Western Kentucky University TopSCHOLAR® Masters Theses & Specialist Projects Graduate School 8-2011 Regiospecific yS nthesis of Ortho Substituted Phenols Ravindra Kotha Balasainath Western Kentucky University, [email protected] Follow this and additional works at: http://digitalcommons.wku.edu/theses Part of the Materials Chemistry Commons, and the Organic Chemistry Commons Recommended Citation Balasainath, Ravindra Kotha, "Regiospecific yS nthesis of Ortho Substituted Phenols" (2011). Masters Theses & Specialist Projects. Paper 1084. http://digitalcommons.wku.edu/theses/1084 This Thesis is brought to you for free and open access by TopSCHOLAR®. It has been accepted for inclusion in Masters Theses & Specialist Projects by an authorized administrator of TopSCHOLAR®. For more information, please contact [email protected]. REGIOSPECIFIC SYNTHESIS OF ORTHO SUBSTITUTED PHENOLS A Thesis Presented to The Faculty of the Department of Chemistry Western Kentucky University Bowling Green, Kentucky In Partial Fulfillment Of the Requirements for the Degree Master of Science By Ravindra Kotha Balasainath August 2011 ACKNOWLEDGEMENTS I would like to express my deep and sincere gratitude to Dr. Donald W Slocum, whose encouragement, guidance and support from the initial to the final level enabled me to develop an interest on the subject. His understanding, encouragement and personal guidance have provided a good basis for the present thesis. It’s a pleasure to thank and express gratitude to Dr. Cathleen J. Webb, Head of the Department of Chemistry, for her various forms of support during my graduate study and the Faculty members of the Chemistry Department at WKU for the guidance during my course work. I would like to thank the committee members Dr. Rui Zhang, Co- Advisor and Dr. Bangbo Yan, Graduate Committee Chair. I would like to thank God for his blessings, express gratitude to my parents and family members, for their unending love, concern and support. I would also like to thank Dr. Paul Whitely, source of support, guidance and direction with this project and Dr. Slocum research group members for providing support and help during my research work. And finally, I would like to thank my roommates for providing support and care. Finally, I dedicate my thesis to my parents Mr. K. G. Balasainatha Guptha, Mrs. K. B. Indira Guptha and my brother Mr. K. B. Deepak. iii TABLE OF CONTENTS 1. List of Figures..........................................................................................................v 2. List of Tables.........................................................................................................vii 3. Abstract………………………………………………………………………….viii 4. Introduction………..................................................................................................1 5. Experimental………................................................................................................9 6. Results and Discussion..........................................................................................19 7. Conclusion……………....……………………………………………………….40 8. Future Work...........................................................................................................44 9. Bibliography..........................................................................................................45 iv LIST OF FIGURES 1. Reaction mechanism of aromatic electrophilic substitution………….…………...3 2. Electrophilic attack at ortho position on monosubstituted benzene………………4 3. Electrophilic attack at para position on monosubstituted benzene….……………4 4. Reaction scheme for typical Mannich Reaction…………………………………..6 5. Reaction Scheme for Synthesis of 2-[(dimethylamino)methyl]phenol…………...7 6. Reaction Scheme for Synthesis of 2-[(dimethylamino)methyl]phenol………….21 7. Extra transition state of the electrophilic attack at ortho position……………….21 8. Mass spectrum for the GC reaction of 2-[(dimethylamino)methyl]phenol……...22 9. Reaction scheme for the formation of tropylium ion…………………………….23 10. 1H NMR spectrum of 2-[(dimethylamino)methyl]phenol……………………….24 11. 1H NMR spectrum of aromatic region of 2-[(dimethylamino)methyl]phenol…...25 12. Plot of % product formation vs Time (h) for the THF:Water solvent system…...26 13. Plot of % product formation vs Time (h) for the Ethanol:Water solvent system..27 14. Scheme for Synthesis of 4-bromo-2-[(dimethylamino)methyl]phenol………..…29 15. Mass spectrum of 4-bromo-2-[(dimethylamino)methyl]phenol…………………30 16. 1H NMR spectrum of 4-bromo-2-[(dimethylamino)methyl]phenol…...………...31 17. Scheme for Synthesis of 4-chloro-2-[(dimethylamino)methyl]phenol………..…32 18. Mass spectrum of 4-chloro-2-[(dimethylamino)methyl]phenol…………………33 19. 1H NMR spectrum of 4-chloro-2-[(dimethylamino)methyl]phenol……………..34 20. Scheme for Synthesis of 4-methoxy-2-[(dimethylamino)methyl]phenol……..…35 21. Mass spectrum of 4-methoxy-2-[(dimethylamino)methyl]phenol……………….36 22. 1H NMR spectrum of 4-methoxy-2-[(dimethylamino)methyl]phenol…………...37 v 23. Reaction Scheme for Synthesis of benzoheterocycles…………………………..44 vi LIST OF TABLES 1. Influence of various directing groups……………………………………………..2 2. Synthesis of 2-[(dimethylamino)methyl]phenol in Acetonitrile medium…..........11 3. Synthesis of 2-[(dimethylamino)methyl]phenol in THF medium……………….11 4. Solvent study of THF: Water system………………………………………….…12 5. Solvent study of Ethanol : Water system………………………………………...12 6. Temperature conditions for the 2-[(dimethylamino)methyl]phenol synthesis…..13 7. Isolations of 2-[(dimethylamino)methyl]phenol with respect to impurities……..14 8. Summary of results of the isolated products…………………………………..…18 9. Diagnostic Mass Spec. Fragments; Mass and % Abundance…………………....39 vii REGIOSPECIFIC SYNTHESIS OF ORTHO SUBSTITUTED PHENOLS Ravindra Kotha Balasainath August 2011 45 Pages Directed by: Dr. Donald W. Slocum and Dr. Rui Zhang. Department of Chemistry Western Kentucky University Phenol is highly reactive toward electrophilic aromatic substitution. By this general approach, many groups can be appended to the ring, via halogenation, acylation, sulfonation, and other processes. Phenol contains the hydroxyl group (–OH), which is a strongly activating ortho/para directing group in aromatic electrophilic substitution (AES). AES gives a mixture of ortho and para isomers, which must be separated. The strong directing ability of phenol can also result in multiple substitutions on the aromatic ring which could be a major concern in the regiospecific synthesis of phenols. AES and Directed ortho-Metalation (DoM) are the only ways to directly substitute a proton on an aromatic ring and to synthesize regiospecifically substituted phenols. Phenol is a versatile precursor to a large collection of drugs, most notably aspirin, but also many herbicides and pharmaceuticals. AES reactions are useful in regiospecific synthesis as a way of introducing many reactive groups on the benzene ring and also help us to design a suitable method for synthesizing compounds in an efficient manner. Dimethylbenzylamine products are obtained as a result of the reaction of phenols with Eschenmoser’s salt (N,N-Dimethylmethyleneiminium iodide). This approach enables us to prepare regiospecifically ortho substituted phenols by using the AES viii protocol. We have discovered that Eschenmoser’s salt has the ability in basic medium containing triethylamine (TEA) to remove the proton and bond to the aromatic ring exclusively in ortho position to the –OH substituent. Our research work focused on efforts to render isolated products with minimum impurities, greener and more atom economical by use of limiting reagent in the reactions. For the purpose of evaluation of the obtained compounds and intermediates we use Gas Chromatography (GC), Gas Chromatography coupled with Mass Spectrometry (GC-MS) and Nuclear Magnetic Resonance (NMR). Our future work is to synthesize novel benzoheterocyclic compounds from the ortho-derivatised phenols as well as multi-substituted aromatic compounds. The dimethylamino methyl group can act as a directing group in the ortho-lithiation process; subsequent ortho-metalation and treatment with electrophiles generates 1,2,3- trisubstituted phenolic derivatives. Thus, phenolic precursors can be transformed into numerous derivatives which can be used in the chemical, agricultural and pharmaceutical industries. ix INTRODUCTION Phenols are acidic in nature, so their handling and reactions differ from those of other aromatic compounds. Our research focused on phenols for preparing benzoheterocycles, derivatives of phenolic analogs which can be used in chemical, agricultural and pharmaceutical industries. This involved the AES procedure to prepare regiospecific ortho-substituted phenols. Although aromatic compounds have multiple double bonds, these compounds do not undergo addition reactions. Their lack of reactivity toward addition reactions is due to the great stability of the ring systems that result from complete π electron delocalization (resonance). Aromatic compounds react by electrophilic aromatic substitution reactions, in which the aromaticity of the ring system is preserved. Background: AES is an organic reaction in which an atom, hydrogen, appended to an aromatic system is replaced by an electrophile. The most important reactions of this type that take place are aromatic nitration, aromatic halogenation, aromatic sulfonation, acylation and Friedel Crafts acylation and alkylation. Substituents can generally be divided into two classes regarding electrophilic