We have never had such an energetic response to the PTC Tip of the Month as we had last month from you, our PTC community audience. Several of you, including Peter Wuts, Danny Levin and Radi Awartani, sent references and even full articles that describe the explosive consequences of mixing sodium hydride with solvents such as DMF, DMSO and DMAc on scale. You were shocked that the simple etherification reported in US Patent 11,142,509 used NaH/DMF on a 14 kg scale.
Peter Wuts (of protecting group fame https://petergmwuts.com/) highlighted the very important article at Org. Process Res. Dev. 2019, 23, 2210. This alarming article reported detailed investigations into the thermal stability of mixtures of NaH with DMF, DMSO and DMAc and studies of the formation of gaseous products from their thermal decomposition.
If you EVER consider using NaH on scale, it is imperative that you read this article before running your first reaction. The introduction in this article will scare you. Then the ARC and DSC data provide the basis for realizing how close you may have been disaster in your career until now. Figure 6 shows pictures of the ruptured Hastelloy C ARC cell and the displaced ARC reactor housing resulting from the cell explosion when testing 4.5 g NaH/DMSO. One look at Figure 6 will cause you to lose sleep if you read the procedure described last month that used 3.68 kg NaH in 71 liters DMF with 14.2 kg of alcohol that was O-methylated.
Danny Levin pointed out that Bretherick’s Handbook of Reactive Chemical Hazards flags NaH/DMF as unpredictably explosive. Danny authored a 70-page chapter on scale up safety entitled “Managing Hazards for Scale Up of Chemical Manufacturing Processes” in ACS Symposium Series Volume 1181 (2014). It is highly recommended that you obtain this chapter even if you think you had all the safety training you need. If you have done a reaction with NaH/DMF, you could still benefit from Danny Levin’s chapter.
Radi Awartani cited an article from Johns Hopkins Lab Safety warning about the safety issues of NaH with DMSO and DMF: https://labsafety.jhu.edu/2019/08/22/sodium-hydride-decomposes-certain-solvents-violently/
We greatly appreciate the input of our loyal knowledgeable readers in the PTC community!
ACTION STEPS
Action Step 1: Before you set foot in your lab the next time, obtain a copies of these references, especially this OPRD article. Then read the article, no later than lunch tomorrow, unless you are about to run a reaction today using NaH/DMF. It might save your life!
Action Step 2: From this moment on and for the rest of your life, if you EVER are tempted to run a reaction using NaH/DMF, NaH/DMSO or NaH/DMAc, contact Marc Halpern of PTC Organics to explore using PTC/NaOH for your base-promoted reaction. Ignore the fact that this might appear to be a marketing message, it’s actually much more important that you go home every day after work in your car than in an ambulance when you make the choice to use PTC-NaOH instead of NaH/DMF.
