Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
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TITLE Ol:` I'IIE INVLNTION
2 Chloroform oeuteration Process
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~ g BACKGROUND OF THE INVENTION
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This invention relates generally to the field
11 of isotope exchange reactions used in the preparation of
12 organic compounds having their hydrogen atoms replaced by
13 deuterium. More particularly, it relates to the produc-
14 tion of deuterated chloroform from chloroform by deuterium
exchange with alkaline solutions of deuterium oxide con-
16 taining sodium deuteroxide. Deuterated chloroform is a
17 solvent which is used in nuclear magnetic resonance spec-
18 troscopy and is sold for this purpose by manufacturers of
19 such solvents.
In the past, deuterochloroform was prepared from
21 hexachloroacetone which is no longer available in bulk
22 quantity needed for deuterated chloroform manufacture.
23 Although it has been known for some time that the hydrogen
24 atom of chloroform may be exchanged with water in strong
base, this exchange was not used in the manufacture of
26 deuterochloroform prior to the present invention.
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SUMMARY OF T~IE INVENTION
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2 In accordance with the present invention, deutero-
3 chloroform ls produced in substantially pure form by
4 deuterium/hydrogen exchange between chloroform vapor and
a solution of an alkali metal deuteroxide in deuterium
,' 6 oxide (heavy water). The process of the invention is
7 carried out by contacting the chloroform vapor in a con-
8 tinuous manner with a hot (65-95C.) solution of sodium
9 deuteroxide in deuterium oxide preferably in the presence
of a phase transfer catalyst for a sufficient period of
11 time to convert the chloroform starting material into
12 substantially pure deuterochloroform; i.e., chloroform in
13 which at least 99.5% of the hydrogen atoms have been re-
14 placed by deuterium.
DETAILED DESCRIPTION OF THE INVENTION
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16 In accordance with the present invention, chloro-
17 form is converted into deuterochloroform by the continuous
18 countercurrent exchange of chloroform with a solution of
19 an alkali metal deuteroxide in heavy water (deuterium
oxide). In one embodiment of the invention, the counter-
21 current exchange is conducted in a long vertical column
22 in the presence of a transfer catalyst and the solution
23 of sodium deuteroxide in deuterium oxide descends in said
24 column at a temperature between about 65-90C. while the
chloroform vapor ascends. The transfer catalyst is selec-
26 ted from tetraalkylammonium deuteroxides in which the alkyl
27 or aralkyl substituents each contain from 1-9 carbon atoms
28 and which include
29 benzyl trimethyl ammonium deuteroxide,
benzyl triethyl ammonium deuteroxide,
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1 tetrabutyl ammonium deuteroxide,
2 tributyl pentyl ammonium deuteroxide, and
3 tetraoctyl ammonium deuteroxide.
4 The amounts of said catalyst employed in the
S exchange reaction is very small, the concentration of
6 catalyst added to the aqueous layer being between 25 and
7 100 mg./liter.
' 8 In carrying out the process of the invention,
9 chloroform vapor is allowed to rise through a hot (70-90C.)
10 sodium deuteroxide (20~ w/v) solution in heavy water
~, 11 containing approximately 1% of a tetra(alkyl or aralkyl)
, 12 ammonium deuteroxide dissolved therein. This exchange
; 13 reaction is preferably carried out in a cylindrical column
14 having an inside diameter of from 1-2 inches, which is
~r 15 between about 10 feet and 50 or 100 feet long. The effi-
t 16 ciency of this process is improved by packing the exchange
17 column with stainless steel helices approximately 1/8 inch
~- 18 diameter and 1/8 inch long. The efficiency of the process
19 is further improved by operation of the exchange reaction
20 in more than one stage. In the multiple stage method of
21 operation, at least two exchange vessels are employed.
22 In the final stage column, partially exchanged chloroform
't 23 vapor is fed into the base of a column which is charged
24 at the top on a continuous basis with a fresh solution of
25 sodium deuteroxide and heavy water. The resultant deutero-
:~ 26 chloroform is substantially completely exchanged (>99.5~)
27 deuterochloroform.
28 The relative flow rates of chloroform vapor and
' 29 sodium deuteroxide/deuterium oxide solution are dependent
30 on the length and number of exchange columns used in the
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1 process. In the practical operation of the exchange
2 process to continuously produce from 1 to 20 kg. of CHC13
3 per day, it is possible to use one or more exchange columns
4 having a chloroform feed rate of from 0.1 ml. to 6.0 ml.
per minute. One such process employs an exchange column
6 approximately 20 feet in length and having a 1 inch dia-
7 meter packed with stainless steel helices 1/8 inch diameter
8 by 1/8 inch in length. An apparatus of this type operating
9 at capacity will produce approximately 1 kg./day of deutero-
chloroform in which 99.5~ of the chloroform hydrogens are
11 replaced by deuterium.
12 An alternate method of operation in similar
13 sized equipment allows the production of chloroform in a
; 14 continuous manner of approximately 12 kg./day of deutero-
chloroform. This alternate process employs exchange col-
16 umns having 1-3/8 inches inside diameter and 45 feet long.
17 In order to increase the efficiency of the exchange reac-
18 tion, three exchange columns are utilized. In accordance
19 with this process, two exchange columns are operated in
parallel as the final stage exchange reactor and one of
` 21 the exchange columns is utilized as the initial exchange
22 reactor column into which untreated chloroform vapor is
23 fed upflow at the rate of about S-6 ml./min. A partially
24 depleted solution of sodium deuteroxide in a mixture of
heavy and light water is fed to the top of the column at
26 the rate of about 1-1/2 to 2 ml./min. The partially ex-
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; 27 changed chloroform, which is removed and condensed from
28 the head of the column, is then revaporized and fed con-
29 tinuously into two such exchange columns operated in paral-
lel as the final stage of the continuous process. In this
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1 manner, the partially exchanc;ed chloroform from the ini-
2 tial column is split into two streams and introduced as
3 chloroform vapor. Each of these final stage columns are
4 operatinq at approximately 1/2 the flow rate of the ini-
tial exchange column with resultant production of deutero-
6 chloroform having 99.5~ of the chloroform hydrogens re-
7 placed by deuterium.
8 Apparatus and starting materials utilized in the
9 process of our invention are carefully prepared since the
final product manufactured, deuterochloroform, is used as
11 a solvent for spectroscopic analysis and must contain a
12 low level of chemical and isotopic impurities.
13 The chloroform employed as starting material in
14 the process of the present invention must itself be of
spectroscopic quality and is fractionally distilled from
16 phosphorous pentoxide which removes traces of water and
17 other impurities such as methylene chloride and ethyl
18 ether.
19 The solution of sodium deuteroxide in deuterium
oxide used as the exchange medium is prepared by the com-
21 plete electrolysis of a saturated solution of sodium
22 chloride in heavy water to give a solution containing
23 15-17 parts by weight of sodium deuteroxide per 100 parts
24 of solution.
The transfer catalysts are used in very small
26 quantity in concentrations of less than 100 mg./ml.~ pre-
27 ferably in the range of from 10 to 95 mg./ml. of sodium
28 deuteroxide solution. In higher concentrations, the
29 catalysts impede the exchange reaction by increasing the
rate of hydrolysis of the chloroform to such an extent
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that almost all of the base is used. The catalysts are
2 readily prepared by adding a t:ri(alkyl or aralkyl) ammo-
3 nium halide to a solution of an alkali metal deuteroxide
4 to produce the corresponding t:ri(alkyl or aralkyl) ammo-
nium deuteroxide.
6 Thus, for example, benzalkonium chloride is con-
7 verted by treatment with sodium deuteroxide to the trans-
8 ferred catalyst, benzalkonium deuteroxide. Likewise, in
9 a similar manner, the following iodides are converted to
the corresponding deuteroxide transferred catalysts:
11 benzyltrimethyl ammonium iodide;
12 benzyltrimethyl ammonium bromide;
13 benzyltriethyl ammonium iodide;
14 tetrabutyl ammonium iodide, bromide;
tributyl pentyl ammonium iodide;
16 tetraoctyl ammonium iodide; and
17 tetraoctyl ammonium bromide.
18 The final product, deuterochloroform containing
19 at least 99.5% of its hydrogens replaced by deuterium is
carefully purified in accordance with the following pro-
21 cedure.
22 The chloroform-d is dried and purified by par-
23 tial fractionation from phosphorus pentoxide. This also
24 removes traces of methylene chloride and ethyl ether from
ethanol. A typical fractionation column has an internal
26 diameter of 1 to 1-1/2 inches, is 5 feet long, and has a
27 vacuum jacket. The preferred packing consists of molecular
28 sieves in the pellet form. The large surface area, absor-
29 bency, and regular shape of this material provide the
most efficient packing used.
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l This fractionation column is important to the
2 process since it reduces the time required from a week to
3 a day and the forerun required from a litre to about
4 lOO rnl. (from 30 kg.). After the impurities are removed,
the chloroform-d is distilled rapidly through a long
6 Vigreux column and is directly passed through activated
7 carbon to remove phosgene and molecular sieves to remove
8 ethylene (from ethanol) and any residual water. The
9 chloroform-d is then of high chemical purity and ready
for packaging.
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1 EXA~~L~
; 2 An apparatus is assembled comprising three ex-
3 change columns, each 45 feet :in length and 1-3/8 inches
4 in diameter. Each exchange column is packed with stain-
less steel helices approximately 1/8 inch in diameter and
1/8 inch is length. Each of the columns is heated exter-
7 nally and insulated with conventional fiberglass insulation.
8 At the top of each column is a stainless steel still headed
9 with an inlet pipe for the sodium deuteroxide solution.
The still head is packed with coarse stainless steel wool
11 to prevent entrainment of the alkali solution with the
12 chloroform vapor exiting the top of the column. Both the
13 base and the top of each column are closed to the atmosphere
14 and at the base of each column there is attached an exter-
nally heated glass still pot having an inlet pipe for the
16 admission of chloroform and an outlet pipe to allow with-
17 drawal of spent sodium deuteroxide solution. The exit
18 pipe for chloroform vapor is provided at the top of the
19 column above the level of the stainless steel packing in
the still head. The exit pipe is not closed to the atmos-
21 phere, but is vented into a collecting vessel for the
22 partially deuterated chloroform.
23 The three columns are connected together in the
24 following manner. The first column provides for the admis-
sion of untreated chloroform, which is admitted to the
26 still pot having a reservoir of sodium deuteroxide solution
27 maintained at a temperature of about 90C. At the head of
28 the column, a solution of sodium deuteroxide in deuterium
29 oxide (17-19~ w/v, containing tetraoctyl ammonium deuter-
` 30 oxide in a concentration of 100 mg./liter) is metered into
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the column head at the rate of about 1.5 ml./min. Chloro-
2 form is introduced into the still pot at the bottom of the
3 column when the column is essentially full of descending
4 sodium deuteroxide solution and the still pot is approxi-
mately half full with the sodium deuteroxide solution.
6 Chloroform is then admitted to the still pot at the rate
7 of about 5.6 ml./min. This admission of sodium deuter-
8 oxide solution and chloroform is continued until the col-
9 umn is at an equilibrium between incoming and partially
deuterated exiting chloroform. At the same time, excess,
11 partially spent sodium deuteroxide solution is withdrawn
12 from the still pot into an appropriate exit tube at a rate
13 to maintain the level of sodium deuteroxide solution in
14 the still pot approximately constant.
The remaining two exchange columns are set up
16 in substantially the same manner as the first described
17 column with the exception that the rate of through-put
18 of chloroform and sodium deuteroxide solution is approxi-
19 mately half that of the first column. They are connected
to the first column in such a manner that the output of
21 partially exchanged chloroform in the first column is split
22 as feed chloroform for the second and third exchange col-
23 umns which are operated in parallel. Operated in this
24 manner, the chloroform recovered from columns 2 and 3 is
substantially completely exchanged deuterochloroform in
26 which at least 99.5~ of the chloroform hydrogens have been
27 exchanged with deuterium. The rate of production of
28 chloroform in this particular mode of operation is approxi-
29 mately 12 kg./day. The chloroform withdrawn from the
column is purified in the manner suggested hereinabove.
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