Prof. Graham Sandford, (Director of Research)
(email at email@example.com)
Research Interests - Organofluorine Chemistry
The introduction of a fluorine atom or a fluorinated group into an organic substrate can have a profound effect on its physical, chemical and biological properties. For example, the enhanced biological activity of many substrates containing one fluorine atom has been applied very successfully to the development of a number of fluorine containing pharmaceuticals and plant protection agents, while structures containing many fluorine atoms find a wide variety of uses as, for example, polymers which possess unique and valuable properties.1 Our work is concerned with the synthesis and fundamental chemistry of many classes of partially and fully fluorinated molecules. In particular, we are interested in developing new methodology for the construction of carbon-fluorine bonds and gaining a greater understanding of the role that fluorine plays on the nature of reactive intermediates in organic synthesis. A typical Ph.D. project involves the use of all the techniques appropriate to synthetic organic chemistry as well as use of specialist equipment for work using gases under high pressure, γ-ray irradiation and/or elemental fluorine, all of which is available in Durham. We interact extensively with industry and recent research projects in the group have been funded by Asahi Glass Co. (Japan), GlaxoSmithKline, SONY (Germany), AWE, DSTL, Pfizer, Solvay (Belgium) and International Paint. A spin-out company, Brock Fine Chemicals (www.brockfinechemicals.com) has recently been established to commercialize various aspects of the fluorine group's expertise.
Direct Fluorination and Microreactor Technology
Elemental fluorine has long been considered to be too reactive and uncontrollable for use as a reagent in organic synthesis and this perception still predominates. Prof. Poliakoff's comments on the popular Periodic Table video series (www.PeriodicVideos.com), 'It was much more exciting than I thought ...you see the flames,' and general comments in standard advanced organic chemistry textbooks (J. March, Advanced Organic Chemistry, 'Direct fluorination of aromatic rings with F2 is not feasible at room temperature because of the extreme reactivity of F2....not yet of preparative significance) are typical.
Despite this background, research into the use of elemental fluorine for organic synthesis at Durham has overcome the many problems of using fluorine gas for the safe synthesis of fine chemicals, in particular, by use of dilute fluorine gas in nitrogen, appropriate solvent choice (high dielectric constant media such as formic acid, sulfuric acid or acetonitrile), reactor vessel design, gas flow regulator systems and stainless steel/monel fluorine gas handling lines have developed over the years to allow selective direct fluorination of a range of aliphatic, dicarbonyl, aromatic, heteroaromatic, heterocyclic, steroid and carbohydrate derivatives to be established and the mechanism (regiochemistry, stereochemistry, selectivity, etc.) of these processes to be assessed. Indeed, direct fluorination of aromatic rings is feasible at room temperature ! Research expanding the use of fluorine gas continues to develop new selective fluorination methodology for the synthesis of a range of aromatic, heterocylic and aliphatic systems.2,3
In particular, a process for the synthesis of a fluoroketoester first carried out in Durham was developed by our industrial collaborators, F2 Chemicals Ltd (UK), for the Pfizer company and forms a key starting material in the multi step synthesis of the widely used anti-fungal agent V-Fend (Voriconazole) throughout the clinical trial, launch and commercialization periods. In the period from January 2008 to March 2011 approximately 17 tonnes of the fluoroketoester were manufactured for Pfizer by F2 Chemicals Ltd. Global sales of V-Fend in the 2008-2010 period total $2.4 billion (Pfizer annual financial reports) and in 2010 was 17th position in Pfizer's best selling products and it is one of the global top 100 best selling pharmaceutical products.
Further reaction control in selective fluorination reactions was achieved by the design, fabrication and commissioning of single and multi-channel continuous flow reactor systems, establishing the use of convenient, inexpensive flow reactors for gas - liquid processes using flow regimes in the laboratory. Techniques for the supply of individual gas and liquid reagents from single sources to a parallel array of many flow channels at the same flow rate and pressure whilst maintaining laminar flow within the reactor channels and telescoped gas - liquid / liquid - liquid processes involving fluorination and ring formation in one continuous flow process have been developed.
Multi-functional polyfluoro-aromatic and heterocyclic chemistry
The polyfunctionality of fluoro-heterocyclic systems has enabled us to synthesize pyridine derivatives bearing five functional groups and the application of this chemistry to rapid analogue synthesis (RAS) of polysubstituted ring-fused bi- and tri-cyclic heterocyclic derivatives for the drug discovery arena is underway and the use of highly halogenated heterocyclic systems as novel drug discovery platforms has been developed.
- Organofluorine Chemistry, (Review article), G. Sandford, Phil. Trans. R. Soc. Lond. A, 2000, 358, 455
- Elemental fluorine in organic synthesis (1997-2006), (Review article), G. Sandford, J. Fluorine Chem., 2007, 128, 90.
- Fluorination of ethers by fluorine and Selectfluor, R.D. Chambers, T. Okazoe, G. Sandford, E. Thomas and J. Trmcic, J. Fluorine Chem., 2010, 131, 933 and all earlier parts of the series.
- Continuous gas / liquid - liquid / liquid flow synthesis of 4-fluoropyrazole derivatives by selective direct fluorination. J.R. Breen, G. Sandford, D.S. Yufit, J.A. K. Howard, J. Fray and B. Patel, Beilstein. J. Org. Chem., 2011, 7, 1048.
- Annelation of perfluorinated heteroaromatic systems by 1,3-dicarbonyl systems,M.W. Cartwright, E.L. Parks, G. Pattison, R. Slater, G. Sandford, I. Wilson, D.S. Yufit, J.A.K. Howard, J.A. Christopher and D.D. Miller, Tetrahedron, 2010, 66 3222.
- Dipyrido[1,2-a;3',4'-d]imidazole systems. M.R. Cartwright, L. Convery, T. Kraynck, G. Sandford, D.S. Yufit, J.A.K. Howard, J.A. Christopher and D.D. Miller, Tetrahedron, 2010, 66, 519.
- Harsanyi, Antal, Lueckener, Anne, Pasztor, Hedvig, Yilmaz, Zahide, Tam, Lawrence, Yufit, Dmitry & Sandford, Graham (2020). a-Fluorotricarbonyl derivatives as versatile fluorinated building blocks: synthesis of fluoro-acetophenone, fluoro-ketoester and fluoro-pyran-4-one derivatives. European Journal of Organic Chemistry 2020(25): 3872-3878.
- Walton, Joshua J., Hiasa, Takumi, Kumita, Hideyuki, Takeshi, Kazumasa & Sandford, Graham (2020). Fluorocyanoesters as Additives for Lithium-Ion Battery Electrolytes. ACS Applied Materials & Interfaces 12(13): 15893-15902.
- Murray, Ben James, Ball, Ellis David, Harsanyi, Antal & Sandford, Graham (2019). 2,3,3,3-Tetrafluoropropene (HFO-1234yf) as a CF3-building block: synthesis of enol ethers and vinyl sulfides. European Journal of Organic Chemistry 2019(47): 7666-7672.
- Sato, Kazuyuki, Sandford, Graham, Konishi, Yukiko, Yanada, Niko, Toda, Chisako, Tarui, Atsushi & Omote, Masaaki (2019). Lewis acid promoted fluorine-alkoxy group exchange reactions for the synthesis of 5-alkoxy-4,4-difluoroisoxazoline systems. Organic & Biomolecular Chemistry 17(10): 2818-2823.
- Heeran, Darren & Sandford, Graham (2019). Multifunctional 2- and 3-fluoropyrroles. European Journal of Organic Chemistry 2019(13): 2339-2343.
- Gong, Xiaojie, Heeran, Darren, Zhao, Qiang, Zheng, Chaoyue, Yufit, Dmitry S., Sandford, Graham & Gao, Deqing (2019). Synthesis of fluoro- and cyano-aryl containing pyrene derivatives and their optical and electrochemical properties. Asian Journal of Organic Chemistry 8(5): 722-730.
- Lisse, Etienne & Sandford, Graham (2018). Synthesis of β-fluoro(dicarbonyl)ethylamines from 2-fluoro-ethylacetoacetate and dimethyl-2-fluoromalonate ester by batch and semi-continuous flow three-component Mannich reactions. Journal of Fluorine Chemistry 206: 117-124.
- Palmer-Brown, William, Dunne, Brian, Ortin, Yannick, Fox, Mark A., Sandford, Graham & Murphy, Cormac D. (2017). Biotransformation of fluorophenyl pyridine carboxylic acids by the model fungus Cunninghamella elegans. Xenobiotica 47(9): 763-770.
- Harsanyi, A., Conte, A., Pichon, L., Rabion, A., Grenier, S. & Sandford, G. (2017). One-step continuous flow synthesis of anti-fungal WHO Essential Medicine Flucytosine using fluorine. Organic Process Research & Development 21(2): 273-276.
- Pattison, G., Sandford, G., Wilson, I., Yufit, D.S., Howard, J.A.K., Christopher, J.A. & Miller, D.D. (2017). Polysubstituted and ring-fused pyridazine systems from tetrafluoropyridazine. Tetrahedron 73(5): 437-454.
- Heeran, D. & Sandford, G. (2016). Fluorination of pyrrole derivatives by Selectfluor™. Tetrahedron 72(19): 2456-2463.
- Abraham, F., Ford, W.E., Scholz, F., Nelles, G., Sandford, G. & von Wrochem, F. (2016). Surface Energy and Work Function Control of AlOx/ Al Surfaces by Fluorinated Benzylphosphonic Acids. ACS Applied Materials & Interfaces 8(18): 11857-11867.
- Willis, N.J., Fisher, C.A., Alder, C.M., Harsanyi, A., Shukla, L., Adams, J.P. & Sandford, G. (2016). Sustainable synthesis of enantiopure fluorolactam derivatives by a selective direct fluorination – amidase strategy. Green Chemistry 18(5): 1313-1318.
- Sato, K., Sandford, G., Shimizu, K., Akiyama, S., Lancashire, M.J., Yufit, D.S., Tarui, A., Omote, M., Kumadaki, I., Harusawa, S. & Ando, A. (2016). Synthesis of fluorinated isoxazoles using SelectfluorTM: preparation and characterization of 4-fluoroisoxazole, 4,4,5-trifluoroisoxazoline and 4,4-difluoro-5-hydroxyisoxazoline systems from one-pot and multi-step processes. Tetrahedron 72(13): 1690-1698.
- Gadsby, J.M., McPake, C.B., Murray, C.B. & Sandford, G. (2016). Synthesis of polyfluorinated terphenyl and styrene derivatives by palladium catalysed C-F bond activation of polyfluoronitroaromatic substrates. Journal of Fluorine Chemistry 181: 51-55.
- Harsanyi, A. & Sandford, G. (2015). Fluorine gas for life science syntheses: green metrics to assess selective direct fluorination for the synthesis of 2-fluoromalonate esters. Green Chemistry 17(5): 3000-3009.
- Harsanyi, A. & Sandford, G. (2015). Organofluorine Chemistry: Applications, sources and sustainability. Green Chemistry 17(4): 2081-2086.
- Breen, J.R., Sandford, G., Patel, B. & Fray, J. (2015). Synthesis of 4,4-difluoro-1H-pyrazole derivatives. Synlett 26(01): 51-54.
- Harsanyi, A. & Sandford, G. (2014). 2-Fluoromalonate esters: fluoroaliphatic building blocks for the life sciences. Organic Process Research & Development 18(8): 981-992.
- Fisher, C.A., Harsanyi, A., Sandford, G., Yufit, D.S. & Howard, J.A.K. (2014). Fluorotetrahydroquinolines from diethyl 2-fluoromalonate ester. CHIMIA 68(6): 425-429.
- Sandford, G., Slater, R., Yufit, D.S., Howard, J.A.K. & Vong, A. (2014). Pyrido[3,2-b][1,4]oxazine and pyrido[2,3-b][1,4]benzoxazine systems from tetrafluoropyridine derivatives. Journal of Fluorine Chemistry 167: 91-95.
- Harsanyi, A., Sandford, G., Yufit, D.S. & Howard, J.A.K. (2014). Syntheses of fluoro-oxindole and 2-fluoro-2-arylacetic acid derivatives from diethyl 2-fluoromalonate ester. Beilstein Journal of Organic Chemistry 10: 1213-1219.
- Shaughnessy, MJ, Harsanyi, A, Li, J, Bright, T, Murphy, CD & Sandford, G (2014). Targeted fluorination of a nonsteroidal anti-inflammatory drug to prolong metabolic half-life. ChemMedChem 9(4): 733-–736.
- Fox, M.A., Pattison, G., Sandford, G. & Batsanov, A.S. (2013). 19F and 13C GIAO-NMR chemical shifts for the identification of perfluoro-quinoline and -isoquinoline derivatives. Journal of Fluorine Chemistry 155: 62-71.
- Bright, TV, Dalton, F., Elder, V.L., Murphy, C.D., O’Connor, N.K. & Sandford, G. (2013). A convenient chemical-microbial method for developing fluorinated pharmaceuticals. Organic & Biomolecular Chemistry 11(7): 1135-1142.
- McPake, C.B., Murray, C.B. & Sandford, G. (2013). Continuous flow synthesis of difluoroamine systems by direct fluorination. Australian Journal of Chemistry 66(2): 145-150.
- Sandford, G. (2013). Efficient Preparations of Fluorine Compounds. Edited by Herbert W. Roesky. ChemMedChem 8(8): 1417.
- Cargill, M.R., Sandford, G., Kilickiran, P. & Nelles, G. (2013). Pd-catalysed sp2-sp cross-coupling reactions involving aromatic C-F bond activation in highly fluorinated nitrobenzene systems. Tetrahedron 69(2): 512-516.
- Hudson, A., Hoose, A., Sandford, G. & Cobb, S.L. (2013). Synthesis of a novel tetra-fluoropyridine containing amino acid and tripeptide. Tetrahedron Letters 54(36): 4865-4867.