Wednesday, June 22, 2011

Process Wednesday: Handling hydrazoic acid safely

A recent paper in Organic Process Research and Development* has a nice section on hydrazoic acid issues concerning the use of sodium azide to displace an aromatic nitro group; the aromatic azide would then participate in a cyclization to an indazole:
Initial hazard testing focused on the evaluation of hydrazoic acid levels in the head space of the reaction or workup mixtures, as this compound is both highly toxic and can form explosive gas mixtures with oxygen or nitrogen above concentrations of 8-12%. Some variation in the lower decomposition level of hydrazoic acid has been reported; however, a recent study appeared to confirm that detonation below 10 vol% should not be possible.  
Maintaining a basic pH during the reaction mixture should ensure that any hydrazoic aid remained ionized and would thus limit levels in the head space and as such was considered desirable. After some screening it was found that addition of 1 equiv of 2,6-lutidine to the reaction mixture served to maintain a basic pH and has no detrimental effect on the reaction profile or rate. Hence, this base was added prior to heating any reactions. Headspace monitoring using FT-IR indicated undetectable levels of hydrazoic acid in the headspace throughout the course of the reaction using a nitrogen sweep of 16 mL/min.  
On the basis of comparison with CO2 in the headspace and the detection limit of the instrument, this data implied a worse-case hydrazoic acid level in the headspace of 60 ppm with this nitrogen sweep, and it was clear that only a very modest nitrogen sweep (about 0.02 mL/min) would be required to keep concentration of hydrazoic acid below 5 vol% which compares favorale with the lower decomposition limit of 10 vol%. As such there was no significant risk with this aspect of the reaction. 
I think this section is a nice example of a good way to approach potentially hazardous reagent issues. Finding out the minimum limits of toxicity/danger, using monitoring equipment and then keeping levels well-below the minimums seems to be a good strategy to me. A good thought process for all of us.

*Wallace et al, Org. Process Res. Dev. ASAP.  

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