Org. Synth. 1945, 25, 65
DOI: 10.15227/orgsyn.025.0065
MESITYLACETIC ACID
[Acetic acid, mesityl-]
Submitted by Reynold C. Fuson and Norman Rabjohn.
Checked by W. E. Bachmann, E. L. Jenner, and G. Dana Johnson.
1. Procedure
A. α
1-
Chloroisodurene. In a
2-l. round-bottomed flask, equipped with a
sealed mechanical stirrer (Note 1), a
gas inlet tube, and a
reflux condenser, are placed
200 g. (1.66 moles) of mesitylene,
1 l. of concentrated hydrochloric acid, and
63 ml. (0.84 mole) of formaldehyde solution (concentration, 37%) (Note 2).
Hydrogen chloride is introduced below the surface of the mixture
(Note 3), which is stirred vigorously and heated in a
water bath kept at 55°. These conditions are maintained throughout the reaction, which requires a total of 5.5 hours. At the halfway point, an additional
63 ml. (0.84 mole) of formaldehyde solution is added
(Note 4).
After the mixture has been cooled to room temperature
(Note 5), it is extracted with three
300-ml. portions of benzene. The combined
benzene extracts are washed successively with water, dilute
sodium hydroxide, and water, dried over
calcium chloride, and filtered. The mixture is distilled through a still head under reduced pressure; the pressure is reduced only slightly while the
benzene is distilling. The yield of
α1-chloroisodurene boiling at
130–131°/22 mm. is
155–170 g. (
55–61%)
(Note 6); the distillate solidifies to a crystalline mass which melts at
37°.
B.
Mesitylacetonitrile. In a
1-l. three-necked flask, fitted with a mechanical stirrer, a reflux condenser, and a
dropping funnel, are placed
77 g. (1.57 moles) of sodium cyanide, 110 ml. of water, and
160 ml. of ethanol. The flask is heated in a boiling water bath, and the contents are stirred until all the
sodium cyanide is dissolved. Then
152 g. (0.90 mole) of α1-chloroisodurene is added slowly, and stirring and heating are continued for 3 hours.
The reaction mixture is allowed to cool to about 40° (Note 7) and extracted with three 300-ml. portions of benzene. The benzene solution is washed well with water, dried over calcium chloride, filtered, and distilled under slightly reduced pressure to remove all the benzene. The residue is then distilled under reduced pressure from a Claisen flask with a wide-bore side arm. The yield of mesitylacetonitrile boiling at 160–165°/22 mm. is 128–133 g. (89–93%) (Note 8). This product is sufficiently pure for the next step. When recrystallized from petroleum ether, it melts at 79–80°.
C. Mesitylacetic acid. To 900 ml. of water in a 3-l. three-necked flask is added 750 ml. of concentrated sulfuric acid. When the mixture has cooled to about 50°, 127 g. (0.80 mole) of mesitylacetonitrile is added (Note 9), and the mixture is refluxed and stirred mechanically for 6 hours. At the end of this period, a large amount of mesitylacetic acid has precipitated from the solution. The contents of the flask are cooled and poured into 3 l. of ice water. The acid is collected on a Büchner funnel and washed well with water. A solution of the acid in dilute alkali is boiled with Norit, and the acid is precipitated from the filtered solution by acidifying with dilute hydrochloric acid. The mesitylacetic acid is collected on a filter, washed well with water, and dried in an oven at about 80°. The yield of mesitylacetic acid melting at 163–166° is 123 g. (87%). After recrystallization from dilute alcohol or ligroin, the acid melts at 167–168°.
2. Notes
1.
The checkers used an
Ace Tru-bore stirrer. This convenient sealed stirrer, which owes its seal to the snug fit between a ground-glass section of the stirrer shaft and a ground-glass bearing, can be obtained from the Ace Glass Company, Vineland, New Jersey.
2.
Commercial
formalin was used. This aqueous-methanolic solution contains
37% formaldehyde by weight. It is sometimes called "40% formalin" because
100 ml. of the solution contains 40 g. of formaldehyde.
3.
The
hydrogen chloride is introduced at such a rate that the bubbles form a little faster than they can be counted.
4.
The yield of monochloromethyl compound seems to be improved slightly by adding the
formalin in two portions instead of introducing the entire amount at the beginning of the reaction.
5.
If the reaction mixture is cooled to too low a temperature, the chloromethyl derivatives will solidify. It is much easier to carry out the extractions while the mixture is still liquid.
6.
The residue consists chiefly of
α1,α2-dichloropentamethylbenzene. The fraction boiling at
131–200°/22 mm. is collected and recrystallized from
petroleum ether; m.p.
105°.
7.
If the reaction mixture is allowed to cool much below this temperature, it will solidify in the flask.
8.
This method has been applied successfully to the preparation of
2,4,6-triethylphenylacetonitrile (b.p.
127°/3–4 mm.; yield,
72%);
durylacetonitrile (m.p.
80–81°; yield,
75%); and
isodurylacetonitrile (m.p.
74–75°; yield,
74%).
9.
If the
mesitylacetonitrile has not been purified by distillation, or if it is added to a boiling solution of
sulfuric acid, the reaction mixture has a tendency to become very dark.
3. Discussion
α
1-Chloroisodurene can be prepared by the action of
chloromethyl ether on
mesitylene in the presence of
stannic chloride3 or
acetic acid.
1 The procedure described is based on that of Nauta and Dienske.
4Mesitylacetonitrile can be prepared by the action of
potassium cyanide on α
1-chloroisodurene
2 or by treating α
1-chloroisodurene with
cuprous cyanide in the presence of
pyridine.
5 The procedure described is based upon the method for the preparation of
benzyl cyanide from
benzyl chloride.
Mesitylacetic acid has been prepared from
2,4,6-trimethylacetophenone by treatment with yellow
ammonium sulfide and hydrolyzing the resulting amide with alkali,
6 by the dry distillation of
2,4,6-trimethylmandelic acid,
7 by heating
2,4,6-trimethylphenylglyoxylic acid with
hydriodic acid and red phosphorus8 or with
hydrazine hydrate,
9 by the action of boiling water on
mesitoyldiazomethane10 (prepared in turn from
mesitylglyoxal monohydrazone), and by treating
mesitylacetonitrile with
potassium hydroxide.
2
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
red phosphorus
ligroin
petroleum ether
durylacetonitrile
isodurylacetonitrile
2,4,6-trimethylacetophenone
ethanol (64-17-5)
calcium chloride (10043-52-4)
sulfuric acid (7664-93-9)
hydrogen chloride,
hydrochloric acid (7647-01-0)
acetic acid (64-19-7)
Benzene (71-43-2)
sodium hydroxide (1310-73-2)
formaldehyde,
formalin (50-00-0)
sodium cyanide (143-33-9)
Cuprous Cyanide (544-92-3)
potassium cyanide (151-50-8)
Norit (7782-42-5)
pyridine (110-86-1)
potassium hydroxide (1310-58-3)
benzyl chloride (100-44-7)
Benzyl cyanide (140-29-4)
hydriodic acid (10034-85-2)
Mesitylene (108-67-8)
hydrazine hydrate (7803-57-8)
ammonium sulfide
chloromethyl ether (542-88-1)
stannic chloride (7646-78-8)
2,4,6-trimethylphenylglyoxylic acid (3112-46-7)
2,4,6-trimethylmandelic acid
Mesitylacetic acid,
Acetic acid, mesityl- (4408-60-0)
mesitylacetonitrile (34688-71-6)
2,4,6-triethylphenylacetonitrile
mesitoyldiazomethane
mesitylglyoxal monohydrazone
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