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How Dangerous Is Too Dangerous? A Perspective on Azide

Chemistry
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A ll chemists should be aware of the risks inherent to their

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work and should consider how to adequately protect

themselves and their colleagues from such hazards. This begs
the question: Can a reaction be so dangerous that, in a general
purpose laboratory, even in the presence of such precautions,
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the residual risk is still too high? We contend that yes, certain
reactions fall into this category: those that employ stoichio-
metric quantities of hydrazoic acid, those that form transition
metal azides, and those that combine inorganic azide with
dichloromethane.
A recent article in this journal authored by Gazvoda et al.
describes a procedure for preparing triazoles from alkynes
using stoichiometric sodium azide, stoichiometric acid, and
catalytic copper, followed by a workup that may include
dichloromethane.1,2 As industrial chemists with decades of
experience safely scaling up azide chemistry, we feel compelled
to share with the research community our three major safety
concerns with this procedure.
In the first case, the combination of sodium azide and acid
affords hydrazoic acid. Hydrazoic acid is both acutely toxic
(mouse LD50 = 22 mg/kg)3 and a powerful explosive; in its
neat form, hydrazoic acid is more explosive than TNT and
orders of magnitude less stable.4 The first scientists to isolate
hydrazoic acid (Curtius and Radenhausen, in 1891)5 found
that “the blast of 50 mg was sufficient to disintegrate the Figure 1. Application of Henry’s Law and Antoine’s Equation to a 2.0
apparatus to dust” and when a subsequent 700 mg batch wt % solution of HN3 in water at 25 °C9
“exploded spontaneously”, it seriously injured the coauthor
(Radenhausen) and the shock wave from the explosion In general, when dilute hydrazoic acid solutions are to be
shattered every glass vessel nearby. There is no safe quantity generated or stored, best practices are to add a low-boiling
when dealing with neat hydrazoic acid. solvent (such as ether or pentane) to dilute any vapor and/or
While dilute hydrazoic acid is safer than the neat compound, condensate.4f Calculations based on the temperature and pH
it remains extremely dangerous. In the gas phase, mixtures with may be necessary to understand appropriate safe concentration
nitrogen containing more than 10% HN3 are explosive.4g In limits.6b,7b Additionally, if a reaction system contains hydrazoic
water, a precise value has not been determined, but it is acid or may generate hydrazoic acid, a continuous nitrogen
generally accepted that solutions of >20 wt % HN3 are purge of the headspace may be employed to prevent
explosive.6 The unique risk posed by hydrazoic acid in solution condensation, and the entire apparatus may be maintained
is that due to its low boiling point (∼36 °C), inadvertent above 37 °C to ensure no hydrazoic acid can condense.
evaporation and recondensation of a dilute, nonexplosive Returning to the procedure for triazole synthesis disclosed
solution can result in a concentrated, explosive solution (see by Gazvoda et al., the second major safety concern is the
Figure 1).7 It is critical to understand that condensed droplets
of concentrated hydrazoic acid require neither oxygen nor a Published: September 2, 2022
spark in order to explode (i.e., the so-called “fire triangle” does
not apply).4b The slightest amount of friction or impact can
result in detonation. Numerous explosions have been reported
when dealing with hydrazoic acid in solution, many of which
have unfortunately led to injuries and deaths.8
Published 2022 by American Chemical
Society https://doi.org/10.1021/acs.joc.2c01402
11293 J. Org. Chem. 2022, 87, 11293−11295
The Journal of Organic Chemistry
combination of copper salts and sodium azide. There have been
more than a dozen documented explosions stemming from
copper(I) azide, copper(II) azide, or unidentified mixtures of
copper with sodium azide or hydrazoic acid.10 The number of
individuals killed by these explosions is at least 16. There is no
general best practice for adding transition metals to reactions
containing inorganic azide or hydrazoic acid, because such an
act is extremely hazardous. Highly explosive, shock-, friction-,
and static-sensitive azide salts have been prepared from Al, Ca,
Ti, V, Cr, Mn, Co, Ni, Cu, Zn, Mo, Pd, Ag, Cd, Sn, Sb, Te, Ba,
Pt, Au, Hg, Tl, Pb, and Bi.4b Copper(II) azide, in particular,
has been reported to be so shock-sensitive that gently
disturbing the crystalline solid, even under water, leads to a
violent explosion.10b Because of this, industrial facilities that
prepare or use inorganic azides take great pains to ensure that
metals are rigorously excluded (i.e., no metal reactor
components, no metal fittings, no metal thermocouples, no
metal scoops or spatulas; even floor drains are covered to
prevent azide from making its way into copper pipes).4b,e
The last major safety concern encountered in the procedure
from Gazvoda et al. is the use of dichloromethane in the
workup. As has been reported numerous times, the
combination of inorganic azide and dichloromethane can
lead to highly explosive, shock-sensitive diazidomethane. As
with hydrazoic acid and copper azide, this dangerous
compound has been implicated in a number of explosions
including those that have led to serious injuries.11
We would like to close with an earnest reminder to all
laboratory chemists that working with inorganic azide requires
diligence. As a general rule, acids, halogenated solvents, and
metals should be strictly avoided. We further recommend that
both authors and reviewers keep these serious safety concerns
in mind when preparing and evaluating manuscripts. We all
must do our part to spread awareness of extreme hazards to
avoid repeating the tragic mistakes of the past.
Daniel S. Treitler orcid.org/0000-0001-5375-4920
Simon Leung
■ AUTHOR INFORMATION
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.2c01402
Notes
Views expressed in this editorial are those of the authors and
not necessarily the views of the ACS.
Both authors are employees of Bristol Myers Squibb. Bristol
Myers Squibb participated in the review and approval of this
manuscript.
■ ACKNOWLEDGMENTS
The authors would like to sincerely thank Andrej Shemet and
Vladislav Lisnyak for help with translation of non-English
publications. Additionally, the authors are indebted to Michael
Dummeldinger for assistance with Henry’s Law/Antoine’s
Equation calculations for hydrazoic acid in the vapor phase.
The authors would also like to thank Gregg Feigelson, Lakshmi
Narasimhan, Zachary Garlets, and Trevor Sherwood for their
careful review of the manuscript.
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11294
pubs.acs.org/joc Editorial
Azide Affords 4-Monosubstituted-1,2,3-Triazoles. J. Org. Chem. 2022,
87, 4018.
(2) Our communications with professor Gazvoda prompted a
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https://doi.org/10.1021/acs.joc.2c01402
J. Org. Chem. 2022, 87, 11293−11295
The Journal of Organic Chemistry pubs.acs.org/joc Editorial

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11295 https://doi.org/10.1021/acs.joc.2c01402
J. Org. Chem. 2022, 87, 11293−11295