Org. Synth. 1977, 57, 80
DOI: 10.15227/orgsyn.057.0080
(PENTAFLUOROPHENYL)ACETONITRILE
[Benzeneacetonitrile, 2,3,4,5,6-pentafluoro-]
Submitted by Robert Filler
1 and Sarah M. Woods
2.
Checked by Andrew E. Feiring and William A. Sheppard.
1. Procedure
A. Ethyl cyano(pentafluorophenyl)acetate. A 2-l., four-necked flask equipped with mechanical stirrer, addition funnel, thermometer, and condenser is charged with 650 ml. of N,N-dimethylformamide (Note 1) and 140 g. (1.01 mole) of anhydrous potassium carbonate. The rapidly stirred mixture is heated to 152–154° and 113 g. (1.00 mole) of ethyl cyanoacetate is added dropwise over 10–15 minutes without further heating. The temperature of the mixture is allowed to drop to 110–120° and maintained within this range while 186 g. (1.00 mole) of hexafluorobenzene (Note 2) is added dropwise over 1 hour. The dark mixture is stirred for 3 hours after the addition is complete, poured into 3 l. of ice water contained in a 5-l. Erlenmeyer flask, and acidified (Caution! Foaming) with 20% sulfuric acid. After being cooled overnight in the refrigerator, the top, aqueous layer is decanted from a lower viscous organic layer. The organic layer is dissolved in 600 ml. of diethyl ether, washed with water, and aqueous 10% sodium hydrogen carbonate, and dried over anhydrous magnesium sulfate. The ether is removed on a rotary evaporator, affording 217 g. (78%) of dark oil which crystallizes on standing (Note 3). An analytical sample is prepared by dissolving 2 g. of the crude material in 5 ml. of boiling 95% ethanol. Hexane is added until mixture becomes turbid. Crystallization occurs when the mixture is cooled with vigorous stirring in an acetone–dry ice bath. The solid is quickly collected on a Büchner funnel and transferred to a sublimator. Sublimation at 30° (0.5–1.0 mm.) affords white crystals, m.p. 38–38.5°, of analytically pure ethyl cyano(pentafluorophenyl)acetate (Note 4).
B. (Pentafluorophenyl)acetonitrile. A 1-l., one-necked flask equipped with magnetic stirrer and a reflux condenser is charged with 139.5 g. (0.500 mole) of crude ethyl cyano(pentafluorophenyl)acetate, 350 ml. of aqueous 50% acetic acid, and 12.5 ml. of concentrated sulfuric acid. The mixture is heated at reflux for 15 hours. After cooling to room temperature, the mixture is diluted with an equal volume of water and cooled in an ice bath for 1 hour. The top layer is decanted from a dark organic layer which settles to the bottom of the flask. The organic phase is dissolved in 200 ml. of ether and washed with water and aqueous 10% sodium hydrogen carbonate. After being dried over anhydrous magnesium sulfate, the ether is removed on a rotary evaporator. The residue is distilled through a 25-cm. jacketed Vigreux column, affording 74–78 g. (71–75%) of (pentafluorophenyl)acetonitrile as a colorless liquid, b.p. 105° (8 mm.), n25D 1.4370 (Note 5).
2. Notes
1.
Technical grade N,N-dimethylformamide was stirred over
anhydrous cupric sulfate, filtered, and distilled under reduced pressure. The submitters used
reagent grade N,N-dimethylformamide without purification.
2.
Hexafluorobenzene was purchased from PCR, Inc., Gainesville, Florida, and distilled (b.p.
80–81°) before use.
3.
In one run the checkers obtained only
135 g. of crude product by this procedure. The aqueous solution which was decanted from the crude product was divided into three portions and each portion was extracted with one
250-ml. portion of ether. The combined
ether extracts were washed with water and
aqueous 10% sodium hydrogen carbonate, dried over anhydrous
magnesium sulfate, and concentrated on the rotary evaporator, affording an additional
83 g. of crude product, for a total of
218 g.
4.
1H NMR (CCl
4), δ (multiplicity, number of protons): 1.38 (t, 3H) 4.35 (q, 2H), 5.05 (s, 1H); IR (CHCl
3) cm.
−1: 3003, 2933, 2257, 1760, 1661, 1527, 1513;
19F NMR (CCl
4, CFCl
3 internal standard): δ 141.2 (sym. m, 2
ortho F), 151.8 (t of t,
J1,2 = 20.3 Hz.,
J1,3 = 2.5 Hz.,
para F), 161.1 (m, 2
meta F). The pKa in
dimethyl sulfoxide is 5.06 ± 0.02.
3
5.
1H NMR (CCl
4), δ: 3.75 (s, with fine structure); IR (neat) cm.
−1: 2985, 2273, 1667, 1527, 1515;
19F NMR (CCl
4, CFCl
3 internal standard), δ 142.4 (sym. m, 2
ortho F), 153.8 (t, with fine structure,
J = 20 Hz.,
para F), 161.7 (m, 2
meta F). The pKa in
dimethyl sulfoxide is 15.8 ± 0.3.
3
3. Discussion
The formation of
ethyl cyano(pentafluorophenyl)acetate illustrates the
intermolecular nucleophilic displacement of fluoride ion from an aromatic ring by a stabilized carbanion. The reaction proceeds readily as a result of the activation imparted by the electron-withdrawing
fluorine atoms.
4 The selective hydrolysis of a cyano ester to a nitrile has been described.
5 (Pentafluorophenyl)acetonitrile6 has also been prepared by cyanide displacement on (pentafluorophenyl)methyl halides. However, this direct displacement is always accompanied by an undesirable side reaction, yielding
15–20% of
2,3-bis(pentafluorophenyl)propionitrile. The reaction of one equivalent of
hexafluorobenzene with one equivalent of
lithioacetonitrile (prepared from
acetonitrile and
n-butyllithium) provides a low yield (
7–10%) of
(pentafluorophenyl)acetonitrile and about a
22% yield of
bis(pentafluorophenyl)acetonitrile (m.p.
65°; the pKa in
dimethyl sulfoxide is 7.95 ± 0.04
3). The yield of the latter compound can be increased by use of excess
lithioacetonitrile.
7
(Pentafluorophenyl)acetonitrile is a useful intermediate to
4,5,6,7-tetrafluoroindole.
8 The nitrile is readily converted to
2-(pentafluorophenyl)ethylamine hydrochloride in
80% yield by catalytic hydrogenation in dilute
hydrochloric acid. Although the salt is stable, the amine undergoes a facile intermolecular nucleophilic aromatic substitution reaction, even at room temperature. However, freshly distilled
2-(pentafluorophenyl)ethylamine is converted by heating in the presence of
anhydrous potassium fluoride in
N,N-dimethylformamide to
4,5,6,7-tetrafluoroindoline (
62% yield) by intramolecular nucleophilic displacement of fluoride ion.
9 The indoline is aromatized by treatment with
activated manganese dioxide,
10 giving
4,5,6,7-tetrafluoroindole (
82% yield). The anion of
(pentafluorophenyl)acetonitrile is converted to
bis(pentafluorophenyl)acetonitrile on treatment with
hexafluorobenzene (
vide supra).
11
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
ethanol (64-17-5)
potassium carbonate (584-08-7)
sulfuric acid (7664-93-9)
hydrochloric acid (7647-01-0)
acetic acid (64-19-7)
ether,
diethyl ether (60-29-7)
acetonitrile (75-05-8)
sodium hydrogen carbonate (144-55-8)
cupric sulfate (7758-98-7)
manganese dioxide (1313-13-9)
Ethyl cyanoacetate (105-56-6)
magnesium sulfate (7487-88-9)
n-butyllithium (109-72-8)
potassium fluoride (7789-23-3)
N,N-dimethylformamide (68-12-2)
hexane (110-54-3)
dimethyl sulfoxide (67-68-5)
Fluorine (7782-41-4)
(Pentafluorophenyl)acetonitrile,
Benzeneacetonitrile, 2,3,4,5,6-pentafluoro- (653-30-5)
hexafluorobenzene (392-56-3)
Ethyl cyano(pentafluorophenyl)acetate (2340-87-6)
octafluorotoluene (434-64-0)
2,3-bis(pentafluorophenyl)propionitrile
lithioacetonitrile
bis(pentafluorophenyl)acetonitrile
4,5,6,7-tetrafluoroindole (16264-67-8)
2-(pentafluorophenyl)ethylamine hydrochloride
2-(pentafluorophenyl)ethylamine
4,5,6,7-tetrafluoroindoline
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