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Research Article Open access CC BY 4.0

Development of Efficient and Selective Processes for the Synthesis of Commercially Important Chlorinated Phenols

Keith Smith, Gamal A. El-Hiti

Organics · pp. 142–160 · Published 8 Jul 2021

10.3390/org2030012

Abstract

para-Selective processes for the chlorination of phenols using sulphuryl chloride in the presence of various sulphur-containing catalysts have been successfully developed. Several chlorinated phenols, especially those derived by para-chlorination of phenol, ortho-cresol, meta-cresol, and meta-xylenol, are of significant commercial importance, but chlorination reactions of such phenols are not always as regioselective as would be desirable. We, therefore, undertook the challenge of developing suitable catalysts that might promote greater regioselectivity under conditions that might still be applicable for the commercial manufacture of products on a large scale. In this review, we chart our progress in this endeavour from early studies involving inorganic solids as potential catalysts, through the use of simple dialkyl sulphides, which were effective but unsuitable for commercial application, and through a variety of other types of sulphur compounds, to the eventual identification of particular poly(alkylene sulphide)s as very useful catalysts. When used in conjunction with a Lewis acid such as aluminium or ferric chloride as an activator, and with sulphuryl chloride as the reagent, quantitative yields of chlorophenols can be obtained with very high regioselectivity in the presence of tiny amounts of the polymeric sulphides, usually in solvent-free conditions (unless the phenol starting material is solid at temperatures even above about 50 °C). Notably, poly(alkylene sulphide)s containing longer spacer groups are particularly para-selective in the chlorination of m-cresol and m-xylenol, while, ones with shorter spacers are particularly para-selective in the chlorination of phenol, 2-chlorophenol, and o-cresol. Such chlorination processes result in some of the highest para/ortho ratios reported for the chlorination of phenols.

Phenols Chemistry Phenol Regioselectivity Reagent Chloride Catalysis Ferric

References (75)

  1. 1 Palleros, D.R. (2000). Experimental Organic Chemistry, John Wiley Sons.
  2. 2 Chikhradze, 2017, The synthesis of phenyl acetylene phenols for development of new explosives [DOI]
  3. 3 Khabarov, 2017, One-step synthesis of picric acid from phenol [DOI]
  4. 4 Benkhaya, 2020, Classifications, properties, recent synthesis and applications of azo dyes [DOI]
  5. 5 Foti, 2007, Antioxidant properties of phenols [DOI]
  6. 6 Hesse, W. (2002). Phenolic Resins. Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH.
  7. 7 Cook, 1960, Phenolic disinfectants [DOI]
  8. 8 Reddy, V.P., and Prakash, G.K.S. (2009). Electrophilic Reactions of Phenols. PATAI’s Chemistry of Functional Groups, John Wiley Sons. [DOI]
  9. 9 Wiley-VCH (1998). Ullmann’s Encyclopedia of Industrial Chemistry, Wiley-VCH. [6th ed.].
  10. 10 Fagan, 1984, The effect of the phenoxyacetic acid herbicides 2,4,5-trichlorophenoxyacetic acid and 2,4-dichlorophenoxyacetic acid as ascertained by direct experimentation
  11. 11 Favaro, 2008, Quantitative determination of chlorophenols in leather by pressurized liquid extraction and liquid chromatography with diode-array detection [DOI]
  12. 12 Igbinosa, 2011, Toxicological profile of chlorophenols and their derivatives in the environment: The public health perspective
  13. 13 Stuart, M.C., Kouimtzi, M., and Hill, S.R. (2009). WHO Model Formulary 2008, World Health Organization.
  14. 14 Griffiths, C., Barker, J., Bleiker, T.O., Chalmers, R., and Creamer, D. (2017). Rook’s Textbook of Dermatology, John Wiley Sons. [9th ed.]. [DOI]
  15. 15 Digison, 2007, A review of anti-septic agents for pre-operative skin preparation [DOI]
  16. 16 Smith, 2015, Catalytic, green and regioselective Friedel-Crafts acylation of simple aromatics and heterocycles over zeolites [DOI]
  17. 17 Smith, 2011, Use of zeolites for green and para-selective electrophilic aromatic substitution reactions [DOI]
  18. 18 Smith, 2006, Regioselective electrophilic aromatic substitution reactions over reusable zeolites [DOI]
  19. 19 Smith, 2004, Regioselective control of electrophilic aromatic substitution reactions [DOI]
  20. 20 Smith, 2012, Highly regioselective di-tert-amylation of naphthalene over reusable HM zeolite catalyst [DOI]
  21. 21 Smith, 2003, Study of regioselective dialkylation of naphthalene in the presence of reusable zeolite catalysts [DOI]
  22. 22 Smith, 2003, Acetylation of aromatic ethers using acetic anhydride over solid acid catalysts in a solvent-free system. Scope of the reaction for substituted ethers [DOI]
  23. 23 Smith, 2003, Acylation of aromatic ethers over solid acid catalysts: Scope of the reaction with more complex acylating agents [DOI]
  24. 24 Smith, 2004, Study of regioselective methanesulfonylation of simple aromatics with methanesulfonic anhydride in the presence of reusable zeolite catalysts [DOI]
  25. 25 Smith, 2014, Regioselective nitration of 2- and 4-nitrotoluenes over systems comprising nitric acid, an acid anhydride and a zeolite [DOI]
  26. 26 Smith, 2014, Regioselective dinitration of simple aromatics over zeolite Hβ/nitric acid/acid anhydride systems [DOI]
  27. 27 Smith, 2013, Highly regioselective dinitration of toluene over zeolite Hβ [DOI]
  28. 28 Smith, 2010, Regioselective nitration of deactivated aromatics using acyl nitrates over reusable acidic zeolite catalysts [DOI]
  29. 29 Smith, 2005, Regioselective mononitration of simple aromatic compounds under mild conditions in ionic liquid [DOI]
  30. 30 Smith, 1998, A novel method for the nitration of simple aromatic compounds [DOI]
  31. 31 Smith, K., Musson, A., and DeBoos, G.A. (1996). Superior methodology for the nitration of simple aromatic compounds. Chem. Commun., 469–470. [DOI]
  32. 32 Smith, K., Butters, M., Paget, W.E., and Nay, B. (1985). New reagent systems for electrophilic chlorination of aromatic compounds: Organic chlorine-containing compounds in the presence of silica. Synthesis, 1155–1156. [DOI]
  33. 33 Mistry, 1986, A superior synthetic method for the bromination of indoles and benzimidazoles [DOI]
  34. 34 Smith, 1992, A new method for bromination and polybromination of carbazoles, β-carbolines and iminodibenzyls by using N-bromosuccinimide and silica gel [DOI]
  35. 35 Jigajinni, V.B., Paget, W.E., and Smith, K. (1981). The synthesis of alkyl chlorides via reaction of trialkylboranes with dichloramine-T or N,N-dichlorourethane. J. Chem. Res., 376–377. [DOI]
  36. 36 Price, D., Iddon, B., and Wakefield, B.J. (1988). Solid Supported Halogenations: A Novel Method for Bromination of Heterocycles. Bromine Compounds: Chemistry and Applications, Elsevier.
  37. 37 Desmurs, J.-R., and Gérard, B. (1991). Controlled Bromination with the Help of Microporous Solids. Advances in Organobromine Chemistry I, Elsevier.
  38. 38 Smith, 1999, Highly selective monochlorination of aromatic compounds under mild conditions by tert-butyl hypochlorite in the presence of zeolites [DOI]
  39. 39 Smith, 1999, Highly selective liquid phase para-bromination of phenyl acetate catalysed by zeolites and metal acetates [DOI]
  40. 40 Smith, K., El-Hiti, G.A., Hammond, M.E.W., Bahzad, D., Li, Z., and Siquet, C. (2000). Highly efficient and selective electrophilic and free radical catalytic bromination reactions of simple aromatic compounds in the presence of reusable zeolites. J. Chem. Soc. Perkin Trans. 1, 2745–2752. [DOI]
  41. 41 Smith, K., and Bahzad, D. (1996). Highly efficient para-Selective bromination of simple aromatic substrates by means of bromine and a reusable zeolite. Chem. Commun., 467–468. [DOI]
  42. 42 Maloney, 2017, Introduction of a simple experiment for the undergraduate organic chemistry laboratory demonstrating the Lewis acid and shape selective properties of zeolites [DOI]
  43. 43 Smith, 1988, High ortho-selectivity in the chlorination of phenols with N-chlorodialkylamines in the presence of silica [DOI]
  44. 44 Smith, 2009, Catalytic mononitration of phenol using iso-propyl nitrate over zeolite catalysts [DOI]
  45. 45 Gnaim, 2004, Shape-selective para-chlorination of phenol using sulfuryl chloride with the aid of microporous catalysts [DOI]
  46. 46 Smith, K., James, D.M., Matthews, I., and Bye, M.R. (1992). Selective para-bromination of phenols via a regenerable polymer-bound tetraalkylammonium tribromide. J. Chem. Soc. Perkin Trans. 1, 1877–1878. [DOI]
  47. 47 Sullivan, 1957, Para-Halogenation of phenols
  48. 48 Nishihara, 1974, Chlorination of phenols
  49. 49 March, J. (1992). Advanced Organic Chemistry: Reactions, Mechanisms and Structure, Wiley. [4th ed.].
  50. 50 Xin, 2017, Selective water-based oxychlorination of phenol with hydrogen peroxide catalysed by manganous sulfate [DOI]
  51. 51 Nahide, 2018, In situ formed IIII-based reagent for the electrophilic ortho-chlorination of phenols and phenol ethers: The use of PIFA-AlCl3 System [DOI]
  52. 52 Xiong, 2018, Ammonium salt-catalyzed highly practical ortho-selective monohalogenation and phenylselenation of phenols: Scope and applications [DOI]
  53. 53 Bugnet, 2002, On the para-selective chlorination of ortho-cresol [DOI]
  54. 54 Watson, 1976, Chlorination with sulfuryl chloride
  55. 55 Watson, 1976, The regioselective para chlorination of 2-methylphenol [DOI]
  56. 56 Watson, 1985, Regioselective para-chlorination of activated aromatic compounds [DOI]
  57. 57 Binns, 1978, p-Chlorophenol
  58. 58 Ogata, Y., Kimura, M., Kondo, Y., Katoh, H., and Chen, F.-C. (1984). Orientation in the chlorination of phenol and of anisole with sodium and t-butyl hypochlorites in various solvents. J. Chem. Soc. Perkin. Trans. 2, 451–453. [DOI]
  59. 59 Olah, G.A., Ohannesian, L., and Arvanaghi, M. (1986). Synthetic methods and reactions; 127. Regioselective para halogenation of phenols, phenol ethers and anilines with halodimethylsulfonium halides. Synthesis, 868–870. [DOI]
  60. 60 Tzimas, 1998, Chlorination of aromatic compounds and catalysts therefor
  61. 61 Smith, 1999, Dialkyl sulfides as selective catalysts for the chlorination of phenols
  62. 62 Tzimas, M. (1995). Selective Control of Chlorination of Phenols. [Ph.D. Thesis, University of Wales Swansea].
  63. 63 Smith, 2019, Regioselective chlorination of phenols in the presence of tetrahydrothiopyran derivatives [DOI]
  64. 64 Tzimas, 1998, Chlorination of aromatic compounds and catalysts therefor
  65. 65 Smith, 1999, Dithiaalkanes and modified Merrifield resins as selective catalysts for the chlorination of phenols
  66. 66 Smith, 2018, Regioselective synthesis of important chlorophenols in the presence of methylthioalkanes with remote SMe, OMe or OH substituents [DOI]
  67. 67 Smith, 2015, Comparison of cyclic and polymeric disulfides as catalysts for the regioselective chlorination of phenols [DOI]
  68. 68 Vo, 2009, Polymers and sulfur: What are organic polysulfides good for? Preparative strategies and biological applications [DOI]
  69. 69 Smith, 2011, The synthesis of polymeric sulfides by reaction of dihaloalkanes with sodium sulfide [DOI]
  70. 70 Smith, K., Hegazy, A.S., and El-Hiti, G.A. (2020). Previously unpublished results from the authors’ group.
  71. 71 Smith, 2020, The use of polymeric sulfides as catalysts for the para-regioselective chlorination of phenol and 2-chlorophenol [DOI]
  72. 72 Smith, 2020, para-Selective chlorination of cresols and m-xylenol using sulfuryl chloride in the presence of poly(alkylene sulfide)s [DOI]
  73. 73 Smith, K., Al-Zuhairi, A.J., and El-Hiti, G.A. (2012). Previously unpublished results from the authors’ group.
  74. 74 Smith, 2011, New polymeric sulfide-borane complexes: Convenient hydroborating and reducing reagents [DOI]
  75. 75 Smith, 2012, Poly(propylene sulfide)–borane: Reagent for organic synthesis [DOI]

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