Microwave Enhanced Hydrogenation Reactions using Solid Hydrogen, Deuterium and Tritium Donors$ Mohammed H. Al-Qahtani, a Nicola Cleator, a Timothy N. Danks, a Russell N. Garman, a John R. Jones,* a Stefan Stefaniak, a Alan D. Morgan b and Alan J. Simmonds b a Department of Chemistry, University of Surrey, Guildford GU2 5XH, UK b Nycomed Amersham, Whitchurch, Cardiff CF4 7YT, UK Microwave enhanced hydrogenation reactions in which H 2 /D 2 /T 2 gases are replaced by various formates proceed very rapidly; the pattern of labelling can be easily modified and the advantages are particularly noteworthy in the case of tritium where problems associated with handling T 2 gas are avoided. Hydrogenation using H 2 gas is one of the most important reactions in organic chemistry. 1 In addition replacement of H 2 with D 2 or T 2 constitutes one of the most widely used methods for preparing deuterium 2 and tritium 3 labelled compounds, which themselves ®nd wide application in the life sciences. 4 Unfortunately all three gases are sparingly soluble in many common solvents with the result that the catalysed reactions, be they heterogeneous or homogeneous, are frequently very slow. As tritium is radioactive this is an additional concern. Consequently our thoughts have turned to the use of solid hydrogen, deuterium and tritium donor sources and here we report our preliminary ®ndings using both thermal and microwave enhanced conditions. Catalytic hydrogen transfer 5 is a special kind of hydro- genation in which the compound to be hydrogenated is heated in the presence of a solvent, catalyst and a hydrogen donor. Amongst the latter we chose the formates, usually the potassium, sodium or ammonium salts, but as they can only donate one hydrogen (the other usually comes from the small concentration of protic solvent present in the reaction mixture) we also synthesized the diformic acid salt of tetramethylethylenediamine (TMEDA): Deuteriated formates are commercially available whilst tritiated potassium formate was prepared at high speci®c activity (2.5 Ci mmol 1 ) by a metal catalysed hydrogen± tritium exchange procedure using T 2 gas. Since the ®rst reports 6,7 of the bene®ts of microwaves in synthetic organic chemistry appeared the ®eld has seen considerable growth but there have been very few appli- cations in the labelled compounds area, the main focus being on radiopharmaceuticals 8,9 containing the short-lived positron emitters 11 C and 18 F. Microwave energy transfer is by dielectric loss and not by conduction or convection so that solvents with high di- electric constants such as dimethyl sulfoxide, dimethylform- amide, water and some alcohols are favoured. The results (Fig. 1) show that with ammonium formate as a donor, the hydrogenation of a-methylcinnamic acid under thermal conditions takes some 2 h at 50 8C and 30 min at 100 8C to go to completion whereas under microwave conditions it is complete in less than 5 min. Furthermore more sterically hindered alkenes such as a-phenylcinnamic acid which are reduced with extreme diculty when using H 2 gas and Wilkinson's catalyst are easily reduced under microwave enhanced conditions. A further feature of the solid donor work is that it gives rise to the possibility of dierent labelling patterns. Whilst it is customary in the homogeneous hydrogenation of alkenes when using D 2 gas and Wilkinson's catalyst to obtain very even addition across the double bond thus: RCH1CHR 0  D 2 4 RCHD0CHDR 0 with the formates there are three possibilities depending on the combination used: H 2 O  DCO 2  , D 2 O  HCO 2  , D 2 O  DCO 2  (or DCO 2 D salt of TMEDA on its own). These expectations are borne out in the results obtained (Fig. 2) for the hydrogenation of cinnamic acid. Whilst the advantages of the procedure (no gas line required, rapid reactions, sterically hindered compounds hydrogenated, labelling patterns varied) for both hydrogen and deuterium are clear it is the tritium work that will bene®t most. The tritium is kept as a solid, which can be safely stored for long periods of time, and is easier to handle than T 2 gas. Furthermore considerably less radio- J. Chem. Research (S), 1998, 400±401$ Fig. 1 Hydrogenation of -methylcinnamic acid: Q 50 8C, thermal conditions; * 100 8C, thermal conditions; R microwave irradiation $This is a Short Paper as de®ned in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there- fore no corresponding material in J. Chem. Research (M). *To receive any correspondence. (e-mail: j.r.jones@surrey.ac.uk). 400 J. CHEM. RESEARCH (S), 1998 Downloaded on 03/04/2013 07:48:12. Published on 01 January 1998 on http://pubs.rsc.org | doi:10.1039/A802040J View Article Online / Journal Homepage / Table of Contents for this issue