Specific solvent issues with the SNAr reaction

In assessing the greenness of an SNAr reaction, solvent issues tend to predominate and the reprotoxic solvents like NMP, MEP, DMF, DMAC, TMU, DMI, DMPU and sulfolane should be avoided or replaced where possible.

DMF

The combination of NaH/DMF is still commonly seen in experimental procedures for SNAr and SN2 reactions. While many small scale experiments proceed without incident, this combination can decompose very exothermically leading to loss of thermal control and potential explosion.

http://www.crhf.org.uk/incident101.html

While less serious than safety concerns listed above, the use of NaH-DMF mixture can lead to by-products resulting from the decomposition of DMF – notably Me2NH.

J. Org. Chem. 2009, 74, 2567–2570 Complications from Dual Roles of Sodium Hydride as a Base and as a Reducing Agent

The use of strong bases, especially Na/K hydrides with any dipolar aprotic solvent should really be avoided

Org. Proc. Res. Dev., 2003, 7,  1029–1033 Safety Notables:  Information from the Literature

Sulfolane

Sulfolane has recently been listed with  H360- may damage fertility or the unborn child.

National Institute of Environmental Health Sciences report on sulfolane

Sulfolane MSDS

DMSO

DMSO has very little adverse data around human and environmental toxicity but can decompose violently at high temperatures. The presence of certain bases/electrophiles can considerably lower the temperature at which this decomposition occurs. These safety issues have been well documented.

Org. Process Res. Dev. 2012, 16,  1994–2000 Safety Concerns in a Pharmaceutical Manufacturing

Journal of Thermal Analysis and Calorimetry, Vol. 85 (2006) 1, 25–30 THERMAL HAZARDS AND SAFE SCALE-UP OF REACTIONS CONTAINING DIMETHYL SULFOXIDE

Org. Process Res.  Dev. 2014, 18 , 1836–1842 Safe Scale up of Pharmaceutical Manufacturing Processes with Dimethyl Sulfoxide (DMSO) as Solvent and a Reactant or a Byproduct

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