Process Wednesday: 10% NBS in DMF will exotherm -- who knew?

Credit: Shimizu et al. Org. Process Res. Dev.

From the pages of OPRD [1], an interesting comment on N-bromosuccinimide and unexpected exotherms with amide solvents -- the authors study it using ARSST:

Recently, an unanticipated exothermic reaction of NBS with DMF was reported.^3c* Both Shinohara and Kunito reported that the dramatic onset temperature of heat generation decreases in differential scanning calorimetry (DSC) of the DMF solution of NBS compared with the crystals.^3c,4 Shilcrat reported that NBS is incompatible with DMA and must not be premixed with it, because an exothermic reaction easily occurs at ambient temperature.⁵ 

...The stabilities of mixtures of NBS and solvents were probed with ARSST experiments using the following procedure. A 5-g sample of 10 wt % NBS in solvent was loaded into the ARSST 10-mL glass test cell with a Teflon-coated thermocouple, which was sealed in a 350-mL vessel and pressurized to 250−420 psi nitrogen to prevent solvent evaporation. The samples were heated from 30 to 150−200 °C at 2−3 °C/min under a polynominal control condition by stirring with a Teflon-coated magnetic stirring bar. 

In the four amide solvents of DMF, DMA, NMP and N,Ndimethylpropionamide, exothermic events were observed at onset temperatures of about 110, 60, 45 and 68 °C, respectively (Figure 1). In DMF, the peak rate of temperature rise (dT/dt). reached 105 °C/min. (Figure 2). The stabilities of NBS in these amide solvents were ranked as follows: DMF > N,Ndimethylpropionamide > DMA > NMP. The presence of the α proton of the carbonyl group is suspected as the cause of the destabilization although the stability of NBS varies with the kind of amide...

The authors perform a lot more experiments with NBS, which I'll summarize below:

• MeCN, dichloromethane and EtOAc are recommended because they show relatively small exotherms when heated with NBS. Toluene reacted with NBS to form benzyl bromide  (not a surprise, really), with a 20°C rise with an onset at 108°C. 
• The authors also analyzed NBS in DMF with RC1e reaction calorimetry; they conclude that it exhibits autocatalytic behavior. 
• The authors note that NBS reacts with dimethylacetamide to form an adduct ; they independently synthesized it to verify. 
• DBDMH is another brominating reagent -- it also shows similar ARSST results with heating in DMF and DMA. 

The authors' conclusion:

Acetonitrile, dichloromethane and ethyl acetate do not show significant incompatibility with NBS and can be recommended as solvents for use with this reagent. However, amides, THF and toluene do show significant incompatibility with NBS with autocatalytic behavior. The use of solutions of NBS in such solvents should be avoided, particularly at high concentration or elevated temperature and with preparation ahead of time.  

Ideally, a procedure should be adopted whereby NBS is allowed to react with the target substrate, either by addition as a solid or as a solution in an inert solvent. Since incompatibilities between NBS and solvents are caused by the radical cascade and the risk of incompatibilities is increased by mixing in impurities such as a radical initiator, consideration of the solvent quality is needed. DBDMH showed the same behavior as NBS, and therefore the same considerations of incompatibility would be needed.

A brief perusal of the OPRD literature does not reveal a lot of uses of NBS in solvents other than acetonitrile, which is good, I think. But a good reminder that chemical safety hazards lurk in the most innocent of compounds and reagents.

1. Shimizu, S.*; Imamura, Y.; Ueki, T. "Incompatibilities between N-Bromosuccinimide and Solvents." Org. Process Res. Dev., Article ASAP DOI: 10.1021/op400360k

*"Kunito, Y. Presented at the Summer Symposium of The Japan Society for Process Chemistry, Funabori, Tokyo, July 2010. He reported that the onset temperature of DSC analysis of the NBS crystal was 175 °C, whereas that of the NBS solution in DMF (NBS/DMF = 1/1) dropped down to 63 °C."