Organic Syntheses, CV 2, 279
[(A) (From Ethoxalylpropionic Ester)]
Submitted by Richard F. B. Cox and S. M. McElvain.
Checked by Reynold C. Fuson and William E. Ross.
1. Procedure
Three hundred forty-five grams (1.7 moles) of ethyl ethoxalylpropionate, b.p.
114–116°/10 mm. (p. 272), is placed in a round-bottomed flask of suitable size carrying a
reflux condenser, and a
thermometer is suspended from the top of the condenser into the liquid. The
ethyl ethoxalylpropionate is then heated until a vigorous evolution of
carbon monoxide begins (130–150°). The temperature of the liquid is gradually raised as the gas evolution diminishes, and finally the liquid is refluxed until no more gas comes off. The
ethyl methylmalonate is then distilled. It boils at
194–196°/745 mm., and the yield is
288 g. (
97 per cent of the theoretical amount).
[(B) (From Malonic Ester)]
Submitted by Nathan Weiner
Checked by Reynold C. Fuson and E. A. Cleveland.
1. Procedure
Forty-six grams (2 gram atoms) of sodium, cut into small pieces, is added to
1 l. of absolute ethyl alcohol (Note
1) in a
2-l. three-necked flask equipped with a
mechanical stirrer and a reflux condenser with a
calcium chloride tube. When all the
sodium is in solution,
320 g. (2 moles) of ethyl malonate (Note
2) is added. Then
200 g. (2.1 moles) of methyl bromide (Note
3) is bubbled into the stirred solution through a tube (at least 4 mm. in diameter) in the third neck of the flask which dips to the bottom of the solution.
The addition of the
methyl bromide consumes about four hours. The reaction proceeds smoothly and with evolution of heat, occasionally reaching the boiling point of the mixture. During the course of the reaction
sodium bromide separates. When the addition of
methyl bromide is complete, the solution is pale orange and faintly alkaline. It is boiled for an additional half-hour then neutralized with glacial
acetic acid and cooled. The
sodium bromide is filtered with suction and washed on the funnel with a little cold alcohol. The major part of the alcohol is then removed by distillation at atmospheric pressure (Note
4). The
sodium bromide is dissolved in 600–700 cc. of water containing
10 cc. of concentrated hydrochloric acid. The resulting solution (Note
5) is added to the residue from the distillation and the mixture shaken well. The aqueous lower layer is separated from the ester and extracted twice with
ether. The ester and
ether extracts are combined and dried by shaking quickly with
calcium chloride and filtering immediately. The
ether is removed, and the ester is shaken for exactly one minute with a cold solution of
10 g. of sodium hydroxide in 30 cc. of water (Note
6). The alkali is drawn off; the ester is washed with dilute acid and dried as before with
calcium chloride. It is then distilled
in vacuo, and the fraction boiling at 96°/16 mm. is taken. There is almost no fore-run or residue. The yield is
275–290 g. (
79–83 per cent of the theoretical amount).
2. Notes
1. The quality of the alcohol is very important, traces of water depressing the yield considerably. Absolute
alcohol, as ordinarily supplied, is best dried by distillation from a
2–3 per cent solution of sodium, a fore-run and the last 25 per cent being rejected.
2. Even the better grades of
malonic ester have been found to contain sufficient impurities to decrease the yield. However, one distillation, at reduced pressure, of even the technical grade of
malonic ester makes it sufficiently pure for this synthesis.
3. Vials of
methyl bromide may be conveniently used by cooling in an
ice bath, breaking the seal, and attaching to the
delivery tube by means of ordinary rubber tubing. The vial is then allowed to come to room temperature, and the evaporation of the liquid keeps it sufficiently cool so that it enters the solution at the desired rate. It is best to dry the gas by passage through a
tower of potassium hydroxide pellets.
If
methyl bromide is not available, it may be generated as follows:
500 g. of 95 per cent sulfuric acid is added slowly, with shaking, to
400 g. of ordinary methyl alcohol, cooled by an ice bath.
Six hundred grams of sodium bromide is suspended in one half of this mixture in a
1-l. round-bottomed flask, fitted with a
two-holed stopper holding a
dropping funnel and a delivery tube. The evolution of
methyl bromide is started by heating the flask with a
water bath at 50°, and the remainder of the methyl alcohol-acid mixture is added slowly from the funnel as the volume of the mixture in the flask decreases. As the rate of evolution of the gas falls off the temperature is slowly raised until no more
methyl bromide is generated and the contents of the flask have become completely solid. The flask is shaken from time to time during the generation to mix the components more thoroughly. The evolved gas is dried by passage through a tower of potassium hydroxide pellets.
4. The removal of the alcohol at atmospheric pressure is best carried out by returning the filtrate to the original reaction flask, in which the mechanical stirrer is retained but the reflux condenser is replaced by a goose-neck and a condenser for downward distillation. The solution is stirred as the alcohol is distilled, thus eliminating the violent bumping that would otherwise occur at the separation of
sodium bromide from the concentrated solution.
5. The use of the
sodium bromide in this way serves the multiple purpose of releasing any ester that may be adsorbed on it, of depressing the solubility of the ester in the water, and of making the water layer sufficiently dense for the ester to float on it.
3. Discussion
The most widely used method of preparing
ethyl methylmalonate is by the alkylation of
ethyl malonate with
methyl iodide,
2,
1 methyl bromide,
3 or
methyl sulfate.
4 A separation of the desired product from traces of unchanged starting material and from
ethyl dimethylmalonate cannot be accomplished by distillation as the boiling points of the three esters lie within three and one-half degrees of one another. Michael
1 found that unchanged
malonic ester can be removed completely by taking advantage of the greater ease with which it is hydrolyzed by alkali, while Gane and Ingold
5 obtained a pure product by hydrolysis, crystallization of the
methylmalonic acid, and re-esterification. It can be inferred from the results of Salkowski, Jr.,
6 with
acetoacetic ester that no disubstitution occurs when
methyl bromide is employed as the alkylating agent. Procedure
B above, which is based on the work of Michael,
1 has been published.
7
Pure
ethyl methylmalonate can also be prepared by the reduction of
methylidenemalonic ester with
Raney nickel;
8 from
ethyl α-bromopropionate through the nitrile,
9 an expensive process because of the cost of the materials and the poor yields; and by the pyrolysis of
ethyl ethoxalylpropionate. This last method, which forms the basis for Procedure
A above, was first described by Wislicenus.
10
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