Org. Synth. 1955, 35, 6
DOI: 10.15227/orgsyn.035.0006
3-BENZYL-3-METHYLPENTANOIC ACID
[Valeric acid, 3-benzyl-3-methyl-]
Submitted by F. S. Prout, R. J. Hartman, E. P.-Y. Huang, C. J. Korpics, and G. R. Tichelaar
1.
Checked by James Cason, K. C. Dewhirst, E. J. Gauglitz, Jr., and William G. Dauben.
1. Procedure
A. Ethyl sec-butylidenecyanoacetate.. In a 1-l. round-bottomed flask fitted with a 24/40 joint are placed 0.45 g. of β-alanine, 113 g. (106 ml., 1.0 mole) of ethyl cyanoacetate (Note 1), 87 g. (108 ml., 1.2 moles) of butanone, 20 ml. of glacial acetic acid, and 100 ml. of benzene. A Barrett-type water separator (Note 2) and a condenser are attached to the flask, and the mixture is heated briskly under reflux until water ceases to be collected in the trap (7–12 hours).
The reaction mixture is decanted into a 500-ml. round-bottomed flask which is attached to a fractionating column (Note 3). The solvent is removed at atmospheric pressure while the oil bath is heated finally at 160°. The residue is distilled at reduced pressure to furnish four fractions: (a) acetic acid and other materials boiling below 95°/16 mm.; (b) ethyl cyanoacetate, b.p. 95–110°/16 mm.; (c) intermediate, b.p. 110–124°/16 mm.; and (d) ethyl sec-butylidenecyanoacetate, b.p. 124–126°/16 mm., nD25 1.4640–1.4648. Fraction d amounts to 117–122 g., and refractionation of fraction c yields an additional 18–24 g.; total yield, 135–146 g. (81–87.5%) (Note 4).
B.
Ethyl 3-benzyl-2-cyano-3-methylpentanoate. A
2-l. three-necked round-bottomed flask, fitted with a
tantalum wire Hershberg stirrer, a condenser, and a
separatory funnel, is arranged for use of a
nitrogen atmosphere.
2 Magnesium (19.2 g., 0.79 g. atom) and
100 ml. of dry ether3 are placed in the flask, and a solution of
100 g. (91 ml., 0.79 mole) of benzyl chloride in 500 ml. of dry ether is added in a period of 1.5–2.0 hours, with stirring, while the mixture boils spontaneously. The mixture is boiled for 15 minutes after completion of the addition, then a solution of
110 g. (0.66 mole) of ethyl sec-butylidenecyanoacetate in 130 ml. of benzene is added over a 30-minute period with spontaneous reflux. The reaction mixture is stirred and heated under reflux for an additional hour. A precipitate separates after about 30 minutes.
The reaction mixture is poured onto about 400 g. of cracked ice and is made acidic with 20% sulfuric acid. After two clear phases have formed the mixture is poured into a separatory funnel, and the lower layer is removed. This aqueous layer is extracted with two 100-ml. portions of benzene and discarded. The three organic extracts are washed separately and successively with 125 ml. of water and 125 ml. of saturated sodium chloride solution, then filtered successively through a layer of anhydrous sodium sulfate.
The combined extract (about 1 l.) is flash-distilled at atmospheric pressure from a 250-ml. Claisen flask. After the solvent and a small amount of fore-run (ca. 15 g., b.p. 45°/3 mm.) have been removed, the product is distilled to yield 157–162 g. (92–95%), b.p. 150–162°/3 mm. (bath temperature, 180–190°), nD25 1.5053–1.5063 (Note 5), (Note 6), and (Note 7).
C. 3-Benzyl-3-methylpentanenitrile. Sixty-seven grams (1 mole) of potassium hydroxide (85%) is dissolved by heating in 360 ml. of ethylene glycol and is added to a 1-l. round-bottomed flask containing 155 g. (0.6 mole) of ethyl 3-benzyl-2-cyano-3-methylpentanoate (above). A condenser is attached with a rubber stopper, and the mixture is heated under gentle reflux for 3 hours (Note 8). The resulting two-phase mixture is cooled, diluted with 350 ml. of water, and extracted with three portions of ether (250 ml., 100 ml., 100 ml.). The three extracts are washed successively with 100 ml. of water and 100 ml. of saturated sodium chloride solution, then filtered through a layer of anhydrous sodium sulfate (Note 9). The combined extracts are flash-distilled at atmospheric pressure from a 250-ml. Claisen flask to remove the ether. The residue is distilled at reduced pressure to furnish 102–105 g. (91–93%) of nitrile, b.p. 150–160°/11 mm. (bath temperature, 190–200°), nD25 1.5111–1.5128 (Note 10) and (Note 11).
D. 3-Benzyl-3-methylpentanoic acid. A solution of 112 g. (1.6 moles) of potassium hydroxide (85%) in 400 ml. of ethylene glycol is added to 93.6 g. (0.5 mole) of 3-benzyl-3-methylpentanenitrile in a 1-l. round-bottomed copper or stainless-steel flask. A condenser with a rubber stopper is attached, and the solution is heated under brisk reflux for 6 hours (Note 12). The reaction mixture is cooled, diluted with 400 ml. of water, and extracted with three portions of ether (250 ml., 100 ml., 100 ml.). The ether extracts are washed successively with two 75-ml. portions of water and then discarded (Note 13).
The combined aqueous phases are acidified to Congo red with 200 ml. of concentrated hydrochloric acid and extracted with three portions of benzene (200 ml., 75 ml., 75 ml.). The benzene extracts are washed successively with 100 ml. of water and 100 ml. of saturated sodium chloride solution, then filtered through anhydrous sodium sulfate. The combined extract is flash-distilled from a 250-ml. Claisen flask at atmospheric pressure (bath temperature, up to 160°). The residue is distilled at reduced pressure to give 94–96 g. (91–93%) of acid; b.p. 173–177°/7 mm. (bath temperature, 207–220°), nD25 1.5160–1.5163 (Note 14) and (Note 15).
2. Notes
1.
Ethyl cyanoacetate was obtained from Kay-Fries Chemicals, 180 Madison Avenue, New York, New York.
2.
The submitters used a Barrett Distilling Receiver, Corning No. 3622, Corning Glass Works, Corning, New York.
3.
The submitters used a
60-cm. heated Vigreux column to effect this fractionation. The checkers used a similar column with partial take-off head.
4.
Fractions
b–d consist entirely of
ethyl cyanoacetate and the product. Pure
ethyl cyanoacetate and
ethyl sec-butylidenecyanoacetate have
nD25 1.4151 and 1.4650, respectively. The purity of fractions
b–d can be estimated by their indexes of refraction, which are proportional to the weight per cent.
5.
The pure product obtained by fractional distillation has
nD25 1.5052. The product obtained by distillation from a Claisen flask is contaminated mainly with
bibenzyl, b.p.
122–125°/3 mm., f.p. 44°. The purity of the product can be estimated by determination of the saponification equivalent in
ethanol.
6.
The use of
dibenzylcadmium gave no improvement in yield.
7.
Phenylmagnesium bromide gives a
79% yield of product, b.p.
178–180°/11 mm.,
nD25 1.5063; and
n-propylmagnesium bromide gives
33–42% yields, b.p.
150–153°/22 mm.,
nD25 1.4429, of alkylation product when essentially the same procedure is used. The yield obtained with
n-propylmagnesium bromide depends upon the efficiency of separation from the reduction product,
ethyl sec-butylcyanoacetate, b.p.
126°/22 mm.,
nD25 1.4277.
48.
After 30 minutes of reflux the second phase begins to separate. The formation of this nitrile layer is probably complete after 2.5–3.0 hours. A small amount of solid, presumably
ammonium carbonate, collects in the condenser during the heating.
9.
When the combined aqueous washes from three runs were acidified, extracted, and distilled, there was obtained
1.8 g. of
3-benzyl-3-methylpentanoic acid,
nD25 1.5158.
10.
This nitrile is contaminated with some lower-boiling
bibenzyl and some higher-boiling amide. The pure nitrile, obtained by fractional distillation, has
nD25 1.5110.
11.
Hydrolyses of
ethyl 2-cyano-3-methyl-3-phenylpentanoate and
ethyl 2-cyano-3-ethyl-3-methylhexanoate (Note 7) by essentially this procedure gave
71% (b.p.
149–151°/16 mm.,
nD25 1.5149) and
68% (b.p.
103–104°/31 mm.,
nD25 1.4291) yields of nitriles, respectively. In the second case, about
12% additional yield of nitrile could be obtained from the acidic fraction, which contains some undecarboxylated product,
2-cyano-3-ethyl-3-methylhexanoic acid.
12.
The two-phase solution becomes homogeneous after 1.5–2.0 hours of boiling. This alkaline solution is very corrosive, and a glass flask can be used only a few times in this reaction. A stainless-steel or copper flask is preferable.
13.
If emulsions are encountered, the addition of a few milliliters of saturated aqueous
sodium chloride clears them readily. The combined
ether extracts contain
4–5 g. of solid, neutral material. This product is mainly
bibenzyl, b.p.
138–143°/7 mm., f.p. 40°.
14.
The best sample of this acid obtained by fractional distillation had
nD25 1.5160; neut. equiv., 207.3 (calcd., 206.3).
15.
Hydrolyses of
3-methyl-3-phenylpentanenitrile and
3-ethyl-3-methylhexanenitrile (Note 11) by the described procedure gave
88% and
95% yields of
3-methyl-3-phenylpentanoic acid (b.p.
190–194°/26 mm.,
n25D 1.5182) and
3-ethyl-3-methylhexanoic acid (b.p.
136–137°/15 mm.,
nD25 1.4377), respectively.
3. Discussion
Ethyl sec-butylidenecyanoacetate has been prepared by this condensation using various amino acids,
5 ammonium acetate,
6 sodium sulfate-piperidine,
7 and
zinc chloride-aniline.
8
The
ethyl 3-benzyl-2-cyano-3-methylpentanoate, 3-benzyl-3-methylpentanenitrile, and
3-benzyl-3-methylpentanoic acid preparations follow the procedure given by Prout, Huang, Hartman, and Korpics.
9
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
sodium sulfate-piperidine
zinc chloride-aniline
ethanol (64-17-5)
sulfuric acid (7664-93-9)
hydrochloric acid (7647-01-0)
acetic acid (64-19-7)
ammonium carbonate (506-87-6)
Benzene (71-43-2)
ether (60-29-7)
ammonium acetate (631-61-8)
magnesium (7439-95-4)
sodium chloride (7647-14-5)
sodium sulfate (7757-82-6)
nitrogen (7727-37-9)
potassium hydroxide (1310-58-3)
benzyl chloride (100-44-7)
ethylene glycol (107-21-1)
Ethyl cyanoacetate (105-56-6)
Phenylmagnesium bromide (100-58-3)
β-Alanine (107-95-9)
butanone (78-93-3)
bibenzyl (103-29-7)
3-Benzyl-3-methylpentanoic acid,
Valeric acid, 3-benzyl-3-methyl- (53663-16-4)
Ethyl 3-benzyl-2-cyano-3-methylpentanoate (70289-04-2)
3-Benzyl-3-methylpentanenitrile
dibenzylcadmium
ethyl 2-cyano-3-methyl-3-phenylpentanoate
ethyl 2-cyano-3-ethyl-3-methylhexanoate (70289-02-0)
2-cyano-3-ethyl-3-methylhexanoic acid
3-methyl-3-phenylpentanenitrile (50843-73-7)
3-ethyl-3-methylhexanenitrile (138808-09-0)
3-methyl-3-phenylpentanoic acid
3-ethyl-3-methylhexanoic acid
ethyl 3-benzyl-2-cyano-3-methylpentanoate, 3-benzyl-3-methylpentanenitrile
n-propylmagnesium bromide
Ethyl sec-butylidenecyanoacetate (868-47-3)
ethyl sec-butylcyanoacetate
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