Durham Research Online Deposited in DRO: 24 August 2015 Version of attached le: Accepted Version Peer-review status of attached le: Peer-reviewed Citation for published item: Mallia, C. J. and Baxendale, I. R. (2016) 'The use of gases in ow synthesis.', Organic process research development., 20 (2). pp. 327-360. Further information on publisher's website: http://dx.doi.org/10.1021/acs.oprd.5b00222 Publisher's copyright statement: ACS Editors' Choice - This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes. 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Page 1 of 83 Organic Process Research & Development 1 2 3 4 The Use of Gases in Flow Synthesis 5 6 7 8 9 Carl J. Mallia, 1 Ian R. Baxendale* 1 10 11 Address: 1Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, 12 13 United Kingdom. 14 15 *Email: Ian R. Baxendale - [email protected]; Tel: +44 191 334 2185 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 1 ACS Paragon Plus Environment Organic Process Research & Development Page 2 of 83 1 2 3 Table of Contents Graphic 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2 ACS Paragon Plus Environment Page 3 of 83 Organic Process Research & Development 1 2 3 Abstract 4 5 6 This review will highlight the potential benefits that can be leveraged by using flow chemistry to 7 8 9 allow a safer and more efficient way of using gases in research. An overview of the different 10 11 approaches used to introduce gases into flow reactors is presented along with a synopsis of the 12 13 14 different gaseous reactions classes already successfully translated into flow. 15 16 17 Keywords 18 19 20 Gases; Flow Chemistry; Tube in Tube reactors; Membrane reactors; Synthesis. 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 3 ACS Paragon Plus Environment Organic Process Research & Development Page 4 of 83 1 2 3 Introduction 4 5 The use of toxic and dangerous gases is highly restricted and controlled in modern synthetic 6 7 laboratories. Increased safety considerations, including precautionary limitations on their use at 8 9 scale, are often mandated for gas processing operations. Understandably, for something as 10 11 12 ethereal as a gas, which cannot be easily contained, leakages are very difficult to prevent when 13 14 conventional synthetic equipment is used. Consequently, dedicated high pressure facility rooms 15 16 are normally built specifically to enable access to gas based transformations. Pressurised gas 17 18 19 reactions are normally continually monitored for leakage using specialised gas and/or pressure 20 21 detectors, with personnel using such facilities having to undergo specialised training. 22 23 24 Furthermore, restrictions on the scales of high pressure reactions are also put in place to mitigate 25 26 risks, making the scale up of these reactions challenging. 27 28 29 Alternative approaches 30 The use of gas surrogates has been developed to circumvent the direct use of certain gases, with 31 32 the in situ liberation of the required gas being the most common method. Several carbon 33 34 1 2 35 monoxide precursors exists such as those derived from aldehydes, formyl saccharine and 36 37 3 4 5 various metal carbonyls, such as Ni(CO) 4, W(CO) 6 and Mo(CO) 6. Similarly, the use of 38 39 40 transfer hydrogenation is often applied as a substitute for gaseous hydrogen, which can be 41 6 42 delivered through a donor such as formic acid via a metal complex (e.g. Ru), often in 43 44 association with diamine or phosphine ligands. It is also possible to use metal free hydrogen gas 45 46 47 substitutes such as Hantzsch esters often promoted by the addition of an auxiliary 48 49 organocatalyst.7 Additional gas substitutes for less common species have also been developed 50 51 such as Selectfluor® (which acts as a F donor) 8 and DABSO as a gaseous sulfur dioxide 52 53 9 54 substitute. Even though these gas substitutes are useful for small scale chemistry, they often 55 56 tend to be either too toxic,10 atom inefficient or too expensive to be used at larger scales. 57 58 59 60 4 ACS Paragon Plus Environment Page 5 of 83 Organic Process Research & Development 1 2 3 Application of gases 4 5 One of the main limiting factors when pursuing a transformation using a gaseous component is 6 7 establishing the required stoichiometry by solubilising sufficient quantities of the gas into the 8 9 reaction media. The low solubility of certain gases like carbon monoxide (Table 1),11 often 10 11 12 deems that high pressures are required, with the concentration of the dissolved gas also showing 13 14 a rapid decrease with an increase in temperature, especially when the boiling point of the solvent 15 16 is approached. Thus, following Henry’s law, when the reaction temperature is elevated, an 17 18 19 increase in pressure is required to maintain the same concentration of dissolved gas. 20 21 11 22 Table 1: Solubility of carbon monoxide in selected solvents at 25 °C. 23 24 Solubility 25 Molar a 26 Solvent C 27 Volume -3 28 n-Heptane 146.46 11.71 x 10 29 -3 30 Cyclohexane 108.75 9.12 x 10 31 Methylcyclohexane 128.35 9.68 x 10 -3 32 -3 33 Toluene 106.86 7.59 x 10 34 Perfluoroheptane 227.33 17.11 x 10 -3 35 36 Perfluorobenzene 115.79 1.35 x 10 -3 37 -3 38 Chloroform 80.94 7.94 x 10 39 Acetone 74.01 10.44 x 10 -3 40 -3 41 Methanol 40.73 9.24 x 10 42 Ethanol 58.68 8.26 x 10 -3 43 44 n-Propanol b 74.79 7.36 x 10 -3 45 -3 46 i-Propanol 76.55 7.89 x 10 47 Isobutanol 92.88 7.03 x 10 -3 48 b -3 49 Dimethylformamide 77.04 1.82 x 10 50 Water 18.07 0.95 x 10 -3 51 52 53 a Concentration in moles per litre at 1 atm. partial pressure of carbon monoxide. 54 b 55 Measurements taken at 20 °C.