Organic Syntheses, Coll. Vol. 6, p.190 (1988); Vol. 55, p.27 (1976).
A 200-ml., round-bottomed flask
equipped with a magnetic stirring bar
is charged with 11.6 g. (0.100 mole) of hexanoic acid (Note 1)
and 10 ml. of carbon tetrachloride
. After 46.9 g. (28.8 ml., 0.394 mole) of thionyl chloride (Note 2)
is added to the solution, an efficient reflux condenser
with an attached drying tube is fitted to the flask. The solution is stirred and heated with an oil bath
at 65° for 30 minutes (Note 3)
. The flask is removed from the oil bath and cooled to room temperature. To the reaction mixture are added successively 21.4 g. (0.120 mole) of finely powdered N-bromosuccinimide (Note 4)
, 50 ml. of carbon tetrachloride
, and 7 drops of 48% hydrogen bromide (Note 5)
. The flask is heated at 70° for 10 minutes (Note 6)
, before the temperature of the bath is increased to 85°, until the color of the reaction becomes light yellow (ca.
1.5 hours; (Note 7)
. The reaction mixture is cooled to room temperature, and the carbon tetrachloride
and excess thionyl chloride
are removed under reduced pressure (Note 8)
. The residue is suction filtered, the solid (Note 9)
is washed several times with carbon tetrachloride (total 20 ml.)
and the combined filtrate collected in a 50-ml. flask. The solvent is removed from the solution as before, and the residue is distilled into a dry ice-cooled receiver (short-path column)
, giving, after a small forerun, 16.1–17.1 g.
) of 2-bromohexanoyl chloride
, b.p. 44–47° (1.5 mm.)
as a clear, slightly yellow oil, n22D
1.4707. This material is of sufficient purity for most synthetic purposes (Note 10)
Practical grade hexanoic acid is obtainable from Matheson, Coleman and Bell
. The submitters report slightly higher yields using purified grade hexanoic acid obtained from Fisher Scientific Company
Thionyl chloride was obtained from Anachemia Chemicals Ltd., Fisher Scientific Company (reagent grade), or Matheson, Coleman and Bell
. The first two were slightly yellow, and the latter was colorless; however, the yields of final product were identical with each brand. The excess thionyl chloride
serves as a drying agent for the hexanoic acid
and as a solvent for the N-bromosuccinimide
, which is not very soluble in carbon tetrachloride
H NMR analysis indicates complete conversion to the acid chloride. This may be monitored by following the disappearance of the triplet (CH2
H) at δ 2.40 and the emergence of a new triplet (CH2
COCl) at δ 2.87.
N-Bromosuccinimide was obtained from Matheson, Coleman and Bell or Aldrich Chemical Company, Inc.
Product yields were optimized using 20% excess, although only 5–10% yield reductions were noted using 5% excess reagent. Recrystallizing the reagent prior to use had no noticeable effect on the overall yield of product.
If the reaction was heated too rapidly to 85°, vigorous foaming resulted.
Initially the reaction mixture is dark red, and there is bromine
vapor in the condenser. Toward the end of the reaction the color lightens considerably and after a short period (ca.
15 minutes) begins to darken again. The heat should be removed when this darkening commences. On standing, the yellow solution may also turn black, but the yield of the product is not noticeably affected. When the stirring is stopped, succinimide
floats to the top of the solution. The reaction may be conveniently monitored by following the disappearance of the triplet (CH2
COCl) at δ 2.87 and appearance of a triplet (CH
BrCOCl) at δ 4.54 in the 1
H NMR spectrum.
The evaporation of solvents under reduced pressure should be performed carefully with vigorous stirring at room temperature. An oil pump
protected with a dry ice trap
and equipped with a manometer is used. Initially the pressure should be adjusted to prevent excessive foaming; it is reduced progressively to approximately 5 mm.
About 10 g. of the solid (succinimide)
The IR and 1
H NMR spectra are identical with those of colorless, doubly distilled material; n22D
When the decolorization procedure was carried out before the first distillation, inconsistent yields were obtained. About 2.5 ml. of a dark viscous liquid (giving a violet solution on dilution in carbon tetrachloride
) remained in the distillation flask.
When more drying agent was employed, the product yield was lower.
A central fraction had n22D
Analysis calculated for C6
BrClO: C, 33.75; H, 4.72; Br, 37.42; Cl, 16.60. Found: C, 33.42; H, 4.77; Br, 37.29; Cl, 16.74. IR (NaCl) cm.−1
: 2955, 2925, 1785, 1470; 1
H NMR δ (multiplicity, number of protons): 0.94 (m, 3H), 1.43 (m, 4H), 2.10 (m, 2H), 4.54 (t, 1H), mass spectrum m/e
: 179, 177 (M–Cl).
The corresponding α-bromo acid is prepared by the following procedure. A 500-ml., round-bottomed flask
is charged with 10.28 g. (0.04826 mole) of 2-bromohexanoyl chloride
and 92 ml. of acetone
. The flask is fitted with a magnetic stirring bar, a thermometer, and a 200-ml. dropping funnel
in which is placed 115 ml. of aqueous saturated sodium hydrogen carbonate (ca. 0.115 mole)
. The flask is cooled to approximately 10°, while the base is added over a period of about 45 minutes. The mixture is acidified with concentrated hydrochloric acid
. An organic layer forms at the top and is separated from the aqueous layer, which is extracted with three 30-ml. portions of chloroform
. The combined organic extracts are dried over anhydrous magnesium sulfate
and the solvent is removed under reduced pressure, giving 9.36 g.
of crude 2-bromohexanoic acid
as a colorless liquid. This product is 96% pure by GC analysis, using a Hewlett-Packard 5750 Research Chromatograph with a 1.8 m. 4% SE-30 column at 130°, and having a flow rate of 60 ml./minute. This product can be distilled through a short-path column, yielding, after an 11% forerun, 7.76 g.
) of 2-bromohexanoic acid
, b.p. 64–66° (0.075 mm.)
, which shows one peak by GC analysis (as above). IR and 1
H NMR spectra are consistent with the structure.
The α-bromination of acids (via
the acid chloride) has been achieved by the Hell–Volhard–Zelinsky reaction or its variances,2
however, this technique can involve reaction times of up to 2–3 days,3
high reaction temperatures (>100°), copious evolution of hydrogen bromide
, and variable yields. A recent procedure,4
while affording good overall yields, involves several steps to achieve the transformation (alkylation, proton abstraction, bromination, deacylation and deësterification).
The submitters have found the N-bromosuccinimide
procedure to be a very general reaction. Alkyl, alicyclic, aryl, and heterocyclic acetic acids have been brominated in 50–80% yield.5
The reaction may be applied in the presence of labile benzylic hydrogens; for example, 3-phenylpropanoic acid
gives exclusively 2-bromo-3-phenylpropanoyl chloride
The procedure has several significant advantages; it is considerably faster than the known methods (overall reaction times of 2 hours are common),7
the use of bromine
is circumvented, and work-up is simplified considerably.
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