Durham E-Theses Elemental uorine as a valid synthetic reagent Skinner, Christopher John How to cite: Skinner, Christopher John (1994) Elemental uorine as a valid synthetic reagent, Durham theses, Durham University. Available at Durham E-Theses Online: http://etheses.dur.ac.uk/5141/ Use policy The full-text may be used and/or reproduced, and given to third parties in any format or medium, without prior permission or charge, for personal research or study, educational, or not-for-prot purposes provided that: • a full bibliographic reference is made to the original source • a link is made to the metadata record in Durham E-Theses • the full-text is not changed in any way The full-text must not be sold in any format or medium without the formal permission of the copyright holders. Please consult the full Durham E-Theses policy for further details. Academic Support Oce, Durham University, University Oce, Old Elvet, Durham DH1 3HP e-mail: [email protected] Tel: +44 0191 334 6107 http://etheses.dur.ac.uk University of Durham A Thesis Entitled Elemental Fluorine as a Valid Synthetic Reagent Submitted by Christopher John Skinner B.Sc.(Hons.) (Hatfield College) The copyright of this thesis rests with the author. No quotation from it should be published without his prior written consent and information derived from it should be acknowledged. A Candidate for the Degree of Doctor of Philosophy 1994 8 SEP 199§ For Valerie, Andrew and Alan. Acknowledgements I would like to thank Professor R. D. Chambers for his help and advice throughout this period of research. I would also like to thank my numerous industrial supervisors Dr. J. Hutchinson (BNFL Fluorochemicals), Mr. J. S. Moilliet (ICI, Zeneca , BNFL Fluorochemicals), Dr. M. J. Atherton (BNFL Fluorochemicals) and Dr. D. Moody (Zeneca FCMO) for their useful discussion and advice. I would also like to thank BNFL Fluorochemicals and Zeneca FCMO for providing the grant. My thesis could not have been completed without the help of Dr. Mike Jones and Miss Lara Turner (mass spectrometry); Dr. Alan Kenwright, Mrs Julia Say and Dr. Ray Matthews (nmr); Mr. Ray Hart and Mr. Gordon Haswell (glass blowing); Mrs Jarka Dorstal (elemental analysis); Dr. G. Sandford (advice and coffee purchasing) and Mr. Tom Homes (all things dangerous). in Memorandum The work described in this thesis was carried out in the University of Durham between the 1^^ October 1991 and 30^^ September 1994. This thesis is the work of the author, except were acknowledged by reference, and has not been submitted for any other degree. The work has been presented, in part, at: 1. Direct Fluorination Revisted, R. D. Chambers, J. Hutchinson, C. J. Skinner and J. Thomson, Presented at the 14^^ International Symposium on Fluorine Chemistry, Yokohama, Japan, July 1994. 2. Halogenation Using Elemental Fluorine, R.D. Chambers, C.J. Skinner, J. Moilliet and M. J. Atherton, Presented at the H^h International Symposium on Fluorine Chemistry, Yokohama, Japan, July 1994. 3. Direct Fluorination of Substituted Aromatic Compounds, R. D. Chambers, J. Thomson, J. Hutchinson, C. J. Skinner and M.J. Atherton, Presented at the 14th International Symposium on Fluorine Chemistry, Yokohama, Japan, July 1994. And in paper or patent form in: 4. Process for the Preparation of 3- or 5-Fluoroaromatic Compounds., R. D. Chambers, C. J. Skinner, M. J. Atherton and J. S. Moilliet, Eur. Pat. Appl. EP 566,268 ( CI. C07B39 / 00) 20 Oct 1993; GB Appl. 92 / 8,123 13* April. 1992. 5. Process for the Poly fluorination of Aromatic Compounds, R. D. Chambers, C. J. Skinner, J. Hutchinson, J. T. Thomson, M. J. Atherton and J. S. Moilliet, U.K Appl 9325757.4 16* December 1993. 6. Halogenation of Aromatics Using Elemental Fluorine, R. D. Chambers, C. J. Skinner, M. J. Atherton and J. S. Moilliet, U.K Appl 9414972.1 26* July 1994. 7. Functionlisation of Heterocyclic Compounds Using Elemental Fluorine, R. D. Chambers, G. Sandford, C. J. Skinner and M. J. Atherton, U.K Appl 9414973.9 26* July 1994. 8. Nitrofluorination of Aromatic compounds Using Elemental Fluorine, R. D. Chambers, C. J. Skinner, M. J. Atherton and J. S. Moilliet, Submitted to Patent Office. IV 9. Process for the Fluorination of Heterocycles Using Elemental Fluorine, R. D. Chambers, C. J. Skinner, G. Sandford and M. J. Atherton, In preparation. 10. Electrophilic Fluorination Using Elemental Fluorine , R.D. Chambers, C. J. Skinner, J. Thomson, J. Hutchinson, Accepted for publication in J. Chem. Soc, Chem. Commun. (November 1994). 11. Elemental Fluorine as an 'Enabler' for the Generation of Powerful Electrophiles from other Halogens, R. D. Chambers, C. J. Skinner, M. J. Atherton and J. S. Moilliet , Accepted for publication in J. Chem. Soc, Chem. Commun (November 1994). Statement of Copyright No part of this thesis may be reproduced by any means, nor transmitted, nor translated into a machine language without the written permission of the author, BNFL Fluorochemicals and ZENECA PLC. Abstract Elemental Fluorine as a Valid Synthetic Reagent C. J. Skinner, Univ. of Durham, 1994. Chapter I Chapter I reviews the uses of elemental fluorine in selective organic synthesis and its use in the generation of selective electrophilic fluorinating agents. Chapter II Chapter II describes a systematic investigation into suitable solvents for the direct fluorination of deactivated aromatic systems. After highlighting 98% formic acid and 98 % sulphuric acid as excellent media for fluorinations, a number of other protonic acids were investigated. The work confirms the power of the resulting in situ fluorinating species is dependent on the pKa of the protonic acid. Chapter III Chapter III describes the use of elemental fluorine, in combination with strong acids, for the generation of powerful electrophilic halogenating agents derived for iodine, bromine and some interhalogens. The use of iodoaromatics in the incorporation of perfluoroalkyl groups into aromatics is also detailed. Chapter IV Chapter IV describes the use of elemental fluorine, in combination with iodine, for the direct fluorination of pyridines and quinoline in the 2- position. The use of elemental fluorine and an alcohol in the 2-alkoxylation of pyridine is also described. Investigation into a number of other potential nucleophiles for the 2- functionalisation of pyridines is also detailed. Chapter V-VII Experimental details relating to Chapters II-IV. Appendix One-Three Relevant ^H nmr, l^C nmr, l^pnmr, FT / IR data and mass spectra data. VI Elemental Fluorine as a Valid Synthetic Reagent Contents I. Elemental Fluorine in Organic Synthesis 1_ 1. Fluorine in Organic Chemistry 1 2. Historical Development of Direct Fluorination 2 3. Properties of Elemental Fluorine 3 a. Physical Properties 3 b. Chemical Properties 4 4. Production of Elemental Fluorine 4 a. Electrochemical 4 b. Chemical Synthesis 6 5. Energetics of Fluorination 6 a. Bond Strength 6 b. Initiation Processes 6 c. Directive Effects 8 6. Fluorine as a Reagent in Organic Chemistry 9 a. Fluorination of Carbon 9 b. Perfluorination 10 c. Fluorine as an Electrophile 11 i. Fluorination of Alkenes 11 ii. Selective Fluorination of Tertiary C-H Bonds 12 iii. Fluorination of Aromatic Compounds 14 1) Benzene 14 2) Haloaromatics 15 3) Fluorobenzene on Molecular Sieve 17 4) Aryl Oxygen Compounds 18 5) Mechanism 21 6) Lewis Acid Mediated Fluorinations 24 7) Radio Labelling 25 8) Site Specific Fluorination 29 d. Electrophilic Reagents Derived from Fluorine 31 i. Introduction 31 ii. A^-Fluoro-A'-Alkylsulfonamides 31 iii. Saccharin derived A'^-Fluorosultams 32 iv. //-Fluorobenzenesulfonimide 33 vii V. A^-Fluoroperfluoroalkylsulfonimide 35 vi. Enantioselective Fluorinations 36 vii. //-Fluoropyridinium Salts 37 viii. A^-Fluoroquinuclidium Salts 42 II. The Direct Fluorination of Deactivated Aromatic Compounds 45 1. Introduction 45 2. Initial Reactions 46 a. Reactor Design 46 b. Fluorination of 4-Fluorobenzenesulphonyl Chloride 46 c. Fluorination of Substituted 4-FIuoro Compounds 47 d. 2,4-Difluorobenzoic Acid 48 e. Fluorination in Trifluoroacetic Acid(TFA) 49 i. 4-Fluorobenzoic Acid 49 ii. 2,4-Difluorobenzoic Acid 50 f. Conclusions 50 3. Effect of Solvent on Fluorination 51 a. Fluorination in a Variety of Solvents 51 b. Dielectric Constant vs. Acidity 53 4. Large Scale Fluorinations • 54 a. Introduction 54 b. Analysis of Product Mixtures 54 i. Sodium Persulphate 55 ii. Copper / Quinoline 55 1) 4-Fluorobenzoic Acid 55 2) Perfluorobenzoic Acid 56 3) Polyfluorobenzoic Acids 57 4) Conclusion 57 iii. Silylation 57 c. Design of a Large Scale Reactor 58 d. Fluorination in Formic Acid 59 i. Fluorobenzene 59 ii. 4-Fluorobenzoic Acid 60 e. Fluorinations in Sulphuric Acid 61 i. 4-Fluorobenzoic Acid 61 ii. Two Stage Fluorination 63 iii. 2,4-Difluorobenzoic Acid 64 f. Conclusions 65 vin g. Fluorination in Other Acids 66 i. Orthophosphoric Acid(85%) 66 ii. Hydrochloric Acid(42%) 67 iii. Hydrobromic Acid(48%) 67 iv. Nitric Acid(90%) 67 1) Fluorobenzene 67 2) 4-Fluorobenzoic Acid 68 3) Mechanism of Fluoronitration 69 V. Hydrogen Fluoride 72 1) 40%HF 72 2) 62%HF 72 3) 100%HF 73 vi. Fluorosulphuric Acid(100%) 73 vii. Trifluoromethanesulphonic Acid(Triflic Acid) 73 viii. 'Super Acids' 73 1) Solid Super Acid (Nafion) 73 2) Fluorination in Antimony Pentafluoride / HF 73 5. Conclusions 76 in. The Synthesis of Haloaromatic Compounds 77_ 1. lodoaromatics 77 a. Introduction 77 b. Common Syntheses of lodoaromatics 78 i. Direct lodination 78 ii. lodination Using A^-Iodosuccinimde 80 iii. Aromatic lodination Using Iodine Fluoride 81 c. lodination of Aromatics Using Elemental Fluorine 82 i. Initial Reactions 82 ii. lodination of Polyfluorobenzenes 83 iii. lodination of a Range of Aromatics 85 iv. Effect of Solvent on the lodination Process 87 1) The Use of Co-Solvents 87 2) Effect of Acid Strength 88 V. Limitations of the lodination Methodology 89 Bromination of Using Elemental Fluorine 90 a.