SYNLETT0936-52141437-2096 © Georg Thieme Verlag Stuttgart · New York 2019, 30, 2233–2246 account 2233 en Syn lett G. Coates et al. Account Breaking Carbon–Fluorine Bonds with Main Group Nucleophiles Greg Coates Feriel Rekhroukh Mark R. Crimmin* Department of Chemistry, Molecular Sciences Research Hub, Imperial College London, White City, London, W12 0BZ, UK [email protected] Received: 23.09.2019 sector.1 Fluorocarbons are also found in health and farming Accepted after revision: 15.10.2019 sectors and it has been estimated that approximately 20– Published online: 12.11.2019 DOI: 10.1055/s-0039-1690738; Art ID: st-2019-a0506-a 25% of pharmaceuticals and 30–40% of agrochemicals con- tain at least one fluorine atom.2 Abstract In this Account we describe a series of new reactions that we, Despite its clear benefits, the fluorochemicals industry and others, have reported that involve the transformation of C–F bonds is not sustainable. Nearly all fluorocarbons on our planet into C–Mg, C–Al, C–Si, C–Fe and C–Zn bonds. We focus on the use of highly reactive main group nucleophiles and discuss aspects of reaction are synthetic. The vast majority of naturally occurring fluo- scope, selectivity and mechanism. rine is in the form of inorganic fluoride, present in mineral 1 Introduction forms based on abundant main group metals such as fluor- 1.1 The Fluorocarbon Industry and Sustainability spar (CaF ) and cryolite (Na AlF ). The fluorochemical in- 1.2 Production of Fluorocarbons 2 3 6 1.3 Properties of Fluorocarbons dustry is now optimised to extract and process sources of 1.4 Our Work inorganic fluoride to make useful organic fluorocarbons. 2 Results and Discussion The latter molecules and materials are often treated as sin- 2.1 Low-Valent Main Group Compounds gle-use, being disposed of at the end of their useful life cre- 2.1.1 Reactions with Fluoroarenes ating waste and environmental damage. 2.1.2 Reactions with Fluoroalkanes 2.1.3 Reactions with Fluoroalkenes The problem of disposal is particularly acute for the re- 2.2 Main Group Nucleophiles (M1–M2) frigerants industry. While second-generation refrigerants 2.2.1 Reactions of M1–M2 Nucleophiles with Fluoroarenes (CFCs) created a hole in the ozone layer, third-generation 2.2.2 Reactions of M1–M2 Nucleophiles with Fluoroalkanes refrigerants (HFCs) are potent contributors to climate 1 2 2.2.3 Reactions of M –M Nucleophiles with Fluoroalkenes change. Strict governmental legislation of these fluorinated 3 Summary and Perspective gases has been in place for some time. The Montreal proto- Key words fluorine, fluorocarbons, main group, reaction mecha- col has been highly effective in tackling ozone depletion This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. nisms, C–F bond activation and most recently this treaty has been modified (Kigali Amendment: effective January 1, 2019) to introduce regula- tion that seeks to reduce HFCs by >80% by 2050. Hydrofluo- 1 Introduction roolefins (HFOs) are now being marketed as direct replace- ments for HFCs as green alternatives with low global- 1.1 The Fluorocarbon Industry and Sustainability warming potentials. Not only is the long-term effect of HFOs, and their decomposition products such as trifluoro- The fluorochemicals industry improves our quality of acetic acid, on the environment unclear but many compa- life. Fluorinated organic molecules play a pivotal role in nies are now selling mixtures of HFCs and HFOs. chemical manufacture. Among their many uses they find There is an immediate need for sustainable approaches applications as refrigerants, aerosols, in polymeric materi- in the fluorochemicals industry. The recycling, repurposing als, as solvents, and as surfactants. For example, fluorinated and reuse of refrigerants such as HFCs and HFOs hold the polymers (Teflon) and fluorinated gases (HFCs) are com- potential to reduce waste, cost and environmental damage. monplace in UK households, businesses and the automotive © 2019. Thieme. All rights reserved. Synlett 2019, 30, 2233–2246 Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany 2234 Syn lett G. Coates et al. Account Figure 1 (a) Production of fluorocarbons from chlorocarbons and hydrocarbons. (b) Trends in C–M and C–F bond strengths in fluorobenzenes. (c) Trends in C–F bond strengths in fluoroalkanes. The key challenge here is the development and implemen- events and yield organic compounds with high fluorine tation of new chemical methods that use the C–F bond as a content, typically perfluorinated or polyfluorinated mole- functional group. cules. The CoF2 by-product can be recycled. Anhydrous hy- drofluoric acid can also be used as a fluorinating agent in an 1.2 Production of Fluorocarbons electrochemical reaction, called the Simmons process, to generate aliphatic C–F bonds from C–H bonds.5 On industrial scales, nearly all fluorocarbons are pre- pared from HF, which is in turn obtained in an aqueous 1.3 Properties of Fluorocarbons form through reaction of fluorite (CaF2) with sulfuric acid – (H2SO4). HF can be used as a source of F and in the presence The properties of fluorocarbons can be traced to unique of a metal catalyst (often chromium-based) can react with aspects of the element fluorine and its position on the peri- chlorocarbons to form fluorocarbons or chlorofluorocar- odic table. Fluorine has a large first ionisation energy (IE1 = –1 – bons (Figure 1a). 401.2 kcal mol ) and electron affinity (EEA = 78.3 kcal mol The main routes to selective fluorination in the life-sci- 1) and is the most electronegative element known (χp = 6 ences sector are via the Swarts halogen-exchange process 4.0). The fluorine atom has one of the smallest radii (rvdW = and the Balz–Schiemann process. These focus on fluoroaro- 1.47 Å), second only to the hydrogen atom (rvdW = 1.20 Å). matics and trifluoromethyl aromatics, respectively, and Hence, it is suitable to consider substitution of H for F in hy- both use anhydrous HF as the fluorinating agent.3 Alterna- drocarbons. Due to the large electronegativity difference p tively, electrolysis of HF yields F2, which although a poor between carbon and fluorine (Δχ = 1.5) however, C–F fluorinating reagent by itself due to its extreme oxidising bonds are significantly different from C–H bonds. C–F nature, can be combined with CoF2 to effect the fluorina- bonds are polar and exceptionally strong. In fact, this is the tion of hydrocarbons in the Fowler process.4 The Fowler strongest single bond between carbon and any element. For process has two main steps, the reaction of CoF2 with F2 to example, the C–F bond-dissociation energy of fluoroben- generate cobalt trifluoride (CoF3), which is then heated zene (C6H5F), fluoroethene (CHF=CH2) and fluoromethane –1 with a hydrocarbon substrate to perform the fluorination (CH3F) are 127.2 ± 0.7, 123.3 ± 0.8 and 115 ± 4 kcal mol 7 (Figure 1a). These conditions lead to multiple fluorination respectively. These are all larger than the C–H bond-disso- This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited. Biographical Sketches Mark R. Crimmin graduated Michael Hill (now at University as a Royal Society University Re- from Imperial College London in of Bath) and Prof. Tony Barrett. search Fellow, initially at Univer- 2004 and completed an MSc by In the same year, he was award- sity College London and now research in organic synthesis at ed a Royal Commission for the back at Imperial. He was ap- Bristol University under the su- Exhibition of 1851 research fel- pointed as a lecturer in 2011, pervision of Prof. V. K. Aggarwal. lowship which he took to Uni- senior lecturer in 2016 and He received his PhD in main versity of California, Berkeley reader (associate professor) in group chemistry and catalysis (USA) to study with Prof. Bob 2019. from Imperial College London Bergman and Prof. Dean Toste. in 2008 supervised by Prof. In 2011, he returned to London © 2019. Thieme. All rights reserved. Synlett 2019, 30, 2233–2246 2235 Syn lett G. Coates et al. Account ciation energy in the corresponding hydrocarbons benzene, Non-covalent interactions play an important role in de- ethene and methane of 112.9 ± 0.6, 110.7 ± 0.7 and termining the reactivity of fluorocarbons. These influence 104.9 ± 0.1 kcal mol–1 respectively.7 the structure of the ground state and can lead to the stabili- Incorporation of fluorine atoms into organic compounds sation of transition states. For example, the reactivity of fluo- influences the properties of these molecules as a whole. For rocarbons can be influenced by: (i) dipole–dipole interac- example, substitution of H for F in benzene results in a tions, (ii) dipole–charge interactions, (iii) hyperconjugation strengthening of the C–H bonds adjacent to the newly in- effects involving donation of electron-density into the low- stalled C–F bond. C–H bond-dissociation energies in fluoro- lying * orbital of the C–F bond, (iv) weak C–F···H–X hydro- benzenes increase with increasing ortho fluorine substitu- gen bonding interactions, and (v) strong electrostatic C– tion. A similar trend, but with a stronger correlation, is ob- F···M interactions.6 served for C–M bonds (Figure 1b).8–10 In contrast, the opposite trend is observed for C–F bond strengths. Macgregor and Whittlesey have examined this effect for a number of polyfluorinated benzenes.11 The C–F bond strengths in fluo- robenzenes have been calculated to decrease by ~ 1.8, 0.5 and 0.2 kcal mol–1 upon substitution of H atoms by F atoms in the ortho-, meta- and para-position respectively (Figure 1c). In combination, these trends lead to substrate bias in C– F activation of fluoroarenes due to a thermodynamic ortho- fluorine effect.