of 3,4-dimethoxy toluene: 1. Methylation of p-cresol to PCME

2. Bromination of PCME to 3-bromo-4-methoxy-toluene

3. Methoxylation of 3-bromo-4-methoxy toluene to 3,4dimethoxy-toluene

3,4-Dimethoxy toluene is used as an intermediate in the pharmaceutical industry. For instance, Roche has been

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producing the bulk drug Ormethoprim using this intermediate. The global demand would be to the tune of 75 tpa. 5.10.

CREOSOL [45] Synonyms:

2-methoxy-p-cresol 2-methoxy-4-methyl phenol 4-methylguaicol

CAS No: [93-51-6] mp: 5.5 C bp: 221.8 C=760 mm Hg MW: 138.2 Mol. formula: C8H10O2 d4 20 : 1.092 ZD 20 : 1.5353

Appearance: oily liquid, irritant Solubility: very slightly soluble in water, vastly soluble in alcohol, chloroform, ether, and benzene Manufacturing process: bromination of p-cresol followed by methoxylation by reacting with methanolic NaOCH3. Uses: as in intermediate in dyestuffs, pharmaceuticals, etc.

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Different derivatives of meta-cresol have been illustrated in Fig. 6.1. There are discussed in detail in the following sections.

6.1. PARA-CHLORO META-CRESOL [1,33] CAS No. [59-50-7] m.p.: 64–66 C b.p.: 235 C MW: 164.2 Mol. formula: C7H7ClO White or slightly pink crystals, phenolic odor and soluble in organic solvent, fats and oils.

Para-chloro meta-cresol (PCMC), an antibacterial, antimold agent is prepared by chlorination of meta-cresol using SO2Cl2. 97

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Figure 6.1

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Derivatives of meta-cresol.

PCMC is of major importance as a preservative for aqueous functional fluids and as a raw material for disinfectants. This is because of its strong antimicrobial effect combined with favorable chemical and physical properties and good biodegradability. PCMC is an established germicidal phenolic biocide used in Western Europe and certain Asian countries. It is also used in Japan and the USA worldwide, germicidal phenolics, such as PCMC, are slowly expanding their niche markets. In spite of competition from less costly quaternary ammonium compounds, germicidal phenolics are preferred in hospitals=health-care units. PCMC has completely replaced pentachlorophenol in the leather industry, particularly as an antimold agent, during chrome tanning of leather. In fact, pentachlorophenol has

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been banned by almost all countries because it is carcinogenic in nature. Bayer AG, Germany used to be the key manufacturer of PCMC and its formulations. However, most of the countries including Germany have decided to procure the material from developing countries. There is substantial cattle population in Australia, Newzealand, Pakistan, W. Europe, USA and of course in India. Because of significant production of hides and skins, PCMC has proved to be extremely popular in these countries. World demand has been estimated at 500 tpa for PCMC and its formulations. India is a major producer of PCMC. It has been reported that Indian companies such as Benzochem, United Chemicals, etc. collectively produce 200–250 tpa PCMC. Most of the material is exported to the USA and W. Europe (Germany, Italy, UK, etc.). Indian demand is around 30– 40 tpa. Atul does not produce PCMC, however, Atul supplies PCMC to the world market including India as a merchant exporter (to Pakistan, USA, etc.) and supplier. It is currently selling at $8=kg. Four to five percent p.a growth has been projected for this material Toxicological: LD50 (oral, rats) LD50 (dermal, rats)

5129 mg=kg >500 mg=kg

Is an irritant to skin and mucous membrane.

6.2. THYMOL [1,30] CAS No. [89-83-8] m.p. : 49–51 C b.p.: 232 C MW: 150.22 d20 4 : 0:9756 n20 D : 1:5227 Mol. formula: C10H14O Colorless crystals, spicy-herbal, slightly medicinal odor. d20 n20 4 : 0:9756 D : 1:5227

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Thymol is present in volatile oil of thyme and ajowan, mint seeds from which it may be extracted with sodium hydroxide, liberated from the sodium compound with acid and purified by crystallization. It has a woody, burnt, smoky odor. Thymol, isopropyl meta-cresol, is a precursor of l-menthol. Meta-cresol with a purity of 98.5% must be used as the starting material for thymol production, because the isomer, 2-iso-propyl-4-methyl phenol derived from p-cresol is the main contaminant and cannot be easily separated from thymol. In the industrial process employed by Bayer AG, Germany, m-cresol and propylene, both in the liquid state, are pumped through a pressure tube reactor, filled with activated alumina. The process is performed at a molar ratio of m-cresol: propylene of 1.07 at 350–360 C, 5 kg=cm2 and LHSV of 0.25 hr1. The reaction product consists of 25% m-cresol, 60% thymol and 15% other products. Thymol of 99% þ purity is obtained by rectification of the crude product [1]. Undesired alkylates of m-cresol (2-,4- and 5-isopropylm-cresol, 2,6- and 4,6-diisopropyl m-cresol) are recycled to the reaction zone to achieve a high overall yield of desired thymol. A gas phase process for thymol manufacture using medium pore-sized zeolites (erionite, mordenite, or ZSM23) as heterogeneous catalyst was developed in 1988. It was reported that reaction temperatures were lower (230– 270 C) than in the older liquid phase process. Reaction pressure was reported to be normal or slightly elevated. Natural thymol is produced in a number of countries including India, Pakistan, China, Indonesia, some countries of Latin America, etc. Annual production has been reported to the tune of 1000 tpa. Most of synthetic thymol is produced in countries not having natural sources. Germany is a major producer. Thymol is mostly converted to menthol, which has significant medicinal uses.

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6.2.1. Menthol CAS No. [89-78-1] m.p.: 43 C(= form) b.p.: 216 C MW: 156.27 d20 4 : 0:890 n20 D : 1:5227 Mol. formula: C10H20O White crystals, cooling odor and taste. Congealing temperature 27–28 C.

() Menthol is a white, waxy crystalline compound having a strong odor of peppermint. Its main source is oil of peppermint from the plant, Mentha arvensis. It is an ingredient of decongestant ointments and nasal sprays and is also used to flavour toothpaste and cigarettes. During recent years, natural menthol is supplemented with synthetic menthol. One popular route is synthesis from Citronellal via isomerization and hydrogenation. However, commercially more economic route is from m-cresol through hydrogenation of thymol. Worldwide production of synthetic l-menthol has grown rapidly, and is expected to reach 3600 tpa by end of 2004. This trend is expected to continue. Growth will not be spectacular but steady. India does not have any l-menthol plant based on meta-cresol. However, the technology is well known and some production is expected in near future. India being a large manufacturer of natural menthol, most of the flavor and fragrance chemical companies did not find it necessary to look for synthetic menthol. However, synthetically made menthol would be much cheaper than the one extracted from natural sources. Besides, consumption of menthol has been growing steadily. Being a major player in the global market, it is logical to expect that synthetic menthol would supplement the natural menthol.

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6.2.1.1. () Menthyl Acetate [30] CAS No. [2623-23-6] b.p.: 227–228 C MW: 198.3 d20 4 : 0:9253 n20 D : 1:447 Mol. formula: C12H22O2

Also known as () 4-menthan-3-yl-acetate Appearance: A colorless liquid with a fresh-fruity peppermint odor. Slightly soluble in water, miscible with alcohol and ether, combustible. Manufacturing process: () Menthyl acetate is prepared by acetylation of () menthol with acetic anhydride in the presence of sodium acetate. Uses: Mainly in peppermint flavors and reconstituted peppermint oils but also to small extent as perfumery. Most of the key players of () menthol make some quantities of () menthyl acetate.

6.2.1.2. Menthyl Salicylate [30]

CAS No. [89-46-3] 2 hydroxy benzoic acid 5-methyl-2-(1-methyl ethyl) cyclohexyl ester. Mol. formula C17 H24 O3 MW 276.37

Clear yellowish syrupy liquid, odorless or fruity odor d25 25

1:045

Insoluble in water, soluble in most organic solvents made by esterification of menthol and salicyclic acid. Uses: As a ‘‘sunscreen’’ to filter out ultraviolet light penetrating the skin.

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6.3. 2,3,6-TRIMETHYL PHENOL (2,3,6-TMP) [1] CAS No. [2416-94-6] Mol. formula : C9H12O MW 136.19 m.p. 62–64 C

2,3,6-Trimethyl phenol, a key intermediate for vitamin E synthesis, is made from m-cresol and is easily the largest derivative of m-cresol. 2,3,6-Trimethyl phenol has been produced selectively by gas phase methylation of m-cresol with methanol at 300–400 C under normal pressure on ortho-selective metal oxide catalysts as used for selective methylation of phenol. The reaction occurs in multitube reactors with a fixed catalyst. Iron oxide catalysts modified with oxides of other metals (Zn, Cr, and Sn) or Mg and Si are particularly suitable. At a temperature of approx. 350 C and an LHSV of 1 hr1 an initial mixture of m-cresol, methanol and steam in a molar ratio of 1.6:1 gives 2,3,6-trimethyl phenol in yields of 90–95% relative to m-cresol at virtually complete m-cresol conversion. Small quantities of 2,5-xylenol and 2,4,6-trimethyl phenol are the main by products. 2,3,6-Trimethyl phenol is purified by distillation from the mixture. The commercial product is 99% pure [1]. 2,3,6-Trimethyl phenol demand is expected to grow worldwide by at least 5% per annum during the next decade. Some industry experts, however, fear that now there is over capacity situation for TMP, which may last for some years. Main producers and their nameplate capacities are: BASF, Germany:

6000 tpa (not m-cresol based) Honshu Chemical, Japan: 5300 tpa (can be expanded to 6400 tpa) Schenectady, USA: 4000 tpa INSPEC (Now LAPORTE), UK: 5000 tpa MERISOL (USA): >3000 tpa

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Vitamin E being the fastest growing vitamin, 2,3,6-TMP constitutes the fastest growing m-cresol derivative. One critical factor for fast growth will, however, depend on availability of m-cresol. Currently, m-cresol is available mostly in Japan, USA, and W. Europe mostly as a co-product during manufacture of BHT from meta–para-cresols. Can also be obtained by methylation of 2,6-xylenol on g-aluminium oxide at about 355 C using a 2,6 xylenol:methanol ratio of 2:1. India does not currently produce 2,3,6-TMP, since at present there is no production of m-cresol. 6.4. 4-NITRO-m-CRESOL [45] CAS No. [2581-34-2] Mol. formula: C7H7NO3 MW: 153.14 m.p.: 127–129 C Yellow to off white crystals toxic by inhalation, irritant

Synonym: 3-methyl-4-nitriphenol Uses: Major use is an intermediate for the agrochemical industry prominently used for the manufacture of Fenitrothion. Manufacturers: Mostly made as a captive product by Sumitomo Chemicals, Japan. A few Chinese companies here also started manufacture of the product for Fenitrothion. Bayer AG used to be a key player. 6.5. META-PHENOXY TOLUENE AND METAPHENOXY BENZALDEHYDE [45] (3-phenoxy toluene)

(3-phenoxy benzaldehyde)

CAS No. [3586-14-9]

CAS No. [39515-51-0]

b.p.: 271–273 C MW: 184.24 d420: 1.051 nD20: 1.5730 Mol. formula: C13H12O

b.p.: 169 C=11 mm MW: 198.22 d420: 1.147 nD20: 1.5950 Mol. formula: C13H10O2

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Meta-phenoxy benzaldehyde is an important agrochemical intermediate for manufacturing synthetic pyrethorids like Decamerthrin, Cypermethrin, and Fevalerate used as pesticides. Pyrethroids, being more potent to pests and less harmful to environment, are having increasing demand. Traditionally m-phenoxy benzaldehyde is manufactured from benzaldehyde via bromination, and phenol. However, synthesis of this important agrochemical intermediate from meta-cresol via meta-phenoxy toluene oxidation has now become commercially more attractive. Sumitomo Chemicals, Japan has an excellent technology for making meta-phenoxy benzaldehyde from m-cresol as follows:

Details of the oxidation catalyst have been kept secret. However, from published literature it would appear that either Cr2O3 or a mixture of Co and Mn acetate is the preferred oxidation catalyst. Conversion of meta-phenoxytoluene to meta-phenoxy benzaldehyde can also be achieved via chlorination. The process is briefly described as follows: (a) Chlorination of m-phenoxy toluene. This step involves side chain chlorination of m-phenoxy toluene in a medium of CCl4 in the presence of a free radical initiator catalyst, azobisisobutyronitrile (AIBN), under refluxing conditions. Meta-phenoxy benzene chloride and m-phenoxy benzal chloride are formed as major products. Following are the stoichiometric reactions: AIBN

C6 H5 OC6 H4 CH3 þCl2 ! C6 H5 OC6 H4 CH2 ClþHCl AIBN

C6 H5 OC6 H4 CH2 ClþCl2 ! C6 H5 OC6 H4 CHCl2 þHCl (b) Hydrolysis of m-phenoxy benzyl and benzal chlorides. Conversion of the mixed chlorides into m-phenoxy benzaldehyde is done by modified Sommelet reaction which

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involves reaction between m-phenoxy benzal chloride and hexamine in the presence of aqueous acetic acid under boiling conditions leading to the formation of m-phenoxy benzaldehyde and hexamine degradation products. The reaction most probably takes place as follows: Aq: acetic acid

m-C6 H5 O C6 H4 CH2 Cl þ ðCH2 Þ6 N4 ! m-C6 H5 O C6 H4 CH2 ½ðCH2 Þ6 N4 þ þ Cl 6H2 O

! m-C6 H5 O C6 H4 CHO þ CH3 NHþ 3 Cl

þ 3NH3 þ 5HCHO Ammonia generated reacts with acetic acid forming ammonium acetate. To regenerate acetic acid from acetate, hydrochloric acid is added towards the end of the hydrolysis reaction. Ammonium chloride also forms, while acetic acid is regenerated. The process of meta-phenoxy benzaldehyde from m-cresol via chlorination was developed in a laboratory=bench scale for Atul by Indian Institute of Chemical Technology, Hyderabad, India but it was never commercialized. A cheap source of chlorine and adequate pollution control facilities might make the process attractive. Japan is a major producer of meta-cresol in the world. They manufacture approx. 4000 tpa of meta-phenoxy benzaldehyde for conversion to pyrethroids. Yanshen Petrochemical Co., China also produces m-cresol as a co-product during production of BHT and has started manufacture of m-phenoxy benzaldehyde from m-cresol. India has a number of meta-phenoxy benzaldehyde plants with a collective capacity of 3000 tpa. However, all plants are based on benzaldehyde bromination. Mitsui Chemicals, Vapi (Gujarat State), Gujarat Insecticides Ltd., Ankleshwar (Gujarat State), Gharda Chemicals (Bombay), ICI Agrochemcials, Manali (Madras) and others have been producing synthetic pyrethroids from m-phenoxy benzaldehyde all these years. Their plant capacities vary from 250 to 600 tpa. Discussions with these companies revealed that they

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would be very happy to procure m-phenoxy benzaldehyde based on meta-cresol from the Indian market. Continued growth of 5–6% p.a. is expected for this product. 6.6. MUSK AMBRETTE [30] CAS No. [83-66-9] m.p.: 84–86 C MW: 268.28 Mol. Formula: C12H16N2O5 Yellow crystals with an intense ambrette-seed odor.

This is a fragrance chemical, mostly as a fixative, which is produced from meta-cresol. Following are the steps:

Musk ambrette has been used as a fragrance chemical in soaps, cosmetics, cigarettes, etc. However, due to its toxicological properties the use of musk ambrette is declining in developed countries. In India, there are three plants producing musk ambrette. Two plants namely Masmaijmer Chemicals and A.M. Aromatics in Tamilnadu and Aswathi Chemicals, Bangalore are producing musk ambrette for the last 12 years. Collectively, they can produce upto 600–700 tpa. Indian demand is estimated at 300–350 tpa. The product is exported to middle East Europe. Some quantities are being sold in the US market. Originally, the technology came from the Netherlands. However, no plants are operating now in the Netherlands or other parts of Europe. Some quantities are made in Japan and China. However, actual production figures are not revealed.

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6.7. m-ANISIC ALDEHYDE [46] CAS No. [591-31-1] Mol. formula: C8H8O2 MW: 136.15 b.p.: 143 C at 50 mmHg 8–90 C at 3 mmHg d415 : 1.119 nD20: 1.5530 Freezing point: >110 C

Synonyms:

m-anisaldehyde 3-methoxybenzaldehyde Appearance: Colorless to a pale yellow liquid with a conspicuous strong odor. Manufacturing process: In spite of all efforts, no effective catalyst system was yet found commercially viable to either directly oxidize m-cresol or the intermediate ether m-cresyl methyl ether (mcme) unlike other two isomers, p-cresol, o-cresol, or PCMC=OCME. The product is commercially made from m-nitrobenzaldehyde as follows:

In place of SnCl2, HCl even iron powder and an organic acid like formic acid can be used. Meta-hydroxy benzaldehyde is then methylated with dimethyl sulfate in an alkaline medium to produce m-anisic aldehyde

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Uses: As an intermediate in the pharmaceutical and flavor and fragrance industry. Commercial uses of the material are yet to be fully established. From time to time enquiries come from a few pharmaceutical companies for quantities as high as 150 tpa. Global demand right now may be expected to be around 250 tpa. Developed countries would perhaps like to source the material from China and India. 6.8. m-ANISYL ALCOHOL [45] Synonyms: m-anisic alcohol CAS No. [591-31-1] Mol. formula: C8H10O2 MW: 138.17 b.p.: 250 C at 723 mmHg d415: 1.111 nD20: 1.5440 Colorless to pale yellow liquid.

Uses: Mostly as an intermediate in pharmaceutical, flavor, and fragrance. Manufacturing process: m-Anisic aldehyde can be directly reduced to the alcohol by hydrogenation using Raney–Nickel catalyst around 90–100 C and 6–7 atm pressure. Other processes also exist but they are not commercially viable. BASF, H&R, Givaudan are also some pharmaceutical majors manufacturing some quantities captively. 6.9. m-CRESYL ACETATE (m-tolyl acetate) CAS No. [122-46-3] Mol. formula: C9H10NO2 MW: 150.18 b.p.: 212 C d415: 1.048

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Appearance: Colorless oily liquid, odor similar to phenol with a reminiscence of acetone. Insoluble in water, soluble in common organic solvents, combustible. Uses: In the pharmaceutical industry as an antiseptic, fungicide. Manufacturing process: Reaction of m-cresol with acetic anhydride

Global demand is not exactly known, but is estimated at 40–50 tpa.

6.10. m-ANISIC ACID [2,45] (3-methoxy benzoic acid) CAS No. [586-38-9] Mol. formula: C8H8O3 MW: 152.15 m.p.: 106–108 C b.p.: 170–172.3 C at 10 mmHg

Appearance: Off-white crystalline powder. Uses: Antiseptic, insect repellent, ovicide, etc. Manufacturing process: Usually made by methylation of meta-cresol followed by oxidation of MCME using a strong oxidizing agent such as KMnO4

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Another route is starting with m-nitrobenzoic acid, reduction and diazotization as in case of m-anisic aldehyde

Again m-anisic acid demand is yet not established. Some quantities are consumed in Japan and China. Current consumption is estimated at 25–30 tpa.

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Various derivatives of ortho-cresol are shown in Fig. 7.1 and are discussed subsequently. 7.1. COUMARIN CAS No [91-64-5] m.p.: 69–73 C b.p.: 298 C MW: 146.15 d420: 0.935 Mol. formula: C9H6O2 Crystalline powder

Coumarin is one of the most important aroma chemicals having unique characteristics not only because of its hay-like bitter sweet odor but also because of its quality as a perfume fixative. It is widely distributed in the plant kingdom, but most of it has been produced synthetically. Mostly used as a perfumery chemical in cosmetics and related industries, it is also used for a few industrial applications. The commercial synthesis of coumarin (by the Raschig process) is based on 113

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Derivatives of ortho-cresol.

side chain chlorination of o-cresol, followed by reaction with phosgene to bis-(o-dichloromethyl)-phenyl carbonate. This treated with acetic anhydride and potassium acetate produces coumarin in 70–75% yield as follows (Raschig process) [8]:

USA is a major producer of synthetic coumarin. Reportedly 600–700 tpa of coumarin is produced in USA. In

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W. Europe, particularly in UK, Germany, and France about 250–300 tpa coumarin is produced. In Asia-Pacific region, Japan is the key player. Japan has been producing 200– 250 tpa of coumarin. India does not produce any quantity of synthetic coumarin. Some quantities of coumarin are produced from natural resources. Atul produces both o-cresol (at Ankleshwar) and phosgene (at Atul). Unfortunately, they have not considered this product seriously, apparently because, they just do not have the right technology. Some companies are, however, working on the synthesis of the product from o-cresol, phenol, and also salicylaldehyde (Perkin reaction) [30]. Mainly used as a flavoring agent and as an intermediate in the pharmaceutical industry. It has a pleasant fragrant odor resembling vanilla. World’s leading producers of coumarin are the following multinational companies: i. Rhone Poulenc, France; ii. Boeringer Manuheim GmbH, Germany; iii. Eastern Chemical (UK) Ltd., UK. The estimated annual outflow of foreign exchange in India due to import of coumarin is in the range Rs. 60–80 million. In spite of this, no adequate efforts have been made to develop the right technology for manufacture of coumarin in India though both the critical raw materials ortho-cresol and salicylaldehyde are made in this country. If the product could be made in India, the demand could be projected around 500 tonnes per annum. Surplus quantity could easily be exported. Given the R&D infrastructure and availability of scientific talent in the country, it is certainly not beyond the Indian scientists to develop an appropriate technology. 7.2. EPOXY-CRESOL–NOVOLAC (ECN) RESINS One of the major uses of ortho-cresol is for manufacture of epoxy-cresol–novolac (ECN) resins CAS No. [37382-79-9]. The acidic reaction of less than an equimolar concentration of formaldehyde with o-cresol yields cresol–novolac resins,

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which can be further reacted with epichlorohydrin to form epoxy, cresol novolacs (ECN) [20].

The epoxy-cresol–novolaks resins are prepared by glycidylation of o-cresol–formaldehyde condensates in the same manner as phenol–novolak resins. o-cresol–formaldehyde condensates are prepared under acidic conditions with HCHO-o-cresol ratios of less than unity. The o-cresol novolacs of commercial significance possesses degrees of polymerization, n, of 1.7–4.4 and the epoxide functionality of the resultant glycidylated resins varies from 2.7 to 5.4. Softening points (Durrain’s) of the products are 35–99 C [31]. The ECN resins are multifunctional, solid polymers characterized by low ionic and hydrolyzable chlorine impurities, high chemical resistance, and good thermal performance. The ECN resins are widely used as base components in high-performance electronic and structural molding compounds, micro-chip encapsulation, high–temperature adhesives, structural molding powders, etc. DOW is the largest US producer of ECNs with its new 10 million pounds (4500 tpa) capacity plant in Freeport, TX. Other producers of ECNs include Ciba-Geigy, Border Chemicals, Shell and Schenectady Chemicals [6]. The worldwide market for ECNs approximately total 30 million pounds (13,640 tpa). USA exports more than 50% of its production to W. Europe and Asia. The major producers of ECN resins in W. Europe are Ciba-Geigy, EMS-Chemie Ag, and Hoechst. Approximately 1500–2000 tpa of ECNs are produced in W. Europe [6]. Japan’s 80% of o-cresol consumption is on account of ECNs production. The ECN resins are growing in Japan at 7–8% per year. Sumitomo Chemical, Nippon Kayaku, and Dainippon Ink and Chemicals lead the markets. A total

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amount 3000 – 4000 tpa of ECN resins are produced in Japan. In India, ECN resins are gradually becoming popular. Hindustan Ciba Geigy and Cibatul (now Atul) are major players.

7.3. OTHER PRODUCTS 7.3.1. Para-Chloro-o-Cresol [1,34]

(

(4-chloro-2-methyl-phenol)

CAS No. [1570-64-5] m.p.: 45–48 C b.p.: 220–225 C MW: 142.59 d20 4 : 1:215 Mol. formula: C6H7OC

The product is made in a similar way as parachlopro-meta-cresol by reacting o-cresol with SO2Cl2. P-chloro-o-cresol is the precursor for the pesticides MCPA (2-methyl-4-chloro-phenoxyacetic acid), MCPP (2-methyl-4-chloro-phenoxy propionic acid) and MCPB (2-methyl-4-chloro-phenoxy butyric acid). MCPP is also known as mecoprop. These phenoxy herbicides are very popular in W. Europe and Japan. Total Western European capacity for p-chloro-ocresol exceeds 21–22,000 tpa. Major producers of PCOC include Coalite Chemicals, UK (9000 tpa) and Rhone-Poulenc (5000 tpa), UK, and BASF (7000 tpa) in Germany. These companies along with Bayer and Chemie Linz, which also produce PCOC in plants with flexible operations are the major producers of the chlorophenoxy carboxylic acid pesticides. In USA, the production of PCOC is virtually nil. Dow Chemical, the largest producer of the phenoxy herbicides, imports PCOC from W. Europe. Phenoxy pesticides are also very popular in Japan. However, production of PCOC does not exceed 100–150 tpa. Most of PCOC is imported from W. Europe.

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Ishihara Sangyo Kaisha Ltd., and Nissan Chemical Industries produce some quantities of PCOC. These two companies and Mitsui Toatsu Chemicals produce MCPA, while Nissan Chemical Industries also produces MCPB. These pesticides are suitable for lawns and dry field farming and are not applied to rice fields. Some Indian companies such as United Phosphorous Ltd. produce PCOC. However, it is learnt that the material is exported to UK. Phenoxy herbicides are not produced in India.

7.3.2. Di-Nitro-o-Cresol [6] (DNOC) CAS No. [534-52-1] m.p.: 87 C MW: 198 Mol. formula: C7H6N2O5

4,6-Dinitro-o-cresol or 4,5-di-nitro-2-methyl phenol is an yellow crystalline compound having m.p. of 87 C (pure grade). It is pseudoacid and readily forms water-soluble ammonium potassium or sodium salts. Dinitro-ortho-cresol, a polymerization inhibitor for the production and distillation of styrene and p-methyl styrene, is produced by nitration of o-cresol. Concentrations of the inhibitor are commonly in the 400–1000 ppm range. The DNOC has also herbicidal and insecticidal properties. Sea Lion Chemical, USA, converts o-cresol to DNOC which is marketed by Wall Chemical. The US market is estimated at 700 tpa. In W. Europe, SNPE Pennwalt, Holland and A.H. Marks and Co. Ltd. produce DNOC, which has applications as a highly phytotoxic dormant insect spray, primarily for application on potatoes. The use of DNOC is not much known to the Indian agrochemical manufacturers as of today. No production has been reported so far. The DNOC as a multipurpose agrochemical is being discussed in more detail in Chapter 8.

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7.3.3. Cresol–Formaldehyde Resins [31] These resins (Resole or Novolac) are used as curing agents or hardeners for epoxy molding compounds for electronics applications such as computer components. O-cresol–formaldehyde resins have been also used to modify phenol–formaldehyde resins, and in laminates. The major producers of cresol–formaldehyde resins are Borden Chemicals and Schenectady Chemicals USA. Approximately 1800 tpa of these resins are produced in USA. Reportedly in W. Europe and Japan, o-cresol is used along with phenol–formaldehyde resins. Three to five percent annual growth for these resins has been projected. In India, both Cibatul (now Atul) and Hindustan Ciba Geigy have been producing some quantities of o-cresol– formaldehyde resins. 7.4. O-ANISIC ALDEHYDE [2,45,46] CAS No. [135-02-4] m.p.: 38–39 C or 3 C (two crystallizable forms) b.p.: 238 C=760 mmHg MW: 136.5 Mol. formula: C8H8O2

Synonyms: o-methoxy benzaldehyde o-anisaldehyde Appearance: White crystalline powder Odor: burned phenolic odor d25 25 : 1:1274 (liquid) 1.258 (solid) 20 ZD : 1:5608 insoluble in water, soluble in alcohol, chloroform, ether, etc., combustible. Assay: 95–99% by GLC Manufacturing process: Manufactured from pure o-cresol (99% purity) in a similar way as p-cresol to p-anisic aldehyde. The following are the steps: i.

O-cresol to o-cresyl methyl ether using dimethyl sulfate in an alkaline medium.

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ii.

Oxidation of OCME to o-anisic aldehyde and its purification. The catalyst system MnO2 (81–82%) in 80% H2SO4 is quite effective.

Repeated experiments in the experimental base of Atul established the process beyond doubt. Yield is 75–80% somewhat less than p-anisic aldehyde. Other catalyst systems Co-acetate= Mn-acetate, Cu and Nickel salts have also been tried. Another important industrial process for manufacture of o-anisic aldehyde is based on methylation of o-hydroxy benzaldehyde or salicylaldehyde based on phenol.

Selection of an appropriate technology for manufacture of o-anisic aldehyde would depend on whether the manufacturer is a phenol major or cresols major. Uses: O-anisic aldehyde is a low volume fine chemical used as an intemediate in pharmaceuticals, dyes, flavor, and fragrances, etc. Uses are limited and the global demand would not exceed 500 tpa. Global key players are BASF, IFF, Givaudan, H&R, etc. 7.5. O-ANISYL ALCOHOL [46] CAS No. [612-16-8] b.p.: 248–250 C MW: 138.7 Mol. formula: C8H10O2

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Synonym: 2-methoxy benzyl alcohol, o-anisic alcohol 1.039 d15 4 1.5470 Z20 D Freezing point >110 C Manufacturing process: Several methods exist for reduction of o-anisic aldehyde to o-anisic alcohol, however, direct reduction by hydrogen using Raney-Nickel catalyst system at 90– 100 C and 5–7 atm pressure has been commercially most attractive. Most of the key players of p-anisic alcohol such as BASF, Givaudan, Koffoeks, etc. also produce some quantities of o-anisyl alcohol. Application areas include flavor and fragrance, pharmaceuticals, etc. Global demand has been estimated at 300–350 tpa.

7.6. O-ANISIC ACID [46] CAS No. [579-75-9] m.p.: 99–101 C b.p.: 200 C MW: 152.15 Mol. formula: C8H8O3

Synonyms: O-anisyl acid, o-methoxybenzoic acid, salicylic acid methyl ether, 2-methxy benzoic acid, 2-anisic acid, etc. Appearance: White to off-white crystalline powder Purity: 98–99% Manufacturing process: Several commercially proven processes exist for o-anisic acid. Briefly they are as follows: i.

Methylation of o-cresol to o-cresyl methyl ether and then oxidation by KMnO4

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ii.

Methylation of o-hydroxybenzoic acid (salicylic acid) using dimethyl sulfate.

Uses: O-anisic acid is used as an intermediate for dyes, photographic chemicals, medicine, and other organic chemical products. It is also used as an insect repellent and ovicide. Sometimes o-anisic acid is used as a substitute for p-anisic acid. Japan uses good quantities of the product. Global demand has been estimated at 100 tpa. 7.7. O-CRESYL ACETATE [46] CAS No. [533-18-6] b.p. : 208 C MW: 150.18 Mol. formula: C9H10O2

Synonym: O-tolyl acetate O-methyl phenyl acetate Liquid, nearly insoluble in cold water, soluble in hot water and organic solvents, combustible. O-cresyl acetate is made by acetylation of o-cresol as follows:

O-cresyl acetate has been widely used as a flavoring agent. No authentic data were available about the global demand. It is, however, believed that major manufacturers of p-cresyl acetate might be making o-cresyl acetate also as a flavor and fragrance compound. Global demand may not exceed 25–30 tpa.

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8.1. GENERAL The disinfectant, bactericidal and fungicidal properties of individual cresols and mixed cresol or cresylic acids had been well known for the last 60 years or so. So much so that within the recommended doses as prescribed by WHO cresols were used in the manufacture of carbolic soaps. Cresols were also used in place of phenol as disinfectant in domestic applications. They were also used as wood preservatives. As mentioned earlier para-chloro-meta-cresol is now one of the preferred preservatives for leather goods. However, it is not only the first generation derivatives of individual cresols but secondary and even tertiary derivatives that have proved to be very important plant growth regulators or agrochemicals apart from their uses as household insect and pest repellents. Synthetically made pyrethroids which are replacing more costly natural pyrethrum or pyrethrins are one such example. 123

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It may be recorded that the term agro-chemical would encompass in a broad sense acaricides, fungicides, herbicides, insecticides, rodenticides plant growth regulators, and others in the allied fields. Among all the cresol derivatives as feedstock for agrochemicals, m-cresol holds a pride of place as a number of synthetic pyrethroids and other pesticides=insecticides are made starting with m-cresol as the base product. DNOC starting with o-cresol is an important agro-chemical. p-Cresol (except its derivative—hydroxy benzaldehyde) has not been much used for synthetic agrochemicals. However, a lot of R&D work is undertaken in various laboratories in the world for making downstream agrochemicals starting with the industrial individual cresols. Some of the very important agrochemicals are discussed here in some detail. 8.1.1. Pyrethroids, Pyrethum and Pyrethrins [26,34] CAS No. [8003-34-7] Common names: pyrethrins, firmotox, pyrethrins and pyrethroids, chrysanthemates, pyrethrum, etc. Chemically, the field pyrethroids consist of hydroxy and non-hydroxy fatty acids, alkanes, carotenoids sterols and triterphenols, flavonoids, etc. Functionally, pyrethroids are a group of insect growth regulators that act as neurotoxins resisting the development of insect larvae. They are especially effective against insects that are destructive in the adult stage. They are considered non-toxic to animals and humans. Pyrethrum consists of dried flower heads of chrysanthemum. The plant is a native of Dalmatia (Yugoslavia-Balkans) and is now widely cultivated in Kenya, East Central Africa, Japan, Brazil, Ecuador, and India. Chrysanthemum flowers are extracted with an organic solvent and the crude extract is further extracted with methanol and then reextracted with normal hexane when the pyrethrum concentrate is formed. The concentrate predominantly consists of pyrethrins which are a mixture of esters of

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pyrethrim I, pyrethrin II, cinerine I, cinerine II, jasmoline I and jasmoline II [34]. Chemical structure of pyrethrin esters is as follows:

Pyrethrine I Pyrethrine II Cinerine I Cinerine II Jasmoline I Jasmoline II

R1 CH3 COOCH3 CH3 COOCH3 CH3 COOCH3

R2 –CH=CH2 –CH=CH –CH3 –CH3 –CH2–CH3 –CH2–CH3

All the esters are yellowish liquid and are unstable in alkalis. They are insoluble in water but soluble in all organic solvents including petroleum ether. CAS registry number of all the pyrethrum constituents is same. However, chemical formulae are some what different. For instance, pyrethrin I is C21H28O3, pyrethrim II is C22H28O5, cinerine I is C20H28O3, cinerine II is C21H28O5, etc. Pyrethrum flowers and pyrethrins are contact insecticides being quite harmless. Functionally, pyrethroids are synthetically made and have similar properties as natural pyrethrum and pyrethrins. They have the same CAS registry number as natural pyrethrum and pyrethins. As mentioned earlier, pyrethrum is an extract from chrysanthemum flowers which contains a mixture of natural compounds including pyrethrins. Pyrethrin powder has been used for many years as an insecticide in domestic applications. Compounds having similar structures and properties have now been synthesized as pyrethroids which are cheaper than natural pyrethrums and more potent. They are even more effective in treating sea lice infestations on solomon and other sea water fish.

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It is not yet fully understood why cypermethrin, a very important pyrethroid, is not toxic to the salmon or other sea water fish. Due to the instability of the natural pyrethrins and the necessity for several chemicals to overcome this synthetic pyrethroids are used as insecticidal agents. These include compounds such as deltamethin, permethin, cypermethrin and fenvalerate, and more recent products such as flucythrinate, fluvalinate, etc. The synthetic pyrethroids are more stable than the natural pyrethrins and equally or more potent pesticides. It is not surprising that in future synthetic pyrethroids will be of more interest than natural pyrethrum. It may also be emphasized that the use of pyrethroid insecticides is encouraged because so far they are considered non-toxic to humans. In 1998, over 500,000 pounds (230 mt) of pyrethroids were used commercially in California, USA. Not much was reported about any adverse effects on the workers using the pyrethroids. However, one school of thought was that pyrethroids were responsible for a number of occupational pesticide illness particularly for a longer exposure. No worker should be exposed for a longer period and a rotational policy should be observed. Metaphenoxy benzaldehyde is an essential building block for the synthesis of pyrethroids. Cypermethrin and fenavalerate are the two most widely known synthetic pyrethroids in India, China, Japan, and also in USA, Canada and Europe. Their uses are increasing steadily. Some wellknown pyrethroids are discussed here in detail.

8.1.1.1. Cypermethrin [26,27] Cypermethrin is the common name accepted by International Organization for Standardization (ISO) for R,S-a-Cyano3-phenoxy benzyl (IR,S)-cis, trans-3-(2,2-dichlorovinyl)-2, 2-dimethyl cyclopropane carboxylate. CAS No. [52315-07-8] Structural formula

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Mol. formula Mw m.p. b.p. Density d20 4

127

C22 H19 Cl2NO3 416.30 60–80 C 170–195 C 1.25

Solubility: Insoluble in water, soluble in methanol, acetone, xylene, methylene dichloride. Pure isomers of cypermethrin form colorless crystals. When mixed isomers are present, cypermethrin is a viscous semi-solid or a viscous, yellow liquid. Uses: Cypermethrin has both domestic and agricultural uses. It is a household insect and pest control chemical and widely used in stores, warehouses, industrial buildings, green-houses, laboratories, hospitals, etc. In the agricultural field, it is used to control many pests, including moth pests of cotton, fruit and vegetable crops. Cypermethrin is a moderately toxic material by thermal absorption or ingestion. It causes irritation to the skin and eyes. If exposed for a long period, it may affect the nervous system. Some of the major manufacturers are – – – – – –

ICI Agrochemicals Division, UK Sumitomo Chemicals Co. Ltd., Japan May & Baker, USA Rhone-Poulenc, France Mitsu Co. Ltd., India United Phosphorous, India

Global demand has been estimated at about 3000 tpa. Sumitomo, Japan and Mitsu, India, the two large manufacturers of metaphenoxybenzaldehyde, are also the two largest manufacturers of cypermethrin.

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As many patents for pyrethroids have expired between 1993 and 1996, the market is now opening up dramatically. 8.1.1.2. Fenvalerate [26,27] Fenvalerate is the accepted common name by the ISO for (RS) -a-cyano-3-phenoxy-benzyl (RS)-2-(4-chlorophenyl) 3-methyl butyrate. CAS No: [51630-58-1] Structural formula

Mol. formula Formula wt.

C25 H22 Cl NO3 419.90

The technical grade fenvalerate is a yellow-brown viscous liquid which may be partly crystallized at room temperature, and has a specific odor. d254 1.175 Solubility: Practically insoluble in water, soluble in acetone, chloroform, cyclohexanone, ethanol, methanol, xylene. Fenvalerate is relatively stable in acid media but not stable in alcohols. Synonyms and trade names: Belmark R, Ectrin, R, Extrin, Fenkil, Fenvalethrin, Sumicidin R, Sumifleece R, Sumifly R, Sumipower R, etc. Uses: It is a good contact and stomach insecticide for a wide range of pests including those resistant to organochlorine, organophosphorous and carbamate insecticides. It effectively controls flies, fleas, leaf eaters, caterpillars and other sucking insects. It is widely used in agriculture, horticulture, and forestry. Most of the manufacturers of metaphenoxybenzaldehyde do manufacture fenvalerate along with cypermethrin. Sumitomo Chemicals Co. Ltd., Japan and Mitsu Co. Ltd., India are the two major players. Currently

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1000–1500 tpa of fenvalerate are being produced globally. Japan and India would continue to be the two primary sources of this material. 8.1.1.3. Fluvalinate [14,26,35] CAS No. [102851-06-9]

Cyano(3-phenoxy phenyl) methyl N-[2 chloro-4-(trifluoromethyl) Phenyl]-d-Valenate

Chemical formula Formula wt Appearance

C26H22ClF3N2O3 502.93 Viscous yellowish Oily liquid

Uses: An insecticide=acaricide; control of a wide range of insects and spider mites on indoor and outdoor ornamentals, apples, pears, peaches, cereals, vegetables, cotton, tobacco, etc. Manufacturing process: The insecticide belongs to the family of trifluoromethyl, pyrethroids. Made from m-phenoxy benzaldehyde. Only known manufacturer is Sandoz (now Novratis) whose trade names are Mavrik, Spur, Klartan, etc. Apparently, some 250–300 tpa of the material are produced. 8.2. FENITROTHION [14,26] Fenitrothion, an organophosphate=contact insecticide, is chemically known as 0,0-dimethyl 0-(4-nitro-m-tolyl) phosphorothioate, or 0-0-dimethyl-0-3-methyl-4-nitrophenol phospherothioate. CAS No. [122-14-5] Structural formula

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Mol. formula Mw Density d20 4 m. p. b. p.

C9H12NO5PS 277.25 1.3227 0.3 C 140–145 C at 0.1 mm Hg

Solubility: Insoluble in water (14 mg=L), soluble in organic solvents such as acetone, alcohol, benzene, toluene, dichloromethane, etc. Also soluble in xylenes, ketones, esters, etc. Appearance: Technical grade is a yellowish brown liquid having an unpleasant odor. Fenitrothion is one of the very important outlets for mcresol and is widely used throughout the world. As stated in an earlier chapter, m-cresol on nitration gives 4-nitro-m-cresol which is then converted to fenitrothion. Important manufacturers of fenitrothion are – – – – –

Sumitomo Chemical Co. Ltd., Japan Cheminova Agro A=S, Denmark Jin Hung Fine Chemicals Co. Ltd., Korea Rallis India, India Bayer AG, Germany

The product is marketed under various trade names such as Folithion (Bayer AG) Sumithion (Sumitomo Chemicals) 9 Agrothion > > = Dicofen Various marketing companies Metathion > > ; Verthion

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Fenitrothion is mainly used in agriculture for controlling chewing and sucking insects on rice, cereals, fruits, vegetables, stored grains, cotton and in forest areas. It is also used for the control of flies, mosquitoes and cockroaches in public health programmes and or indoor use (WHO, 1992). Fenitrothion enters the air through volatilization from contaminated surfaces and may drift beyond the target during spraying. Fenitrothion is stable in water only in the absence of sunlight or microbial contamination. In soil, biodegradation is the primary route of degradation though photolysis may also play a role. On the basis of testing in an adequate range of studies, it was concluded that fenitrothion is unlikely to be genotoxic. It was also concluded that fenitrothion is unlikely to pose a carcinogenetic risk to humans. It has been estimated that the global demand of fenitrothion is to the tune of 2000– 2500 tpa. Growth of late has been somewhat stagnant. 8.3. ACIFLUORFEN-SODIUM [26] CAS No. [62476-59-9] Synonyms: Sodium 5-(2-chloro-a, a, a-trifluoro-p-tolyloxy) 2-nitrobenzoate, Sodium-5[2 chloro-4-(trifluoromethyl) phenoxy] 2 nitrobenzoate

Chemical formula Formula wt. White powder m.p.

C14H6Cl F3N Na O5 383.7 124–125 C

Uses: Selective contact herbicide, absorbed by the foliage and roots with negligible translocation. Sunlight enhances

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the activity. Used primarily for pre- and post-emergence control of many broad-leaved weeds and some grasses in peanuts, soyabeans, rice and wheat, etc. Solubility in water at 25 C, in methanol, ethanol, ethyl acetate, chloroform CCl4, etc. Severe eye irritant though non-corrosive. Acute oral LD50 for rats, rabbits, etc. This herbicide can be manufactured from m-cresol though one or two manufacturers use alternate route without use of m-cresol. BASF, Rohm and Hass and Rhone-Poulenc (now Mobile Chemical Co.) are manufacturing acifluorfen. Global demand is estimated to the tune of 750 tpa. 8.4. TOLCLOFOS-METHYL [26] This is apparently the only agrochemical manufactured from p-cresol. Two process routes have been established, both using 2,6-dichloro-p-cresol as a key intermediate. Sumitomo Chemical Co. Ltd., Japan is perhaps the only manufacturer of tolclofos-methyl with an annual production of 500 tons.

CAS No. m.p. Synonyms

Appearance Trade names

[57018-04-9] 78–80 C 0–2,6-dichloro-p-tolyl 0,0-dimethyl phosphorothionate 0,(2,6-dichloro-4-methyl-phenyl) 0,0 dimethyl phosphoro thioate Colorless crystals Rizolex, Risolex, S-3349 (all of Sumitomo)

Uses: Control of soil borne diseases caused by Rhizoctonia, Selerotium and Typhula SPP on Potatoes, Sugar-beet, cotton, peanuts, vegetables, etc. [26].

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8.5. DNOC [26,35]

Synonyms:

4,6-dinitro-ortho-cresol 2-methyl-4,6 dinitro phenol CAS No. [534-52-1]

DNOC as a basic o-cresol derivative has been discussed in an earlier chapter. Some aspects of this multipurpose agrochemical, an insecticide, an acaricide, a herbicide and also a fungicide, are discussed here in some detail. Trade names

Manufacturers

Antinonnin Selinor Entar-A Trifina ChemSect Marks Pennwalt Holland Tifa, FMC FMC

(Bayer) (Bayer) (Sandoz) (Pennwalt Holland) (Tifo)

The product, having a melting point of 86 C when pure, is yellowish crystalline powder and is explosive when dry. DNOC is corrosive to metals in presence of water. Mode of action: Non-systematic insecticide and acaricide with contact and stomach action. Uses: Control of over wintering of aphids, psyllids, ermine moths, winter moths, scale insects and spider mites on prone fruit, control on insects in vines, annual broadleaved weeds in cereals, maize, legumes, etc. Phytotoxicity: Very phytotoxic Formulations: Suspension concentrate, emulsifyable concentrate, wettable powder mixed formulations; with Petroleum oils.

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Toxicity: (i) to mammals Acute oral LD50 for rats 25–40, mice 24 Goats, 100 mg=kg (ii) to fish LD50 for carp 6–13 mg=L 8.6. BROMOXYLIN [26,35]

Synonyms:

3,5-dibromo-4-hydroxy benzonitrile 3,5-dibromo-4-hydroxy phenyl cyanide CAS No. Chemical formula Formula wt. Melting pt. Appearance Trade marks

[1689-84-5] C6H2Br2CNOH or C7H3Br2NO 276.93 194.195 C (sublimes at 135 C=0.15 mm Hg Pres) Colorless crystals Bucktril May & Baker MB 10064 Brominil Amchem Products, Inc. Bromotril (Makkhteshhim-Agan)

Manufacturers: Union Carbide (now closed), May & Baker, Rhone-Poulenc Marks, Makhteshim-Agan Solubility: Practically insoluble in water soluble in xylenes, methanol, ethanol acetone, etc. Uses: Bromoxylin is a selective contact herbicide with limited systematic activity for post-emergence control of annual broad-leaved weeds, onions, garlic, mint, turf, etc. Manufacturing processes: Bromoxylin may be made by i.

bromination of 4-hydroxy benzaldehyde followed by reaction with hydroxylamine hydrochloride

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ii. by the action of sodium hypobromite as the brominating agent on 4-hydroxy benzonitrile The first process is discussed below: i.

ii.

iii.

Bromoxyline, a popular herbicide, is sold sometimes as bromoxylin octanoate made by reacting bromoxylin with

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octanoic acid or octanoyl chloride in the presence of pyridine

Formulation Emulsifiable concentrate types Suspension concentrate Compatible with many other herbicides Toxicity to mammals: Acute oral LD50 for rats 190 mg=kg rabbits 260 mg=kg non-irritating to skin (rabbits) Toxicity to birds: Acute oral LD50 50 mg=kg for pheasants, ducks 200 mg=kg Toxicity to fish: LC50 (48 hr) for harlequin fish 5 mg=L. Non-toxic to bees.

8.7. IOXYNIL [26,35]

Synonyms: 3,5-di-ido 4-hydroxy-benzonitrile 3,5-di-iodo 4-hydroxy phenyl cyanide CAS No. Chemical formula Formula wt. m.p. Trade names

Manufacturers

[1689-83-4] C7H3I2NO 370.92 212–213 C Sublimes at 140 C=0.1 mm Hg Bentrol (Union Carbide, now not available) Mate (May & Baker) Totril (May & Baker) Intril (Makhteshim-Agan) Trevespan (Celamerck) Union Carbide (now closed)

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May & Baker Makhteshim-Agan Marks

Solubility: Practically insoluble in water, soluble in organic solvents, xylene, ethanol, CCl4 etc. Manufacturing process: May be made by starting with 4-hydroxy benzaldehyde which is iodinated and then converted to the nitrile, or is first converted to the nitrile using hydroxyl amine hydrochloride and then iodinated with iodine monochloride. As in the case of bromoxylin, ioxylin is also converted to ioxyline octanoate, a multipurpose herbicide, by reacting with octanoic acid

May & Baker is a major player of ioxynil and its octanoate. Uses: Post-emergence control of a wide range of annual broad-leaved weeds, onion, garlic, luks, sugar cane, foarge grasses. Often used in combination with bromoxylin and other herbicides. Similar formulations as bromoxylin are used. Toxicity levels are also more or less same. 8.7.1. Global Marketing Scenario Apparently both bromoxylin and ioxylin and their octanoate esters may look simple to make and market. However, only a very few multinational companies such as May & Baker, RhonePoulenc, BASF, Makhteshim-Agan are the key players. Collectively they produce approximately 1000 tpa of the material. Apparently, there is no manufacturer of bromoxylin= ioxylin in Asia including India. The product bromoxylin is

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known to one agrochemical major in India, namely, Gharda Chemicals. They have been conducting R&D work in this field for quite some time. However, details are not known. Non-availability of p-hydroxy benzaldehyde in India is a major reason. China produces good quantities of p-hydrobenzaldehyde as a by-product during production of salicylaldehyde. China in future may turn out to be a major producer of both bromoxylin and ioxylin. 8.8. MECOPROP (MCPP) [26,35]

2-(4 Chloro-2 methyl phenoxy) propionic acid CAS No. [93-65-2] Cl C6H3(CH3) O CH CH3COOH Trade names: RD-4953 (Boots Co. Ltd.) ISO-Cornox (Boots Co. Ltd.) Mecopar Meccoturf Compitox Clovotox Herrifex

Manufacturing process: made by condensation of 2 chloropropionic acid with 4-chloro-o-cresol (PCOC). The later product PCOC has been discussed in some detail in Chapter 7.

2-Chloro propionic acid

PCOC

Uses: A multipurpose herbicide.

MCPP

þ HCl

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Properties: Solid m.p. 93–94 C, Insoluble in water, Soluble in alcohol, acetone and ether Toxicity: Toxic by ingestion and inhalation, irritant to skin and eyes Use: A herbicide 8.9. MCPA [26,35]

CAS No.

Chemical formula:

Trade names:

(94-74-6) (4-chloro-2-methyl phenoxy) acetic acid (4-chloro-o-toloxy) acetic acid 2-methyl-4-chloro-phenoxy acetic acid C6H3ClOCH3CH2COOH or C9H9ClO3 mol.wt. 200.62 Agritox, Agroxone, Cornox, methoxone

Properties: White crystalline solid, m.p. 118–120 C, practically insoluble in water. Toxicity: LD50 orally in rats 700 mg=kg, Sodium salt [3653-48.3] Chiptex, C9 8HCl NaO3, mol. wt. 222.60, Very soluble in water. Uses: Herbicide Among the pioneering companies were ICI, Foster, Diamond alkali, etc. Main raw material: m-cresol 8.10. 8.10.1.

OTHER HERBICIDE=INSECTICIDES FROM M-CRESOL [14] Clomeprop

This herbicide, used in paddy rice, is manufactured from m-cresol through chlorination to 2,4-dichloro-m-cresol.

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Originally introduced by Mitsubishi Petrochemical Co., it is now produced by Rhone-Poulenc Yuka Agro in Japan. 8.10.2.

Metolcarb (MTMC)

This insecticide originally introduced by Nihon Nohyaku Co. is now manufactured by Sumitomo Chemical Co., Japan and possibly by Jin Hung Fine Chemicals Co. Ltd., Korea. m-Cresol is the key raw material for this carbamate insecticide, USA and some countries of Europe would prefer to import this insecticide from Japan=Korea. Global demand has stagnated.

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9 Cresol Derivatives—Building Blocks for Pharmaceuticals

9.1. GENERAL Phenol and cresol derivatives, particularly p-cresol derivatives, have provided important building blocks for the pharmaceutical industry. There are a number of pharmaceutical compounds derived from p-cresol derivatives: dilitiazem hydrochloride, the largest one. Trimethoprim, Nadifloxacin, and sulmetozin are other prominent examples. Para-anisic aldehyde and p-anisic alcohol are two important p-cresol derivatives which have provided critical feedstocks for some of the important bulk drugs. Trimethoprim made from 3,4,5-trimethoxybenzaldehyde is another example. p-Cresol has already replaced gallic acid as the preferred starting material for 3,4,5-trimethoxy benzaldehyde. As more R&D work is undertaken, there will no doubt emerge more finished pharmaceutical items not only from p-cresol but also from o-cresol and m-cresol. Growth of meta-cresol has indeed been remarkable after the process was commercialized for 141

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conversion of m-cresol to 2,3,6-trimethyl phenol for ultimate synthesis of vitamin E, the most potent a-tocopherol having the highest growth rate. 9.2. DILITIAZEM HYDROCHLORIDE [36,37] The popularly known bulk drug dilitiazem, manufactured and marketed as dilitiazem hydrochloride, is having the following important properties. Structural formula: CAS no: [33286-22-5] Mol. formula: C22H27CIN2O4S MW: 450.98 Pale yellow crystals

Chemically dilitiazem hydrochloride is 1,5-benzothiazepin-4(5H)-one, 3-(acetyloxy)-5-[2-(dimethylamino) ethyl]-2, 3-dihydro-2(4-methoxyphenyl)-mono hydrochloride, (þ)-cis. The finished product is a white to off-white crystalline powder with a bitter taste. It is soluble in water, methanol, and chloroform. Drug formulations of dilitiazem hydrochloride also contain microcrystalline cellulose NF, sucrose stearate, eudragit, talc USP, magnesium stearate NF, hydroxy-propyl methyl cellulose USP, titanium dioxide USP, polysorbate NF, gelatin USP, etc. Dilitiazem hydrochloride is a calcium antagonist hypertension drug. It produces its antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in perepheral vascular resistance. The magnitude of blood pressure reduction is related to the degree of hypertension. Dilitiazem was introduced in early 1970s. Though the bulk drug has been made only by three or four companies in the world, the formulated product is sold in many countries

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under various brand names. Some of the popular brand names are Cardizen, Dilzem, Tildiem, Herbusser, Aetiazem, Angizem, Calcicard, Tiazac, etc. The most critical raw material for the production of Dilitiazem is p-anisic aldehyde. Approximately, 2.3–2.4 kg of p-anisic aldehyde is required per kg of dilitiazem. Other important raw materials are D(þ) alpha phenyl ethylamine (0.35 kg=kg), 2-aminothiophenol (1.9 kg=kg), methyl chloroacetate (1.9 kg=kg), sodium methoxide (1.6 kg=kg), chloroform (5.5 kg=kg), methanol (9 kg=kg), isopropyl alcohol (5 kg=kg), etc. Technology for production of dilitiazem from p-anisic aldehyde was earlier patented in the early 1970s. However, patent rights had since expired and it is now produced in quite a few countries. In fact, now, improved technologies are available in Japan, India, Holland, Israel, and other countries. Global production of dilitiazem has been currently estimated at 1000 tpa. Production has been estimated as follows: DSP, Andino (Holland) Japan India Israel

350–400 tpa 150–200 tpa 350–400 tpa 100 tpa

Considering the importance of the drug, it will be safe to assume that there will be a growth of 7–8% during the next five years. It is interesting to note that India is currently the largest manufacturer of p-anisic aldehyde and is capable of meeting the total demand of dilitiazem since a number of Indian companies have established dilitiazem producing facilities. For instance, Dr. Reddy’s Laboratories, Nicholas Piramal Ltd., Divi’s Laboratories and Natco Pharma, all based in Hyderabad, Andhra Pradesh, India have modern technologies for production of dilitiazem, and they are collectively capable of producing 1000 tpa of dilitiazem. However, actual production has been much less. The scenario may change if one or two global majors decide to close down their production and decide to source the material from India.

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9.3. TRIMETHOPRIM [36,37] CAS no: [738-70-5] Mol. formula: C14H18N4O3 MW: 290.32 m.p.: 196–202 C

Other names: 2,4-Diamino-5-(3,4,5-trimethoxybenzyl) Pyrimidine, 2,4-Diamino-5-(3,4,50 -trimethoxybenzyl) pyrimidine) Solubility: Very soluble in HCl, slightly soluble in water, sparingly soluble in alkalies. Trimethoprim, a wide spectrum drug, is closely related to a number of antimalarials but it does not have good antimalarial activity by itself. However, it is a potent antibacterial agent. Earlier this drug was introduced in combination with sulfamethoxazole, but it is now available as a single agent. It was widely used for urinary tract infections as well as for acute otitis media, menigococcal infections, etc. The major raw material for synthesis of trimethoprim is 3,4,5-trimethoxy benzaldehyde. Other raw materials are b-methoxy propionitrile and sodium guanidine (guanidine nitrate). Synthesis of trimethoprim from 3,4,5-TMBA based on the conventional process would proceed as follows: 1. Bishomologation of the benzaldehyde (by reduction to the alcohol, conversion to the chloride and then malonic ester CH2(COOC2H5)2 synthesis to hydrocinnamic acid.

2. Formylation with ethyl formate HCOOC2H5 and base gives hydroxy methylene derivative. 3. Condensation of that intermediate with guanidine (H2N)2 C ¼ NH gives pyrimidine.

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4. The hydroxy group is then converted to the amine by successive treatment with POCl3 and NH3. The conventional technology for synthesis of trimethoprim from 3,4,5-TMBA was introduced as early as 1970; USA, Canada, countries of W. Europe like UK, Germany, France, Switzerland, Spain, Denmark, Finland, etc. and also India, China and Japan in Asia were manufacturing this bulk drug. Since then major improvements have taken place in the technology front particularly in China and India where this drug is still very popular. For instance, considerable work has been carried out by the Department of Energy Utilization and Chemical Engineering, China University of Mining and Technology. They have reported that efficient synthesis of trimethoprim from 3,4,5-TMBA was accomplished by condensation with methanolic sodium methoxide, methanol and acrylonitrile via prior base-catalyzed 1,3-prototropic isomerization of cinnamonitrile converted into the enol ether, followed by addition with methanol at 90 C and cyclocondensation directly with guanidine in DMSO at 110 C with the removal of methanol. Apparently, trimethoprim has reached the top level of its life cycle and quite expectedly the global demand during the next decade will remain somewhat stagnant. Most countries of N. America and Europe are now importing the bulk drug mostly from India and China. The global demand of the bulk drug is estimated at 500 tpa. Almost 300 tpa is made in India. In India, the formulated drug is marketed under different brand names by Burrow’s Welcome, Searle India (now known as RPG Life Sciences) among others. The bulk drug is made by Inventaa, Hyderabad and Alpha Drugs, Bombay. Zora Pharma, an Ahmedabad-based company, had facilities for manufacture of both 3,4,5-TMBA

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and trimethoprim. They have recently closed down their facilities and are in the process of selling out their facilities. In fact, there are at least 10 companies in India having expertise and know-how for making trimethoprim from 3,4,5-TMBA; Indian companies will continue to play a key role in supply of trimethoprim to the world market.

9.4. NADIFLOXACIN [44] CAS no: [124858-35-1] Mol. formula: C19H21FN2O4 m.w.: 360.39 m.p.: 245–247 C

9-fluoro-6, 7 dihydro-8-(4-hydroxy-1-piperidinyl)-5-methyl1-oxo-1H, 5H-benzo [ij] quinolizine-2 carboxylic acid Colorless prisms from ethanol–water solution. LD50 male, female mice and rates (mg=kg). Fluorinated quinolone, antibacterial widely used in the treatment of acne. Manufactured from p-cresol via p-anisic aldehyde via p-anisyl alcohol. The drug was introduced only 7–8 years ago and is covered under patent rights. Otsuka Chemicals, Japan is a major manufacturer of the drug and they import substantial quantities of p-anisyl alcohol from India. US Patent 4399, 134 (1982, 1983) and Belgium Patent 891, 046 both are held by Otsuka. Currently 50–60 tpa of nadifloxacin is manufactured by Otsuka. It is expected that once patent rights expire, there will be increase in production as there is good demand in Indian subcontinent and south-east Asia. Countries in Europe and USA would perhaps like to source the material from Japan and India rather than manufacture the same.

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9.5. VITAMIN E Any of the group of related substances (a-, b-, g, -d tocopherols) constitutes vitamin E which is a natural antioxidant. The a-form is the most potent having the following structural formula and properties [38]:

CAS no: [59-02-9] Mol. formula: C29H50O2 MW: 430.72 m.p.: 45.6 C bp: 210–220 C=0.1 mm Hg d420: 0.950 nD20: 1.5050

b- and g-Tocopherols C28 H48O2, each contain one fewer methyl groups than a-tocopherols; in d-tocopherols both the methyl groups are missing. a-Tocopherol, i.e., vitamin E, is being produced from 2,3,6-trimethyl phenol obtained from m-cresol or 2,6-xylenols as explained in Chapter 6. 2,3,6-Trimethyl phenol is oxidized to trimethyl quinone which is catalytically reduced to trimethyl hydroquinone. Phytol, CAS no. [150–86-7] C20H40O, an alcohol obtained by the decomposition of chlorophyll is an odorless liquid, BP 202–204 C=10 mm Hg and has been used in the synthesis of vitamin E. On reaction with trimethyl hydroquinone phytol is converted to a-tocopherol, etc. a-Tocopherol, the most potent vitamin E, has been used in medicine, nutrition, antioxidants for fats, animal feed additive. Also known as dl-a-tocopherol, or dl-2,5,7,8-tetramethyl2-(40 ,80 ,120 -trimethyl tridecyl)-6-chromanol, a-tocopherol is a clear yellow, viscous oil.

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a-Tocopherol is a natural biological antioxidant present in many vegetable oils as follows [39]: quantities are all in mg=kg. Wheat germ oil Soybean oil Sunflower oil Walnut Peanut Coconut Palm oil Olive Cotton seed

560–1200 306–120 350–700 560 80–330 5–10 180–260 1–240 40–560

Approximate a-tocopherol content of selected foods of animal origin (mg=kg) is as follows [39]: Beef Chicken Pork

6 4 5

Hard Cod Shrimp

12 2 7

Egg Buffer Milk

5–11 10–33 0.2–1.1

Vitamin E obtained from natural products is, however, much costlier than the one synthesized from 2,3,6-trimethyl phenol, via 2,3,6-trimethyl hydroquinone and phytol. Vitamin E is used in a variety of applications of which the main ones are enhancement of animal feeds, vitamin supplements in humans, polyolefin antioxidant, food additives, cosmetics and toiletries and in medicinal applications. More uses of vitamin E are coming to the limelight and uses are multiplying after availability of the synthetic product. In fact, it is the fastest growing vitamin in the world: – Vitamin E is an extraordinary antioxidant. – Vitamin E keeps your skin youthful by protecting against UV-radiation. – Vitamin E relieves symptoms of arthritis and other inflammatory diseases. – Vitamin E reduces the risk of prostate cancer in men and can inhibit the growth of breast cancer cells – Vitamin E as food supplements substantially reduces risk of heart attack and stroke. – Vitamin E is an antiaging antioxidant, reverses the age related, ‘‘slump’’ in immune function and keeps

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your brain cells from aging, it delays the onset of Alzheimer’s disease [40]. Global demand of vitamin E has been growing and growing and has been projected at about 800–1000 tpa by end of 2004.

9.6. PENTAZOCINE [44] (2R, 6R, 11R-) rel-1,2,3,4,5-6-hexahydro-6,11-dimethyl-3(3-methyl, 2butenyl)-2,6-methano-3 benzazocin-8-ol 2 dimethyl allyl-5,9-dimethyl-20 -hydroxy benzomorphan 3-(3-methyl-2 butenyl)-1,2,3,4,5,6 hexahydro 6,11dimethyl-2,6-methano-3- benzazocin-8-ol.

CAS no: [359-83-1] Mol. formula: C19H27NO m.w.: 285.42 m.p.: 145.4–147.2 C

Mixed opioid agonist–antagonist Crystals from methanol þ Water LD50 in male rats 175 36 mg=kg This is a controlled substance. Theraputic category humans (narcotic). Theraputic category veterinary (narcotic). Preparation: from p-cresol via p-anisic aldehyde via panisic alcohol. BE Patent No. 611000 to Sterling drug since expired. India has become a large source of this drug. M=s Ranbaxy drug Co., a global leader in the field of pharmaceuticals, are a large manufacturer of this drug. They have been consuming good quantities of p-anisyl alcohol from Atul. One or two smaller players have also entered the field.

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10 Flavors, Fragrances, and Food Additives from Cresol Derivatives

10.1.

GENERAL

Since the dawn of civilization, say, 5000 years ago perfumes and perfumery chemicals encompassing flavors and fragrances and even pleasant food additives attracted attention in India and were used in temples, religious rites and even for personal sophistication. The earliest reference to such materials was to be found in the Vedas, say, during 2000– 2500 BC. In particular, sandalwood, camphor, saffron, etc. were mentioned in connection with certain rites. Perfume takes its name from the Latin word perfumare (to fill with smoke), since in its original form it was incense burned in Egyptian temples. Similarly China was a pioneering country in the field of flavors and fragrances since they were known to the Chinese some 3000 years ago. These were all natural products and perhaps they became popular in Europe at a later date. It is only during the last few decades that synthetic perfumery products (flavors, fragrances, and 151

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food additives) became well known and grew rapidly. A perfumery chemical that includes both flavors and fragrances is usually defined as a mixture of pleasantly odorous substances incorporated in a suitable vehicle (usually highly refined ethyl alcohol). Till about 100 years ago practically all the products used as perfumes were of natural origin. Mother nature is the best known organic chemist and was lavish in creating hundreds of plants, herbs, flowery plants, etc. in all parts of the world. Through ages of scientific research men learned the techniques of analysis and were more or less successful in finding out the ingredients that these perfumes consisted of. Man learned to synthesize the natural ingredients causing the fragrance and since has made tremendous progress in creating thousands of molecules in expanding the kingdom of flavors and fragrances. Man also started finding the correct blend of the ingredients to create a perfect artificial perfume. In some cases, synthetically prepared blends of perfumes were even better than those procured from natural sources since impurities present in natural perfumes could be eliminated.

10.2.

ESSENTIAL OILS

Various oils present in natural extracts have been classified as fixed oils or high boiling oils and essential or volatile oils. Very popular fixed oils are neem oils (nonedible), coconut, ground nut, soya, Sunflower, mustard etc. oils (edible). Some of the popular essential oils are rose oil, eucalyptus, lemon grass, jasmine, etc. oils of fragrance grade and cumin, coriander, cardamom, clove etc. of flavor grades. Essential oils or volatile oils are useful for their fixative properties as well as their odor. Among the fixative essential oils are clary, sage, ventiver, Patchouli orris, and sandalwood, etc. Usually, they have low boiling points not more than 285–290 C. Many of the naturally derived essential oils have been used in aromatherapy and in the manufacture of health products, cosmetics, and perfumes. Just as natural essential oils,

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synthetic bends of various perfumery chemicals are today commercially made for general use as flavors and fragrances. Many components of natural essential oils are cresols or allied products. Some of these essentials oils giving their therapeutic actions and principal constituents are outlined here vide Table 10.1. Most of these oils are produced commercially although some of them are little known. Attempts have been also made by the global key players to produce matching synthetic blends from components made by organic chemical synthesis. Needless to emphasize that synthetically made essential oils are much cheaper than those obtained from natural sources. There are more than 150 natural essential oils and natural extracts from which a large number of important fine chemicals in the field of flavor and fragrances have been extracted, isolated, and sold as blends in predetermined quantities. Table 10.1 gives some details of only those natural substances containing cresols, precursors such as cymenes, derivatives such as thymol, menthol, and other allied products. Some of the widely used synthetic fixatives are amyl benzoate, phenethyl, phenyl acetate, cinnamic alcohol esters, acetophenone, musk ambrette, musk ketone, musk xylols, vanillin, coumarin, etc. [41]. The organic chemical compounds occurring in essential oils may be classified as follows: 1. Esters of benzoic, acetic, salicyclic, and cinnamic acids. 2. Alcohols such as linalool, geraniol, terpenol, menthol, borneol, etc. 3. Aldehydes: vanillin, p-anisic aldehyde, benzaldehyde, cinnamic aldehyde, etc. 4. Phenols: eugenol, thymol, carvacrol. 5. Ketones: carvone, menthone, camphor, methyl nonyl ketone, etc. 6. Esters: cineole, encalyptole, anethole, etc. 7. Lactone: coumarin 8. Terpenes: camphene, pinene, limonene, etc. 9. Hydrocarbons: cumene, cymene, styrene, etc. [41].

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Table 10.1 Essential Oils Obtained from Natural Sources (containing Cresols or Allied Products) Sr. no.

Latin name

Common name

1

Acacia dealbata

Mimosa

2

Alpinia Galangal officinarum

3

Anethum gravolens

Dill

4

Anthrisens cerefolium

Chervil

5

Arnica montana

Arnica

6

Asarum canadense

Snakeroot

Therapeutic uses Antiseptic, astringent

Principal constituents Mainly hydrocarbons, palmic aldehyde, anisic acid, acetic acid, and phenols Pinene, cineol, eugenol, and sesquiterpenes

Antiseptic, bactericidal, diaphoretic, stimulant, stomachic Carvone (30–60%) Antispasmodic, limonene, eugenol, bactericidal, pinene, etc. carminative, digestive, stimulant, hypotensive, stomachic Mainly methyl Antiseptic, chavicol, 1-allylcarminative, 2,4-methoxydepurative, benzene, and diaphoretic, anethole, etc. digestive, diuretic, stimulant, stomachic, tonic Anti-inflammatory, Thymohydro-quinone stimulant, dimethyl ether, vulnerary isobutyric ester of pheorol, etc. Anti-inflammatory, Pinene, terpinol, euginol, methyl antispasmodic, euginol, etc. carminative, diuretic, diasphoretic, expectorant, stimulant, stomachic (Continued)

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Table 10.1 (Continued ) Sr. no.

Latin name

Common name

7 Betula alba

White birch

8 Betula lenta

Sweet birch

9 Boronia Boronia megastigma

10 Boswellia carteri

Frankin cense

11 Cananga odorate var. genuine

Ylang ylang

12 Carum carvi

Caraway

Therapeutic uses

Principal constituents

Anti-inflammatory, 1. Mainly betulenol and other antiseptic, sesquiter penes cholagogue, 2. In the tar oil; diaphoretic, phenol, cresol, diuretic, xylenol, guaicol, febrifuge, creosol, tonic pyrocatechol, etc. Almost entirely Analgesic, antimethyl salicylate inflammatory, (98%) antipyretic, antiseptic, astringent, diuretic, tonic Aroma therapy, Notably ionone, (Aromatic) also eugenol, triacontane, phenols, ethyl alcohol, etc. Anti-inflammatory, Pinene, dipentene, cymene, terpinene, antiseptic, octyl acetate, astringent, octanol, etc. digestive, expectorant, sedative, tonic, etc. Methyl benzoate, Aphrodisac, methyl salicylate, antidepressant, eugenol, benzyl anti-infectious, acetate, terpenes, antiseptic, pinene, pararegulator, sedative, tonic, etc. cresol, etc. Mainly carvone Antihistaminic, and limonene antimicrobial, with carveol, antiseptic, pinene, etc. astringent, expectorant, larvicidal, stimulant, stomachic, tonic, etc. (Continued)

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Table 10.1 (Continued ) Sr. no.

Latin name

Common name

13 Chenopodium Worm seed ambrosio dies var. anthelminticum 14 Cinnamomum Camphor camphora

15 Cinnamomum Cassia cassia

16 Cinnamomum Cinnamon zeylanicum

17 Citrus Lime aurantifolia

Therapeutic uses

Principal constituents

Ascaridole, Anthelmintic, cymere, limonene, antirheumatic, turpinene, etc. antispasmodic, expectorant, etc. Anti-inflammatory, White camphor contains mainly antiseptic, cineol, pinene, antiviral, terpineol, bactericidal, menthol, counter thymol, etc. irritant diuretic, etc. Leaf and lark oil Antidiarrheal, contains mainly antiemetic, cinnemic antimicrobial, aldehyde, astringent, etc. methyl eugenol, salicylaldehyde, and methyl salicylaldehyde 1. Leaf—eugenol, Anthelmintic, eugenol antidiarrheal, acetate, antidote, cinnamal (to poison) dehyde, etc. antimicrobial, 2. Bark—cinnamalantiseptic, dehyde, digestive, eugenol, stimulant cymene, stomachic, pinene, etc. cineol, etc. Limonene, Antirheumatic, pinenes, citral, antiseptic, cymene, cineols, antiviral, etc. bactericidal, restorative, tonic, etc. (Continued)

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Table 10.1 (Continued ) Sr. no.

Latin name

Common name

Bitter 18 Citrons orange aurantium var. amara

19 Coriandrum sativum

Coriander

20 Croton eleuteria

Cascarilla bark

21 Cuminum cyminum

Cumin

22 Cymbopogone Lemon citratus grass

23 Dipteryx odorata

Tonka

24 Dryobalanops Borneol aromatica

Therapeutic uses Anti-inflammatory, antiseptic, astringent, bactericidal, fungicidal, sedative (mild) stomachic, tonic Analgesic, aphrodisiac, antioxidant, antirheumatic, bactericidal, digestive, fungicidal, etc. Astringent, anti microbial, antiseptic, digestive, expectorant, tonic etc. Antioxidant, antiseptic, antispasmodic, antitoxic, bactericidal, etc. Analgesic, antidepressant, antimicorbial, antiseptic, astringent, bactericidal, etc. Insecticidal, narcotic, tonic, etc. Analgesic, antidepressant, antiseptic, antispasmodic, antivirial stimulant, etc.

Principal constituents Over 90% monoterpenes, including camphene, pinene, cymene, etc. Mainly linalool, borneol, anethole, gerariol, etc.

Cymene, eugenol, limonene, terpineol, etc.

Cuminaldehyde, pinenes, cymene, limonene, etc.

Citral, geraniol, methyl eugenol, borneol, etc.

Coumarin and others D-borneol, terpenes, pinene, camphene, etc.

(Continued)

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Table 10.1 (Continued ) Sr. no.

Latin name

Common name

Therapeutic uses

Principal constituents

25 Eucalcyptus globulus var. globulus

Blue gumeucalyptus

Analgesic, antineuralgic, antirheumatic, anti viral, balsamic, deodorant, diuretic, etc.

Cineol, camphene, cymene, terpinene, etc.

26 Foeniculum vulgare

Fennel

27 Gaultheria Winter procumbens green

28 Hyacinthus orientalis

Hyacinth

29 Illicium verum

Star anise

30 Jasminum officinale

Jasmine

Aperitif, antiinflammatory, anti microbial, antiseptic, laxative, stimulant, etc. Analgesic, antiinflammatory, antirheumatic, astringent, etc. Antiseptic, balsamic, hypnotic, sedative, etc.

Anethole (50– 60%), anisic acid, anisic aldehyde, camphene, limonene, etc. Methyl salicylate, formaldehyde, etc.

Phenylethyl alcohol, benzaldehyde, cinnamaldehyde, benzyl alcohol, eugenol, methyl eugenol and hydroquinone, etc. Trans-anethole (80–90%) etc.

Antiseptic, carminative, insect repellent, stimulant, etc. Over one Analgesic, anti hundred depressant, anticonstituents inflammatory, including benzyl antiseptic, anti acetate, benzyl spasmodic, etc. alcohol, methyl anthranilate, cis-jasmone, etc.

(Continued)

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Table 10.1 (Continued ) Sr. no.

Latin name

Common name

31 Juniperus communis

Juniper

32 Juniperus oxycedrus

Cade

33 Liquid ambar Levant orientalis Styrax

34 Melaleuca Tea tree alternifolia

35 Mentha piperita

Peppermint

36 Mentha spicata

Searmint

Therapeutic uses Antirheumatic, antiseptic, astringent, antispasmodic, antitoxic, etc. Analgesic, antimicrobial, antiseptic, disinfectant, para, citicide, etc. Anti-inflammatory, antimicrobial, antiseptic, bactericidal, balsamic, expedorant, etc. Anti-infectious, antiinflammatory, antiseptic, antiviral, bactericidal, balsamic, expectorant, etc. Analgesic, antiinflammatory, anti microbial, antiviral, astringent, carminative, expectorant, etc. Anesthetic, antiseptic, antispasmodic, astringent, digestive, decongestant, etc.

Principal constituents Pinene, cymene, terpinene, camphene, etc.

p-Cresol, guaicol, cardinol, etc.

Mainly styrene with vanillin, cinnamic alcohol, phenyl propyl alcohol, etc.

Terpinene-4-ol, cineol, pinene, cymene turpinenes, etc.

Menthol (29–48%) menthone (20–31%) menthyl acetate, cineol, etc. L-carvone, menthone, menthol, cineol, etc.

(Continued)

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Table 10.1 (Continued ) Sr. no.

Latin name

Common name

37 Myristica fragrans

Nutmeg

38 Pimenta dioica

Allspice

39 Pimpinella anisum

Aniseed

40 Syzygium Clove aromaticum

41 Thymus vulgaris

Common thyme

42 Trachyspermum copticum

Ajowan

43 Vamilla planifolia

Vanilla

Therapeutic uses Analgesic, anti oxidant, anti rheumatic, antiseptic, antispasmodic, digestive, etc. Anesthetic, analgesic, antioxidant, antiseptic, etc. Antiseptic, antispasmodic, diuretic, etc. Anthelminthic, antibiotic, antirheumatic, antioxidant, antiseptic, etc. Antimicrobial, antirheumatic, antiseptic, antispasmodic, etc. Powerful antiseptic, germicide, carminative, etc. Balsamic

Principal constituents Monoterpenes camphene, cymene, geraniol, borneol, etc.

Mainly euginol, also methyl euginol, cineol, etc. Trans-anethole (75–90%) Eugenol, eugenol acetate, etc.

Thymol and carvacrol, cymene, turpinene, etc. Thymol, cymene, carvacrol, etc.

Vanillin (with over 150 other constituents) hydroxy benzaldehyde, eugenol, etc.

It is interesting to note that many key global players in the field of aroma chemicals have integrated essential oil complexes encompassing both natural extracts and those derived from organic chemical synthesis. For essential oils based on natural extracts, traditional processes such as steam

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distillation, enfluerage, maceration, expression, solvent extraction using conventional solvents such as normal hexane, acetone, and liquid carbon dioxide have been widely used for many key ingredients. The following chart shows the different ways in which aromatic materials are prepared [55].

Generally speaking the term, ‘‘essential oils’’ has been rather loosely applied to all aromatic products or extracts obtained from natural sources. This is not true since many fragrance products used by the perfumery industry are only partially composed of essential oils and they are produced by different methods as shown in the chart. Pure essential oils are extracted directly from different parts of plants, depending on the oil content and the type. Some are extracted from flowers, others from leaves, stems, the rind of fruit, berries, resin, or roots. As discussed above there are a variety of extraction methods, including distillation, expression (i.e., forcing out by pressure), solvent extraction, effleurage (the process of

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extraction of perfume by absorbing it from flowers in contact with cold fats), maceration (softening by steeping), the phytonic process, and supercritical CO2 expression. The extraction process used depends on the plant. For instance, lemon or lime, orange, grape fruit, and bergamot are usually expressed because the oils are present in the peels and the oils are released when the peel is ruptured. Others, that include lavender, clary sage, chamomile, and rose geranium, are usually distilled. Some flowers, like rose, for example, are distilled and solvent extracted, resulting in either a rose absolute or rose Otto. Extraction of pure essential oils such as rose or jasmine usually requires laboratory size equipment and considerably a large amount of material for a small yield of oil. However, this still makes the operation commercially very attractive considering that the final product is very costly. The process of enfleurage or extraction by absorbing the flowers in cold fats has been adopted for fragrant flowers of jasmine and tube rose which continue to manifest their characteristic fragrance even in plucked conditions. Solvent extraction will result in partial destruction of the fragrant manifestations. Fats, however, should be saturated and odorless to prevent contamination of the desired product. In the conventional process of extraction with volatile solvents, both concretes and alcohol soluble-absolutes having a near natural odor is obtained making the effleurage and maceration processes redundant. Solvent extraction is affected by using perfumery grade solvents like petroleum ether (boiling points 60–80 C), pure n-hexane, acetone, or even benzene. However, supercritical fluid extraction (SCFE) using carbon dioxide beyond the critical point and very high pressure is the most efficient and modern technology which is gradually becoming more popular for a multiproduct extraction system. SCFE is shortly a two-step process which uses a dense gas as a solvent such as carbon dioxide above its critical temperature (31 C) and critical pressure (74 bar) for extraction. Figure 10.1 briefly shows the process. The feed, generally ground solid, is charged into the extractor through a

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Figure 10.1 dioxide.

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Supercritical fluid extraction (SCFE) using carbon

high-pressure pump (100–350 bar). After extraction at reduced temperature and pressure conditions, the extract, i.e., the product precipitates out in the separator. The extract-free CO2 stream is recycled to the extractor. SCFE process has wide application areas in the fields of spice oils and oleoresins, herbal medicines, flavors and fragrances, food colors, and preservatives, etc. Work is being carried out in various academic and industrial R&D centers for reduction in capital cost for establishing SCFE facilities. By way of illustration one may cite the commendable work done by the Chemical Engineering Department of the Indian Institute of Technology, Bombay, India, where a state-of-the-art multipurpose SCFE pilot plant has been developed, designed and made operational during the last few years. It is claimed that based on their pioneering work, SCFE plants now cost 20–25% less than original conventional plants. It will be logical to presume that SCFE will not be limited to natural products extraction only. Gradually, the process will be extended to synthetic flavor and fragrance chemicals,

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food colors, pharmaceutical intermediates, where organic solvents are nowadays used for extraction purpose. Since supercritical CO2 is a dense fluid and inert, it will be found suitable for extraction purposes of synthetic aroma chemicals from a mixture of product and impurities. Field of the final product is higher and quality much better vis-a`-vis conventional extraction process. Use of SCFE for industrial chemicals separation and extraction will ensure a clean process and eco-friendly system. Use of SCFE for separation of m-cresol from a mixture of meta–para-cresols, mixture of xylenols, and cresol derivatives will no doubt open up new possibilities. It is heartening that a few companies are already working on this line, as is evident from proceedings of various international seminars and conferences during the last few years. Some of the high-value pharmaceutical produces are also being seriously persued. Many of the constituents of flavors and fragrances are based on p-cresol, m-cresol, o-cresol derivatives or their precursors, such as cymenes. This will be discussed shortly. The old order changeth, and in the industry of perfumery, flavors and fragrances, or aroma chemicals business there is a constant change. Many big aroma chemicals manufacturers have taken over the businesses of a large number of smaller aroma chemical companies. Briefly, we will discuss about the global aroma chemical business and the Indian scenario before discussing on the target topic, i.e., role of cresols and derivatives in flavor and fragrance and perhaps in the food additive industry.

10.3.

GLOBAL SCENARIO [42]

Though there are hundreds of companies engaged in the business of aroma chemicals, it is strange that the top eight full service companies—manufacturers in all three categories of flavors, fragrances, and aroma chemicals—enjoy two-thirds of the World’s total business. A few hundred small companies account for only one-third of the business. Table 10.2 shows the market shares of the top multinational companies in flavor, fragrance, and other aroma

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Table 10.2 Chemicals Sr. no. 1 2 3 4 5 6 7 8

165

Market Shares of Flavor, Fragrance and Other Aroma

Company

Market share (%)

IFF Givaudan-Roure Quest Haarman & Reimer Firmenich Takasago Bush Boake Allen Dragoco Subtotal All others Total

14.2 11.9 9.4 8.9 7.2 6.2 3.8 3.1 64.7 35.3 100.0

chemicals. Total business in the year 2000 was estimated at US $12 billion. It might reach approximately US $14 billion by the middle of 2004. The availability of basic ingredients and their prices no doubt decide about the size of business. Most of the big multinational companies are no doubt active in most of the important cities in the world, either they have manufacturing bases or offices. For example, major players that are active in aroma chemicals have built their factories in various parts of the world in order to meet the local demands. Today the fragrance business worldwide is represented by the International Fragrance Association (IFRA) which was originally comprised of 14 member countries (Table 10.3). Thanks to internationalization of business, most of the key players in the business of flavors and fragrances know exactly where they should establish manufacturing facilities for the aroma chemicals. This will do doubt be dictated by the political scenario of a particular country, availability of reasonably trained and cheap labor cost, and most importantly the availability of the basic raw materials (natural and also synthetically made). Needless to emphasize that China and India—the two largest countries in the world—with more than 2 billion people will be two major

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Table 10.3 Member Countries of IFRA Current (as of 1996)

Future ?

Australia Brazil Canada France Germany Italy Japan Mexico Netherlands Singapore Spain Switzerland UK USA

China India A number of East European countries

business centers. Both these countries have abundance of natural resources in the field of aroma chemicals and both have become suppliers of chemical, pharmaceutical, and dyestuff intermediates. New technologies are also being developed or implemented at regular intervals. 10.4.

INDIAN SCENARIO

India holds a pride of place among the oldest civilized countries. More than 5000 years ago, India was a civilized country. It is not at all surprising that perfumes were used by the Indians long ago. Not only as perfumes, they were used for aroma therapy and other powerful effects of these aromatic ingredients of natural origin. Time elapsed. Years passed by. Now at the beginning of a new millennium, India is not what it was 5000 years ago. India is a very fast developing country, in fact India is very much a developed country in many fields. In the field of bulk chemicals, fine chemicals, pharmaceuticals, India has a pride of place. India has already received world attention in the field of synthesis of fine chemicals encompassing flavor and fragrances and other aroma

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chemicals—both natural and synthetic. Some of the aroma chemicals made in India in the year 2000 is shown in Table 10.4. Many of these chemicals are based on cresols. By the end of the year 2003, many more will be added to this list. It is important to note that 80% of these aroma chemicals are exported to various countries in the world. There is little doubt therefore that India is emerging as a major source of flavor and fragrance chemicals. (Source: Flavors and Fragrances Association of India or FAFAI, 2000). 10.5.

INDUSTRIAL CRESOLS AS COMPONENTS OF AROMA CHEMICALS AND FOOD PRODUCTS

Easy availability of pure p-cresol, o-cresol, and m-cresol particularly in the developed countries of USA, UK, Germany, France, Switzerland, Japan, and even in China and India led to development and commercialization of a large number of cresol derivatives. These have been discussed in details vide Chapters 5–7. Gradually, pure cresols and many of their derivatives proved to be very attractive as components of flavors, fragrances, and even as food additives. Briefly, these have been also discussed while talking about very properties and applications of the derivatives in those chapters. Here, a summary is presented for the interested readers. Mixed cresols or cresylic acid and the pure isomers have been used as fragrance chemicals for many years. Many of the top aroma chemicals companies have been using cresols in small percentages for many of their perfumes. One major example is Liver Brothers Ltd., who through their subsidiary companies in the countries of the Indian subcontinent has been using cresols for their carbolic soaps, (Lifebuoy brand). Here, cresols are used both as disinfectants as well as fragrance agents. Cresols precursors namely, p-cymene, m-cymene, and o-cymene which were traditionally used as fragrance

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Table 10.4 List of Aroma Chemicals Made in India 1 Acetanisol Acetophenone Acetyl carene Acetyl cumene Acetyl longifolene Alcohol C10 (n-decyl) Alcohol C12 (n-lauryl) Alcohol C8 (n-Octyl) Aldehyde C10 Aldehyde C11 (undecylenie) Aldehyde C12 (MNA) Aldehyde C14 Aldehyde C16 Aldehyde C7 Allyl amyl glytcolate Allyl caproate Allyl cyclohexyl propionate Astralide Aurantinc Allyl cyclohexyl propionate Astralide Aurantine Allyl cyclohexyl propionate Allyl heptoate Allyl phenoxy acetate Amyl acetate Amyl benzoate Amyl butyrate Amyl caproate Amyl cinnamate Amyl cinnamic aldehyde Amyl formate Amyl isobutyrate Amyl phenyl acetate Amyl propionate Amyl salicylate

2

3

Benzaldehyde Benzophenone Bensophenone Benyl acetate Benzyl acetate Benzyl alcohol Benzyl benzoate Benzyl butyrate Benzyl cinnamate Benzyl formate Benzyl isoamyl ether Cinnamyl propionate Citral Citral dimethyl acetate Citronellal Cintronellol Citronellyl acetate Citronellyl butyrate Citronellyl formate Citronellyl nitrile Citronellyl priopionate Coumarin Cresols Cyclohexyl acetate Cyclohexyl propionate Cylohexyl salicylate Dicyclopentadienyl acetate Dicyclopentadienyl butyrate Dicyclopentadienyl isobutyrate Dicyclopentadienyl Propionate Diethyl phthalate Dihydroanethole Dihydroisojasmone Dihydromyrcenyl acetate Dimethyl benzyl carbind

Dimethyl hydroquinone Dimethyl resorcinol Dimethyl octanol Dipentene Diphenyl methane Diphenyl oxide Estragol (methyl chavicol) Ethyl acetate Ethyl butyrate Ethyl caproate Ethyl cinnamate Ethyl heptoate Ethyl laurate Ethyl oxyhydrate Ethyl phenyl acetate Ethyl propionate Ethyl undecylinate Ethyl valerinate Eucalyptol Eugenol Benzyl isobutyrate Benzyl isovalerinate Benzyl methyl ether Benzyl phenyl acetate Benzyl phenyl ethyl ether Benzyl priopionate Benzyl salicylate Bensylidine acetone Beta naphthol isobutyl ether Borneol crystals Bromstyrol Camphor Carene acetate Carene formate Cinnamic alcohol Cinnamic aldehyde Cinnamyl acetate Cinnamyl formate

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Table 10.4 (Continued ) 1 Amyl valerinate Anethole Anisic aldehyde Isobutyl benzoate Isobutyl phenyl acetate Isobutyl salicylate Isodecyl acetate Isoeugenol Isoeugenyl acetate Isononyl propionate Isopulegol=linalool Ex. basil oil Longifolene epoxide=menthanyl Acetate Menthol crystals Menthone Methyl acetophenone Methyl amyl ketone Methyl anthranilate Methyl benzoate Methyl cinnamate Methyl eugenol Methyl hexyl ketone Methyl ionone Methyl isoeugenol Methyl salicylate Musk ambrette Musk ketone Musk xylol Eugenyl acetate Geraniol ex-citronella Geranil ex-jamrosa Geraniol ex-palmarosa Geranyl acetate Geranyl butyrate

2 Dimethyl benzyl carbinyl Acetal Geranyl formate Geranyl nitrile Geranyl phenyl acetate Geranyl propionate Guaicawood acetate Hydroxycitronellal dimethyl Acetate Hydroxycitronellal Indole Ionone alpha Ionone beta Ionone pure Isobornyl acetate Rose crystals Rose oxide Methyl hexyl ketone Methyl phenoxy acetate Methyl phenyl acetate Santalol Stryallyl acetate Styrallyl propionate Terpionate Terpineol Terpionyl acetate Thymol Gricyclodecane dimethylol Vetiverol Vetiveryl acetate Yara yara N hexyl acetate N hexyl isobutyrate N hexyl salicylate Netrol

3 Isobornyl methoxy Cyclo hexanol Isobutyl acetate Nerolin bromelia Neryl acetate OTB cyclohexyl acetate Para methyl qinoline Para cresyl phenyl acetate Paracresol Paracresyl acetate Paracresyl benzyl ether Paracresyl isobutyrate Paracresyl methyl ether Parateriary butyl cyclohexyl Acetate Phenoxy ethyl isoobutyrate Phenyl acetic acid Phenyl ethyl acetate Phenyl ethyl phenyl acetate Vanillin Phenyl ethyl alcohol Phenyl ethyl amyl ether Phenyl ethyl butyrate Phenyl ethyl cinnamate Phenyl ethyl formate Phenyl ethyl isobutyrate Phenyl ethyl methyl ethenyl Phenyl ethyl propionate Phenyl ethyl salicylate Pinene Propynyl guaethol PTB cyclohexyl acetate raspberry ketone Rhodinol

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chemicals from natural sources are now made available through the toluene alkylation process and are more easily available and used. Perfumery grades of p-anisic aldehyde and p-anisic alcohol made from p-cresol are used by most of the top aroma chemicals companies such as IFF, Givaudan, BASF, H&R, Dragaco, S.H. Kelkar, etc. Some of the esters and ethers of p-cresol and its derivatives have become very popular in the manufacture of synthetic perfumes. Prominent among them are p-cresyl methyl ether, p-cresyl acetate, p-cresyl phenyl acetate, etc. Some of them are very popular in the manufacture of Indian agarbattis (incense sticks). Thymol and menthol which were traditionally obtained from the natural sources are now synthetically made from m-cresol and are much cheaper as flavor and fragrance chemical than the natural ones. BAYER AG of Germany is the largest manufacturer of synthetic thymol and menthol. Among the synthetic musks used as perfumery fixatives, musk ambrette made from m-cresol is still very popular though it has been reported that many companies no longer use it as it has been declared as carcinogenic. Coumarin a major perfumery fixative and also a food additive is made from o-cresol. Raspberry ketone, a popular flavor and fragrance chemical, used as food additive may be made from p-cresol through its oxidation product p-hydroxy benzaldehyde. BHT made from p-cresol=m–p-cresol is still the best known antioxidant for food and animal feeds.

Indeed, the list of cresols and their derivatives as flavor and fragrance chemicals and in some cases as food additive is endless. Almost every year some new developments are taking place. In a nutshell, cresols and their derivatives will be used in large volumes not only as intermediates for industrial chemicals and pharmaceuticals but also in the field of aroma chemicals.

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Most of the aroma chemicals and food additives particularly, synthetic ones have been classified not only by Chemical Abstracts Service (CAS) registry numbers but also by FEMA, i.e., Flavor and Extract manufacturer’s Association of the United States numbers and also by COE, i.e., Council of Europe numbers. Additionally, these chemicals have to conform to FCC, i.e., Food Chemicals codex. The list of aroma chemicals (Perfume and Flavor Chemicals) has been increasing every year and cresols, their precursors and downstream derivatives have been playing important roles in the field of aroma chemicals as emphasized again and again.

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11.0.

BACKDROP

The concept of clean technology and green chemistry has been around for nearly 15 years now and it is heartening to note that these ideas are penetrating into a wider cross-section of the process industry. Companies have now recognized the need for protection of the environment and the eco-system by recovering important by-product chemicals. This enables them not only to comply with the stringent regulations of the Environment Protection Agencies (EPA) or the Pollution Control Board (PCB) but also reaps harvest by achieving better financial results and widening the product mix benefit. More often than not in spite of the visible benefits of adopting the most modern technologies which are safe and 173

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clean, companies are compelled to continue production of their main products from capital cost point of view. Next best solution for such companies is to keep improving the old and existing technologies by introducing proper technologies for treatment of the waste streams, recover valuable by-products and improve the operations of the plants as a whole apart from earning extra revenues as a result of sale of these valuable by-products. In a cresols complex producing para-cresol and some of the downstream derivatives such as p-anisic aldehyde or other oxidation products such as 3,4,5-trimethoxy benzaldehyde, etc., important inorganic chemicals can be recovered and sold not only towards improvement of the eco-system but also for betterment of the bottom-line from sales of these by-products from the waste streams. In accordance with the norms prescribed by the Environment Protection Agencies or Pollution Control Boards in various states of India and other countries, liquid effluents in any case are to be treated properly before discharge. Total solid content and pH of the liquid effluents after treatment are important parameters. Accordingly the right and logical solution will be to remove the soluble salts as sellable by-products and discharge the neutral effluents having pH in the proximity of 7. This will call for waste recovery systems and minimize waste streams. In a phenol=cresols or xylenols plant, using the conventional sulfonation and caustic fusion technologies, inorganic chemicals which are recovered are sodium sulfite, sodium sulfate and hydrated calcium sulfate also known as gypsum. These are all sellable by-products and depending on the method of treatment and recovery will fetch reasonable prices, and more importantly, will ensure a better eco-system. For some of the cresol derivatives such as p-anisic aldehyde based on oxidation of p-cresyl-methyl ether (PCME) using 80–82% MnO2 and sulfuric acid (80%) good quantities of spent MnSO4 along with excess acid are invariably produced and the waste streams have to be neutralized and solid Mn-sulfate has to be recovered towards waste minimization.

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In the same process during the up-stream conversion of say, p-cresol to PCME during etherification process, sodium sulfate is invariably produced as a liquid by-product and that needs careful processing of liquid PCME and separation of the inorganic layer from the organic mass. A proper system for recovery of sodium sulfate from the mass is no doubt one of the preconditions for a GMP and production of p-anisic aldehyde with a proper eco-system. Similarly use of cobalt acetate–manganese acetate as a catalyst for the oxidation processes of p-cresol to p-hydroxy benzaldehyde or 3,4,5-trimethoxy benzaldehyde will generate waste streams from which co-acetate and Mn-acetate are to be recovered and recycled. Use of other catalysts for other processes will similarly generate waste liquid streams containing unused surplus catalysts or as converted salts which need to be processed and make the liquid waste stream as much free from inorganic impurities as possible. Not only from ecological=environmental points of view, this is necessary but also commercially this will make the operations more viable and attractive. Processing of the waste streams and recovery of the inorganic by-products are discussed here in some detail.

11.1.

SODIUM SULFITE AND SODIUM SULFATE

These are two very important sodium salts obtained either as main products through reactions of SO2 or SO3 with caustic soda or sodium carbonate. Sometimes NaHSO3 or even H2SO4 is used for direct production of sodium sulfate. However, considerable quantities of these salts particularly sodium sulfite are produced during production of phenol, cresols or xylenols through sulfonation–caustic fusion process of benzene, toluene or mixed xylenes or a xylene isomer. Some quantities of sodium sulfate are also formed during production of the hydroxy benzenes including resorcinol and naphthols. Solutions of sodium sulfate are produced in numerous reactions of sodium compounds with sulfuric acid or with

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sulfur dioxide and oxygen or air. These solutions must be treated to prevent pollution and towards waste minimization. Both sodium sulfite and sulfate are recovered from the solutions by crystallization and drying=calcination. Markets of by-product sodium sulfite=sulfate are no doubt dependent on the market of the main products and also the price fluctuations of caustic soda particularly in the pulp and paper industry. Sodium sulfate is also obtained as a major by-product along with manganese sulfate during production of p-anisic aldehyde from p-cresol. It may be mentioned that during reaction of p-cresol with dimethyl sulfate for production of the intermediate p-cresyl-methyl ether sodium sulfate is the main by-product. These reactions are briefly shown below: (i) Sodium sulfite=sulfate from benzene=toluene= xylenes or naphthalene for production of the hydroxy benzene (phenol), hydroxy methyl benzene (cresols), dimethyl hydroxy benzene (xylenols) or dihydroxy benzenes (resorcinol) or naphthols. In these processes, aromatic sulfonic acids are formed via sulfonation. These are then converted to hydroxy compounds via neutralization and caustic fusion. Following chemical reaction is shown by way of illustration: C6 H4 CH3 OH

Na2 CO3

H2 SO4

! C6 H4 CH3 SO3 H Toluene sulfonic acid

Toulene

C6 H4 CH3 SO3 Na

!

or Na2 SO3

! Na SO þ 2 3

NaOH

Sodium salt of toluene sulfonic acid H2 SO4

C6 H4 CH3 ONa Sod: cressolate

!

SO2 or CO2

Cresol þ Na2 SO3 and Na2 SO4

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(ii) p-Cresol to p-cresyl methyl ether (PCME) C6 H4 CH3 OH

NaOH

!

p-cresol

C6 H4 CH3 ONa Sodium cresolate

ðCH3 Þ2 SO4

! Na2 SO4 þ C6 H4 CH3 OCH3 ðPCMEÞ (PCME is then converted to p-anisic aldehyde via oxidation with MnO2 (80–82%) and H2SO4.) Depending on the waste recovery process and purification both sodium sulfite and sodium sulfate described above are approximately 80% pure and can still be disposed of easily as sellable by-products. Also depending on the process of drying both sodium sulfite or sulfate are either anhydrous or hydrated. Pure salts have the following properties [2,44]: Sodium Sulfite CAS no. [7757-83-7] Chemical formula Na2SO3 (anhydrous) Mol. wt. 126.04, d204 2.633 Hydrated Na2SO37H2O (heptahydrate), Mol. wt. 252.04, and d204 1.539 Anhydrous sodium sulfite is sold as small crystals or powder. It is fairly stable and does not oxidize as readily as the hydrated sulfite Na2SO37H2O exists as efflorescent crystals, is unstable oxidizing in the air to sulfate. Commercial heptahydrate is not more than 90% pure as it contains Na2SO4. Also possible to sell as 98.99% pure salt, loses water of crystallization at 150 C Uses: Chiefly as photographic developers, bleaching wool and paper and pulp industry

Sodium Sulfate CAS no. [7757-82-6] Chemical formula Na2SO4 Mol. wt. 142.04 Anhydrous form (salt cake) exists as powder or orthorhombic bipyramidal crystals, mp 800 C, and d204 2.7 As hydrated salt popularly known as Glauber’s salt Na2SO410H2O—odorless crystals having mp 32.4 C, m.w. 322.04 Uses: Manufacture of glass, paper and pulp industry, for standardizing dyes, in freezing mixtures, also in dyeing and printing textiles, filler in synthetic detergents, ceramic glazes, etc., manufacture of sodium salts

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11.2.

CALCIUM SULFATE

During the process of neutralization of sulfonic acids produced from aromatic hydrocarbons say benzene or toluene, sometimes CaCO3 and Na2CO3 (Soda ash) are used which produce CaSO4 as one of the by-products. Depending on the process of purification, this can be either anhydrous CaSO4 or hydrated known popularly as gypsum (CaSO42H2O). The old process of Honshu, Japan, which was licensed to Atul products, India, is still in use and CaSO4 in the form of gypsum is produced. There are serious problems of solid waste disposal as this is a very impure form of gypsum mostly used for land filling purpose. Process chemistry can be summarized as follows: CaCO3

H2 SO4 ! C6 H5 CH3 ! C6 H4 CH3 SO3 H Na 2 CO3 C6 H4 CH3 SO3 Na

Toluene

ðToluene

Sod: salt of toluene

sulfonic acidÞ

sulfonic acid

þCaSO4 þ Na2 SO3 þ excess CaCO3

CaSO4 is obtained mostly as hydrated (gypsum). Following are the properties of CaSO4 [2,44] CAS no. [7778-18-9] (Dehydrated CaSO4) mol. wt. 136.14 Also known as anhydrous sulfate of lime, anhydrous gypsum is having somewhat pinkish colour. As hydrated CaSO4 it has the following properties: CAS no. [13397-24-5] Chem. formula CaSO42H2O, MW 172.14 Also known as native calcium sulfate, precipitated calcium sulfate or gypsum. Gypsum in pure form (more than 90%) is used: – in manufacture of Portland cement – in soil treatment to neutralize alkali carbonates

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– – – – – – – – –

179

for the manufacture of plaster of paris for artificial marbles for making white pigment as a filler or glaze in paints as a filler in paper as insecticide dusts for water treatment as polishing powder for land filling

In anhydrous form as CaSO4 is used – as a desiccating agent – for wall boards as gypsum boards – for tiles and blocks It may not be out of place to mention that gypsum produced at Atul is of very low quality (less than 70% purity as CaSO4) as it is contaminated with both organic and inorganic impurities and has mostly a negative value for disposal. However, it is possible to upgrade the quality through removal of the organic impurities and contaminated calcium salts through repeated hot water washings and recrystallization. 11.3.

MANGANESE SULFATE

This is the most important inorganic by-product formed during production of p-anisic aldehyde from p-cresol via the intermediate product p-cresyl-methyl ether (PCME). Manganese dioxide MnO2 (80–82%) in presence of sulfuric acid (80%) converts PCME to p-anisic aldehyde and a by-product stream rich in manganese sulfate and excess spent sulfuric acid used in the oxidation reaction as shown below:

C6 H4 CH3 OH

ðCH3 Þ2 SO4

!

ðp-cresolÞ C6 H4 OCH3 CHO þ MnSO4 p-anisic aldehyde

MnO2 ð8082%Þ

! C6 H4 CH3 OCH3 H 2 SO4 ð80%Þ ðPCMEÞ

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+ surplus H2 SO4 + insoluble compounds present in MnO2 ; i.e., pyrolusite ore. Before discharge, the final liquid effluent stream after recovery of p-anisic aldehyde must be neutralized, and filtered. MnSO4 is subsequently recovered as a dried powder after evaporation, crystallization, and drying. Manganese sulfate recovery system is described below (see Fig. 11.1): 1.

Firstly, separation of the aqueous phase from anisic aldehyde production. A plate and frame filter press is used to separate the insoluble solids (silica, etc.) from the aldehyde stream. The solids collected on the filter cloths are washed and dropped directly into an agitated tank for final removal.

Figure 11.1

Recovery of manganese sulfate from spent acid.

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2. Secondly, soluble manganese sulfate solution along with spent sulfuric acid (11–13% H2SO4) is fed to the neutralization section and adequate quantities of manganous oxide (MnO) are added in an agitated vessel. MnO will react with residual H2SO4 to produce additional quantities of MnSO4 and a proper alkaline pH is maintained. However, insoluble impurities from MnO are to be separated in a filter press. 3. Lastly, MnSO4 solution in water is then fed to a drying section for removal of water from the manganese sulfate solution. An evaporation-cum-crystallizer-cumcentrifuge separates the solids (MnSO4) and mother liquor. Mother liquor is recycled to the evaporationcum-crystallization system, and wet MnSO4 in the slurry form is fed either to a spray dryer or fluidized bed dryer or even a rotary drum dryer for separation of dried MnSO4 which is usually 98–99% pure. Pure manganese sulfate has the following properties [2,44]: CAS no. [7785-87-7] Chemical formula MnSO4 anhydrous, MW 151.01, d204 3.25 gm=cc Or commercially available, monohydrate MnSO4H2O melting point (anhydrous) 700 C boiling point (decomposes) 850 C MnSO4 is readily soluble in water, but has a negative solubility coefficient at temperature higher than 24 C. The solid contents of a MnSO4 solution saturated at 24 C is 39.3 wt%, at 100 C, the solid content drops to 26.2 wt% [52]. Manganese sulfate is either white (gray) as anhydrous salt or pinkish in hydrated forms. MnSO4 is by far the most important manganese compound and has several uses: – as a starting material for electrolytic MnO2 (EMD) – for fungicides such as Manel – for production of other manganese compounds such as manganese carbonate (MnSO4 þ Na2CO3 ! MnCO3 þ Na2SO4)

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– for textile printing and glass making – as a fertilizer – as a micronutrient additive for animal feeds Until recently the manufacture of hydroquinone via oxidation of aniline with MnO2 and H2SO4 was a major source of fertilizer grade MnSO4 (approx. 78% by weight). 2C6 H5 NH2 þ 4MnO2 þ 5H2 SO4 ! 2C6 H4 O2 þ 4MnSO4 ðAnilineÞ

ðQuinoneÞ

þ ðNH4 Þ2 SO4 þ 4H2 Quinone is separated from the reaction mixture by distilling with steam and MnSO4 is recovered from the remaining solution. A commercial product containing some ammonium sulfate is obtained by filtering and evaporating the solution followed by drying [53,54]. Both the manganese oxides MnO, CAS no. [1344-43-0] and manganese dioxide [1313-13-9] are primarily produced from pyrolusite ore rich in MnO2. MnO2 is reduced to MnO using finely powdered coal, hydrogen, CO, etc. in absence of air. Pure MnO is also produced from manganese carbonate heat (MnCO3) at a temperature above 200 C, MnCO3 ! MnO þ CO2. Similarly pure MnO2 can be produced in an inert environment by high temperature decomposition (above 850 C) of MnSO4 heat

MnSO4 ! MnO2 þ SO2 As mentioned in Chapter 5, MnSO4 solution can be electrolyzed to MnO2 and H2SO4 in a closed loop cycle and recycled to produce para-anisic-aldehyde from PCME. There will be no waste streams in this process and only make up quantities of H2SO4 will be required. However, the oxidation process has to be controlled carefully. 11.4.

COBALT ACETATE AND MANGANESE ACETATE

Either individually or in combination, these are excellent catalysts for oxidation of aromatic hydrocarbons (methyl groups) to aldehydes and acids.

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It is reliably learnt that one Japanese company is using Co-acetate–Mn-acetate in a predetermined ratio for oxidation of PCME to p-anisic aldehyde. Similarly these mixed acetate catalysts have been used for oxidation of p-cresol to p-hydroxy benzaldehyde at a high pressure (say 10 kg=cm2) and also 3,4,5trimethoxy benzaldehyde manufacture for conversion of the methyl group to aldehyde as discussed in Chapter 5. Use of this catalyst system is an established fact for oxidation of p-xylene to purified terephthalic acid (PTA) or dimethyl terephthalate. More often than not waste streams containing these mixed acetates, more particularly, individual cobalt or manganese acetates are recovered, purified, and recycled after regeneration towards environment control and minimization of waste materials. Properties of cobalt acetate, better known as cobaltous acetale, and manganese acetate are briefly examined here [2,44]:

Cobalt acetate

Manganese acetate

CAS no. [71-48-7] Chemical formula (CH3COO)2Co or C4H6CoO4 Mol. wt. 177 Exists as reddish violet deliquescent crystals

[638-38-0] (CH3COO)2Mn or C4H6O4 Mn anhydrous 173.03 Hydrated Mn-acetate is as pale-red crystals (CH3COO)2 Mn4H2O d204 1.59 mp 80 C MW 245.03 Uses: mordant in dyeing, manufacturing blisters, drier for paints and varnishes, and catalyst (oxidation)

d204 1.7043 The tetrahydrate form Co(CH3COO)2 4H2O loses water at 140 C Uses: catalyst (oxidation and esterification), mineral supplement in feed additives, foam stabilizer, and paint and varnishes drying agent

Cobalt acetate has been made from cobalt hydroxide Co(OH)2 or carbonate and an excess of dilute acetate acid or from powdered cobalt and acetic acid. The process is somewhat similar to that of MnSO4 and the product is purified by subsequent crystallization and drying.

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Mn-acetate has been more conventionally made from metallic manganese and acetic acid, also from MnO and acetic acid in presence of water or from Mn(OH)2 or MnCO3. Final recovery is done after purification via crystallization and drying. Pure cobalt and manganese metals are not available in most countries and China remains as a major supplier of the metals to the world. Both manganese acetate and cobalt acetate have therefore been made more conveniently from MnO, Mn(OH)2, MnCO3 and Co(OH) 2 and CoCO3. Economically recovery of manganese acetate and cobalt acetate from the waste streams is therefore very attractive apart from minimization of waste material and protection of the total eco-system (see Fig. 11.2).

11.5.

SUMMARY

This is to be specifically noted that recovery of pure inorganic salts may not be always very simple. Firstly, these waste streams are contaminated with organic impurities which are to be removed by solvent extraction and repeated washings, sometimes with hot water. Secondly before recovery of the by-products these waste streams are to be neutralized with acids or alkalies depending on the pH which has to be brought to the level of 7, i.e., neutral pH. Sometimes neutralized liquid streams are recycled to the system without further unit operations; however, insoluble solids such as silica, etc., are to be separated via filtration and removed as solids. Occasionally these waste solids are also to be discarded and discharged in storage bins if they are not suitable for land filling purpose. In any case, minimization of waste materials has to be carried out for GMP and total quality management (TQM) practices. The concept of ‘‘green’’ chemistry or ‘‘clean’’ technology is now one and half decades old. Often the question is asked how ‘‘green’’ is my chemistry. Both chemistry and chemical engineering are to be taken into consideration for adopting a clean technology [10].

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Figure 11.2 Manufacture of manganese acetate powder.

In the long run only those companies using ‘‘clean’’ technology will survive. Waste minimization and recovery are important aspects of achieving clean technology. Economic, environmental, and safety needs are always to be kept in mind for practicing clean technology. Development of a new technology involving ‘‘green’’ chemistry and a total clean technology is time consuming and capital intensive. Improving an existing technology through waste minimization is found to be more acceptable. Water management is another aspect that has to be kept in mind. After removal and recovery of the by-products, mostly inorganic chemicals, soluble or insoluble, it might be possible to recycle the used water, which will naturally result in water minimization and better water management.

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As in the case of many fine chemicals, waste minimization in the liquid streams is a must in the field of cresols and allied products. Many plants producing cresols from coal carbonization process have been closed down because of inherent problems of production of waste materials and byproducts. Same is the story with producers of p-anisic aldehyde using MnO2 as the catalyst. Some manufacturers found it economically not viable to recover both sodium sulfate and manganese sulfate from the waste streams involving etherification of para-cresol and oxidation of p-cresyl methyl ether. These plants were eventually closed down which has been discussed adequately in earlier chapters. In sum, waste liquid streams are to be treated, and important inorganic chemicals are to be recovered which will not only control the safety, health, and environment (SHE) system but will also make the process economically more viable. Adoption of new technologies producing ‘‘zero’’ waste material will no doubt be the best alternative but may not be always easily possible. Therefore minimization or if possible, total ‘‘elimination’’ of solid waste ‘‘material’’ from the liquid effluents and recycle of water to the plant will benefit the manufacturers and the eco-system in more ways than one.

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12 Conclusions

12.1.

CURRENT SCENARIO

Consequent upon development and successful implementation of technologies for separation of individual isomeric cresols from a cresols-mix, a series of downstream derivatives of p-cresol, m-cresol, and o-cresol were identified and commercially produced. These individual cresol derivatives have been gainfully used in diversified process fields such as pharmaceuticals, antioxidants, dyestuffs, herbicides, flavor and fragrance chemicals, and other speciality products. It was heartening to see that for many end products, individual cresols proved to be very effective alternative feedstocks to more conventional and traditional ones such as phenol. For instance, p-hydroxy benzaldehyde was hitherto obtained as a by-product during production of salicyl aldehyde from phenol based on Reimer–Tiemann reaction. In fact, phenol-based p-hydroxy benzaldehyde is only 15% of the mixed aldehydes, and 85% of the product is o-hydroxy benzaldehyde or salicylaldehyde. Direct oxidation of p-cresol to 187

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p-hydroxy benzaldehyde has opened up new possibilities and this promises to be an important building block for a host of very important downstream derivatives. This has been discussed briefly in Chapter 5. Similarly, raspberry ketone has so far been made from phenol (and methyl vinyl ketone). However, in view of easy availability of p-hydroxy benzaldehyde from p-cresol at a reasonable price, raspberry ketone can now be made by condensation of alkali catalysed p-hydroxy benzaldehyde and acetone followed by mild hydrogenation of the double bond. It has been established that o-cresol-based o-cresolformaldehyde resins have proved to be very effective as addition=substitution products in more popular phenol– formaldehyde resins for industrial laminates (printed circuit board), etc. Antioxidants, particularly, BHT are produced from phenol by only one unit in Russia, otherwise, in all other plants in the world p-cresol (or even m–p-cresol) is the critical feedstock for production of BHT. o-Cresol-based epoxy resins, particularly in Japan, have proved to be very attractive and is partly replacing epoxy resins made from phenol via bisphenolA. However, one main advantage of phenol vis-a`-vis cresols is that phenol is indeed a versatile bulk chemical (capacity 100,000 tpa in a single plant) compared to cresols which are fine chemicals (plant capacities 6000–20,000 tpa depending on the selection of technology). So the question is quo vadis? Where do we go from here? Should we not re-examine the technologies used for making cresols and their downstream derivatives? Should we not adopt clean technologies or green chemistry? Should we not select appropriate technologies keeping the environment in mind. Any modern process must be eco-friendly. If we cannot protect the environment, we are doomed. A proper balance of the ecology is the crying need of the hour. While talking about clean technologies or green chemistry, let us focus our attention on the age-old sulfonation=caustic fusion process for the production of cresols. The process is anything but eco-friendly. A lot of undesirable and unattractive byproducts—the solid wastes are generated causing environ-

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mental problems. Depending on the chemical used for neutralization of toluene sulfonic acids and post fusion acidification method, gypsum, Na2SO3, Na2CO3, Na2SO4, etc. are generated, which are chemically impure and very low value chemicals, which create disposal problems. In developing countries such as China and India, the sulfonation process will continue to be used for some more time because of different reasons, however, in developed countries of USA, Western Europe, and Japan, production facilities using sulfonation process are gradually getting closed down or are being replaced by the alkylation process. In the alkylation process also, manufacturing units should use zeolites in place of traditional Spa or anhydrous AlCl3 in the Friedel–Crafts reaction of toluene and propylene keeping ‘‘clean’’ technology in mind. Needless to emphasize that only those companies will survive in the long run who will use Q-max (UOP process) or an equivalent process for both cumenes production from benzene or cymenes from toluene. UOP’s proprietary zeolitic catalyst or an equivalent zeolite catalyst should be used but definitely not pollution creating SPA or anhydrous AlCl3 catalysts. The moot point is that plants using cymenes process for production of p-cresol=BHT and m-cresol should have a capacity of, say, 12–20,000 tpa producing 8000–12,000 tpa p-cresol and 4000–8000 tpa m-cresol otherwise such units as of today might not be viable. These units combining cymenes production, isomerization of o-cymene to para- and meta-cymenes and conversion of p-cymene and m-cymene to p-cresol and m-cresol, are capital intensive though they offer the ‘‘clean’’ technologies and ‘‘green’’ chemistry. Additionally, production cost will be lower and para- and meta-cresols could be produced in block operations depending on demand and immediate market of a particular cresol. By-products including o-cresol are eliminated and the process is eco-friendly. Chinese company, Yanshen Petrochemicals Co., and the two Japanese companies, Sumitomo and Mitsui, using alkylation process are producing m-cresol and BHT though UOP=Kellog’s process of cymenes and cresols production has been fully established.

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Merisol, the world’s largest cresols player, operates natural cresol producing facilities at Sasolburg, South Africa, and separation unit at Houston, USA. Merisol is the only company in the world that operates a plant separating pure p-cresol and m-cresol from a mixture of m–p-cresols using UOP’s unique ‘‘Cresex’’ process—an extension of UOP’s Sorbex process. It is an eco-friendly process separating 99% pure para- and meta-cresol using a special adsorption and desorption technique based on UOP’s proprietary molecular sieve technology. Surprisingly, UOP has not licensed ‘‘Cresex’’ process to any other cresols player in the world. This process has a lot of future possibilities and it may not be illogical to assume that other companies in the world will no doubt come out with similar technologies in near future. Chiyoda Co. Japan is one such example. It is learnt that even PMC inc., USA, the only virgin cresols manufacturer in USA, has decided to close down its cresol plant and sell out the facilities to interested buyers. Some other coal tar-based units and a few companies recovering cresols from petroleum waste liquors are also closed down. The message is very clear. Government regulations in most of the countries will not permit operations of those units which create pollution and upset the ecosystems. Selection and use of eco-friendly appropriate technologies will be the thrust areas in future. Whatever has been stated for cresol plants regarding selection of clean technologies will also hold good for downstream derivatives of pure cresols. For instance, BASF, Germany, has been operating its p-anisic aldehdye plant based on its proprietary electrochemical process which is clean and environment friendly. Nippon Shokubai of Japan has been producing p-anisic aldehyde by oxidation of p-cresyl methyl ether (PCME) using an environment friendly undisclosed catalyst which is regenerable and does not cause pollution problems. This is not the case with other manufacturers of p-anisic aldehyde, who use the ageold process of oxidation of PCME by 81–82% MnO2 and 80% H2SO4 which generate solid wastes and also a by-product MnSO4 which is not easily disposable, and creates pollution problems. This is one main reason why the USA plant at

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Kansas (which was operated by Koch, later on by Allied signals which sold it to Inspec which in turn sold it to Laporte) has been closed down. p-Anisic aldehyde plant operated by Atul, India at Ankleshwar, Gujarat state, will continue to operate for some more time since pollution control laws in India are not as stringent as in USA. However, a long-term solution will be identification and development of a suitable oxidation catalyst which will be of low volume and preferably regenerable compared to very high volume and impure MnO2 which is currently being used. Another solution could be electrochemical conversion of MnSO4 to MnO2 and H2SO4 which could be recycled and which could make the process economically more viable. The same is true for smaller p-anisic aldehyde players in India, who are using the same technology as Atul, however, Atul is miles ahead as they are making sellable MnSO4 in powder form (98–99% pure) and have developed both domestic and international market. A better solution will no doubt be to establish an alternative technology which will be ecofriendly. While selecting an appropriate technology for a cresolbased downstream unit, one should consider flexibility of operations and must examine possibilities for making more products using the same facilities after incorporating some balancing equipments. For instance, a plant producing BHT must also consider production of other butylated products, more specifically, antioxidants such as butylated hydroxy anisole (BHA) and tert-butyl hydroquinone (TBHQ). For some end uses, BHA=TBHQ are used as synergestic antioxidants with BHT. Going a step further, the plant can be made more versatile so that other alkylated cresols can be produced. One classical example is manufacture of thymol based on alkylation of m-cresol using propylene. Only major difference in the production of BHT vis-a`-vis thymol is that for making BHT via butylation of p-cresol one uses a Lowery–Bornstead acid catalyst such as H2SO4, whereas for thymol production via propylation of meta-cresol one has to use a Lewis acid such as

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AlCl3 or a modern zeolite catalyst. Versatility of the product mix will help the promoters in more ways than one as it will guarantee more profitability and better utilization of the assets should there be a declining market for one of the products such as BHT. This is true for other cresol derivatives which should be as far as possible well integrated so that the facilities become truly multipurpose. This would reduce the cost of production for each of the products in the complex. 12.2.

FUTURE POSSIBILITIES

Brief profiles of industrial chemical cresols and downstream derivatives encompassing the fields of agrochemicals, pharmaceuticals, flavors, and fragrances etc., have been highlighted in the preceding chapters. While some of the identified products have been very successfully commercialized, it would call for more intensive R&D work in the allied fields for perfection of technologies, their commercial exploitations and finding out global applications for many more products. Sulfonation of toluene is still the most widely used process for production of cresols. But as explained earlier keeping clean technology and protection of environment in mind it is needless to emphasize that alkylation of toluene is the future technology. Accordingly, cheaper and less capital-expensive processes for separation of cymenes and cresols will be necessary. UOP’s Cymex and Cresex’ process need to be reexamined. Not only cost reduction for various steps will be necessary but also UOP or other companies such as Kellog= Chiyyoda will have to license their technologies with process guarantees so that sulfonation process is gradually phased out and alkylation process is adopted not only by the developed countries but also developing countries like China and India. Again there are other processes which need to be looked into particularly for separation of para- and meta-cresols. For instance, supercritical CO2 as a medium of separation of natural products is becoming gradually popular in many

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countries. Critical R&D work will be necessary to establish if supercritical CO2 can be used for selective separation of metaand para-cresols. This is also a capital-intensive process but holds a lot of promises being a very clean technology. Organic solvents such as benzene, toluene, hexane, etc. have been effectively used for isolation of many of the cresols derivatives. For instance, toluene is used for separation of p-anisic aldehyde. It is to be seen if pressurized hot water, say at 80 C, can be used for isolation of organic chemicals such as p-anisic aldehyde. Some work has already started in many R&D laboratories for similar systems. While talking about clean technologies, one may also cite the case of replacement of the hydroxy (–OH) group by a methoxy (–OCH3) group by using dimethyl sulfate as in the case of para-cresyl methyl ether from p-cresol. Use of methanol and a suitable catalyst, say zeolites, should be established. This would reduce much of environment-related problems, by eliminating disposal of solid effluent such as sodium sulfate. Similarly, considering that cresols and most of their derivatives have toxicological and occupational health problems, necessary data should be made available in a cresols complex. This will help in minimizing hazards related to safety, health, and environment (SHE). In sum, a clean and appropriate technology will be absolutely necessary for industrial chemical cresols and their derivatives. Lastly, it will be worth examining the viability of establishing a cymenes–cresol plant as a part or an extension of a cumene–phenol plant. It sounds logical because some of the upstream facilities such as catalyst (zeolite) handling system and propylene storage and handling facilities will be common. Considering the end-use pattern, there will even be logistics in a phenol and cresols plant. There will be a synergy in operations of the phenol and cresols sections. One main factor that has to be kept in mind is the size of a phenol plant (100,000 tpa or more) vis-a`-vis a cresols plant (approx. 20,000 tpa). Also, cresols chemistry is more complex in nature compared to the phenol process, as a number of isomers are involved in a cresols plant, whereas there is no isomer formation in a phenol plant.

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More R&D work will be necessary to optimize and reduce the undesirable formation of by-products in a cymene and cresol plant. Once the necessary balancing equipments for the separation of cymenes and cresols are incorporated, an integrated phenol–cresols concept will help the manufacturer to reduce both capital and operating costs of the individual phenol and cresols plants. In addition, any under-utilized capacity in a phenol plant can be taken care of, by incorporating cresols facilities in the same complex. This will help the manufacturer in more ways than one.

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Julai, L. The Illustrated Encyclopedia of Essential Oils. Barnes & Noble Books: New York, 1995, 69–236 pp.

Index

3,4,5-TMBA, 83 Acifluorfen, 132 Adduct formation and separation, 53 Alkyl phenols, 5 a-Tocopherol, 148 Antioxidant, 148 Aromatic hydrocarbons, 19 benzene, toluene, para- and orthoxylenes, 19 Aromatization of isophorone, 51 BHT, 170 antioxidant for food and animal feeds, 170 Butyl methoxy dibenzoyl methane, 74 Butylated hydroxy toluene, 41 Chemical Sunscreens, 74 Clean technology, 185 recovery, 185 waste minimization, 185

Commercial feasibility, 53 Coumarin, 113 aroma chemicals, 113 perfume fixative, 113 Cresex technology, 47 Cresols, 1, 167 dimethyl phenols, 1 disinfectants, 167 fragrance agents, 167 hydroxy xylenes, 1 Crystallization, 42 Dealkylation, 46 Degree of hypertension, 142 Dilitiazem, 142 Dissociation constant, 56 incomplete dissociation, 56 Distillation, 42 Dye intermediate, 73 Essential oils, 152 Esterification, 93 Etherification process, 175 201

202 Feedstock, 40, 41 Fenitrothion, 131 Fenvalerate, 128, 129 Fixative essential oils, 152 clary, sage, vetiver, patchouly, orris, sandalwood, 152

Gypsum, 178 Hooker–Raschig process, 37 Hot water washings, 179

Insecticidal agents, 126 International Fragrance Association, 165 Irritation to the skin and eyes, 127 Isophorone, 50

Liquid effluents, 174

m-Anisic acid, 110 antiseptic, insect repellant, ovicide, 110 m-Anisic aldehyde, 108 pesticides, 105 pharmaceutical, flavor and fragrance industry, 109 m-Cresyl acetate, 109 antiseptic, fungicide, 110 Menthol, 101 flavoring for toothpaste and cigarettes, 101 fragrance chemical, 107 ingredient of decongestant ointments, 101 Menthyl salicylate, 102 sunscreen, 102 Meta-phenoxy benzaldehyde, 105 Mixed cresols, 9, 14 cresylic acids or tar acids, 14

Index Mother liquor, 40 Musk ambrette, 107 Nadifloxacin, 146 Para-chloro meta-cresol, 97 antimold agent, 98 preservative, 98 raw material for disinfectants, 98 Para-toluene sulfonic acid, 25 Perfumes and perfumery chemicals, 151 Perkin reaction, 115 Pesticide=herbicide intermediate, 91 Phenols, 1 carvacrol, 3 thymol, 3 Photographic chemical, 73 Physical Sunscreens, 75 Potent antibacterial agent, 144 Properties of toluene, 21 Pyrolysis, 50 Rasching process, 114 Raspberry ketone, 86 Recrystallization, 179 Solid waste disposal, 178 Sommelet reaction, 105 Stomach insecticide, 128 Sulfonation, 176 Sweetening, 15

Vanillin, 77 Eugenol, 78 Guaiacol, 78 Veratraldehyde, 79 Waste Minimization, 174 Waste streams, 186 Water management, 185