KINETIC AND MECHANISTIC INVESTIGATIONS ON THE NUCLEOPHILIC SUBSTITUTION REACTIONS OF TOSYL CHLORIDE WITH p-substituted PHENOL(S) AND TRIETHYLAMINE

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ARUNMOZHITHEVAN, M.Sc., M.Ed., (Reg. 26138/Ph.D.1/Chemistry/P.T./Oct.2008) Under the guidance of Dr. N. VEMBU, M.Sc., M.Phil., Ph.D., Associate Professor and Head P.

1 KINETIC AND MECHANISTIC INVESTIGATIONS ON THE NUCLEOPHILIC SUBSTITUTION REACTIONS OF TOSYL CHLORIDE WITH p-substituted PHENOL(S) AND TRIETHYLAMINE A thesis submitted to BHARATHIDASAN UNIVERSITY for the award of the degree of DOCTOR OF PHILOSOPHY IN CHEMISTRY By C. ARUNMOZHITHEVAN, M.Sc., M.Ed., (Reg /Ph.D.1/Chemistry/P.T./Oct.2008) Under the guidance of Dr. N. VEMBU, M.Sc., M.Phil., Ph.D., Associate Professor and Head P.G. AND RESEARCH DEPARTMENT OF CHEMISTRY URUMU DHANALAKSHMI COLLEGE TIRUCHIRAPPALLI TAMIL NADU, INDIA JULY 2013

3 Dr. N. VEMBU, M.Sc., M.Phil., Ph.D., Associate Professor and Head, P.G. and Research Department of Chemistry, Urumu Dhanalakshmi College, Tiruchirappalli , Tamil Nadu, India. Mobile: Date : CERTIFICATE This is to certify that the thesis entitled KINETIC AND MECHANISTIC INVESTIGATIONS ON THE NUCLEOPHILIC SUBSTITUTION REACTIONS OF TOSYL CHLORIDE WITH p-substituted PHENOL(S) AND TRIETHYLAMINE submitted to Bharathidasan University, Tiruchirappalli, for the award of the degree of DOCTOR OF PHILOSOPHY IN CHEMISTRY, embodies the result of the bonafide research work carried out by C.ARUNMOZHITHEVAN, under my guidance and supervision in the P.G. and Research Department of Chemistry, Urumu Dhanalakshmi College, Tiruchirappalli , Tamil Nadu, India. I further certify that no part of the thesis has been submitted anywhere else for the award of any degree, diploma, associateship, fellowship or other similar titles to any candidate. (N. VEMBU) Research Supervisor

4 DECLARATION I do hereby declare that this work has been originally carried out by me under the supervision of Dr. N. VEMBU, Associate Professor and Head, P.G. and Research Department of Chemistry, Urumu Dhanalakshmi College, Tiruchirappalli , Tamil Nadu, India, affiliated to Bharathidasan University, Tiruchirappalli and this work has not been submitted elsewhere for any other degree. Tiruchirappalli, July, 2013 (C. ARUNMOZHITHEVAN)

5 ACKNOWLEDGEMENTS At the outset, I convey my profound thanks to my research supervisor and convener Dr. N. Vembu, Associate Professor and Head, Department of Chemistry, Urumu Dhanalakshmi College, Tiruchirappalli for the scholarly guidance and constant support he has given me for the successful completion of the study. I was greatly benefitted by his thorough knowledge of the subject. I would like to thank Thiru S. Subramaniam, Chairman, Mookambigai College of Engineering, Keeranur, for having permitted me to pursue my Ph.D., research. I acknowledge the encouragement and support given by Dr. M.G. Venugopalan, Principal, Mookambigai College of Engineering, Keeranur for my research work. Dr. S. Sekar, Principal, Urumu Dhanalakshmi College, Tiruchirappalli deserves praise for the kind support he extended throughout the research period. I take this opportunity to express my deep sense of gratitude to the Doctoral Committee Member Dr. P. Dharmalingam, Associate Professor, Department of Chemistry, Urumu Dhanalakshmi College, Tiruchirappalli for his timely help and encouragement. I must express my heartful thanks to Dr. R. Renganathan, Professor, Dr. K. Srinivasan, Associate Professor, School of Chemistry, Bharathidasan University, Tiruchirappalli, Dr. K.G. Sekar, Associate Professor, Department of Chemistry, National College, Tiruchirappalli and Dr. P.R. Venkatraman, Associate Professor, Department of Chemistry, E.V.R. College, Tiruchirappalli, for their valuable suggestions and help in the execution of my research work.

6 vi I thank sincerely Dr. M.K. Valsakumari, Professor and Head, Department of Chemistry, Mookambigai College of Engineering, Keeranur for her help during the period. I also thank all the faculty members and non-teaching staff of the Department of Chemistry, Urumu Dhanalakshmi College, Tiruchirappalli, for their help and co-operation throughout this work. I express my thanks to the faculty members of Chemistry, Mookambigai College of Engineering, Keeranur for their support during my research work. My special thanks are due to Meivazhi Mr. N. Parthasarathi, Mr. P. Sasikumar, Assistant Professor, Department of Chemistry, M.I.E.T. Engineering College, Tiruchirappalli and Dr. P. Thiruvasagam, Assistant Professor III, Department of Chemistry, SASTRA University, Thanjavur, for their constant encouragements. I thank my parents, brothers and sisters for sharing my family responsibilities during the period of research. I express my deep sense of gratitude to my beloved wife G. Anuradha, son Master C.A. Nambiarooran, niece M.K. Kalaiaruvi, for their understanding, willing co-operation and constant encouragements for the completion of my research work. I wish to record my heartful thanks to Mr. M. Nagarajan and Mrs. Malathi Nagarajan, M/s. Nagu Computers, Thanjavur, for the neat execution of the typographic work. I thank the Almighty for the grace He has showered on me during the period of research. C. Arunmozhithevan

7 Acknowledgements List of Tables List of Figures List of Graphs List of Spectrums List of Abbreviations CONTENTS v x xii xvi xviii xx Chapter Title Page I INTRODUCTION Scope of Chemical Kinetics Macroscopic and Microscopic Kinetics Factors Affecting Reaction Rates Influence of Temperature on Reaction Rates Activation Energy (Ea) and Chemical 4 Reaction Thermodynamic Formulation of Conventional Transition State Theory Influence of Substituents on Reaction Rates Linear Free -energy Relationships Aliphatic Nucleophilic Substitution Nucleophilic Substitution at a Sulfonyl Sulfur Atom -The S N 2 Mechanism Reaction of Oxygen Nucleophile Reaction of Nitrogen Nucleophile Reaction of Sulfur Nucleophile Sulfonates Sulfonyl Halide Solvent Effects and Chemical Reactivity Influence of Solvents on Reaction Rate The Effect of Solvent on the Reaction Medium 21

8 viii Correlation of Reaction Rate with Solvent Properties at 23 Macroscopic Level Dielectric Constant (ε) Dipole Moment ( D ) Refractive Index (n) Viscosity ( ) Surface Tension ( ) Correlation of Reaction Rate with Properties of Solvent 25 at Microscopic Level The Grunwald and Winstein Solvent Polarity 25 Scale (Y) (or Bentley- Schleyer) Lassau and Jungers logk 2(n-Pr3 N + MeI) Scale Kosower Factor (Z) Dimroth-Reichardt E T (30) Scale Abraham-Kamlet Taft Scale ( * Scale) The Effect of Solvent on Nucleophilicity 28 II SCOPE OF THE PRESENT INVESTIGATION 30 III EXPERIMENTAL Chemicals Rate Constants Measurement by Conductivity Method Product Analysis in the Reaction of Tosyl Chloride 42 with p-substituted Phenol(s) and Triethylamine IV RESULTS AND DISCUSSION Nucleophilic Substitution at Sulfonyl Sulfur. Kinetic Investigation on the Reactions of Tosyl Chloride with p-substituted Phenol(s) and Triethylamine in Acetone / Acetonitrile Concentration Effects Effect of Substituents in the Nucleophile Activation Parameters Isokinetic Relationships Linear Free Energy Relationships Correlation of the Reaction in Acetonitrile (ACN ) and Acetone 145

9 4.2. Kinetics of the Reaction of Tosyl Chloride with p-substituted Phenol(s) and Triethylamine in Methanol Effect of Substituents in the Nucleophile Activation Parameters Isokinetic Relationships Linear Free Energy Relationships Solvent Effect on the Reaction of Tosyl Chloride with p-substituted Phenol(s) and Triethylamine Effect of Solvents A Qualitative Approach Effect of Solvents A Quantitative Approach Correlation of Reaction Rate with Dielectric Constants ( ) and Related Properties of the Solvents Simple Regression Analysis Multiple Regression Analysis Triple Regression Analysis 192 V SUMMARY 203 REFERENCES xxii Contributions by the Research Scholar ix

10 Table LIST OF TABLES Title Page 1.1. Transition states for S N 2 reactions of the four charge types Second order rate constants for the reaction of tosyl chloride with p-substituted phenol(s)-net 3 in acetone/ acetonitrile (ACN) at different concentrations at 303K Second order rate constants for the reaction of tosyl chloride with p-substituted phenol(s) - NEt 3 in acetone / acetonitrile (ACN) at different temperatures A comparison of second order rate constants of reaction of tosyl chloride with various p-substituted phenol(s)- triethylamine complexes in acetone/ acetonitrile (ACN) at 303K Activation parameters for the reaction of tosyl chloride with p - substituted phenol(s)-net 3 in acetone / acetonitrile (ACN) Second order rate constants for the reaction of tosyl chloride with p-substituted phenol(s) - NEt 3 in methanol at three different temperatures Activation parameters for the reaction of tosyl chloride with p-substituted phenol(s)-net 3 in methanol Second order rate constants for the reaction of tosyl chloride with p-substituted phenol(s) -NEt 3 in various solvents at 303K A comparative study in the second order rate constants of the reaction of p-substituted phenol(s) NEt 3 and tosyl chloride with dielectric constant of the some solvents at 303 K Solvent properties at macroscopic and microscopic level Summary of the simple regression of 3 + log k 2 versus solvent parameter 169

11 xi Table ` Title Summary of the best-fit simple regression equation in predicting the effect of solvent parameters on reaction rate Page Summary of the dual (multiple) regression of 3+log k 2 versus solvent parameters Summary of the best fit multiple (dual) regression equation in predicting the effect of solvent parameters on reaction rate Summary of the multiple regression (Triple) of 3+log k 2 versus solvent parameters Summary of the best fit triple regression equation in predicting the effect of solvent parameters on reaction rate

12 Figure LIST OF FIGURES Title Page 1.1. Schematic energy diagram, showing the relative energies of the initial state, the final state, and the activated state Eyring s plot of 1 / T versus ln k 2 / T Nucleophilic substitution at a sulfonyl sulfur atom - The S N 2 mechanism Tosyl chloride (TsCl) Kosower factor (Z) Dimroth-Reichardt E T (30) scale (4-nitrophenyl) H NMR estimation values of (4-nitrophenyl) 13 C NMR estimation values of (4-nitrophenyl) Differential scanning calorimetry (DSC) curve of (4-nitrophenyl) (a) (4-cyanophenyl) (b) 4.1.1(c) 4.1.1(d) 1 H NMR estimation values of ( 4-cyanophenyl) 13 C NMR estimation values of ( 4-cyanophenyl) Differential scanning calorimetry (DSC) curve of (4-cyanophenyl) (a) (4-chlorophenyl) (b) 1 H NMR estimation values of ( 4-chlorophenyl) 109

13 xiii Figure 4.1.2(c) 4.1.2(d) Title 13 C NMR estimation values of ( 4-chlorophenyl) Differential scanning calorimetry (DSC) curve of (4-chlorophenyl) Page (a) (4-bromophenyl) (b) 4.1.3(c) 4.1.3(d) 1 H NMR estimation values of (4-bromophenyl) 13 C NMR estimation values of (4-bromophenyl) Differential scanning calorimetry (DSC) curve of (4-bromophenyl) (a) (4-fluorophenyl) (b) 4.1.4(c) 4.1.4(d) 1 H NMR estimation values of ( 4-fluorophenyl) 13 C NMR estimation values of ( 4-fluorophenyl) Differential scanning calorimetry (DSC) curve of (4-fluorophenyl) (a) (4-iodophenyl) (b) 4.1.5(c) 4.1.5(d) 1 H NMR estimation values of ( 4-iodophenyl) 13 C NMR estimation values of (4-iodophenyl) Differential scanning calorimetry (DSC) curve of (4-iodophenyl) (a) (4-methoxyphenyl) (b) 1 H NMR estimation values of (4-methoxyphenyl) 125

14 xiv Figure 4.1.6(c) 4.1.6(d) Title 13 C NMR estimation values of ( 4-methoxyphenyl) Differential scanning calorimetry (DSC) curve of (4-methoxyphenyl) 1 Eyring s plot of T versus k ln 2 for the reaction of T tosyl chloride with p-xc 6 H 4 OH-NEt 3 in ACN 1 Eyring s plot of T versus k ln 2 for the reaction of T tosyl chloride with p-xc 6 H 4 OH-NEt 3 in acetone Page Leffler s plot of S # versus H # for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in ACN Leffler s plot of S # versus H # for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in acetone Modified Leffler s plot of S # versus Ea for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in ACN Modified Leffler s plot of S # versus Ea for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in acetone Exner s plot of log k₂(303k) versus log k₂(313k) for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in ACN Exner s plot of log k₂(303k) versus log k₂(313k) for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in acetone Hammett plot of σ p versus log k₂ for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in ACN at 303K Hammett plot of σ p versus log k₂ for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in acetone at 303K

15 xv Figure Title Page Bronsted plot of pka versus log k₂ for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in ACN at 303K Bronsted plot of pka versus log k₂ for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in acetone at 303K Plot of log k₂(303k) ACN versus log k₂(303k) acetone for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt Eyring s plot of 1 T versus k ln 2 for the reaction of T tosyl chloride with p-xc 6 H 4 OH-NEt 3 in methanol Leffler s plot of S # versus H # for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in methanol Modified Leffler s plot of S # versus Ea for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in methanol Exner s plot of log k 2 (303K) versus log k 2 (313K) for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in methanol Hammett plot of σ p versus log k 2 for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in methanol at 303 K Bronsted plot of pka versus log k 2 for the reaction of tosyl chloride with p-xc 6 H 4 OH-NEt 3 in methanol at 303 K p-substituted phenol(s)-net 3 with complete proton transfer complex p-substituted phenol(s)-net 3 in hydrogen bonded complex

16 Graph LIST OF GRAPHS Title Page 6. Reaction of tosyl chloride with p-nitrophenol-net 3 [0.025] mol dm -3 in acetone at 303 K 14. Reaction of tosyl chloride with p-cyanophenol-net 3 [0.025] mol dm -3 in acetone at 303 K 22. Reaction of tosyl chloride with p-chlorophenol-net 3 [0.025] mol dm -3 in acetone at 303 K 30. Reaction of tosyl chloride with p-bromophenol-net 3 [0.025] mol dm -3 in acetone at 303 K 38. Reaction of tosyl chloride with p-fluorophenol-net 3 [0.025] mol dm -3 in acetone at 303 K 46. Reaction of tosyl chloride with p-iodophenol-net 3 [0.025] mol dm -3 in acetone at 303 K 54. Reaction of tosyl chloride with p-methoxyphenol- NEt 3 [0.025] mol dm -3 in acetone at 303 K 60. Reaction of tosyl chloride with p-nitrophenol-net 3 [0.025] mol dm -3 in ACN at 303 K 68. Reaction of tosyl chloride with p-cyanophenol-net 3 [0.025] mol dm -3 in ACN at 303 K 76. Reaction of tosyl chloride with p-chlorophenol-net 3 [0.025] mol dm -3 in ACN at 303 K 84. Reaction of tosyl chloride with p-bromophenol-net 3 [0.025] mol dm -3 in ACN at 303 K 92. Reaction of tosyl chloride with p-fluorophenol-net 3 [0.025] mol dm -3 in ACN at 303 K 100. Reaction of tosyl chloride with p-iodophenol-net 3 [0.025] mol dm -3 in ACN at 303 K 108. Reaction of tosyl chloride with p-methoxyphenol-net 3 [0.025] mol dm -3 in ACN at 303 K

17 xvii Graph Title Page 1. Reaction of tosyl chloride with p-nitrophenol-net 3 [0.025] mol dm -3 in acetone at 288 K 2. Reaction of tosyl chloride with p-nitrophenol- NEt 3 [0.025] mol dm -3 in acetone at 293 K 8. Reaction of tosyl chloride with p-nitrophenol- NEt 3 [0.025] mol dm -3 in acetone at 313 K 62. Reaction of tosyl chloride with p-nitrophenol- NEt 3 [0.025] mol dm -3 in ACN at 313 K 63. Reaction of tosyl chloride with p-nitrophenol- NEt 3 [0.025] mol dm -3 in ACN at 323 K 64. Reaction of tosyl chloride with p-nitrophenol- NEt 3 [0.025] mol dm -3 in ACN at 333 K 116. Reaction of tosyl chloride with p-methoxyphenol- NEt 3 [0.025] mol dm -3 in methanol at 303 K 117. Reaction of tosyl chloride with p-methoxyphenol- NEt 3 [0.025] mol dm -3 in methanol at 313 K 118. Reaction of tosyl chloride with p-methoxyphenol- NEt 3 [0.025] mol dm -3 in methanol at 323 K

18 Spectrum LIST OF SPECTRUMS Title Page FT-IR spectrum of (4-nitrophenyl) (a) 4.1.1(b) 4.1.1(c) 4.1.2(a) 4.1.2(b) 4.1.2(c) 4.1.3(a) 4.1.3(b) 4.1.3(c) 4.1.4(a) 4.1.4(b) 1 H NMR (DMSO-d6) spectrum of (4-nitrophenyl) 13 C-NMR (DMSO-d6) spectrum of (4-nitrophenyl) FT-IR spectrum of (4-cyanophenyl) 1 H-NMR (DMSO-d6) spectrum of (4-cyanophenyl) 13 C-NMR (DMSO-d6) spectrum of (4-cyanophenyl) FT-IR spectrum of (4-chlorophenyl) 1 H-NMR (DMSO-d6) spectrum of (4-chlorophenyl) 13 C-NMR (DMSO-d6) spectrum of (4-chlorophenyl) FT-IR spectrum of ( 4-bromophenyl) 1 H-NMR (DMSO-d6) spectrum of (4-bromophenyl) 13 C-NMR (DMSO-d6) spectrum of (4-bromophenyl) FT-IR spectrum of ( 4-fluorophenyl) 1 H-NMR (DMSO-d6) spectrum of (4-fluorophenyl)

19 xix Spectrum 4.1.4(c) 4.1.5(a) 4.1.5(b) 4.1.5(c) 4.1.6(a) 4.1.6(b) 4.1.6(c) Title 13 C-NMR (DMSO-d6) spectrum of (4-fluorophenyl) FT-IR spectrum of ( 4-iodophenyl) 1 H-NMR (DMSO-d6) spectrum of ( 4-iodophenyl) 13 C-NMR (DMSO-d6) spectrum of (4-iodophenyl) FT-IR spectrum of ( 4-methoxyphenyl) 1 H-NMR (DMSO-d6) spectrum of (4-methoxyphenyl) 13 C-NMR (DMSO-d6) spectrum of (4-methoxyphenyl) Page

20 LIST OF ABBREVIATIONS ACN - Acetonitrile Ar - Aromatic A N D N - Nucleophilic association and nucleophilic dissociation BANSYL - 5-Dibutylamino-l-naphathalenesulfonyl chloride Bp - Boiling point BSC - Benzenesulfonyl chloride CTST - Conventional transition state theory DANSYL - 5-Dimethylamino-1-naphathalenesulfonyl chloride DMAP - Dimethylaminopyridine DMF - Dimethylformamide DMSO - Dimethyl sulfoxide Et - Ethyl FT-IR - Fourier transform infrared GLC - Gas liquid chromatography LFER - Linear free energy relationship LSA - Least - squares analysis Me - Methyl Mp - Melting point NEt 3 - Triethylamine NMR - Nuclear magnetic resonance Nu - Nucleophile Ph - Phenyl RNA - Ribo nucleic acid SAMe - S-adenosyl-L-methionine S N 2 - Bimolecular nucleophilic substitution SPT - Substituted phenyl thiazolidines THF - Tetrahydrofuran TLC - Thin layer chromatography TMS - Tetramethylsilane

21 xxi TNS TS TsCl UV - 2-p-Toluidinylnaphthalene-6-sulfonate - Transition state - Tosyl chloride (p-toluenesulfonyl chloride) - Ultra-violet SYMBOLS k 2 ms D E T(30) ( 1) (2 2) - Second order rate constant - milli siemens - Dielectric constant - Dipole moment - Dimroth-Reichardt constant - Kirkwood function - Density * - Polarity / Polarizability (Kamlet-Taft-Abraham scale) logk 2(n-Pr3 N + MeI) Z Y n R (or) r s F E a K - Viscosity - Surface tension - Lassau & Jungers scale - Kosower value - Grunwald-Winstein value - Number of values - Regression value - Standard estimation of error - Goodness of fit - Energy of activation (or) Activation energy - Equilibrium constant

22 Contributions by the Research Scholar

23 LIST OF ARTICLES PUBLISHED [1] Vembu, N., and Arunmozhithevan, C., Solvent Effect on the Reaction of Tosyl Chloride with p-substituted Phenol(s) and Triethylamine., Der Chemica Sinica., 4(2)(2013): [2] Vembu, N., and Arunmozhithevan, C., Nucleophilic Substitution at Sulfonyl Sulfur. Kinetic Investigation on the Reactions of Tosyl Chloride with p-substituted Phenol(s) and Triethylamine in Acetone / Acetonitrile., Der Chemica Sinica., 4(1)(2013): [3] Vembu, N., and Arunmozhithevan, C., Kinetics of the Reaction of Tosyl Chloride with p-substituted Phenol(s) and Triethylamine in Methanol., Der Chemica Sinica., 4(1)(2013):46-55.

International Journal of Advanced Scientific Research and Management, Volume 3 Issue 7, July 2018

International Journal of Advanced Scientific Research and Management, Volume 3 Issue, July 2018 ISSN 24-38 Regression analyses of log k 2 against various solvent for the reaction of p-toluenesulfonyl Chloride