Oct., 1950
Cl4 TRACER STUDIES I N SYNTHESIS OF
i\/IALONIC A\CID-2-C14
4659
001 AnaZ. Calcd. for CHX3OsK: K, 26.5; CH20, 20.4. o i y n ‘ y ; 2 8 0 Found: K,26.2; CH20,20.0. Monoclinic prismatic crystals for goniometric study are best obtained from water-ethanol solution. Rapid cooling b i ‘‘‘~~1160 1 1 f j O h T produces needles, but thin plates, approximately hexag001 onal in cross section and developed on the 100 face are obtained by slow cooling. The cleavage of this plate Fig. 2. (shown in Fig. 2) is principally parallel to the (001) and (011) faces. Its refractive indices are: a, 1.50 (parallel fifty minutes more a t this temperature the whole was to the b axis); 8 , 1.505; % 1.515. Density by flotation raked into ice (reverse dilution causes decomposition), filtered and washed with dilute ammonia. The vacuumwas found t o be 2.127 a t 25 . Unit cell dimensions (A,) are a = 14.32 * 0.04, b = dried R D X (m. p. 195-197’) weighed 12.4 g. or 84% of 9.73 * 0.03, c = 20.11 * 0.06 with 6 = 1U2.3 * 0.3”; theoretical. This was heated cautiously with 50 ml. of the cell volume is thus 2737 cu. A., which accommodates the 60% nitric acid until by-product decomposition was complete after two minutes, then diluted with 50 ml. of water, atomic weight equivalent of 24 molecules of potassium methylenesulfamate. The axial lengths have been cooled and filtered. The product, washed with 3y0 checked by the face-diagonal measurements, 001 = 22.30 ammonia and gacuum dried weighed 11.8g. and melted A. and 110 = 17.35 A. Extinctions are consistent with a t 204.3-204.7 From Sulfur Trioxide.-The yield was essentially space-group Cs~~(PI,,,), namely, (h01) when It 2 arc the(b) same as that shown above when 0.01 mole of tripotasodd and (0kO)when k is odd. sium triazacyclohexanetrisulfonatewas added t o a solution Spacings and relative intensities from the powder dif- of 0.0225 mole of stabilized liquid sulfur trioxide in 0.11 fraction pattern serve in absence of satisfactory melting mole of absolute nitric acid, but the crude (198-201’) and point as identification of the salt. the refined (204.5-204.8’) melting points were slightly better. However the violence of solution of sulfur trioxide I/Ii I/I1 dlw d/n ’ d/n dln I/II I/I1 in nitric acid (even a t -40’) recommends the procedure 1.0 3.98 0.4 3.18 0.35 2.00 0.25 3.64 with phosphorus pentoxide for laboratory use.
.
+
0.9 3.35 8 3.47 .5 5 27
.4 3 10 .35 8.71
.3 7.05 .3 2.59
.25 2.11 .2 6.39 .2 2.46
Summary
1. Molecular weight determinations by X-ray diffraction studies of the crystal and by freezing point determination of its aqueous solution show that when formaldehyde and potassium sulfamate react they form tripotassium 1,3,51,3,5-Trinitro-1,3,5-triazacyclohexane (RDX) triazacyclohexane-l,3,5-trisulfonaterather than A. From Phosphorus Pentoxide.-Into a 200 ml. three- potassium methylenesulfamate, necked flask equipped with a wide sweep powerful stirrer 2. This trimeric structure is confirmed by was placed 34.4 ml. (0.8 mole) of absolute nitric acid. The stirred acid, maintained at 0’ was treated with 28.4 g. nitration studies since only the trimer, 1,3,5(0.2 mole) of phosphorus pentoxide over two minutes. trinitro-l,3,5-triazacyclohexaneis produced in This mixture was chilled and stirred while 29.4 g. (0.066 absence of 1,3,5,7-tetranitro-l,3,5,7-tetrazacyclomole) of tripotassium 1,3,5-triazacyclohexane-1,3,5-tri- octane. sulfonate was added over thirty five Finutes so as to mainThe apparent molecular weight of the salt was determined by the freezing-point lowering of aqueous solution at several concentrations as shown in Fig. 1. The pH of these aqueous solutions was exactly 7.0.
tain a reaction temperature of 25-30
[CONTRIBUTION FROM C14 Tracer
THE
.
After one hundred
TORONTO, CANADA
RECEIVED FEBKTJARY 4, 195U
CHEWSTRY DIVISIOK OF OAK RIDGES A T I U N A L LABORATORY, OAK RIDGE, TENNESSEE]
Studies in the Synthesis of Malonic Acid-2-C14 and Diethyl Malonate-2C14 1
BY Gus A. ROPP Although the isotope dilution method for determining the amount of each of several istopically labeled components in a difficult mixture has been de~cribed,~J little attention has been called to its particularly valuable application to determination of successive yields in a series of organic reactions where the scale is so small as to make isolation and identification of the successive products impossible. I n the present (1) This document is based on work performed under Contract Number W-7405. eng. 26 for the Atomic Energy Project at Oak Ridge National Laboratory. (2) Calvin, Heidelberger, Reid, Tolbert and Yankwich, “Isotopib Carbon,” John Wiley and Sons,Jnc., New York, N. Y., 1949, Appendix I. (3) Keston, Udenfriend and Levy, THISJOURNAL, 69, 3161 (1947).
examples, the syntheses of carbon-14 labeled malonic acid and diethyl malonate by independent methods are described. In the first and most successful synthesis, a modification of the “Organic S y n t h e ~ e s ”pro~ cedure was used and the yields of products and of certain intermediates were determined by dilution of appropriate aliquots with the corresponding non-radioactive compounds and radioactive assay of purified derivatives. Potassium acetate-2-C14 having a millimolar5 activity of 8 pc. was converted Via bromoacetic and cyano(4) Blatt, “Organic Syntheses,” Coll. Vol. 11, J o h n Wile? a n d Sons, New York, N. Y.,1943, p. 376. (5) It was suggested by Dr. 0. K. Neville that this tertii be used instead of “molar specific activity of 8 ~ c per . mmole.”
acetic acids tu iiialonic acid-2-C14in 7 That the malonic acid was labeled in methylene group was proved by its conversion to tl-(2-furanyl)-propenoic acid-2-C L4 of identical millimolar activity. In the second procedure, ethyl acetate-2-C1 having a rnillirnolar activity of 25 pc. was converted to diethyl malonate-2-C1* in 28.5% ,yield oiu diethyl oxalacetate which was catalytically decarbonyhted in the gas phase6 a t 330". Intermediate yields were not deterininecl, but a radioactivity balance was obtained, i t was therefore possible to deteriiiiiie ;It which deps t h y losses iii t h e yield occurred. Although orily trdrer levels oi rdioactivity were used in this work, the processes were designed i'ur use ori a 10 inniol. scale with the highest available carbon-14 niillimolar activities (approximately 3 millicuries per millimole) arid required refined small scale apparatus. Experimental The n e t combustion arid g& counting iiiethods dexribed by Xeville7 were used for all radiochemical assays. 1. Malonic Acid-2-CL4 Synthesis: (a) Brornoacetic Acid-2-C11. --Ten millimoles, of potassium xetate-2-el4 having a millimolar activity of a . 8 pc. was converted by heating with phosphoric acid to 590 mg. (98% yield) of 'icetic acid (8.1 pc. per mmole, or a total activity of 79.6 p c . ) which mas distilled quantitatively into a tared pearihaped flask in which all subsequent reactions were performed and which could be converted to :i continuous extractor for separation of the ultimate product, malonic d d . Two drops of acetic anhydride (equivaleut to 0.63 inmols. of acetic acid), 3 mg. red phosphorus, and 0.6 1111. dry bromine were added,s and alter bromination was completed by heating one hour a t 125-135", hydrogen bromide and excess bromine were removed by bubbling in dry carbon dioxide a t 50 Crud( hronio,icetic acid 1.793 rng.) remained as a cleai oil. Benzylamine Salt.- A zaniplc (13.i mg.) of thc crude iuted 79-fold with C P . e zolution, and the benzylcrvitallized fro117 aretolit , 111. p . 97-972" -iwJz. i'llcc. 1 0 1 < S i l l O , \ i i I 131 ::2 i s 1~01111~1: Br, 31.4, 31.6. The millimolar activity \\ as 0.W.I gc. corresponding t o 6.3 pc. per mmol. for the uridiluted bromoacetic acid. The millimolar activity of the acetic acid diluted with acetic anhydride was 79.6/(9.8 t 0.63) = 7.6 wc., and hence the purity of the hromoacetic acid was 6.3/7.6 = The yield of pure bromoaretic tcid was 1393 X 0.K3,'l (10.0 0.63) = 7Xc' h,tied on potassium acetate. [b) Malonic Acid-2-C14 Solution.-The crudr btorno.icetic acid-2-C'i was ~ o i erterli n to a iolution (tot,rl w t 7.%8 g.) of sodium rnalonate-%-Cll. 3-(2-Furanyl)-propenoic Acid-Z-CI .-A sample 161.b ing.) of the solution %;isdilutrd 17-fold vith C.P . malonic acid and converted to pure 2-furanacrylic acid,1° millimolar activity 0.048 p c . corresponding to 0.048 X 17/7.6 = 10.7% m a l a i c acid in the solution or a. yield of 0.107 X 7.858/104 (10.0 0.63) 2 76yoof rrialonic acid in solution based on potassium acetate
+
+
( 6 ) .4ltwegg and Maillard, 1.;. S. Patent 1,524,968; tl. A , , 19, iibi 1925). :7) Neville, 'CHIY JouwAt., TO, 3603 !I9481 ) Ward, J . C h a m So-., 1163 (1Y22:. 1 Huchler, Carsorb and Edds, Tiirs J 0 i i ~ x 4 cllmeu, "Organic Svuth 'I~arkS l'., i ' a l i . j, 2
I
c) Isolation of Malonic Acid-Z-Cl4.-The sodium l i d -
otute solution was cooled in ice and acidified t o methyl
led by bul~blmg111 mhydrous hydrogen chloride. The up by attschmcnt of the necessary taperie reaction bulb, and ether extraction for 4xty-sis houri wparated 820 mg. of tan solid (74% crude yield based 011 10.6 mmol. of potassium acetate). After drying a t 1 inicron pressure one hour, a sample (39.1 mg.) of the crude product was diluted 20-fold and the gross activity \\ decomposed by stirring a t ( 1 with 7 nil. imizene and I .3 nil 2.86 .I' sulfuric x i d , .ind r separation of the aqueou? Liycr, thc benzerie iolution washed three times by s,tirriug with 2 . 5 ml. portions of combiiicd 'iqueouy I rb contained 2 X ~c .4yoof the starting J ityi. Crude diethyl -C14 mg., 31' yield based on ethyl obtained by v,Lcuuin dktillation of the berie which contained 4.0 U( 4 X f , of tlit st:irting a(./,
(c\ Decarbony1ation.-The crude diethyl oxahcetdte2-Cl' was passed during one hour as vapor a t 0.1 to 150 microns pressure up a 7-inch vertical 8-mm Pyrex tubc column filled with glass beads arid crushed soft glas5 and kept at 340460 O by a surrouridiiig electrically heatt ti jacket. The top of thc column wa5 sealed to .i\ ~ i i t i i i i line through a U-trap a t -190" in which 186 nig diethyl malonate ( w t . yield 3670 based on ethyl a containing 21.0 p c . activity (25.2y0of the starting activity) wab condensed. The distillation residue contained 12.2 pc. (representing 14.6% of the starting activity). Thus, a total of 757" of the starting activity WdS recovered. Malonic Acid-2-Cl4.-The yield of 100wo diethyl tnalonate-2-CY4 was determined by diluting the above crude product 100-fold with C. P. diethyl malonate and saponifying the mixture with cold 20% sodium hydroxide. The resulting malonic acid was purified and found t o contain
Oct., 1950
ORIENTATIONEFFECTS OF AROMATIC MERCURATION
0.15 pc. per mmol. equivalent to 15 pc. per mmol. for the undiluted diethyl malonate-2-C14 product. Hence, the chemical purity of the diethyl malonate-Z-C1* was 16/ 25.7 = 58%, and the weight yield of 100% diethyl malonate based on sodium acetate-2-CI4 was 0.93 X 0.68 X 36% = 19%. The weight yield of 100% diethyl malonate based on unrecovered ethyl acetate-2-Cad was 36 X O S / (1.00 0.267) 28.6%.
-
Acknowledgments.-The author wishes t o express appreciation to 0. K. Neville and W. G. Brown- who made helpful suggestions in the course of this work and t o B. M. Tolbert and
[CONTRIBUTION FROM T d E
4-16 1
W. L. Johnson who furnished procedures for the preparation of diethyl oxalacetate.
Summary Potassium acetate-2-C14 has been converted in 76% yield to malonic a~id-2-C'~.Ethyl acetate-2-C14has been converted to diethyl malonate2-CI4 in 28.5% yield. Isotope dilution technique has been applied in studying the reactions involved. RECEIVED MARCH6, 1950
OAK RIDGE,TENN.
GEORGE HERBERT JONES LABORATORY O F THE UNIVERSITY
The Mechanism of Aromatic Mercuration.
OF CHICAGO]
I. Orientation Effects
BY WM. J. KLAPPROTH~ AND F. H. WESTHEIMER
Introduction The orientation effects during aromatic substitution are today fairly well understood.3 During nitration, for example, the OH, NH2 and CH3 substituents, present in an aromatic molecule, direct an incoming nitro group to a position ortho or para to the substituent already present, whereas a nitro substituent directs further nitration to the meta position. It is therefore interesting that mercuration, which occurs quite readily in the aromatic series and which appears ( d e iltfra) to be electrophilic substitution, shows a number of anomalies. For although phenol and aniline are mercurated in the ortho and para position^,^ mercuration of toluene is accompanied by considerable meta substitution,j the mercuration of nitrobenzene is reported to be almost random,6 and mercuration of benzoic acid? yields exclusively the compound substituted ortho to the carboxyl group. I t has recently been discovered that mercuration with ionized mercuric salts in strong acid s ~ l u t i o n *takes ~ ~ place very much more readily than does the classical mercuration with mercuric acetate in non-polar solvents. It therefore seemed a t least possible that the lack of orientation effects in the mercuration of nitrobenzene, etc., was due to the fact that mercuric acetate exists largely, and in non-polar solvents perhaps exclusively, as undissociated molecules, whereas (1) Presented at the Eleventh National Organic Chemistry Spmposium, June, 1949, at Madison, Wisconsin. (2) Atomic Energy Commission Predoctoral Fellow; American Cyanamid Co., Stamford, Conn. (3) See, for example, G. W. Wheland. "The Theory ofResonance," John Wileg & Sons, Inc., New York,N. Y., 1944, pp. 256-272. (4) E. Mameli, Gars. chim. ita!., 141, 352 (1922); 0. Dimroth, tier., 81, 2032 (1902). (5) S. Coffey, J . C h e w Soc., 137, 1029 (1925). (6) J. JDrgens, Rcc. Irau. chim., 4S, 61 (1926); S. Coffey, J. Chcm. Soc., 3215 (1926). (7) 0 . Dimroth, A n n . . 446, 148 (1925). (8) F. Westheimer, E. Segel and R. Schramm, T H r s J O U R N A L , 69, 773 (1947). (9) R . Schramm. W. Klapproth and F.Westheimer, J Phys Chem., in press.
the common electrophilic substituting reagents probably exist either as ions (e. g.,lo N02+) or as highly polarized molecules. The investigations here reported show that mercurations of nitrobenzene and of toluene by mercuric perchlorate in aqueous perchloric acid solutions display the usual orientation effects for electrophilic substitution. Analytical Methods The various isomeric mercury compounds obtained on mercuration of nitrobenzene are not readily separable. These compounds were therefore treated with bromine in chloroform solution. This reaction has been shown l1 to lead to replacement, without rearrangement, of the mercury by a bromine atom. The isomeric bromonitrobenzenes can easily be analyzed (for the proportion of meta isomer) by taking advantage of the fact that the halogen atom ortho or para to the nitro group is activated toward replacement reactions, whereas the halogen atom in meta nitrobromobenzene is inert. The reagent chosen for this replacement was piperidine; the sum of the ortho and para isomers was determined by titrating the resulting solution for inorganic bromide ion.
fqr
+ CsHl&H
PI
+ C~H~ONH
(a.nd ortho)
-+
-
110
reaction
(10) For a good review, see R. Gillespie and D. Millen, Quarf. Rev., 4, 227 (1948). (11) M. Kharasch and L. Chalkley, Jr., THISJOURNAL, 43, 607 (1921).
