LABORATORY SAFETY FACT SHEET #26

Synthesizing, Purifying, and Handling Organic Azides

Organic azides are potentially-explosive substances that can and will decompose with the slightest input
of energy from external sources (heat, light, pressure). Additionally, small molecules containing the azido
functionality tend to decompose violently which may result in injury if proper safety precautions are not
utilized.

Organic azides have received renewed interest for their shear diversity of potential organic transformations
but also in no small part to the recent introduction of the concept of ‘Click Chemistry.’

1

 This renewed

interest must be paralleled with a reiteration of the safety precautions one must undertake. In addition to
summarizing the multitude of these synthetic transformations in which azide can participate, recent reviews
have also outlined safety precautions one should take when utilizing these energy-rich molecules. These
manuscripts should be mandatory reading for anyone working with, or around azides.

2

Obtained by simple nucleophilic displacement of a halogen or by copper (I)-catalyzed aryl coupling,
organic azides can be prepared, purified, and handled safely provided one takes the following precautions:

NaN

3

:

•

Azide ion has a similar toxicity as that of cyanide ion (LD

50

 = 27 mg/kg for rats). Be sure to use

appropriate gloves when weighing azido salts.

•

Sodium azide reacts violently with several common laboratory organics such as: CS2, bromine,
Bronstead acids, and heavy metals. When attempting a new reaction, be relentless in your background
research to determine the reactivity of sodium azide to ALL reaction components.

•

NEVER use chlorinated solvents as reaction media! Utilizing dichloromethane or chloroform will
result in the formation of explosively-unstable di- and tri- azidomethane, respectively (refer to section
on C/N ratios below).

•

Heavy metals (e.g., Cu, Pb, Ba) form shock and pressure sensitive compounds with azide anions. This
may affect us in that an ‘azide residue’ may form of metal parts.

Organic Azides:

•

All organic azides decompose with introduction of external energy. Any azide synthesized should be
stored below room temperature (-18°C) and in the dark.

•

When designing your target azide, keep in mind the following equation.

1

 Notice that this equation

takes into account all nitrogen atoms in your azide, not just those in the azido group. 

N

 signifies the

number of atoms.

                                                                   

3

≥

+

N

O

C

N

N

N

                                                   (eq. 1)

•

In practice, organic azides that contradict the above equation can be made, and in some cases, be stored safely.
Consider the following points as strict guidelines in the preparation and storage of organic azides. As with all
synthetic procedures a small scale (ca. 0.5-1.0 gram) should be run first to determine the nature of the product:

- 

n

-nonyl azide (C/N=3) will be the smallest azide isolated and stored in its pure form. This azide, when

stored properly, can be done so in multigram quantities (up to 20 grams). In practice, the octyl derivative is
equally safe (C/N=2.7).

- Azides smaller than C/N=3 (but greater than C/N=1) can be synthesized and isolated, but by no means
should these molecules be stored in its highest purity. Rather, if storage is necessary store these azides as
solutions below room temperature (concentrated to no more than 1M, less than 5 grams material).

- Under no circumstances should azides with C/N < 1 be isolated. However, these molecules may only even
be considered for synthesis if the azide is a transient intermediate species, AND the limiting reagent in the
reaction mixture, AND with maximum quantities of 1 grams. For instance, methyl azide can be synthesized
in situ and immediately reacted with an excess of a terminal acetylene.

1

•

Never use distillation or sublimation as purification techniques! Purification should be limited to extraction
and precipitation. Column chromatography may contribute to decomposition so only purify azides that satisfy
equation 1.

•

Organic azide waste should be placed in a separate, explicitly-labeled container designated solely for azide
waste. Extra caution must be taken to make certain that azide waste not come in contact with acid. Acids will
protonate the azide ion and from the highly-toxic hydrogen azide (toxicity similar to that of hydrogen cyanide).

1

. Kolb, H.C.; Finn, M.G.; Sharpless, K.B. 

Angew.  Chem. Int. Ed.

 

2001

, 

40

, 2004-2021.

2

. Brase, S.; Gil, C.; Knepper, K.; Zimmerman, V. 

Angew. Chem. Int. Ed.

 

2005

, 

44

, 5188-5240. And all references therein.

3

. Smith, P.A.S. Open-Chain Nitrogen Compounds, vol. 2, Benjamin, New York, 1966, 211-265.

4

. Feldman, A.K.; Colasson, B.; Fokin, V.V. 

Org. Lett

. 

2004

, 

6

, 3897. Thibault 

et al.

 manuscript in preparation