Benzotrifluoride and Derivatives: Useful Solvents for Organic Synthesis and Fluorous Synthesis James J. Maul 1 · Philip J. Ostrowski 2 · Gregg A. Ublacker 3 · Bruno Linclau 4 · Dennis P.Curran 4 1 Occidental Chemical Corporation, Technology Center, Grand Island, NY 14072, USA. E-mail: [email protected]. 2 Occidental Chemical Corporation, Niagara Falls, NY 14303, USA. E-mail: [email protected]. 3 Occidental Chemical Corporation, Dallas, TX 75244, USA. E-mail: [email protected]. 4 Department of Chemistry, University of Pittsburgh, Pittsburgh, PA 15260 USA. E-mail: curran+@pitt.edu Benzotrifluoride (BTF, trifluoromethylbenzene, a,a,a-trifluorotoluene, C6H5CF3) and related compounds are introduced as new solvents for traditional organic synthesis and for fluorous synthesis. BTF is more environmentally friendly than many other organic solvents and is available in large quantities.BTF is relatively inert and is suitable for use as a solvent for a wide range of chemistry including ionic, transition-metal catalyzed and thermal reactions. It is especially useful for radical reactions, where it may replace benzene as the current solvent of choice for many common transformations. BTF and related solvents are also crucial compo- nents of fluorous synthesis since they can dissolve both standard organic molecules and highly fluorinated molecules. This chapter provides an overview of the reactivity and toxico- logical properties of BTF and analogs and then summarizes their recent uses as reaction solvents in both traditional organic and new fluorous synthesis. Keywords. Benzotrifluoride, Reaction solvent, Organic synthesis, Fluorous synthesis, Green chemistry. 1 Introduction . 80 2 General Introduction to Benzotrifluoride . 81 2.1 Industrial Preparation of BTF . 81 2.2 Benzotrifluoride Analogs . 82 2.3 The Chemistry of BTF . 82 2.3.1 Aromatic Electrophilic Substitution . 82 2.3.2 Aromatic Nucleophilic Substitution . 83 2.3.3 Other Reactions . 83 2.4 Uses of BTFs as Synthetic Intermediates in Chemical Synthesis . 84 2.5 Uses of BTFs in Non-reactive Applications . 84 2.6 Toxicological and Environmental Properties of BTFs . 85 2.6.1 Toxicology Summary of BTFs . 85 2.6.2 Environmental Impact of BTFs . 87 2.6.3 Information on Disposal of BTFs . 88 3 Benzotrifluoride as a Solvent in Traditional Organic Synthesis . 89 3.1 Introduction . 89 3.2 Solvent Properties of BTF – Comparison with Other Solvents . 89 3.3 Thermal Reactions . 90 Topics in Current Chemistry,Vol. 206 © Springer-Verlag Berlin Heidelberg 1999 80 D. P.Curran et al. 3.4 Radical Reactions . 91 3.5 Lewis-Acid Reactions . 92 3.6 Functional Group Transformations . 94 3.7 Oxidations and Reductions . 94 3.8 Transition Metal Reactions . 94 3.9 Phase Transfer Reactions . 97 3.10 Limitations of BTF . 98 3.11 Evaluation of Other Uses of BTF: Extraction, Chromatography . 99 4 BTF as a Solvent in Fluorous Synthesis . 99 4.1 Introduction: Fluorous Synthesis . 99 4.2 Solubility Issues in Fluorous Synthesis . 99 4.3 Examples ofFluorous Synthesis in BTF . .100 4.3.1 Radical Reactions Using Fluorous Tin Hydrides . 100 4.3.2 Fluorous Synthesis of Isoxazolines . 101 4.3.3 Fluorous Tin Azide Cycloadditions . 102 4.3.4 Derivatization of Highly Fluorous Substrates . 102 5 Conclusions . .103 6 References . .104 Abbreviations BTF benzotrifluoride (trifluoromethylbenzene, a,a,a-trifluoro- toluene DBA dibenzylidene acetone 3,4-DCBTF 3,4-dichlorobenzotrifluoride TCE sym-tetrachloroethane DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDC N-(3-dimethylaminopropyl)-N¢-ethylcarbodiimide hydrochloride HFMX hexafluorometaxylene, 1,3-bis-(trifluoromethyl)benzene HFPX hexafluoroparaxylene, 1,4-bis-(trifluoromethyl)benzene LAH lithium aluminium hydride MABTF 3-amino-benzotrifluoride MCBTF 3-chlorobenzotrifluoride MNBTF 3-nitrobenzotrifluoride PCBTF 4-chlorobenzotrifluoride PPTS pyridinium para-toluenesulphonate TFMBA 2-trifluoromethyl benzoic acid 1 Introduction Benzotrifluoride (BTF, trifluoromethylbenzene, a,a,a-trifluorotoluene) (Fig. 1) is a clear, free-flowing liquid with a boiling point of 102°C, a melting point of Benzotrifluoride and Derivatives: Useful Solvents for Organic Synthesis and Fluorous Synthesis 81 Fig. 1 –23°C, and a density of 1.2 g/ml (25°C). It has a characteristic odor resembling other aromatic solvents like toluene. BTF is slightly more polar than THF and ethyl acetate and slightly less polar than dichloromethane and chloroform. BTF belongs to an important group of trifluoromethyl-substituted aromatic compounds, which have broad applications as intermediates or building blocks for crop protection chemicals, insecticides and pharmaceuticals, as well as dyes. Related higher boiling compounds that are produced in multimillion pound quantities include 4-chlorobenzotrifluoride (PCBTF) and 3,4 dichlorobenzotri- fluoride (3,4-DCBTF). While these materials are manufactured as intermediates,BTF and its analogs are relatively inert and hence, potentially useful as solvents for reactions and extractions (Sects. 3 and 4), as well as for non-chemical applications such as sol- vents for coatings and cleaning of surfaces (Sect. 2.5).The trifluoromethyl group on the aromatic ring is very stable to basic conditions even at elevated tempera- tures, and somewhat stable to aqueous acid conditions at moderate temperatu- res (Sect. 2.3.3). BTF has recently become available at low price. Moreover, its lower toxicity (see Sect. 2.6) and higher boiling point (which minimizes losses during evaporation) make it an ecologically suitable replacement for solvents like dichloromethane and benzene. Despite these favorable characteristics, BTF is relatively unknown as a solvent. However, our experience [1] and that of others is beginning to show that BTF is indeed suitable as solvent for many dif- ferent reactions. In this chapter, we provide an overview of the features of BTF and related solvents and summarize their recent uses as reaction solvents in both traditional organic synthesis and new fluorous reactions. This information should prove helpful to others evaluating when and how to employ BTF as a sol- vent in organic synthesis. 2 General Introduction to Benzotrifluoride 2.1 Industrial Preparation of BTF BTF is prepared industrially from toluene in two synthetic steps: 1) free radical perchlorination of the methyl group, followed by 2) fluorine/chlorine exchange of the three chlorine atoms with anhydrous hydrogen fluoride (Scheme 1). The chlorination step may be catalyzed by light of suitable wavelength (UV) and is conveniently carried out in the liquid phase.The fluoride/chloride exchange can be catalyzed by the presence of metal halide compounds, such as pentahalide (Cl, F) salts of antimony and molybdenum, and is effected under a variety of 82 D. P.Curran et al. Scheme 1 conditions of temperature and pressure including liquid phase (high pressure and temperature) [2–4], liquid phase (ambient pressure) [5–9] or vapor phase (low pressure high temperature) [4]. 2.2 Benzotrifluoride Analogs 4-Chlorobenzotrifluoride (PCBTF), 2,4-dichlorobenzotrifluoride (2,4-DCBTF) and 3,4-dichlorobenzotrifluoride (3,4-DCBTF) share major aspects of their syn- theses with BTF. PCBTF and 2,4-DCBTF are manufactured from 4-chloro- toluene and from 2,4-dichlorotoluene as outlined in Scheme 1. 3,4-DCBTF is prepared by the electrophilic (metal halide catalyzed) chlorination of PCBTF (Scheme 2). Hexafluoroxylenes have been synthesized from the corresponding xylenes (ortho, meta and para) by sequences similar to that outlined in Scheme 1. Scheme 2 2.3 The Chemistry of BTF The chemistry of BTF is centered in three areas: aromatic electrophilic substitu- tion as influenced by the CF3 group, aromatic nucleophilic substitution as influ- enced by the CF3 group, and the stability of the CF3 group itself to hydrolytic conditions of acid and base. 2.3.1 Aromatic Electrophilic Substitution Groups on aromatic rings are classified in aromatic electrophilic substitution reactions by their resonance and inductive effects. The trifluoromethyl group exerts no resonance effect and it exerts a negative Inductive (–I) effect (electron withdrawing) on the aromatic ring. Consequently, the CF3 group deactivates the ring to aromatic electrophilic substitution and directs primarily toward the meta position. This is exemplified in Scheme 3, by the nitration of BTF to pro- vide m-nitro-BTF (MNBTF). The subsequent reduction of MNBTF provides m- amino-BTF (MABTF), which is an important chemical intermediate (Sect. 2.4). For similar mechanistic reasons, chlorination of BTF with Cl2 yields m-chloro- BTF (MCBTF) and chlorination of PCBTF yields 3,4-DCBTF (Scheme 2). Benzotrifluoride and Derivatives: Useful Solvents for Organic Synthesis and Fluorous Synthesis 83 Scheme 3 2.3.2 Aromatic Nucleophilic Substitution Aromatic nucleophilic substitution is promoted by functions with –I and –R (Resonance) effects that are ortho or para to the group undergoing aromatic nucleophilic substitution. The negative Inductive (–I) effect of the CF3 group is usually insufficient, on its own, to effect such substitution of the chloride atom of PCBTF.However, with the assistance of one or two nitro-groups, the reaction is quite facile (Scheme 4) and of major commercial significance. The interme- diate 4-chloro-3,5-dinitro-BTF is prepared by the nitration of PCBTF (aromatic electrophilic substitution) and the chlorine atom is readily replaced by substi- tuted amines (aromatic nucleophilic substitution) to produce several herbici- des.Aromatic nucleophilic substitution on 3,4-DCBTF