PROCESS FOR PREPARATION OF DEUTERATED METHYLENE CHLORIDE

Abstract: A process for the preparation of deuterated methylene chloride. The process comprises contacting methylene chloride with an aqueous phase containing deuteroxide ions in the presence of a phase-transfer catalyst.

Description: Background of the Invention The present invention relates to the synthesis of deuterated methylene chloride, in general, and to the synthesis of deuterated methylene chloride under phase-­ transfer catalysis (P-T-C) conditions, in particular. Dideuterio-methylene chloride (dichloromethane -d₂; CD₂Cl₂) has become increasingly important in industrial and research applications as a reagent for chemical reactions, as a solvent for inorganic and organic compounds in various NMR spectroscopy, and in other applications where the properties of methylene chloride are desirable but where its protons must be replaced by deuterium. In particular, CD₂Cl₂ is being recommended for applications where CDCl₃ or even CH₂Cl₂ were formerly used. For example, because many inorganic compounds and complexes are more soluble in CD₂Cl₂ than in CDCl₃, it has been recommended that CD₂Cl₂ be used as a solvent in place of CDCl₃ in NMR spectroscopy. In addition, reports have indi­ cated that CD₂Cl₂ is less toxic to mammals than is CH₂Cl₂ and for that reason it may be preferable to use CD₂Cl₂ in certain applications. Although CD₂Cl₂ offers many advantages over other reagents, at the present there is not a method of preparation that provides high yields of a highly deuterated methylene chloride at a low cost. For instance, Atkinson et al. in Chem . Abstr. l970, 72 , ll0766y disclose a method of deuteration of CH₂Cl₂ to CD₂Cl₂ that is carried out in a homogeneous solu­ tion; CH₂Cl₂ in dimethyl sulfoxide is mixed with D₂O containing NaOD and refluxed 24 hours to provide methylene chloride containing 33% D. It was reported that this product could be further enriched to 42% D by repeating the process (recycling). In the absence of dimethyl sulfoxide, no exchange occurs. In many applications, however, it is prefera­ ble to use methylene chloride having a content in excess of 99% D. To achieve such a high percent of D/H sub­ stitution by using the method of Atkinson et al. would require a number of enriching cycles at 24 hours of refluxing per cycle. Because of the number of recycles required in order to obtain methylene chloride having a D content in excess of 99%, the productivity of the process would be poor. Moreover, because methylene chloride is soluble in dimethyl sulfoxide, it is not feasible to remove the deuterated product (CD₂Cl₂) by simple layer separation. Furthermore, their exchange fails in the absence of dimethyl sulfoxide. As a conse­ quence, the cost of preparing CD₂Cl₂ by the Atkinson et al. process would be relatively high. Other methods for preparing deuterated methy­ lene chloride have been reported in the chemical litera­ ture. Myers et al. ( J. Chem. Phys. l952, 20 , l420-l427) and Shimanouchi et al. ( J. Mol. Spectrosc. l962, 8 , 222-235) describe the preparation of deuterated methy­ lene chloride by heating chloroform-d (CDCl₃) with metallic zinc in CH₃CO₂D. Leitch et al. ( Can. J. Chem. l953, 35l-356) describe treating CD₂O with PCl₅ to yield CD₂Cl₂. In the former method, the yield is poor and much of the costly CDCl₃ and CH₃CO₂D are destroyed in the process. In the latter method, the required starting material (CD₂O) is very costly and difficult to prepare in anything other than small laboratory amounts. Accordingly, a need has remained for an improved simple and economic method for preparing and isolating deuterated methylene chloride on a large scale. Summary of the Invention The present invention is thus directed to a method for preparing deuterated methylene chloride; a method of preparation which provides the deuterated methylene chloride in high yields; and a method of pre­ paration which minimizes the cost of raw materials and which does not require an excessive number of recycles to obtain dideuterated methylene chloride having a D content in excess of 99%. Briefly, therefore, the present invention is directed to a process for the preparation of deuterated methylene chloride. The process comprises contacting methylene chloride with an aqueous phase containing deuteroxide ions in the presence of a phase-transfer catalyst. Other objects and features will be in part apparent and in part pointed out hereinafter. Description of the Preferred Embodiment In accordance with the present invention, it has surprisingly been found that deuterium may be essen­ tially quantitatively exchanged for the hydrogens of methylene chloride under phase-transfer conditions, without the need of cosolvents, and without decomposi­ tion of the product. In this process, methylene chloride is contacted with an aqueous phase that is basic in nature and comprises deuteroxide ions (OD⁻). Preferably, the aqueous phase is a concentrated base and in a most preferred embodiment the aqueous phase com­ prises a saturated or supersaturated solution of base in an aqueous medium. Thus, for example, the aqueous phase may comprise a deuteroxide base dissolved in water, a base dissolved in D₂O or a metal oxide mixed with D₂O. Regardless of the manner in which the aqueous phase is prepared, however, it is preferred that the relative amount of deuterium atoms to hydrogen atoms be as high as possible. Thus, it is particularly preferred that the aqueous phase be prepared by dissolving a deuteroxide base such as NaOD in D₂O or by dissolving an alkali metal oxide such as sodium oxide (Na₂O) in D₂O. Most preferably, the aqueous phase is prepared by dissolving sufficient sodium oxide in D₂O in the molar ratio of about l to 5, respectively. Certain tetraalkylammonium salts have been found to have an especially advantageous effect in pro­ moting the exchange of deuterium for hydrogen of methy­ lene chloride including methyltricaprylammonium chloride and tetrabutylammonium (TBA) chloride, bromide and hydrogen sulfate. The most preferred phase transfer catalyst is TBA hydrogen sulfate. Various other quater­ nary ammonium and phosphonium salts and cationic sur­ factants may be used in accordance with the present invention, and a substantial number of these may be expected to provide reasonable conversions per cycle. However, it must be recognized that changes in the alkyl substituents as well as of the anion of the salts can significantly affect the efficiency of the reaction. To achieve deuteration of the methylene chloride under base-catalyzed phase-transfer conditions, it is necessary that the phase-transfer agent be present in a catalytic amount. Although the amount of catalyst will vary according to the desired rate of reaction and the particular catalyst selected, it is generally pre­ ferred that the amount of the catalyst be in the range of about 0.l to about 20 mole percent of the methylene chloride. For the methyltricaprylammonium chloride and TBA salts, it is particularly preferred to use a molar ratio of catalyst to methylene chloride somewhere in the range of about 0.004 (0.4 mole percent). Higher concen­ trations of catalyst may be used with a corresponding increase in the rate of reaction. Similarly, lesser concentrations of catalyst may be used with a corre­ sponding decrease in the rate of reaction. The relative proportions of aqueous phase and methylene chloride may be varied and the ratio of the two is not considered to be narrowly critical. Where the aqueous phase comprises a solution of NaOD in D₂O as described above, it is preferred that the methylene chloride/sodium deuteroxide/D₂O have a molar ratio of about l/l/2, respectively. In a preferred embodiment, the D/H substitu­ tion of methylene chloride is thus achieved by its reaction with the aqueous base and D₂O in the presence of a catalytic amount of a phase-transfer agent. As the reaction proceeds, the DOD and OD⁻ content of the aqueous phase is progressively depleted as the CD₂Cl₂ content of the organic phase is increased. Ultimately, an overall equilibrium is reached at which the hydrogen/deuterium ratio within the methylene chloride is constant, wherein this equilibrium ratio is controlled by the total number of hydrogen and deuterium atoms which are available for exchange. A theoretical equilibrium maximum of D/H exchange for a particular reaction, therefore, can be calculated by determining the percent of exchangeable deuterium atoms in the total of exchangeable deuterium plus hydrogen atoms in the reaction mixture. Accordingly, methylene chloride with a desired degree of D/H substitution can be prepared in two dif­ ferent manners. First, it can be prepared through a selection of system parameters which will provide a theoretical maximum of D/H exchange in a single reaction that is at least equal to the desired degree of substi­ tution. Alternatively and preferably, the desired degree of D/H substitution may be achieved through one or more recycles of the methylene chloride through the reaction scheme. Thus, after a first reaction of the methylene chloride with an aqueous phase containing a source of deuterium, the partially deuterated methylene chloride is separated from the first aqueous phase and then treated with a second (fresh) aqueous phase and catalyst. This sequence can be repeated to achieve the desired percent of D in the methylene chloride. After recovery of the CD₂Cl₂ product, the residual aqueous phase(s) contain substantial amounts of deuterium in the form of D₂O, DOH and NaOD. Distilla­ tion of the aqueous phase, therefore, affords D₂O, DOH and H₂O from which the D₂O can be recovered and used again in this deuteration procedure to prepare deuter­ ated methylene chloride. The recovery and reuse of the D₂O substantially contributes to the economy of this process. Furthermore, the process of the present inven­ tion offers the additional advantage of ease of recovery of the product CD₂Cl₂. Conveniently, the CD₂Cl₂ product can be recovered by decanting the reaction mix­ ture or through the use of distillation. The following examples illustrate the inven­ tion. Example l D/H Exchange of CH₂Cl₂ With D₂O-NaOH under P-T-C Conditions (Aliquat 336) (a) Control Reaction With H₂O, 3 hours A solution composed of CH₂Cl₂ (l mL; 0.0l6 mol) and methyltricaprylammonium chloride (Aldrich Chemical Co., Milwaukee, WI, sold under the trademark of Aliquat 336) (0.03l g; 0.000l mol) was added to a 50% w/w (weight percent) aqueous solution of NaOH (l mL; 0.0l9 mol). This mixture was stirred under argon at room temperature for 3 h and then diluted with CCl₄ (4 mL) and H₂O (l mL). The organic layer was separated, dried (MgSO₄), and submitted to ¹H NMR and IR studies. ¹H NMR (CCl₄): δ5.29 (s, area 5.60, CH₂ of CH₂Cl₂). IR (CCl₄ solution, double beam with CCl₄ in the reference cell): 3055 (CH₂ asym str.), 2990 (CH₂ sym str.), 2935, 2860, 269l, 2406, 2304, l424 (CH₂ scis.), l38l (w), l262 (CH₂ wag.), ll57 (CH₂ twist.), ll40 (s), 897 (CH₂ rock.), 739 (s), 706 (s), 64l (w), 62l cm⁻¹. (b) Reaction With D₂O, 3 hours. To l mL of a 50% w/w solution of NaOH (0.0l9 mol) in D₂O (99.7% D, Wilmad Glass Co., Inc., Buena, NJ) was added a solution composed of l mL (0.0l6 mol) of CH₂Cl₂ and 0.03l g (0.000l mol) of Aliquat 336. This mixture was stirred for 3 h, then diluted with 4 mL of CCl₄ and l mL of D₂O. The isolated organic layer was dried (MgSO₄) and submitted to ¹H NMR and IR studies. ¹H NMR (CCl₄): δ5.29 [br s (split at about half height), area 4.50, CH of CHDCl₂ and CH₂ of CH₂Cl₂]; thus, the CH₂Cl₂ underwent l9.6% D/H exchange. [% D/H exchange = l00 - [integration area (CH₂Cl₂ + CHDCl₂) from reaction with D₂O - ­ integration area (CH₂Cl₂) from controlreaction with H₂O] × l00. For this determination, a portion of the CCl₄ solution was transferred to an NMR tube to a specific height and the ¹H NMR integration area was compared to that of the CCl₄ solution from the control reaction (CH₂Cl₂-H₂O) worked up and placed in an NMR tube in the identical manner.] Since the maximum calculated exchange at equilibrium is 60% under these conditions, the observed exchange represents 33% of the theoretical maximum. The presence of CHDCl₂ and CD₂Cl₂ in the crude mixture was confirmed by IR spectroscopy. IR (CCl₄ solution, double beam with CCl₄ in the reference cell): 3055 (CH₂ asym str. of CH₂Cl₂), 30l9 (CH str. of CHDCl₂), 2985 (CH₂ sym str. of CH₂Cl₂), 2960, 2932, 2304 (CD₂ asym str.), 2250 (CD str. of CDHCl₂), 2205 (CD₂ sym str.), l424 (CH₂ scis.), l408 l262 (CH wag. of CH₂Cl₂), l2l8 (CH bend. of CHDCl₂), ll4l, l085, l02l, 957) CH₂ wag. of CD₂Cl₂, 885 (CD bend. of CHDCl₂), 739, 695 (s), 64l (w), 6l5 cm⁻¹. The observed CHD and CDD vibrations of CHDCl₂ and CD₂Cl₂ are identical to those reported by T. Shimanouchi and I. Suzuki ( J. Mol. Spectrosc. l962, 8 , 222-235). (c) Control Reaction with H₂O, 28.5 hours The procedures of part (a) above were repeated except that the period for reaction was 28.5 h. The ¹H NMR spectrum exhibited an integration of 4.l0 for Cl₂CH₂ ( δ5.29). (d) Reaction With D₂O, 28.5 hours The procedures of part (b) above were repeated except that the period for reaction was 28.5 h. Inte­ gration of the ¹H NMR signals at δ5.29 (Cl₂CH₂ and Cl₂CHD) was l.8l; which (based on the standard area of 4.l0 determined with the same instrument setting) indicated that there was 55.8% D/H exchange when calculated as set out in part (b) above (93% of the theoretical maximum). The IR spectrum was qualitatively similar to that obtained in (b), but the vibrations associated with the D-C-D group became far more prominent. Example 2 Treatment of CH₂Cl₂ With D₂O-NaOH in the Absence of Phase-Transfer Catalyst The experiments with D₂O described in Example l were carried out in the absence of phase-­ transfer catalyst for 24.5 h and 28.5 h, respectively. Unlike the results of the D₂O experiments of Examples l (b) and (d), the IR spectra of the organic layers were identical to that of CH₂Cl₂; no C-D vibrations were exhibited. No D/H exchange occurred. Example 3 D/H Exchange of CH₂Cl₂ With D₂O-Na₂O Under P-T-C Conditions (Aliquat 336) (a) In The Presence of Air (atmospheric O₂; absence of moisture) A 3-necked flask immersed in an ice-water bath and connected via stopcock (closed) to an argon-filled balloon, was charged with 5.00 g (0.25 mol) of D₂O (99.7% D, Wilmad Glass Co.), followed by the addition of 3.l0 g (0.049 mol) of Na₂O (Alfa Products/Morton Thiokol, Inc., Danvers, MA), in small portions. Because Na₂O reacts violently with water, the addition was carried out slowly and evenly with constant stirring. The argon-filled balloon connector was then opened and the reaction vessel was purged with argon by venting through a loosely stoppered neck. The stopper was then replaced tightly but the connector to the argon-filled balloon was kept open. It should be noted that the air (O₂ but not moisture) quite rapidly diffuses through the thin rubber of an argon-filled balloon; in l4 hours the reaction would have been subjected to many volumesof dry air. The ice-water bath was then removed. To this stirred mixture was injected (through a rubber septum) a solution composed of 8.50 g (0.l0 mol) of CH₂Cl₂ and 0.l7 g (0.0004 mol) of Aliquat 336. The resulting mix­ ture was stirred for l4 h after which time an aliquot of the organic layer (upper layer) was taken for direct ¹H NMR analysis. % D/H exchange = l00 - [(integration area observed (CH₂Cl₂ + CHDCl₂) integration area of external pure CH₂Cl₂ )] × l00. ¹H NMR (neat): δ5.32 [s, peak split at half height, integration area 3.20, CHDCl₂ and CH₂Cl₂]. ACS-grade CH₂Cl₂ external ¹H NMR standard: inte­ gration area 5.80 ( δ5.32). From these data it was calculated that 45% D/H exchange had occurred in the l4-h period, or 63% of the maximum attainable % D at equilibrium (under these conditions, the maximum (equilibrium) D/H exchange is 7l%). (b) In The Absence of Air (atmospheric O₂ and moisture). Reaction (a) was repeated but after the argon purge of the reaction vessel the stopcock to the argon-­ filled balloon was closed before the CH₂Cl₂-Aliquat 336 solution was injected through the rubber septum. The reaction mixture was thus sealed from the ambience during the l4-h reaction period. ¹H NMR (neat) analysis (see (a) above) after the l4-h reaction indicated that 44% D/H exchange had occurred (63% of that possible at equilibrium). A comparison of (a) and (b) shows that the presence of air (O₂, absence of moisture) seems to have little effect on the rate of this D/H exchange reaction. Example 4 Kinetic Studies of D/H Exchange of CH₂Cl₂ With D₂O-Na₂O Under P-T-C Conditions. (Aliquat 336) In a three-necked, round-bottomed flask (cooled in an ice-water bath) was placed 5.00 g (0.25 mol) of D₂O (99.9% D, Norell, Inc., Landisville, NJ), followed by the careful addition of 3.l0 g (0.049 mol) of Na₂O in small portions while the solution was being stirred. The ice bath was then removed and a solution composed of 8.50 g (0.l000 mol) of CH₂Cl₂ and 0.l7 g (0.0004 mol) of Aliquat 336 was added. Aliquots of the organic layer were taken for direct ¹H NMR analysis after reaction periods of 20 h, 44 h, 74 h and ll9 h and the percentages of D/H exchange were determined as described in Example 3 (a). The maximum possible % D/H exchange (calculated for equilibrium) is 7l.00%. The observed % D/H exchange (with percent relative to maxi­ mum possible in parentheses) are as follows: 20 h, 62.35% (87%); 44 h, 66.l3% (93%); 74 h, 70.86% (l00%); ll9 h, 73.l3% (l00%). Example 5 The Enhancement of Incorporation of Deuterium into CH₂Cl₂ by the use of Sequential Recycling Run A. Into a 500-mL round-bottomed flask cooled in an ice-water bath was added l6.70 g (0.84 mol) of D₂O (99.7% D) followed by l0.33 g (0.l6 mol) of Na₂O in small portions with stirring. Although this run was carried out under argon, this precaution is not required. The ice-water bath was then removed and a solution composed of 29.00 g (0.34 mol) of CH₂Cl₂ and 0.55 g (0.00l4 mol) of Aliquat 336 was added. After the reaction proceeded for 30 h, an aliquot of the organic layer was removed for ¹H NMR analysis; 7l.22% D/H exchange had occurred, which is l00% of the cal­ culated equilibrium maximum. First Recycle. The above crude mixture was cooled with an ice-water bath and the organic layer (upper layer) was separated via pipette from the aqueous layer. The isolated organic layer was then treated with fresh D₂O, Na₂O and catalyst in the same proportions and manner as stated above for the methylene chloride. ¹H NMR analysis of an aliquot taken from the organic layer after 4l h of reaction indicated a total of 93.l2% D/H exchange had occurred, which is l00% of the calculated equilibrium maximum. Second and Third Recycles. The second and third recycles, respectively, were performed as described above for the first recycle. ¹H NMR analysis of an aliquot removed from the organic layer after 30 h and 34 h of reaction for the second and third recycles, respectively, indicated that a total of 98.65% and 99.l2% D/H exchange had occurred, both of which represent l00% of the calculated equilibrium maxi­ mum, respectively. The methylene chloride, isolated after the third recycle by distillation, b.P. 38.8 °C [azeotrope: methylene chloride - l% water ("Handbook of Chemistry and Physics", 5l Edition, Chemical Rubber Co., Cleveland, page D-3l)], was shown by ¹H NMR to have incorporated 98.77% D. Run B. Into a 500-mL glass-jacketed flask was placed l6.70 g (0.84 mol) of D₂O (99.9% D, Norell Inc.); cold water (5 °C) was allowed to flow through the glass jacket. To this cold D₂O, l0.33 g (0.l6 mol) of Na₂O was slowly added in small portions while the solution was stirred. The cold water in the jacket was then replaced with water 24°C and a solution composed of 29.00 g (0.34 mol) of CH₂Cl₂ and 0.55 g (0.00l4 mol) of Aliquat 336 was added to the reaction solution. Stirring was continued for l5.5 h after which time an aliquot was removed from the organic layer and analyzed by¹H NMR, which indicated that the methylene chloride had undergone 42.4% D/H exchange. The contents of the NMR tube were poured back into the reaction flask and stirring was continued for an additional l0 h; ¹H NMR analysis of the organic phase indicated that the methy­ lene chloride had undergone 61.2% D/H exchange (86% of equilibrium maximum). The reaction mixture was then distilled (hot water at 50-60°C flowing into the glass jacket) and 25.60 g of the deuterated methylene chloride (bp 38.8 °C, azeotrope: methylene chloride - l% water) was collected. First Recycle. In the same manner as described immediately above, l6.70 g (0.84 mol) of D₂O (99.9% D) was placed in a cold-water jacketed flask followed by the addition of l0.33 g (0.l6 mol) of Na₂O in small portions. Water at 24 °C was then allowed to flow through the jacket and a solution of partially deuterated methylene chloride (25.60g), collected as described above, and 0.55 g (0.00l4 mol) of Aliquat 336, was added to the mixture. ¹H NMR indicated that after 24 h of reaction the methylene chloride contained 83.00% D (9l% of equilibrium maximum). The crude mixture was then distilled (hot water at 50-60 °C flowing in the jacket), and 2l.50 g of the deuterated methylene chloride (b.p 38.8 °C, azeo­ trope containing l% water) was collected. Second and Third Recycles. The partially deuterated methylene chloride (2l.50g) collected by distillation, above, was treated again with D₂O, Na₂O, and Aliquat 336 as described above for the first recycle. ¹H NMR analysis of the organic layer after 2l h of reaction indicated that the methylene chloride now contained 94.2% D (97% of the equilibrium maximum). Continued stirring for an addi­ tional ll h raised the value to 95.9% D (98% of the equilibrium maximum). Distillation of the organic layer afforded l8.70 g of this deuterated methylene chloride. The D/H exchange procedure was repeated again (third recycle) with the l8.70 g of distillate for a period of 55 h and the product, collected by distilla­ tions b.p 38.8 °C, l5.37 g, was shown by¹H NMR analysis to contain 98.57% D (99.6% of the equilibrium maximum). ¹H NMR (neat distillate): δ 5.32 (s, barely detectable, CHDCl₂). IR (neat distillate): 3350 (w), 3l35 (w), 3020 (vw, CH str. of CHDCl₂), 2962 (w), 2305 (s, CD₂ asym str. of CD2Cl₂), 2205 (s, CD₂ sym str. of CD₂Cl₂), 2l00 (w), l390 (w), l250 (w), ll35 (br, 998 (w), 955 (s, CD₂ wag. of CD₂Cl₂), 888 (w, CD bend of CD₂Cl₂), 865 (w), 7l5 (s), 680 (w), 635 (w) cm⁻¹. The results from runs A and B of Example 5 are summarized below in Table I. a) Values determined on undistilled product except where indicated otherwise. b) The maximum theoretical (equilibrium) extent of D/H exchange after each recycle procedure was calculated a priori , i.e., not from the determined % D of that methylene chloride, but from the calculated % D, although the results would not differ significantly. c) % D of distilled (isolated) product. Example 6 D/H Exchange of CH₂Cl₂ With D₂O-Na₂O Catalyzed by Aliquat 336. Determination of relative rate of Exchange and Extent of Decomposition of Methylene Chloride. A l-L round-bottomed flask equipped with a condenser (water cooled, l0 °C) fitted with a calcium chloride drying tube was charged with l6.70 g (0.84 mol) of D₂O (99.7% D., Wilmad Glass Co.) and stirring was begun while the flask was immersed in an ice water bath. In small portions l0.33 g (0.l7 mol) of Na₂O was added followed by a solution composed of 29.00 g (0.34 mol) of CH₂Cl₂ and 0.55 g (0.00l4 mol) of Aliquat 336. The resulting mixture was stirred at l0-l5 °C and aliquots of the organic layer were taken after l, 2, 3, 5, and 6 h of reaction, respectively, and analyzed directly by ¹H NMR. The results are summarized in Table II below. The residual reaction mixture was kept over­ night in the freezer and ll.70 g of organic material (upper layer) was isolated via pipette from the frozen lower aqueous layer and distilled to provide 4.90 g of partially deuterated methylene chloride. The aqueous layer, 25.l0 g, was allowed to melt and 2.55 g was removed, acidified with lN HNO₃ (until pH ca. l), and treated with 5% aqueous AgNO₃ solution. The precipi­ tated AgCl was collected, washed thoroughly with dis­ tilled water followed by acetone, and dried in an oven (90° C, 20 min) to afford 0.07 g (0.0005 mol) of AgCl, which extrapolates to 0.70 g (0.005 mol) of AgCl cal­ culated based on the total aqueous layer. Taking into account the 0.00l4 mol of Cl⁻ emanating from the Aliquat 336 used, no more than 0.0036 mol of Cl⁻ came from the methylene chloride; i.e. no more than l% of the methylene chloride underwent decomposition or reaction other than D/H exchange during its 6-h contact with 50% alkali under these P-T-C conditions. This result indi­ cates that dichloromethyl anion (Cl₂CH⁻), in con­ trast to trichloromethyl anion (Cl₃C⁻), undergoes α -elimination substantially more slowly than protonation/deuteration, and that methylene chloride undergoes negligible S N 2 displacement of Cl⁻ by ⁻OH (⁻OD) even under these phase-transfer conditions. In summary, methylene chloride undergoes D/H exchange under these conditions essentially without any decomposition, in surprising contrast to chloroform. Example 7 D/H Exchange of CH₂Cl₂ with D₂O-Na₂O phase transfer catalyzed with Tetrabutylammonium Hydrogen Sulfate (TBA Hydrogen Sulfate). To a round-bottomed flask, immersed in an ice-water bath and equipped with a cold-water condenser fitted with a CaCl₂ drying tube, was added 5.00 g (0.25 mol) of D2O followed by 3.l0 g (0.049 mol) of Na₂O added in small portions while the mixture was stirred. The ice-water bath was then removed, and to the stirred mixture was added a solution composed at 8.50 g (0.l0 mol) of CH₂Cl₂ and 0.l36 g (0.0004 mol) of tetrabutylammonium hydrogen sulfate (Sigma Chemical Co., St. Louis, Missouri). Aliquots of the organic layer (upper layer) taken for¹H NMR analysis provided the following results: 3 h, 63.04% D/H exchange (89% of maximum equilibrium value); 4 h, 65.30% D/H exchange (92% of maximum equilibrium value). The calculated D/H exchange at equilibrium is 7l.0%. These data show that the rate of D/H exchange is much faster catalyzed with tetrabutylammonium hydro­ gen sulfate compared with Aliquat 336. The difference would have been very much larger had the sample been compared earlier in the exchange well before equilibrium was approached in the TBA hydrogen sulfate-catalyzed reaction. Example 8 D/H Exchange of CH₂Cl₂ with D₂O-Na₂O Phase-Transfer catalyzed with Tetrabutylammonium chloride (TBA Chloride) In a manner like that described in Example 7, D/H exchange of CH₂Cl₂ was carried out in the presence of tetrabutylammonium chloride (Aldrich Chem. Co.) [0.lll g (0.0004 mol)] instead of TBA hydrogen sulfate. ¹H NMR analysis of an aliquot of the organic layer (upper layer) after 3 h of reaction indicated that 44.7% D/H exchange had occurred (63% of the maximum equilibrium amount.) Example 9 D/H Exchange of CH₂Cl₂ with D₂O-Na₂O Phase-Transfer catalyzed with Tetrabutylammonium Bromide (TBA Bromide). In a manner like that described in Example 7, D/H exchange of CH₂Cl₂ was carried out in the presence of tetrabutylammonium bromide (Aldrich Chem. Co.) [0.l29 g (0.0004 mol)] instead of TBA hydrogen sulfate. ¹H NMR analysis of an aliquot of the organic layer (upper layer) after 3 h of reaction indicated that only l.l% D/H exchange had occurred (l.5% of the maximum equilibrium amount). Because of this unexpectedly poor yield of D/H exchange, the attempt was repeated with fresh materials. The results were similar: only 2.3% D/H exchange had occurred over the 3-h period (3.2% of the maximum equilibrium amount). Examples, 7, 8, and 9 all describe the use of a tetrabutylammonium salt as the phase-transfer catalyst in these D/H exchanges of CH₂Cl₂. A comparison of the results illustrate the unexpected importance of the role of the counteranion of the quaternary ammonium catalyst. Thus, the hydrogen sulfate catalyst is of the order of several powers of l0 times more effective than the bromide, while the chloride is intermediary in activity. Surprising also, from the one comparison available in this series, is the observation that the structure of the alkyl groups of the quaternary ammonium catalyst appears to have but little influence on the rate of this exchange, viz ., CH₃N⁺((CH₂)₇CH₃)₃Cl⁻ (Aliquat 336) and (CH₃CH₂CH₂CH₂)₄N⁺Cl⁻ (TBA chloride) under almost identical conditions induce D/H exchange at about the same rates - a result quite unexpected in light of literature reports (e.g., W.J. Spillane, P. Kavanagh, F. Young, H.J.M. Dou, and J. Metzger, J. Chem. Soc., Perkin Trans. l l98l, l763-l768). These results are compared in Table III. In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results are attained. As various changes could be made in the above methods and products, without departing from the scope of the invention, it is intended that all matter con­ tained in the above description shall be interpreted as illustrative and not in a limiting sense.

Claims: 1. A process for the preparation of deuterated methylene chloride comprising contacting methylene chloride with an aqueous phase containing deuteroxide ions in the presence of a phase-transfer catalyst. 2. A process according to claim l, wherein the phase-transfer catalyst comprises a tetraalkylammonium salt. 3. A process according to claim 2, wherein the phase-transfer catalyst comprises methyltricaprylyl­ ammonium chloride, tetrabutylammonium hydrogen sulfate, tetrabutylammonium chloride or tetrabutylammonium bromide. 4. A process according to any one of claims l to 3, wherein the aqueous phase is prepared by the addition of a base to D₂O. 5. A process according to claim 4, wherein the aqueous phase is prepared by dissolving sodium oxide in D₂O. 6. A process according to any one of claims l to 5, wherein the mole percent of the phase-transfer catalyst based on the methylene chloride content is in the range of about 0.l% to about 20%. 7. A process according to any one of claims l to 6, wherein the molar ratio of methylene chloride to deuteroxide ions to D₂O is about l/l/2, respectively. 8. A process according to any one of claims l to 7, further comprising decanting the methylene chloride from the aqueous phase after the two are contacted in the presence of a phase transfer catalyst. 9. A process according to claim 8, further comprising freezing the aqueous phase prior to the step of decanting and thereafter decanting the methylene chloride from the frozen aqueous phase. l0. Deuterated methylene chloride produced according to the process comprising contacting methylene chloride with an aqueous phase containing deuteroxide ions in the presence of a phase-transfer catalyst.

Inventors: MEYERS, CAL Y., SHAN-YU-KING, ROCH
Applicants: MEYERS, CAL Y., SHAN-YU-KING, ROCH
Application year: 1987
Main classification: C07B59
IPC codes: C07C17, C07B59, B01J31, C07C19, C07B61, C07C67