Specific Solvent Issues / Safety Issues with Sulphide Oxidations

Oxidation is generally thermodynamically favored and many oxidation reactions are highly exothermic, thus careful consideration of safety factors is required before any scale-up. Key issues are the potential for a thermal runaway and the stability of the oxidizing agent. Many such as peroxides and peracids such as MCPBA have known incompatibilities with several solvents.

W metal catalyzed oxidation with H₂O₂

Shilcrat, S. C. Process Safety Evaluation of a Tungsten Catalyzed Hydrogen. Org. Proc. Res. Dev. 2011, 15, 1464-1469.

Instability of concentrated MCPBA in DCM and DMF and thermal incidents with DMF with acids/bases/halogens and oxidants including MCPBA.

Zhang, X.; Hu, A.; Pan, C.; Zhao, Q.; Wang, X.; Lu, J. Safer Preparation of m-CPBA/DMF Solution in Pilot Plant. Org. Proc. Res. Dev. 2013, 17, 1591-1596.

Yang, Q.; Sheng, M.; Huang, Y. Potential Safety Hazards Associated with Using N,N-Dimethylformamide in Chemical Reactions. Org. Proc. Res. Dev. 2020, 24, 1586-1601.

Yang, J.; Jiang, J.; Jiang, L.; Pan, X.; Pan, Y.; Ni, L. Thermal instability and kinetic analysis on m-chloroperbenzoic acid. Journal of Thermal Analysis and Calorimetry 2019, 135 (4), 2309-2316.

General safety ranking of oxidants

Dallaston, M. A.; Bettencourt, C. J.; Chow, S.; Gebhardt, J.; Spangler, J.; Johnston, M. R.; Wall, C.; Brusnahan, J. S.; Williams, C. M. Ranking Oxidant Sensitiveness: A Guide for Synthetic Utility. Chem. Eur. J. 2019, 25, 9614-9618.

Safe use of air/O₂ in the presence of flammable solvents

Osterberg, P. M.; Niemeier, J. K.; Welch, C. J.; Hawkins, J. M.; Martinelli, J. R.; Johnson, T. E.; Root, T. W.; Stahl, S. S. Experimental Limiting Oxygen Concentrations for Nine Organic Solvents at Temperatures and Pressures Relevant to Aerobic Oxidations in the Pharmaceutical Industry. Org. Proc. Res. Dev. 2015, 19, 1537-1543.

Flow/continuous processing

The application of flow chemistry /continuous processing can have application in the oxidation of sulphides where reactions are often exothermic and use oxidants that would give rise to special handling issues in large batch reactors.

The ability to work under pressure and elevated temperature can also mean that less reactive but greener most atom efficient terminal oxidants like air/O2 or H2O2 can be employed.

Martin, B.; Sedelmeier, J.; Bouisseau, A.; Fernandez-Rodriguez, P.; Haber, J.; Kleinbeck, F.; Kamptmann, S,; Susanne, F.; Hoehn, P.; Lanz, M.; Pellegatti, L.; Venturoni, F.; Robertson, J.; Willis, M. C.; Schenkela, B.Toolbox study for application of hydrogen peroxide as a versatile, safe and industrially-relevant green oxidant in continuous flow mode. Green Chem., 2017, 19, 1439-1448.

Kulkarni, A. A.; Nivangune, N. T.; Joshi, R. R.; Joshi, R. A. Continuous Flow Multipoint Dosing Approach for Selectivity Engineering in Sulfoxidation. Org. Proc. Res. Dev. 2013, 17, 1293-1299

Reddy, G.; S.; Reddy, N. S.; Manudhane, K.; Krishna, M. V. R.; Ramachandra, K. J. S.; Gangula, S. Application of Continuous Flow Micromixing Reactor Technology for Synthesis of Benzimidazole Drugs. Org. Proc. Res. Dev. 2013, 17, 1272-1276.

Silva, F.; Baker, A.; Stansall, J.; Michalska, W.; Yusubov, M. S.; Graz, M.; Saunders, R.; Evans, G. J. S.; Wirth, T. Selective Oxidation of Sulfides in Flow Chemistry. Eur. J. Org. Chem. 2018, 2018, 2134-2137.

On-line monitoring

The use of PAT or continuous reaction monitoring can be to avoid over-oxidation where sufoxides are the target, and avoid accumulation/concentration of potentially hazardous oxidizing agents like peracids.

Cohen, D.; Cosbie, A.; Milburn, R. R.; Shaw, S.; Xie, Y. Application of In Situ Raman Spectroscopy To Facilitate Use of Hydrogen Peroxide on Kilogram Scale. Org. Proc. Res. Dev. 2014, 18, 1807-1811.

Šahnić , D.; Meštrović , E.; Jednačak , T.; Habinovec , I.; Vuković, J. P.; Novak, P. Monitoring and Quantification of Omeprazole Synthesis Reaction by In-Line Raman Spectroscopy and Characterization of the Reaction Components. Org. Proc. Res. Dev. 2016, 20, 2092-2099.