Organic Syntheses, Coll. Vol. 5, p.351 (1973); Vol. 41, p.16 (1961).
An efficient condenser (60 cm. or longer)
is fitted with an adapter
to which is sealed a length of 9-mm. tubing extending nearly to the bottom of a 5-l. round-bottomed flask
, which serves as the distillation receiver (Note 2)
and (Note 3)
. The adapter should be connected to the receiver with a two-hole stopper
carrying a drying tube
if anhydrous diazomethane
is desired. The receiver
is placed in a well-mixed ice-salt mixture, and sufficient anhydrous ether (about 200 ml.)
is added to cover the tip of the adapter.
In a 5-l. round-bottomed flask are placed 3 l. of U.S.P. solvent grade ether
, 450 ml. of diethylene glycol monoethyl ether (Note 4)
, and 0.6 l. of 30% aqueous sodium hydroxide
solution (Note 5)
. The mixture is chilled in an ice-salt bath
to 0° (Note 6)
, and 180 g. (0.5 mole) of N,N'-dimethyl-N,N'-dinitrosoterephthalamide
(70% in mineral oil) (Note 7)
is added in one portion. The flask is immediately transferred to a heating mantle and connected by a gooseneck to the condenser. The yellow color of diazomethane
appears in the receiver almost immediately. About 2 l. of ether
is distilled in 2–2.5 hours (Note 8)
; the distilling ether
is practically colorless at this point. The tip of the adapter should be kept just below the surface of the distillate during the distillation. The distillate contains 0.76–0.86 mole
) (Note 9)
and (Note 10)
as determined by titration.2
When the apparatus has been protected with a drying tube, the diazomethane
is suitable for reaction with an acid chloride without further drying.
is not only toxic but also potentially explosive. Hence one should wear heavy gloves and goggles and work behind a safety screen or a hood door with safety glass, as is recommended in the preparation of diazomethane
described by De Boer and Backer.3
As is also recommended there, ground joints and sharp surfaces should be avoided. Thus all glass tubes should be carefully fire-polished, connections should be made with rubber stoppers
, and separatory funnels
should be avoided, as should etched or scratched flasks. Furthermore, at least one explosion of diazomethane
has been observed at the moment crystals (sharp edges!) suddenly separated from a supersaturated solution. Stirring by means of a Teflon-coated magnetic stirrer
is greatly to be preferred to swirling the reaction mixture by hand, for there has been at least one case of a chemist whose hand was injured by an explosion during the preparation of diazomethane
in a hand-swirled reaction vessel
It is imperative that diazomethane
solutions not be exposed to direct sunlight or placed near a strong artificial light because light is thought to have been responsible for some of the explosions that have been encountered with diazomethane
. Particular caution should be exercised when an organic solvent boiling higher than ether
is used. Because such a solvent has a lower vapor pressure than ether
, the concentration of diazomethane
in the vapor above the reaction mixture is greater and an explosion is more apt to occur.
Both the toxicity and explosion hazards associated with diazomethane
are discussed by Gutsche.4
If it is desired to determine the yield of diazomethane
by titration, the receiver should be calibrated so that the volume of the distillate can be measured without the necessity of transferring to a graduated vessel.
The submitters have used equipment having all connections made with ungreased 29 / 42 ground-glass joints. This is contrary to previously recommended practice (Note 1)
. The submitters feel that ground-glass joints do not represent an added hazard, and that their use expedites the completion of consecutive runs. In the course of many preparations, however, a film of polymethylene was found to accumulate on the joints and prevent a tight fit. This film can be removed by a brief treatment with hot concentrated alkali and vigorous rubbing.
In some forty preparations made by the submitters, one explosion occurred which was attributed to the cracking of the adapter tube during the distillation. The adapter and the drying tube were disintegrated, but the receiver and the contents of the distilling flask were not affected, indicating a local detonation that was not sustained.
The checkers did not use glassware with ground-glass joints. New unmarked flasks and condenser were used which were connected together with fire-polished glass tubing and rubber stoppers.
Practical grade 2-(2-ethoxyethoxy)ethanol (Matheson, Coleman and Bell)
can be used without further treatment. In a few preparations, the submitters encountered difficulty with the formation of a very stiff gel of disodium terephthalate
in the flask during distillation. In one case, this difficulty was traced to the use of an old bottle of 2-(2-ethoxyethoxy)ethanol
from another source.
This relatively large volume of cosolvent was found to give optimum yields. The submitters have found that the evolution of diazomethane
from a stirred suspension of the reagent in ether
and 40% aqueous sodium hydroxide
is extremely slow and incomplete.
Caution! It is extremely important that the flask contents be cooled to at least 0°. The reaction is rapid and a considerable amount of diazomethane is generated at this temperature.
This material is available from Eastman Organic Chemicals and Aldrich Chemical Company. It is also available from E. I. du Pont de Nemours and Company, who use the trade name Nitrosan for it. The 30% white mineral oil acts as a stabilizer. The material may be stored indefinitely at room temperature. It sometimes turns green on long standing, but this does not affect the yield of diazomethane
(private communication from B. C. McKusick).
The yield of diazomethane
is slightly lower if the distillation is carried out more slowly.
The average yield in some thirty runs was over 80%
; yields as high as 95%
have been obtained. It is probable that a second receiver in series would permit the recovery of a small additional amount of diazomethane
The checkers decomposed the small amount of diazomethane
remaining in the reaction flask by careful addition of 100 ml. of acetic acid
The great advantages of the present method are the availability, moderate cost, and high stability of the nitrosamide, and the suitability for large-scale preparations. The procedure is rapid and simple, and the yields are consistently higher than in any other method tried by the submitters.
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