Note: Descriptions are shown in the official language in which they were submitted.
~95~
~ PROCESS FOR THE ISOLATION OF 1,4,7,10,13,16-
; HEXAOXACYCLOOCTADECANE
The invention relates to a process for the isolation
of 1,4,7,10,13,16-hexaoxacyclooctadecane from a mixture
also containing one or more other macrocyclic polyethers.
Hereinafter 1,4,7,10,13,16-hexaoxacyclooctadecane will
also be referred to by its trivial name "18-crown-6". Its
structural formula is shown on the Formula page (compound 9).
18-Crown-6 can be prepared by heating tetraethylene
glycol and bist2-chloroethyl) ether in the presence of tetra-
hydrofuran as a solvent and potassium hydroxide, see l'Synthesis"
101976, 515-516. The reaction mixture thus formed contains
18-crown-6, potassium chloride, water and by-products, i.a.
macrocyclic polyethers having a ring of larger size than
18-crown-6. The solvent was evaporated from the reaction
mixture to give a brown slurry to which dichloromethane was
added. The potassium chloride was filtered off from the solu-
tion thus obtained, the filtrate was dried (MgS04), the solvent
was evaporated from the dried filtrate to yield a residue of
crude 18-crown-6. This residue was distilled to give a dis-
coloured distillate containing 18-crown-6. This distillate
was dissolved in acetonitrile and the solution was cooled to
-45 C. The resultant precipitate of 18-crown-6-acetonitrile
complex was collected by filtration. Distillation of this
complex gave a distillate of pure 18-crown-6.
A disadvantage of this procedure is that the 18-crown-6
is distilled twice and that expensive measures must be taken
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to prevent the occurrence of powerfu] and destruct;ve
explosions during these distillations, see "Chemical &
Engineering News", September 6, 1976, page 5 and December 13,
1976, page 5. Moreover the 18-crown-6 is obtained in a fairly
low yield.
The Applicants have found a process for the isolation of
18-crown-6 in which the 18-crown-6 is obtained in high yield
and need not be distilled, thus avoiding the explosions
mentioned hereinbefore.
Accordingly the invention provides a process for the
isolation of 1,4,7,10,13,16-hexaoxacyclooctadecane from a
mixture also containing one or more other macrocyclic poly-
ethers, characteri2ed by reacting the 1,4,7,10,13,16-hexaoxa-
cyclooctadecane with nitromethane in the presence of a solvent
for the said macrocyclic polyethers, to precipitate a complex
of 1,4,7,10,13,16-hexaoxacyclooctadecane and nitromethane,
separating precipitated complex from the mixture containing
the complex, dissociating separated c.mplex and separating the
components from each other.
Surprisingly, nitromethane is selective in that, when
contacted with a mixture containing 18-crown-6 and one or
more other macrocyclic polyethers, it only forms a complex
with 18-crown-6. Hence, the 18-crown-6-nitromethane complex
obtained according to the invention does not or hardly contain
macrocyclic polyethers other than 18-crown-6.
As the 18-crown-6-nitromethane complex gives off nitro-
methane vapour the complex can simply be dissociated into
18-crown-6 and nitromethane by allowing it to stand in the open
air. The complex is rapidly dissociated by heating it at sub-
atmospheric pressure and removing the nitromethane vapour formed,leaving pure or almost pure 18-crown-6. Heating may take place
at a temperature of, for example, 35C to 125C at a pressure
of, for example, 5 to 1500 Pa.
The process according to the invention must be carried
out in a solvent for macrocyclic polyethers in which the
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18-crown-6-nitromethane complex can be precipitated. Such a
solvent may substantially consist of nitromethane. A solvent
is taken to consist substantially of a specified compound
when the content of this specified compound in the solvent is
higher than 50 ~OW.
According to a feature of the invent;on the solvent sub-
stantially consists of an ether. Preferred ethers are dialkyl
ethers and cyclic ethers. Examples of dialkyl ethers are
diethyl ether, di-n-butyl ether and di-n-hexylether. The
18-crown-6-nitromethane complex is considerably less soluble
in diethyl ether than in nitromethane at the same temperature,
so that a considerably larger part oE the 18-crown-6 present
in the starting mixture can be isolated. Attractive examples
of the cyclic ethers are l,4-dioxane and tetrahydrofuran.
According to another feature of the invention the solvent
substantially consists of an alkanol, a hydrocarbon (or a
mixture of hydrocarbons) or water. Examples of suitable alkanols
are those having in the range of from one to five carbon atoms,
for example methanoltethanol, 2-propanol and tert-butanol.
Examples of suitable hydrocarbons are benzene, toluene, the three
xylenes and heptane. Particularly attractive solvents are
methanol and benzene. 18-Crown-6, dissolved in water may be
removed therefrom by reaction with nitromethane to form a
precipitate of the 18-crown-6-nitromethane complex in nitro-
- 25 methane-containing water. Mixtures of solvents may be used,
for example of diethyl ether and ethanol.
The 18-crown-6-acetonitrile complex is very difficult
to precipitate from the solvents mentioned in the last three
paragraphs, if at all, as this complex is too highly soluble
in these solvents.
The reaction between 18-crown-6 and nitromethane is
preferably carried out at a temperature in the range of from
-25C to ~35 C, and, when the solvent substantially consists
of nitromethane, of from 0C to -25C, 90 as to enable a
very large part of the 18-crown-6 to be isolated. Where the
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solvent substantially consists of an ether, an alkanol, a
hydrocarbon (or a mixture of hydrocarbons) or water, the
reaction between 18-crown-6 and nitromethane is very suitably
carr;ed out at a temperature in the range of from 0 C to +35 C.
Ambient temperature, for example, a temperature between 15C
and 25 C, is very suitable.
The 18-crown-6-nitromethane com?lex can easily be separated
from the mixture containing the complex9 for example by
filtration, centrifugation or decantation.
The 18-crown-6-n;tromethane complex contains two molecules
of nitromethane per molecule of 18-crown-6. Accordingly, the
18-crown-6 is reacted with nitromethane using a molar ratio of
nitromethane to 18-crown-6 of at least 2:1. Preferably, this
molar ratio is not higher than 20:1. This range is not crit;cal,
molar ratios of nitromethane to 18-crown-6 outside this range
may be used, if desired.
The 18-crown-6-nitromethane complex may be precipitated
in any suitable manner, for example by adding nitromethane
to the starting mixture and, ;f desired, cooling the mixture
thus obtained to a suitable temperature, or by dissolving
the starting mixture in d;ethyl ether and adding nitro-
methane at ambient temperature to the solution obtained, or
by dissolving the star~-ing mixture in any other of the
above-mentioned solvents, for example methanol, adding nitro-
methane and, if desired, cooling the mixture obtained to asuitable temperature. The starting mixture may be solid or
liquid at the temperature at which the 18-crown-6 is reacted
with nitromethane.
The 18-crown-6 in the starting mixture may have been formed
by any process. Very good results have been obtained by
reacting tetraethylene glycol with a bis(2-haloethyl~ether,
halo representing chloro, bromo or iodo, in the presence of an
alkali metal hydroxide. If desired, the alkali metal halide
formed and solvent, if present, may be removed from the reaction
mixture obtained, leaving the 18-crown-6-containing start;ng
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mixture. Other examples oE processes for the preparation of
18-crown-6 are:
(1) Elimination of hydrogen chloride from 17-chloro-
3~6~9~12~15-pentaoxaheptadecanol~ followed by ring
closure, in the presence of potassium tert-butoxide,
see British patent specification 1,285,367.
(2) Catalytic oligomeriPation of ethylene oxide, see
German Offenlegungsschrift 2,401,126.
(3) Reaction of triethylene glycol with 3,6-d;oxa-1,8-di-
chlorooctane in the presence of potassium hydroxide
and 10% aqueous tetrahydrofuran, as described in
J.Org.Chem. 39 (1974) 2445-2446.
The invention will now be illustrated by reference to the
following Examples.
Preparation of crude 18-crown-6
A 3-litre three-necked round-bottomed flask, fitted with
a mechanical stirrer, a reflux condenser and a 250 ml dropping
funnel was charged with potassium hydroxide pellets (416 g.
containing 6.3 mol KO~), tetraethylene glycol (1.25 mol) and
tetrahydrofuran (lO00 ml). The reaction vessel was placed
in a heating mantle and gently heated. After 15 minutes a
solution of bis(2-chloroethyl)ether (3.125 mol) in tetrahydro-
furan (150 ml) was added in one stream from the dropping funnel
to the vigorously stirred reactants. The reaction mixture was
then heated under reflux, with stirring for 18 hours. Sub-
sequently, the reaction mixture was cooled and the solventwas removed under a pressure of 1.9 kPa to give a brown slurry
to which dichloromethane (750 ml) was added. The resulting sus-
pension of potassium chloride was filtered and the potassium
3Q chloride filtered off was washed with dichloromethane (100 ml).
The combined f;ltrate and washings were dried over anhydrous
magnesium sulphate and the solvent was evaporated at a pressure
of 1.9 kPa to give a residue of crude 18-crown-6 (396 g) con-
taining 0.531 mol of 18-crown-6 (yield 42.5%, calculated on
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start;ng tetraethylene glycol), potassium chloride and at least
eight other compounds among which
1,4,7,10,13,16,19,22,25,28,31,34-dodecaoxacyclohexatria-
contane, hexaethyleneglycol and unreacted tetraethylene glycol.
This crude 18-crown-6 was used as described hereinafter.
EX~PLE I - Isolation of 18-crown-6 in nitromethane at -20 C
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Crude 18-crown-6 (3.021 g), prepared as described above,
was dissolved in nitromethane (4 ml). The solution formed was
cooled to -20C and the 18-crown-6-nitromethane complex pre-
cipitated was filtered off (1.248 g). The complex was kept
for 30 minutes at 70C and a pressure of 13 Pa, leaving
18-crown-6 in a yield of 37æ calculated on starting tetra-
ethylene glycol, or 87% calculated on 18-crown-6 in the crude
18-crown-6. The purity of the 18-crown-6 was higher than
99.5æ.
Comparative Experiment A - Isolation of 18-crown-6 in
aceton _rile at -20 C
Crude 18-crown-6 ~3.021 g), prepared as described above,
was dissolved in acetonitrile (4 ml). The solution formed
was cooled to -20C and the 18-crown-6-acetonitrile complex
was filtered off. The complex was kept for 30 minutes at
70 C and a pressure of 13 Pa, leaving 18-crown-6 in a yield of
27% calculated on starting tetraethylene glycol, or 63æ cal-
culated on 18-crown-6 in the crude 18-crown-6. Comparison with
Example I shows that complexation with nitromethane allows
the 18-crown-6 in a much higher yield.
Comparative Experiment B - Isolation of 18-crown-6 in
acetonitrile at -45C
This experiment is according to the process described in
"Synthesis" 1976, 515-516.
Crude 18-crown-6 (39.6 g), prepared as described above,
was distilled at a pressure of 20 Pa to give a distillate
(21.3 g) boiling at 140-210 C. This distillate was mixed with
acetonitrile (53 ml) at 20C and the mixture formed was cooled
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to -45 C. The resultant 18~crown-6-acetonitrile complex was
filtered off and subjected to distillation at a pressure of
2 Pa to give a distillate of 18-crown-6 in a yield of 25%
calculated on starting tetraethyLene glycol, or 59% calculated
on 18-crown-6 in the crude 18-crown-6. Comparison with
Example I shows that complexation with nitromethane at -20 C
allows the 18-crown-6 in a much higher yield than complexat;on
with acetonitrile at -45C followed by distillation oE
18-crown-6.
EXAMPLE II - Isolation of 18-crown-6 in nitromethane at +20 C
Crude 18-crown-6 (3.04 g), prepared as described above, was
mixed with nitromethane (5ml) at 20 C. After 16 hours the
precipitate formed was filtered off and kept for 30 minutes at
70C and a pressure of 13 Pa, leaving 18-crown-6 in a yield
of 28% calculated on starting tetraethylene glycol, or 66%
calculated on 18-crown-6 in the crude 18-crown-6. Comparison
of this yield with the higher yield obtained in Example I shows
the favourable influence of the temperature of -20C when
nitromethane is used as the solvent.
EX~PLE III - Isolation of 18-crown-6 in diethyl ether at +20 C
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Crude 18-crown-6 (3.5 g), prepared as described above, was
extracted with four 20-ml portions of diethyl ether. The
residue of potassium chloride thus obtained was filtered off,
the four filtrates were combined, and the solvent was evaporated.
Then, a mixture of nitromethane (0.7 ml) and 5.1 ml of diethyl
ether was added at 20 C, which caused an immediate precipi-
tation of the 18-crown-6-nitromethane complex. The co~plex
precipitated was filtered off and kept for 30 minutes at 70C and
a pressure of 13 Pa, leaving 18-crown-6 in a yield of 37%
calculated on starting tetraethylene glycol, or 87% ca]culated
on 18-crown-6 in the crude 18-crown-6. Comparison of this yield
with the lower yield of Example II shows the favourable ;nfluence
of the diethyl ether.
EXAMPLE I~ _ lation of 18-crown-6 in methanol at +20C
Crude 18-crown-6 (3.16 g), prepared as described above, was
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mixed with nitromethane (0.6 ml) and methanol (4.4 m]) at
20C. After 16 hours the precipitate formed was filtered off
and kept for 30 minutes at 70 C and a pressure of 13 Pa,
leaving 18-crown-6 in a yield of 13~, calculated on starting
tetraethylene glycol, or 31%, calculated on 18-crown-6 in
the crude 18-crown-6. Comparison of this yield with the higher
yields obtained in the Examples II and III shows that in this
case diethyl ether and nitromethane are more attractive
solvents than methanol.0 EXA~IPLE V - Separation of 18-crown-6 from macrocyclic
polyether No. 3 in diethyl ether
Nitromethane (0.6 ml) was added at 20C to a solution of
18-crown-6 (1.13 mmol) and macrocycl;c polyether No. 3 of the
formula page (1~15 mmol) in diethyl ether (6 ml). The precipitate
formed was filtered off, washed at 20C with 1 ml of a diethyl
ether/nitromethane (10/1 v/v) mixture and dried with dry air
at 20 C. The dried precipitate was the 18-crown-6-nitromethane
complex. The complex contained 92% of the starting amount of
18-crown-6 and the molar ratio of 18-crown-6 to macrocyclic
polyether No. 3 in the dried precipitate was 97:3. The complex
was kept for 30 minutes at 70C and a pressure of 13 Pa leaving
18-crown-6 containing 3% macrocyclic polyether No. 3.
EXAMPLES VI to XI - Precipitation of the 18-crown-6-nitro-
methane complex in various solvents
Nitromethane (1.48 mmol) was added to a solution of
18-crown-6 (0.19 mmol) and macrocyclic polyether No. 3 of
the formula page (0.19 mmol) in a solvent (1 ml) at 25C.
The 18-crown-6-nitromethane complex precip;tated was filtered off.
The filtered material was kept for 30 minutes at 70 C and a
pressure of 13 Pa, which caused dissociation into nitromethane,
which was sucked off, and 18-crown-6. Then, the 18-crown-6
was weighed and the yield of it on the starting amount of
18-crown-6 was calculated. Six solvents were tested in this
manner. Table I presents the results. The purity of the
18-crown-6 was 99% in each of the ~xamples.
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Table I
Example Solvent Yield of The complex crystallized
18-crown- _ _ out
6, % immediately over a
period of
1 to 4 h
.__
VI diethyl ether 92 yes
VII tetrahydrofuran 52 - yes
VIII 1,4-dioxane 23 - yes
IX methanol 79 yes
X benzene 45 - yes
XI water 35 yes
Comparative Experiment C-Precipitatlon of the la-crown-6-
acetonitrile complex in diethyl ether
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Acetonitrile (1.48 mmol) was added to a solution of
18-crown-6 (0.19 mmol) and macrocyclic polyether No. 3 of the
formula page (0.19 mmol) in diethyl ether (1 ml) at 25 C. The
18-crown-6-acetonitrile complex crystallized out immediately
and was filtered off. It contained 40% of the starting amount
of 18-crown-6. Comparison with Example VI shows that nitro-
methane had complexed a much larger part of the 18-crown-6 than
acetonitrile. The purity of the 18-crown-6 was more than 99~.
Comparative Experiments D to H-Attempted precipitation of
the 18-crown-6-acetonitrile complex in five solvents
The experiments of Examples VII to XI were carried out
with acetonitrile (1.71 mmol~ instead of nitromethane (1.15 mmol).
In none of the five experiments was a precipitate formed.
Comparative Experiments I to P -Attempted preparation of
complexes of nitromethane with macrocyclic polyethers
other than 18-crown-6
These eight comparative experiments were carried out with
the macrocyclic polyethers listed in Table II. Their structural
formulae are shown on the formula page. Each macrocyclic poly-
ether has been given a number which is mentioned in Table II
and on the formula page.
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Table II
Comparative ' Macrocyclic polyether
Experiment number nsme
I 1 2,3,11,12-dibenzo- 1~4,7,10,13,
16-hexaoxacyclooctadeca-2,11-
diene
J 2 2,3-benzo-1,4,7,10,13,16-
hexaoxacyclooctadeca-2-ene
K 3 1,4,7,10,13-pentaoxacyclo-
pentadecane
L 4 2,3-benzo-1,4,7,10,13,16,19-
heptaoxacycloheneicosa-2-ene
M 5 2,5,8,15,18,21-hexaoxatri-
cyclo/20.4Ø0 ' 7hexacosane
N 6 3,5-benzo-1,7,10,13,16-penta-
oxacyclooctadeca-3-ene
0 7 3,4-benzo-1,6,9,12,15-penta-
oxacycloheptadeca-3-ene
P 8 1,10-diaza-4,7,13,16,21,24-
hexaoxabicyclo/8,8,8/hexa-
cosane
================================================================
Tn Comparative Experiment No. I nitromethane (1.15 mmol)
was added to a saturated solution of macrocyclic polyether
No. 1 in diethyl ether (1 ml) at 25C. In Comparative
Experiments J to P nitromethane was added to a solution of 100 mg
of the macrocyclic polyether in diethyl ether at 25C. In none
of the eight experiments was a precipitate formed.
Comparative Experiment Q-Attempted preparation of a macrocyclic
.
polyether l-nitromethane complex
Nitromethane (1.15 mmol) was added at 25C to a saturated
solution of macrocyclic polyether 1 (see Table II and
formula page) in methanol (1 ml). No precipitate was formed.
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