1630
VOL.
NOTES
band characteristic of gem-dimethyl compounds; C-F absorption a t 1180-1250 cm.-l was present in the spectrum as were three triplets centered a t 989, 908, and 731 cm.-l The major mass spectrum peaks were a t 65 (intensity loo), 51 (CRH', rearrangement peak, 3.8), and 45 (8.5). The proton NMR spectrum had only the triplet expected for the difluoropropane; the F19 NMR spectrum had five fluorine resonance bands a t 230 to 310 C.P.S. higher field than external trifluoroacetic acid. Apparently two of the seven bands expected for the difluoropropane structure were hidden by the background. Vapor phase chromatography confirmed the purity of the sample. When the reaction was carried out by adding the bromine trifluoride t o the acetone (2.0 ml.) in hydrogen fluoride, 2,2-difluoropropane (548 ml., 91yo), containing a trace of l,l,l-trifluoroethane (by V.P.C.analysis) was obtained. Methyl ethyl ketone. A solution of 4 ml. of bromine trifluoride in 40 ml. of hydrogen fluoride was treated dropwise with 3.0 ml. (0.0335 mole) of methyl ethyl ketone in the usual fashion. The cold traps collected 688 ml. (STP), (0.0307 mole) of gas. The infrared and mass spectra (strong 69 and 65 m/e peaks) revealed a mixture of 1,l-difluoroethane and l,l,l-trifluoroethane. Only two peaks were present in the vapor phase chromatogram; 46% of the peak area was due to the difluoroethane and 54% was due to the trifluoroethane. The retention times were the same as those of authentic samples. Methyl i ~ ~ p r ~ ketone. p y l From the addition of 4 ml. of bromine trifluoride to 3.0 ml. (0.028 mole) of methyl isopropyl ketone there was obtained 715 ml. (STP), (0.032 mole) of gas. The infrared and mass spectra identified this as a mixture of 2,2-difluoropropane and 1,1,l-trifluoroethane. The trifluoroethane comprised 5975 of the vapor phase chromatogram peak area; the other 41% of the area was due to the difluoropropane. Trace amounts of three impurities were revealed by this chromatogram. A portion of the sample was fractionated in vacuo through 130" and 196" 130" ; traps. The 2,Z-difluoropropane was retained a t its infrared spectrum was identical with that of the material produced in the acetone fluorination. 1,1,I-Trifluoroethane, identified by infraredg and mass spectra, was retained a t 196'.
-
-
-
Acknowledgment. Mr. A1 Kennedy obtained the mass spectral data reported here; Dr. Keith S. McCallum and Mrs. Carolyn Haney supplied the infrared and NMR spectra. Their splendid cooperation is acknowledged gratefully. ROHM& HAASGo. REDSTONE ARSENAL RESEARCH DIV. HUNTSVILLE, ALA.
Synthesie and Spectral Properties of the Dideuterosuccinic Acids C. R. CHILDS,J R . , AND ~ ~ K. B L O C H ' ~ Received July 25, 1960
26
succinic acid, and 2,2-dideuterosuccinic acid have been synthesized. The infrared spectra of these compounds have been found to differ from one another and from unlabeled succinic acid. The infrared spectra of their dimethyl esters are also distinguishable one from another. In addition, the infrared spectrum of tetradeui erosuccinic acid differs from that of the dideutero- and unlabeled succinic acids. 2,3-Dideuterosuccinic acid has been prepared p r e v i o ~ s l y . ~Table -~ I summarizes the infrared spectra of the deutero- and unlabeled succinic acids, and Table I1 summarizes the infrared spectra of their dimethyl esters. -4s can be seen from the tables, the differences in the spectra are most marked in the region between 7-15 p. EXPERIMENTAL
Materials and methods. Deuterium gas in purity greater than 99.5% was obtained from the General Dynamics Corp. Liquid Carbonic Division, 767 Industrial Road, San Carlos, Calif. Palladzurn (10%) on carbon powder was obtained from Baker and Company, Inc., Catalysts, Lot No. 4838. Fumaric aczd: Eastman (98 %). Maleic anhydride: Eastman White Label. Succinic acid: Mallinckrodt AR, after crystallizations from acetonitrile, m.p., 192-193'. Ethyl acetate: Merck reagent ethyl acetate was distilled freshly from calcium hydride before each catalytic reduction. Acetonztrile: Fisher Certified Reagent, was refluxed for 12 hr. over calcium hydride and distilled. Tetradeuterosuccinic acid was kindly supplied b j Dr. T. T. Tchen. Deuterium chloride: Phosphorus oxychloride (5 ml.) was added to 5 ml. of quinoline, freshly distilled over calcium hydride, and distilled through a small Vigreux column. The distilled phosphorus oxychloride from the middle fraction (1.43 ml. or 2.4 g.) was added to 7.5 ml. of deuterium oxide. This mixture was then distilled through a small Vigreux column and the constant boiling deuterium chloride of approximately 2OYo concentration was collected. Melting points were taken on a Fisher-Johns Melting Point Apparatus on 18 mm. circular micro cover glasses. They are uncorrected. Deuterium analyses.' All samples were diluted with unlabeled carrier to contain t o a final concentration between 0.05 and 0.15 atom per cent excess deuterium. Samples equivalent to about 3 mg. of water were burned in a standard microcombustion train packed with wire-form cupric oxide (Mallinckrodt AB); the water of combustion from each sample was collected in an individual zinc train by freezing with Dry Ice; the zinc train was evacuated t o about 0.1 mmd of mercury, seakd, and heated for a t least 30 min. a t 430 in a tube furnace. The zinc train was then connected directly to a Consolidated-Nier model 20-201 isotope ratio mass spectrometer. The instrument was calibrated during each set of analyses with heavy water samples of known concentrations. Infrared specfra and nuclear magnetic resonance spectra. Infrared spectra were taken on a Perkin-Elmer, Model 21, infrared spectrophotometer in the region 2-15 p. Samples of
+
(3) H. Erlenmeyer, W. Schoenauer, and H. Sullman, Helu. In connection with some biosynthetic studies, meso-2,3-dideuterosuccinic acid, ~ ~ - 2 ~ 3 - d i d e u t e r oChim. - Acta, 19,1376 (1936).
(4) E. 0. Weinmann, M. G. Morehouse, and R. J. Winder, (la) Predoctoral Fellow, National Science Founda- J . Biol. Chem., 168,717 (1947). ( 5 ) D. Rittenberg, S. Ratner, and H. D. Hoberman, tion (1 year) and National Heart Institute (2 62, 2249 (1940). years). (lb) Supported from Grants-in-Aid from U. S. J . Am. Chem. SOC., (6) Method similar to that of San Pietro (ref. 7). Public Health Service, Sational Science Foundation, and (7) A. San Pietro in S. P. Colowick and N. 0. Kaplan the Eugene Higgins Trust Fund of Harvard University. (Eds.), Mefhods in Enzymology, Vol. IV, Academic Press, (2) M. T. Leffler and R. Adams, J . A m . (Jhpm, SOC.,58, 1552 (1936). Inc., New York, 1957, p. 479.
MAY
1961
1631
NOTES
TABLE I INFRARED SPECTRA OF DEUTERO SUCCINIC ACIDS Non-deuterated (2P
mesoSymmetrically Dideuterated ( 1 P
D Aymmetrically Dideuterated (2Y
3.40-3. 41b(27y sd 3.80-3,81 (39) ss 3.95 (45)ss
3.43 (32) s 3.81(41)ss 3.97 (45) 6.9
3.30-3.31(15-26)~ 3.41-3.42(1526)~ 3.82-3.83(3240)~~ 3 . 9 5 (41-46) ss
5.90 ( 0 3 ) s 7.07 (12)s
5.90 (05) s 7.07 (25) s
5.72-5.76(03-10)~ 5.90 (02-05) s 7.07 (08-20) s
7.63-7.64 (17) s
7.65 (07-17) s
Unsymmetrically Dideuterated (2Y 3.30-3.31 (30-35) s 3.38-3.42 (30-35) s 3 . 8 1 (40-43)bs
5.88-5.89 (02-03) s 7.07 (23-27) s
TetraDeuterated ( 2.93 (71) s 3.33 (56) b 3.42 (55) s 3.76 (66) s 3.91 (65) s 4.44 (52) s 4.82 (55) s 5.90 (05) s 7.11 (49) s 7.36 (26) b
7.66-7.76 (20-22) b 7.73 (33) 8
7.70 (20) b 7.82 (11-23) s 7.90(38)ss 8.34-8.35 (08) s
8 . 3 9 (32) s
8.23 (11-22) s 8.38 (49-52) ss 8.48 (50-55) ss
8.09-8.10 (51-54) s 8.37-8.40(52-55)~ 8.48 (59-63) ss
8.51-8.52 (37) s 8.68-8.69 (75-77) 6 8.84-8.87(75-77)~ 9.45-9.47 (72-75) s 10.05 (54-60)
9.48 (52) s 9.60 (57) s 9.92 (61) s
10.01-10.02(67-69)~~
10.25(62)bs 10.95-10.98(35)~b 10.88142) vi) 11.22 (45) t1s 11.55(69) hs
10 92-11.02 (19-31)vb
10.57 (50) bs 10.84-10.97 (39-46) vb
10.59 (54) s 11.02 (65) vb
1 1 61-11.62 (63-66) bs
11.94 (80) vb 12.38 (78) vb 12.43 (56) s 13.90 (83)b
14.01-14.02 (76-79) h
13.93-14.00 (83-85) b 14.53 (69) vb
a Kumber of spectra upon which values are based. Absorption peak in microns. Transmittance ( % transmission). Type of absorption peak: b = broad; bs = broad shoulder; s = sharp; ss = sharp shoulder; vb = very broad.
the free succinic acids (0.5 mg.) were mixed with 200 mg. of potassium bromide (Harshaw Chemical Co. Cleveland 6, Ohio, infrared quality). Spectra of the dimethyl esters were taken in carbon disulfide (approximately 15 mg. per ml.) in sodium chloride cells. The settings of the machine were as follows: response, 1; gain, 5; speed, 3; suppression, 4. Each spectrum was calibrated by employing a 0.03 volt test signal, and air. The peak found a t 2.673 p was used to calibrate the region from 2-5 p, the peaks found a t 6.411, 6.487, 6.631, and 6.855 p were used to calibrate the region 5-12 p, and the peak found a t 14.986 p was used to calibrate the region 12-15 p. Nuclear magnetic resonance spectra were taken on the pure dimethyl esters of the three dideuterosuccinic acids and on unlabeled dimethyl succinate with a Varian 4300B NMR spectrometer a t 60 megacycles. Only two peaks were observed, the peak for the methyl hydrogens occurring a t lower field strength than the peak for the methylene hydrogens. The difference between the two peaks for the dimethyl 2,3-dideuterosuccinates was 64 f 1 cycles/sec. and the difference between the peaks for the unlabeled dimethyl succinate and the dimethyl 2,2-dideuterosuccinate was 63 =k 1 cycles/sec. The ratio of the areas under the two peaks for unlabeled dimethyl succinate was 3:2, while the areas under the peaks for the dimethyl dideuterosuccinates were in the ratio of 3 :1 . The peaks due to the methyl hydrogens were sharp in all cases, and in dimethyl succinate the perrk due to the niethyleno hydrogens wae also shnrp, T h
peak due to the methylene hydrogens in dimethyl 2,2-dideuterosuccinate was broad, and the peaks due to the methylene hydrogens in the dimethyl 2,3-dideuterosuccinatees were also broad but exhibited a small shoulder occurring at higher field strength which could not be resolved from the main peak. This is most likely due t o the presence of small amounts of dimethyl monodeuterosuccinate. Spnthesis of deuterosuccinic acids. DLB,S-Dideuterosuccinic acid? To 1.16 g. of fumaric acid, recrystallized several times from water, dried in a high vacuum, and dissolved in 10 ml. of ethyl acetate, 100 mg. of 10% palladium on carbon powder was added. The catalytic reduction was run at atmospheric pressure with magnetic stirring and the uptake of deuterium was complete in 7 hr. The catalyst was filtered off, the ethyl acetate removed in vacuo, and the residue recrystallized several times from acetonitrile, m.p., 194.0194.5'. (8) The assignment of the isomers aa meso and DL is based on the well known fact that hydrogenations over platinum, palladium, or nickel catalysts are likely to be predominantly cis (ref. 10). This is also confirmed by the findings of T. T. Tchen (ref. 11) that the two isomers are distinguishable in the stereospecific succinic dehydrogenase reaction. (9) G. W. Wheland, Advanced Organic Chemistry, John kiley & Sons, Inc, New York, 1949, second ed., p. 299. (10) T. T, Tohgh, J. Am, C h m , Soc., 82,4115 (1960).
1632
VOL: 26
NOTES
INFRARED
(I)= Non-deuterated 3.34b (79)C sd 3.39 (69) s 3.52 (88) ss 5.72 (05) s 7.10 (66) s 7.37 (44) s
TABLE I1 SPECTRA O F DIMETHYL ESTERS OF DEUTERATED SUCCINIC ACIDS (1)" meso-Symmetrically dideuterated 3.34 (73) s 3.40 (60) s 3.53 (88) sa 5.72 (04) s
(3)= DLSymnietrically dideuterated 3.34 3.39-3.40 3.54 5.72
(1)" Unsymmetrically dideuterated
(72-82)s (60-71)~ (85-90)st (00-03)s
3.35 (70) s 3.40 (59) s 3.54 (84) ss 5.77 (03) s 7.38 (51) ss
7.50-7.51 (42-58) bs 7.59 (59) 8
7.61 (37) bs 7.68-7.71 (21-39) b
8.29 (30) b 8.63 (07) s
7.78 (28) s 7.96 (18) s
8.00-8.01 (18-35) s
7.98 (09) s
8.37 (09) s 8.62 (13) s
8.37-8.38 (10-22) 8.62-8.64 (12-24)
8.36 (12) b 8.63 (18) s 8.84 (43) ss
9.09 (53) 89 9.31 (53) s 9.56-9.57
(53-64) ss
9.66 (35) 8 9.75 (73) s
9.72 (42-57)s 9.82-9.83 (40-56) s
9.99 (60)s 11.87 (64) s
11.89
(73)
9.70 (42) s
b
12.03 (69) b 12.15 (73) b 12.31-12.33 (66-67)b 12.57(76)s 12.80 (75) b
*
" Number of spectra upon which values are based. Absorption pcak in microns. Transmittance ( % transmission). Type of absorption peak: b = broad; bs = broad shoulder; s = sharp; ss = sharp shoulder; vb = very broad. Deuterium analysis: Calcd. for 2 atoms, 33.33 atom 70 excess D. Found, 33.13 atom yo exces8 D. meso-d,~--Dideuterosuecinicacid." 2,3-Maleic acid was prepared by hydrolysis of maleic anhydride which had been freshly distilled a t reduced pressure. The maleic acid was used immediately before appreciable isomerization could take place. The procedure for catalytic reduction was exactly analogous to the preparation of the DL isomer, m.p. 195.5196.0'. Deuterium analysis: Calcd. for 2 atoms 33.33 atom % excess D. Found, 33.17 atom yoexcess D. 8,d-Dideuterosuccinic acid. 2,2-Dideuterosuccinic acid was prepared from the triethyl ester of 1,1,2-tricarboxyethane by replacing the tertiary hydrogen with deuterium, saponification of the ester in heavy water, and decarboxylation of the resulting acid. (11) meso 2,3-Dideuterosuccinic acid was also synthesized by the catalytic reduction of maleic anhydride, and the subsequent hydrolysis in aqueous solution of the 2,3-dideuterosuccinic anhydride formed, m.p. 191-192'. Deuterium analysis: Calcd. for 2 atoms, 33.33 atom % ' excess D. Found, 28.83 atom % excess D. The low amount of deuterium found can be accounted for by the findings of Weinmann et al.' who showed that 2,3dideuterosuccinic loses deuterium slowly at room temperature when in neutral aqueous solution. Nonetheless, the infrared spectrum of this sample, was very nearly identical with that of the meso 2,3dideuterosuccinic with the higher deuterium content. (12) Original preparation (ref. 13). (13) C. A. Bischoff, A n n a l a der Phannacie, 214, 38 (1882). (14) Method of preparation (ref. 15).
Trielhyl ester of I , I , d - t t i c a r b ~ z y e t h a n e ~To ~ * 200 ~ ~ ~ ml. of tetrahydrofuran, distilled from calcium hydride wae added 4.3 g. of sodium hydride (56% oil emulsion). Diethyl malonate (16 9.) was added slowly and the solution stirred under prepurified nitrogen for 1 hr. The homogeneousand slightly yellow solution was cooled to 0" and 16 g. of ethyl bromoacetate was added in one portion. The reaction took place very rapidly as indicated by the precipitation of sodium bromide and with slight warming. The reaction mixture was allowed to come to room temperature and then was stirred for 15 min. When necessary the pH of the solution was adjusted to 7 a t this stage. After removal of the solvents i n vacuo, the residue was shaken with 100 ml. of water and 100 ml. of ether. The ether layer was washed with 100 ml. of water, dried over magnesium sulfate, the ether removed in vacuo, and the residue distilled. The ester, b.p. 124-125' at 1.2 mm. of mercury was obtained in 68.3% yield. Conversion of triethyl ester tu 9,d-didmterosm'nic acid. Approximately 20 ml. of tetrahydrofuran was distilled from calcium hydride into a 50-ml. three-necked flask fitted with a drying tube, a bubbler, a condenser, and a magnetic stirrer. Dried, prepurified nitrogen was used to flush the system. A 56% oil emulsion of sodium hydride (1.5 9.) was added. The triethyl ester of 1,1,2-tricarboxyethane (2.22 g.) was added dropwise through a capillary tip. The mixture wae stirred under prepurified nitrogen for 2 hr. and then deuterium oxide was added very slowly through the capillary tip until all the excess sodium hydride had been destroyed. Then 10 ml. of deuterium oxide was added and the tetrahydrofuran removed on a rotary evaporator employing water pump vacuum a t room temperature. The system was pro(15) Sven-Olov Lawesson and Tamara Busch, Acta. 13, 1717 (1959).
Chem.Scand.,
M A Y 1961
NOTES
tected from moisture by Drierite. The remaining solution was stirred for 6 hr. to complete saponification of the cster. Then enough deuterium chloride of approximately 20y0 concentration was added to the solution to bring the pH to 1, the solution was then frozen and placed on a rotary evaporator connected by way of a lyophilization trap to a high capacity oil pump, and lyophilized. The residue was rinsed to the bottom of the flask with anhydrous ether, the ether removed i n vacw and the flask was fitted with a condenser and placed in an oil bath at 180". The tricarboxylic acid was decarboxylated producing succinic acid which sublimed either as the free acid or as the anhydride and collected a t the neck of the flask. A solution of 2.15 g. of barium hydroxide octahydrate in 10 ml. of hot water was added to the sublimate in a 40ml. centrifuge tube. Any undissolved barium hydroxide was transferred with another 10 ml. of hot water to the centrifuge tube, and the solution was heated with stirring for 15 min. for complete precipitation of the barium succinate. The solution was then centrifuged for 5 min., and the precipitate dissolved in 10 ml. of 2.4N hydrochloric acid. The solution was frozen immediately and lyophilized. The residue was extracted with ether in a Soxhlet apparatus for 24 hr. The succinic acid so obtained was recrystallized from acetonitrile several times, m.p. 189-190'. Deuderium analysis: Calcd. for 2 atoms, 33.33 atom % excess D. Found, 33.67 atom yoexcess D. The dimethyl esters were made by using diazomethane and distilled at reduced pressure. Sapmifiation of diethyl succinate i n deuterium ozide.16 Diethyl succinate, 871 mg. was added to 10 ml. of deuterium oxide and then 500 mg. of sodium hydroxide was added and the mixture was stirred at room temperature with a magnetic stirrer for 1 hr. by which time saponification appeared to be complete. Phosphorus oxychloride (0.5 ml.), freshly distilled from quinoline, was added to acidify the solution to a pH less than 1. The solution was then continuously extracted with ether for 24 hr., the ether removed i n UUCILO, the residue dissolved three times in 10 ml. of water, and the mater lyophilized. The succinic acid was then recrystallized several times from acetonitrile, and analyzed for deuterium. Deuterium analysis showed 0.515 atom yo excess deuterium.
Acknowledgments. The NMR spectra were run l y Mr. Luther K. Herrick and Mr. Thomas J. Curphey assisted vith their interpretation. DEPARTMENT OF CHEMISTRY HARVARD UNIVERSITY CAMBRIDGE 38, MASS. (16) This experiment was run aa a control experiment, in order to show that very little deuterium is introduced into the succinic acid when the diethyl ester is saponified in deuterium oxide. The succinic acid was found to contain 0.515 atom yo excess D or only o.773Y0 of the quantity calculated for complete exchange of the Cmethylene hydrogens.
The Amount of para-Isomer Formed in the Bromination of Biphenyl' ERNSTBERLINER, GEORGEL. ZIMYERMAN, A N D CILLIAN C. PEARSON Received Septembet 19, 1960
The amount of p-isomer formed in electrophilic substitution in biphenyl is known for bromination by positive bromine12as well as for chlorination'
1633
and n i t r a t i ~ n but , ~ ~no ~ direct value has been determined for bromination by molecular bromine, although indirect evidence indicates that it may be large.6 Having recently studied the kinetics of bromination of biphenyl in 50% aqueous acetic acid under conditions under which molecular bromine was identified as the only substituting agent,? it was of interest to learn how much substitution took place in the 4position under those conditions. The amount of p-bromination in biphenyl was determined by the isotopic dilution method, using molecular bromine containing the radioactive isotope BrS2, exactly as described for the determination of the amounts of p-isomer in the bromination of naphthalene.8 The conditions in the individual determinations were similar to those in the kinetic runs,' Le. reactions were carried out a t 25' in 50% (by volume) aqueous acetic acid, which was 0.01M ( 0 . M in one run) in sodium bromide, 0.4M in sodium perchlorate, 0.006M in biphenyl and approximately 0.002211 in bromine. Four independent determinations were carried out and the weighted average of the percentages of 4-bromobiphenyl formed was found to be 93.9 f 2.4, which represents the amount of 4-isomer in the total bromination product. Disubstitution is not likely to occur under those conditions, and the remaining material probably consists chiefly of 2-bromobiphenyl, with perhaps a small amount of the 3-isomer. I n bromination of biphenyl by positive bromine (H20Brf or Br+)2 the amount of para-substitution is 41.7y0; in molecular chlorination3 it is about 47% and in nitration in acetic anhydride 234325'%. The results for bromination by molecular bromine are therefore reasonable, because molecular bromine is a more selective substituting agent than either positive bromine, molecular chlorine or the nitronium ion. It is also in agreement with a value of 90% of 4,4'-dibromobiphenyl obtained with an excess of bromine in the bromination of biphenyl in acetic acid.Q (1) Taken from the senior honors thesis of G. C. Pearson, 1959. (2) P. B. D. de la Mare and M. Hassan, J. Cham. SOC., 3004 (1957). (3) P. B. D. de la Mare, D. M. Hall, M. hf. Harris, and M. Hassan, C h m . & Znd., 1086 (1958). (4) M. J. S. Dewar, T. Mole, D. S. Urch, and E. W. T. Warford, J . Chem. SOC.,3573 (1956). (5) 0. Simamura and Y. Mizuno, Bull. Chem. SOC.Japan, 30, 196 (1957) [Chem. Abstr. 52, 3742 (195S)j. For nitration in sulfuric acid (estimated value: 4770 of para-isomer) see €1. C. Gull and E. E. Turner, J . Chem. SOC.,491 (1929). (6) See for instance, P. B. D. de la Mare, J . Chem. SDC., 4450 (1954). (7) E. Berliner and J. C. Powers, J . A m . Chem. Soc., In press. (8) E. Berliner, F. J. Ochs, and G. L. Zimmerman, J . Org. Chem., 23,495 (1958).
