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Understanding the Solvent-Free Nucleophilic Substitution Reaction

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Understanding the Solvent-free Nucleophilic Substitution Reaction Performed in the High Speed Ball Mill (HSBM): Reactions of Secondary Alkyl Halides and Alkali Metal-Halogen Salts A thesis submitted to the Graduate School of the University of Cincinnati in partial fulfillment of the requirements for the degree of Master of Science in the Department of Chemistry of the McMicken College of Arts and Sciences by Sarah B. Machover B.A. Chemistry Washington University in St. Louis May 2006 Committee Chair: James Mack, Ph.D. April 2011 An Abstract of a Thesis Understanding the Solvent-free Nucleophilic Substitution Reaction Performed in the High Speed Ball Mill (HSBM): Reactions of Secondary Alkyl Halides and Alkali Metal-Halogen Salts Sarah B. Machover Governments around the world continue put forth new regulations to reduce the amount of solvent emissions into the environment.a R&D chemists must take on this challenge in order to make safer solvent choices and solvent reduction priorities in the beginning stages of product development. As the scientific community embraces the ideals of Green chemistry and moves towards more environmentally responsible research, it is necessary to understand the capacity of these new techniques on well- established reactions, e.g. SN1 and SN2 reactions. It has been proven that the nucleophilic substitution product of an SN2 reaction on a primary alkyl-halogen substrate can be formed in a High Speed Ball Mill (HSBM) under solvent-free conditions.1 The results of a nucleophilic substitution reaction performed on a secondary alkyl halide substrate in an HSBM under solvent-free conditions were previously uncharted. The mechanism of the reaction between a secondary alkyl-halogen can be considered SN1 or 2 SN2 depending on a variety of factors. The success of the SN1 reaction, a first-order nucleophilic substitution, is largely dependent on the solvent used. This is because of the charged species formed in the first step of the reaction: bond heterolysis. By using the HSBM under solvent-free conditions, the medium which stabilizes the intermediate and transition states of the SN1 reaction mechanism is removed. This investigation looks at the results from the reaction of a hindered secondary alkyl halide and an alkali metal-halogen salt in a solvent-free environment in order to answer the questions: What, if any, products are formed? and How does this compare to the predicted products as seen in classic SN1 reactions? a Governmental regulations on solvent emissions can be found at the websites: epa.gov, legislation.gov.uk, and Canada.gc.ca. i ii Acknowledgements To those for whom I may have been out of sight, but was never out of mind…Thank You. “With the power of conviction there is no sacrifice.” - Pat Benetar, “Invincible” Special thanks go to my family, Givaudan Flavors, and Dr. Mack for their endless enthusiasm and support. iii Table of Contents Chapter Page 1. Introduction and Background……………………………………………………1-24 Green Chemistry……………………………………………………….............1 Solvent…………………………………………………………………………...4 Grinding…………………………………………………………………............5 Nucleophilic Substitution Reaction………………………………………..7-19 The SN2 Reaction……………………………………………………...8 Solvent Effects…………………………………………………....11-14 Solvation……………………………………………………...11 Solvolysis……………………………………………………..12 Hydrogen Bonding………………………………………......12 Dielectric Constant…………………………………………..13 Ion Effects…………………………………………………………15-16 Common-Ion Effect………………………………………….15 “Special” Salt Effect………………………………………….15 The SN1 Reaction……………………………………….….…..........16 Hard-Soft Acid-Base (HSAB) Principle…………………………………......19 Kornblum’s Rule……………………………………………………………….21 Swain-Scott Nucleophilicity………………………………………………..…23 Conclusion……………………………………………………………….….…24 2. Rationale and Design…………………………………………………………..25-66 The Finkelstein Reaction……………………………………………………..25 Nucleophilic Displacement of a Secondary Carbon: Benzhydryl iv Substrates…………………………………………………………………………..26-30 Mechanism Overview…………………………………………..…....28 Ball-Milled Reactions…………………………………………………......30-65 Bromodiphenylmethane (6).………………………………….….30-42 HSAB Principle and Altering the Nucleophile…………….33 Results of Reactions with Different Alkali Metal-Halogen Salts……………………………………………………………………35 Chlorodiphenylmethane (7)…………..…………………………......42 bis(Diphenylmethyl)ether (5) and other Oxygenated Products....47 Hetero-coupling Reactions………………………………….…...50-61 Mixing Studies………………………………………………..55 Reactions with Benzyl iodide (15)………………………….57 Mechanism Summation……………………………………………...60 Reactions in Vials of Alternative Materials: Copper, Teflon®, and Nickel…………………...………………………………..…...62-65 Copper and Teflon® Vial Reactions………………………..62 Nickel Vial Reactions……………………………….…….....64 Conclusion……………………………………………………………………..65 3. Experimental Methods……………………………………………………………..67 4. References………………………………………………………………..……….105 Appendix: Spectra and X-ray Chrystallography…………………………………………..110 v List of Tables and Figures Figure Page 1.1 – The four main classes of nucleophilic substitution reactions…………………………8 1.2 – Kinetic Energy Diagram of the SN2 Reaction………………………………………....10 1.3 – Solvation of a sodium cation by water…………………………………………………12 1.4 – Kinetic Energy Diagram of the SN1 Reaction…………………………………………17 2.1 – Mechanism of a 4-member transition state for neutral nucleophilic substitution………………………………………………………………………..26 2.2 – Concerted transition state for the solvent-free nucleophilic substitution of benzhydryl halides (A) ………………………..……………………………………………….28 2.3 – Concerted transition state for the solvent-free alkali metal-carbon bond formation mechanism……………………………………………………………………29 2.4 – Iododiphenylmethane (3), 1,1,2,2-tetraphenylethane (4), and bis(diphenylmethyl)ether (5), respectively……………...……………………………………29 2.5 – X-ray crystallographic image of bis(dipenymethyl)ether (5) ….…………………….30 2.6 – Six-member transition state leading to the homo-coupling with the assistance of the nucleophilic salt……………………………………………………………….……………51 2.7 – Four-member transition state leading to the homo-coupling without the participation of the nucleophilic salt…………………………………………………………….……………51 2.8 – Reaction of the diphenylmethide (C) and the benzhydryl substrate (A) to synthesize the homo-coupled product (4)………………………..……………………….53 2.9 – 1,2-dibenzylbenzene (11), 1,4-dibenzylbenzene (12), and ethane-1,1,2-triyltribenzene (13), respectively.................................................................58 2.10 – Resonance structures of diphenylmethide (C) leading to the synthesis vi of the aromatic substitution products (8, 11, 12)……………………………………………59 A.1 – GC-MS of bromodiphenylmethane (6) ……………………………………………...110 A.2 – GC-MS of chlorodiphenylmethane (7) ……………………………………………....111 A.3 – GC-MS of iododiphenylmethane (3) ………………………………………….……..112 A.4 – GC-MS of fluorodiphenylmethane (14) …………………………………………..…113 A.5 – GC-MS of 1,1,2,2-tetraphenylethane (4) …………………………………………...114 A.6 – 1H NMR of 1,1,2,2-tetraphenylethane (4) ………………………………………..…115 A.7 – Close-up of the 1H NMR of 1,1,2,2-tetraphenylethane (4) ….………………….…116 A.8 – 13C NMR of 1,1,2,2-tetraphenylethane (4) ……………………………………….....117 A.9 – X-ray crystallographic image of bis(diphenylmethyl)ether (5) …………….…..….118 A.10 – GC-MS of bis(diphenylmethyl)ether (5) …………………………………………...119 A.11 – 1H NMR of bis(diphenylmethyl)ether (5) ……………………………………..……120 A.12 – Close-up of the 1H NMR of bis(diphenylmethyl)ether (5) ………………………..121 A.13 – 13C NMR of bis(diphenylmethyl)ether (5) ………………………………………….122 A.14 – GC-MS of diphenylmethane (9) ……………………………………….……………123 A.15 – 1H NMR of diphenylmethane (9) ……………………………………….…..………124 A.16 – Close-up of the 1H NMR of diphenylmethane (9) ……………………………...…125 A.17 – 13C NMR of diphenylmethane (9) ……………………………………….………….126 A.18 – GC-MS of p-benzyltriphenylmethane (8) …………………………….……………127 A.19 – 1H NMR of p-benzyltriphenylmethane (8) ………………………………………....128 A.20 – 13C NMR of p-benzyltriphenylmethane (8) ………………………………………..129 A.21 – Close-up of the 13C NMR of p-benzyltriphenylmethane (9) …………...………...130 A.22 – GC-MS of 1,2- or 1,4-dibenzylbenzene (11 and 12) ……………………….…….131 A.23 – GC-MS of 1,2- or 1,4-dibenzylbenzene (11 and 12) ……………………….…….132 A.24 – 1H NMR of 1,2- and 1,4-dibenzylbenzene (11 and 12) …………….……….…...133 A.25 – Close-up of the 1H NMR of 1,2- and 1,4-dibenzylbenzene (11 and 12) ……….134 vii A.26 – 13C NMR of 1,2- and 1,4-dibenzylbenzene (11 and 12) ………….……………...135 A.27 – Close-up of the 13C NMR of 1,2- and 1,4-dibenzylbenzene (11 and 12) ……....136 A.28 – GC-MS of benzyl iodide (15)….……………..……………………………………...137 A.29 – 1H NMR of benzyl iodide (15) …………………………………..…………………..138 A.30 – Close-up of the 1H NMR of benzyl iodide (15) ……………………………….…...139 A.31 – 13C NMR of benzyl iodide (15) …………………………………...…………………140 A.32 – GC-MS of dibenzyl ether (16) …………………………………...………………….141 A.33 – 1H NMR of dibenzyl ether (16) …………………………………...…………………142 A.34 – Close-up of the 1H NMR of dibenzyl ether (16) ………………...………………...143 A.35 – 13C NMR of dibenzyl ether (16) …………………………………..………………...144 Scheme 1.1 – Reaction rate equation of the SN2 Reaction……………………………………………9 1.2 – Nucleophilic substitution of tert-butyl bromide by methanol to afford 2-methoxy-2- methylpropane and hydrogen bromide………………………………………………………12 1.3 – Reaction rate equation of the SN1 Reaction…………………………………………..17 1.4 – Pearson’s equilibrium reaction used to make hard and soft determinations………19 1.5 – Acid-Base exchange equation………………………………………………………….20 1.6 – The reaction of silver nitrite with an alkyl bromide affords the nitrite ester,
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