Hazard Awareness

Diazomethane is a yellowish, explosive, and highly toxic gas with a boiling point of -23^oC and a melting point of -145^oC. It can be explosive in its pure and undiluted form but has also been known to detonate unexpectedly in the diluted form. Bright light, sharp/rough edges, and scratched glassware all have been known to trigger diazomethane explosions, as have certain metal ions in drying agents (e.g. CaCl₂, MgSO₄, CaSO₄, and Na₂SO₄).

In addition to its explosive nature, diazomethane is an irritant and highly toxic (more toxic than hydrogen cyanide) by inhalation or contact with skin or eyes. It is also a sensitizer, and long term exposures can lead to asthma-like symptoms, including chest discomfort, headache, weakness, and/or collapse.

Diazomethane is useful as a powerful and fact acting alkylating agent and carbene source for laboratory work; however, these same characteristics make is an equally powerful genotoxic compound.

Substitution

Whenever possible, trimethylsilyldiazomethane (also known as TMS-diazomethane, CAS# 18101-18-1) should be used in place of diazomethane because it is more stable and less likely to explode (however, it is still highly toxic).

Engineering Controls

Work involving diazomethane should be carried out only within a properly functioning chemical fume hood with some form of shielding being used. Diazomethane distillations must use a blast shield that protects the researcher from the apparatus without hindering their ability to manipulate the experiment.

Working with diazomethane in its pure and undiluted form is discouraged because it is so dangerous. Diluting it in diethyl ether is highly recommended. If work with concentrated diazomethane is unavoidable, specialized diazomethane distillation equipment (with flame-polished joints) is commercially available along with instructions from Sigma-Aldrich.

A blast shield	A researcher using hood sashes as a shield	A large-scale diazomethane distillation setup with clear glass joints.

Administrative Controls

Inexperienced laboratory workers should not attempt to create or manipulate diazomethane reactions without first getting guidance from senior laboratory personnel. Work with diazomethane should only be performed with a standard operating procedure (SOP) in place. The SOP should include emergency response, quenching procedures, and storage policies.

Personal Protective Equipment

Standard laboratory personal protective equipment (PPE) (laboratory coat, safety eyewear, and gloves) should be used when working with diazomethane; due to the chemical's explosive and highly toxic nature, a face shield and double gloving are recommended.

Emergency Response

Spills of diazomethane should be handled with the utmost urgency. If a spill happens inside a chemical fume hood, immediately close the sashes and let it evaporate; activate the emergency exhaust (if equipped). Immediately evacuate the lab if there is a large spill (>100 mL) outside the chemical fume hood. Open the chemical fume hood sashes if possible before evacuating, and activate fire alarms to alert others to evacuate the building. For small spills (<100 mL), it is probably enough to evacuate the lab.

First aid for diazomethane inhalations is immediate exposure to fresh air followed by prompt care at an emergency room. Because Safety Data Sheets (SDS) of diazomethane is not available (it is too dangerous to transport), take the SDS for TMS-Diazomethane to inform emergency health workers of diazomethane's hazards.

Eye and skin exposures should be treated by flushing with large quantities of water for 15 minutes. Adding soap for skin exposures can help neutralize diazomethane by allowing it to react with a substrate.

Working With Diazomethane

Generation Procedure

Use a new 500 mL Erlenmeyer flask that is free of scratches or chips and equipped with a magnetic stir bar. Ground glass joints should also be avoided. Add 40% aqueous potassium hydroxide solution (~50-100 mL) and diethyl ether (~100-100 mL). Place this flask into an ice bath on top of a magnetic stirrer. Let the mixture stir at a moderate rate until the ether layer has had time to chill. Add portion-wise a diazomethane derivative of your choice. Add only one spatula at a time, and wait approximately two minutes between additions while keeping the ethereal mixture cold throughout.Critical note: To avoid explosions, stir the ethereal/KOH solution vigorously enough to avoid localized variation in concentration and temperature one the derivative is added. This is also the reason for slow, portion-wise additions of the derivative.

As the nitrosoamine derivative is added, the ether layer will gradually become more yellow. After adding ~10-15 grams of the nitrosoamine derivative, the ether layer should have a bright yellow color. Depending on the nitrosoamine derivative, this should yield approximately 50-150 mmol of diazomethane. It is now ready for use. The generated diazomethane has been dissolved in the ether layer (hence the yellow color) and can be decanted into a container to be placed in storage for short periods of time (see Storage section below), or it can be used immediately. When transferring solutions of diazomethane, use plastic (i.e. funnels, pipettes) when possible; sharp, rough ended and scratched glassware can cause diazomethane to detonate. If the concentration determination of the diazomethane solution is desired, perform a titration of the yellow diazomethane solution with benzoic acid. See all three Organic Syntheses reference in this document of anhydrous synthesis of diazomethane.

Diazomethane synthesis

Quenching

Do not dispose of diazomethane solutions via normal waste streams due to its explosive and highly toxic nature. Quench diazomethane first and then dispose of it through normal waste streams.

To quench excess diazomethane, cool the reaction mixture to 0^oC and add a few drops of acetic acid into the reaction mixture. Add drops of acetic acid until the yellow color of diazomethane disappears and nitrogen gas formation ceases. This will also neutralize the residual KOH solution left over from the diazomethane generation procedure.

Storage

Note: Storage of diazomethane solutions is highly discouraged!

Due to diazomethane's explosive and highly toxic nature, it should be stored in a freezer only for short periods of time (one to two weeks). It is best to make small amounts of diazomethane as needed, but if the work being done requires periodic small amounts, then store ethereal solutions of diazomethane in a freezer in a tightly stoppered (rubber stopper) bottle that has been parafilm-sealed. Do not store diazomethane below its melting point (-145^oC) as this may cause crystallization that triggers an explosion. Avoid cryogenic storage of diazomethane outside the use of dry ice or a freezer. Be sure the bottle has no scratches and place a few pellets of potassium hydroxide in it as a drying agent. Do not use any other drying agent, as diazomethane will react with certain metal ions to cause explosions. Be sure to indicate the contents on the container label. The precursors (e.g. diazald, N-nitrosomethlurea) should be stored in a refrigerator to help reduce reagent degradation and enhance reagent quality.

References

Vogel’s Textbook of Practical Organic Chemistry 5^th Ed., B.S. Furniss; A.J. Hannaford; P.W.G. Smith; A.R. Tatchell, Longman Group UK Limited, 1989, ISBN 0-582-46236-3

Bretherick’s Handbook of Reactive Chemical Hazards 6^th Ed., P.G. Urben (Ed.), Oxford, Butterworth-Heinemann, 1999, ISBN 0-7506-3605-X

Handbook of Reagents for Organic Synthesis – Reagents, Auxillaries and Catalysts for C-C Bond Formation, edited by Robert M. Coates and Scott E. Denmark, John Wiley & Sons, Inc., 1999, ISBN 0-471-97924-4

T. H. Black, Aldrichimica Acta, Vol. 16, Issue 1, 1983, pg.3-10.

Large scale batch process for diazomethane.  US Patent No. 5817778, Oct. 6, 1998.

Organic Syntheses, Coll. Vol. 2, p.165, 1943.

Organic Syntheses, Coll. Vol. 4, p.250, 1963; Vol. 36, p.16, 1956.

Organic Syntheses, Coll. Vol. 5, p.351, 1973; Vol. 41, p.16, 1961.

NIOSH Pocket Guide to Chemical Hazards, DHHS (NIOSH) Publication No. 2005-149, Sep. 2007.