Organic Syntheses, Coll. Vol. 6, p.751 (1988); Vol. 51, p.31 (1971).
A. 1,1,3,3-Tetramethylbutyl isonitrile.
A 3-l., three-necked, round-bottomed flask
fitted with a Hershberg stirrer
, a 500-ml. pressure-equalizing addition funnel
, and a nitrogen-inlet tube
is flamed dry under a nitrogen
atmosphere and allowed to cool. The nitrogen-inlet tube is replaced with a low-temperature thermometer
, and the nitrogen line is attached to a Y-tube placed on the addition funnel. To the flask are added 118 g. (0.752 mole) of N-(1,1,3,3-tetramethylbutyl)formamide (Note 1)
and 1500 ml. of N,N-dimethylformamide (Note 2)
. The addition funnel is charged with a premixed (Note 3)
solution of 89 g. (55 ml., 0.75 mole) of thionyl chloride
and 250 ml. of N,N-dimethylformamide
. The flask is immersed in an acetone–dry ice bath
, and moderately fast stirring is started. When the temperature of the flask reaches −50°, the solution in the funnel is added at a rate such that the temperature ranges between −55° and −50° (about 10 minutes are required for the addition). After the addition is complete, the bath is removed momentarily, allowing the reaction temperature to rise to −35°. The bath is then replaced, and 159 g. (1.50 mole) of dry sodium carbonate (Note 4)
is added directly to the mixture (Note 5)
. After the addition the bath is removed, and the flask contents are stirred for an additional 6 hours at room temperature (Note 6)
. The reaction mixture (Note 7)
is poured into a 6-l. Erlenmeyer flask
containing 3 l. of ice water (Note 8)
. The reaction flask is rinsed with 300 ml. of pentane
and sufficient water to dissolve the inorganic material that may be present (Note 9)
. The washings are added to the Erlenmeyer flask. The mixture is stirred vigorously for 5 minutes, and the layers are separated. The upper layer is washed twice with 100-ml. portions of water and dried over anhydrous sodium sulfate
. The solution is filtered, and the pentane
is removed by distillation. The crude product is distilled through a 1.5 × 15 cm. Vigreux column
; the fraction collected at 55.5–56.6°
(11 cm.), yields 86–90 g.
) of 1,1,3,3-tetramethylbutyl isonitrile
0.7944. The compound shows strong absorption in the IR (CCl4
) at 2130 cm.−1
attributable to the isonitrile function. The 1
H NMR spectrum (neat, external tetramethylsilane reference) shows peaks at δ 1.08 (s, 9H, C(CH3
), 1.43 (t, J14N-H
= 2 Hz., 6H, C(CH3
), and 1.58 (t, J14N-H
= 2.3 Hz., 2H, CH2
B. N-(2-Methylbutylidene-1-d)-1,1,3,3-tetramethylbutylamine (Note 10)
. A 1-l., three-necked, round-bottomed flask
fitted with a Teflon paddle stirrer
, a 500-ml. pressure-equalizing addition funnel, and a nitrogen-inlet tube is flamed dry under a nitrogen
atmosphere and allowed to cool. The nitrogen-inlet tube is replaced with a thermometer, and the nitrogen line is attached to a Y-tube placed on the addition funnel. A solution of 27.8 g. (35.1 ml., 0.200 mole) of 1,1,3,3-tetramethylbutyl isonitrile in 300 ml. of anhydrous diethyl ether
is added to the flask. The flask is cooled to 0° with an ice–salt bath
, and 0.2 mole of 2-butyllithium in hexane (Note 11)
is transferred to the addition funnel with a syringe. The alkyllithium solution is added to the stirred (Note 12)
solution at such a rate that the temperature never exceeds 5°. After the addition is complete, the mixture is stirred for 15 minutes as the temperature slowly drops to −5°, and 8 ml. (0.4 mole) of deuterium oxide (Note 13)
is injected rapidly into the reaction mixture (Note 14)
. The ice bath
is removed; the mixture is stirred for 30 minutes and filtered through a Büchner funnel
into a 1-l., round-bottomed flask. The reaction flask is rinsed with pentane
, and the rinse is added to the flask. After evaporation of the solvent, 33.7–34.9 g.
) of the aldimine is collected by distillation through a 1.5 × 15 cm. Vigreux column, b.p. 52.5–54° (1.5 mm.)
1.4321. The IR spectrum (neat) shows strong absorption at 1663 cm.−1
, attributable to the isonitrile function.
is prepared in 86–90%
yield by refluxing 194 g. (1.50 moles) of 1,1,3,3-tetramethylbutylamine
with 138 g. (3.00 moles) of formic acid in 400 ml. of toluene
. Azeotropic distillation using a Dean-Stark trap gradually removes all water and excess formic acid
. The toluene
is removed by distillation at atmospheric pressure, and the product is distilled at reduced pressure, b.p. 76–77° (1 mm.)
1.4521, yielding 203–214 g.
Industrial grade N,N-dimethylformamide
is purified by distillation, first at atmospheric pressure to remove most of the water in the initial small fraction, and then by distillation at reduced pressure from barium oxide
, b.p. 63° (30 mm.)
A temperature rise of about 30° is observed.
Commercial anhydrous sodium carbonate
is dried in a vacuum oven
at 130° for 1 hour.
The mixture can be left stirring overnight since isonitrile is stable to the reaction conditions. Alternatively, a hot-water bath
can be used, with very fast stirring, to heat the mixture quickly to 35°. The bath is then removed, and after 1 hour of additional stirring, the mixture is ready for the workup procedure.
Isonitriles are presumed to be toxic
, and it is recommended that the workup procedure be performed in a hood
. Unlike most isonitriles, however, 1,1,3,3-tetramethylbutyl isonitrile (TMBI)
is not malodorous. It has a sweetish pine odor, which becomes unpleasant only after continued inhalation.
The addition of the reaction mixture to water is exothermic.
The inorganic salts are not always soluble in the amount of water specified.
This procedure uses the commercially available 2-butyllithium
reagent. The submitters state that the corresponding Grignard reagent may also be used. A 300-ml., three-necked, round-bottomed flask
is fitted with an addition funnel, a reflux condenser
, a magnetic stirring bar
, and a nitrogen-inlet tube. Magnesium turnings (3.65 g., 0.150 mole)
and 80 ml. of anhydrous tetrahydrofuran (Note 17)
are added to the flask, and a nitrogen
atmosphere is maintained. 2-Bromobutane (20.6 g., 0.150 mole), 0.25 ml. of 1,2-dibromoethane, and 70 ml. of tetrahydrofuran
are placed in the addition funnel. Stirring is begun, and the solution is added dropwise at a rate which sustains refluxing. After the addition is complete, the solution is stirred until room temperature is reached. The amount of Grignard reagent prepared is determined (Note 18)
. To this Grignard solution is added 14.2 g. (0.102 mole) of 1,1,3,3-tetramethylbutyl isonitrile (Note 19)
. After stirring for 4–6 hours (Note 20)
, the solution is cooled in an ice bath to 0°. To the rapidly stirred solution (Note 21)
is injected 6.0 ml. (0.30 mole) of deuterium oxide (Note 13)
. The ice bath is removed, and the mixture is stirred for 10 minutes before 50 ml. of water is added (Note 22)
. The contents of the reaction flask are decanted into a 1-l. separatory funnel
containing 200 ml. of ether
. The aqueous layer is separated, and the ether
layer is washed with 100 ml. of saturated sodium chloride
. The magnesium salts remaining in the reaction vessel are washed twice with 100-ml. portions of ether
. The ether
extracts are washed with 100 ml. of saturated sodium chloride
. The combined ether
solutions are dried over anhydrous sodium sulfate
and evaporated with a rotary evaporator
, giving the crude aldimine. Distillation (see Part B) yields 13.7 g.
) of the pure aldimine. Hydrolysis and steam distillation (as described in Note 15) yield 5.85 g.
, overall) of the aldehyde (Note 23)
The commercially available organolithium reagent is titrated with benzoic acid
, using triphenylmethane
as an indicator according to the procedure of Eppley and Dixon.2
The checkers used product available from Alfa Inorganics, Inc.
During the addition of the alkyllithium the mixture becomes gelatinous. As this happens, the stirring rate is increased to ensure thorough mixing.
having an isotopic purity of >99% was used. The product available from Columbia Organic Chemicals Company, Inc., was used by the checkers.
The stirring should be very rapid at this point or frothing will occur. The flask temperature will reach 30° during deuteriolysis. It is important that the temperature of the ice–salt bath remains at −10° to −15°.
The submitters recommend the following procedure for steam distillation of low-boiling aldehydes. A 500-ml., three-necked flask
is fitted with two addition funnels, one of which has a double-bore stopcock
for external drainage. This addition funnel is fitted with a cold finger (−5°) and an inlet tube leading to a bubbler and a nitrogen
source. The aldimine is placed in the other addition funnel. While the aldimine is added dropwise to the refluxing oxalic acid
solution, the distillate passes up the equalizing pressure tube of the collecting funnel and is condensed by the cold finger. The water layer is periodically drained back into the flask. After distillation, the aldehyde is washed with saturated sodium chloride
, then drained from the funnel through the external tube.
The submitters found that GC analysis of the undistilled aldehyde, conducted on a column packed with 16% LS-40 on Chromosorb P/AW at 100°, indicated a purity of 98.6%. 1
H NMR (CCl4
) analysis indicated an isotopic purity of 97.9% (trace of impurity at δ 9.60 due to CH
O. If the crude aldimine is hydrolyzed, the aldehyde is obtained in 96% overall yield; however, the purity is only 94% by GC analysis. The checkers found no detectable impurity by GC in the distilled aldehyde, and the NMR spectrum indicated very high isotopic purity.
The molarity is determined3
by adding an excess of standardized acid and back-titrating with base. The moles of Grignard reagent present are determined based on a volume of 150 ml. When ether
is used to prepare the Grignard reagent, an actual measurement of the volume is necessary. This can be done conveniently by transferring the solution back into the addition funnel with a large graduated syringe. The Grignard reagent content averages 0.102 mole.
After 4 hours, periodic aliquots are taken and worked up. The disappearance of the isonitrile absorption at 2130 cm.−1
and the appearance of the imine absorption at 1665 cm.−1
are used for analysis. Usually within 6 hours the isonitrile peak vanishes or remains at a very low constant intensity indicative of completion of the reaction.
The sudden quenching with deuterium oxide
minimizes the exchange between the 1-metalloaldimine and the active hydrogen
at the C-2 position of the already-deuteriated aldimine. Performing the reaction in refluxing tetrahydrofuran
produces an exchange (approximately 10%) with incorporation of deuterium
in the C-2 position. If only the 1-H-aldehyde is desired, 50 ml. of water is added dropwise.
Saturated ammonium chloride
solution slowly hydrolyzes the aldimine to the aldehyde, which, in this case, is undesirable.
NMR analysis shows that deuterium
incorporation at the C-1 position is 95.3% and at C-2, 5%.
Chemical Abstracts Nomenclature (Collective Index Number);
1,1,3,3-tetramethylbutyl isonitrile (TMBI)
Benzyl and vinyllithium
diethyl ether (60-29-7)
ammonium chloride (12125-02-9)
thionyl chloride (7719-09-7)
magnesium turnings (7439-95-4)
sodium chloride (7647-14-5)
sodium carbonate (497-19-8)
sodium sulfate (7757-82-6)
formic acid (64-18-6)
Oxalic acid (144-62-7)
Benzoic acid (65-85-0)
calcium sulfate (7778-18-9)
oxalic acid dihydrate (6153-56-6)
deuterium oxide (7789-20-0)
1,1,3,3-tetramethylbutyl isonitrile (14542-93-9)
Butanal-1-d, 2-methyl- (25132-57-4)
n-Hexylmagnesium bromide (3761-92-0)
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