,MARIONE. HILL
2866
Vol. 82
niatography showed only one radioactive spot which cnrresponded with a n authentic sample of I.
For the purposes of paper chromatography studies, each urine sample was extracted with ether at neutral pH and Z-Butyl-l-C~4-aminomethyl-8-ethoxy-l,4-benzodioxane again at pH 2. The neutral extracts were chromatographed Hydrochloride (111).--Sodium b ~ t y r a t e - 1 - C(0.5 ~ ~ mmole, using the buffered system described The acid 860 pc), 5 ml. of dry benzene, 0.05 ml. of thionyl chloride extracts were chromatographed on Whatman #1 paper using and one drop of pyridine were stirred at room temperature a 1: 1 1-butanol-1.5 N ammonium hydroxide system. Carfor 2 hr. One and one-half grams of 2-arninomethyl-8boxylic acids were visualized by spraying with brom phenol ethoxy-1,4-benzodioxane (free base) in 5 ml. of benzene was blue. The radioactive spots on chromatograms were loadded and the mixture refluxed for 5 hr. After cooling, catcd in an automatic scanning device. Phenol spots were ether and 1N NaOH were added and the whole transferred found by spraying with diazotized sulfanilarnide.I2 to a separatory funnel. The organic layer was separated Isolation of 2-Carboxy-8-ethoxy-l,4-benzodioxane (VI) and washed with additional 1 N NaOH, 1 S HC1 and water. from Dog Urine.-A total of 400 mg. of I containing tracer By evaporation t o dryness the radioactive amide was reamounts of I1 was administered to dogs at a dose level of 2.5 covered as a n oil which crystallized upon standing, n1.p. 99mg./kg. (i.p.) and 24-hr. urine collections made. The urine lolo. (800 ml.) was then made p H 2 and extracted continuously Anal. Calcd. for C1SH2104K: S ,5.02 Found: N , 3.84. with diethyl ether to yield after evaporation a black t a r (150 mg.) When warmed with benzene ( 2 5 ml.) part of the Reduction of the intermediate amide was effected by tar dissolved. The benzene solution after cooling was refluxing 16 hr. with 100 mg. of lithium aluminum hydride in placed on a prepared silica gel (Davidson) column and the a mixture of 25 ml. of ether and 25 ml. of benzene. After column developed with benzene-ethylacetate mixtures. cooling, 1N NaOH (10 ml.) was added and the organic layer The fractions containing peak radioactivity were combined recovered by centrifugation. The product was extracted into 1N HC1 and after neutralization re-extracted into ether. and sublimed a t 90' (0.1 mm.) t o yield 15 mg. of white The crude hydrochloride obtained by saturation of the ether crystals n1.p. 124-127". These were identical in X-ray diffraction pattern, infrared and ultraviolet spectra and Xi with dry hydrogen chloride was purified by recrystallization from ethyl ether-methanol. The product, Z-butyl-l-C14- value to authentic 2-carbox~.-8-ethoxy-1,4-benzodioxane. Studies on Human Urine.-Morning urine collections from aminomethyl-8-ethoxy-1,4-benzodioxane hydrochloride (111), 12 patients receiving 25 mg. of ethoxybutamoxane per day weighed 134 nig. (89yG) and melted a t 196-195". This were made. The urine samples were then extracted with material had the same X-ray pattern as I1 and a n authentic ether first at pH 2 and then at p H 8. sample of I and was one spot material when paper chromatoWhether or not VI was present in the acid extract could graphed. be settled by paper chromatography so t h a t it was necesZ-Carboxy-8-ethoxy-l,4-benzodioxane(VI).-This acid not sary to resort to column chromatography. T o the acid was prepared by the procedure described by Koog for the preparation of the unsubstituted analog. Oxidation of 0.5 g. extract was added, as a tracer, 1 mg. of radioactive acid VI obtained from dog urine (see above). The acid extract of 2-hydroxymethyl-8-ethoxy-l,4-benzodioxaneyielded 5.9 was then chromatographed in the same manner as described g. (5870) of 2-carboxy-8-ethoxy-l,4-benzodioxane(VI). above. The peak radioactive fractions were combined and The acid after purification by sublimation melted a t 126found t o weigh slightly less than 1 mg., showing t h a t no VI 127'. was present in human urine. Anal. Calcd. for Cl1Hl2O6: C, 58.93; H , 5.40. Found: The extracts made a t p H 8 were paper chromatographed C, 58.72; H, 5.43. and sprayed with phenol reagent. Animal Experiments.-Methods for collecting and countAcknowledgments.-The authors are indebted ing uriiie and respiratory carbon dioxide samples from ratslo and from dogs4 (Chihuahua) have been described. The for valuable suggestions to E. C. Kornfeld, J. dose level in rats was 10 mg./kg. and 2.3 mg./kg. in dogs. hlills and I. H. Slater. Thanks are due to W. M. The dose was administered intraperitoneally in aqueous soluMiller for technical assistance and to Ann Vantion. Each set of r a t data in Table I represents the mean of four animals (the standard deviation was less than 57, of Camp, D. 0. Woolf and Jean Pieper for physical observed mean values in most cases). The dog data is data. based on a single animal. (9) J. Koo, S. Avakian and C. J. hfartin, T ~ I JOURNAL, S 77, 5373 (1955). (10) R. E . IvIcMahon, rbrd., 80, 411 (19SS).
[CONTRIBUTION O F
THE
(11) A. Brosd, 0. Hafliger and 0. Schnider, Areneim. Forsch., 5 , 6 2 (195.5). (12) R . J. Block, R . LeStrange a n d G. Zweig, "Paper Chromatography," dcademic Press, Inc., New York, N . Y . , 1952, P. 64.
CHEMISTRY RESEARCH DEPARTMENT, u.S. SPRING, MD.]
SAVAL
ORDNAKCE LABORATORY, SvHITE
OAK,
SILVER
Transesterification in Sulfuric Acid1" BY MARIONE. HILL'^ RECEIVEDM A Y1, 1959 ",l,(i-'l'richlori)ptietiol or its acctate and sonic eyeniplary halogen substituted alcohols arid their acetates produce good yields of esters by transesterification with nrgatively substituted methyl esters or the free acids in 100yc or fuming sulfuric acid solution. Evidence is presented that the reaction proceeds by cleavage of the starting ester in the sulfuric acid solution followed by establishment of new equilibria which favor the formation of the product ester.
Introduction However we have observed that esters such as 2,4,6Previous studies have shown that simple esters of trichlorophenyl and 2,2,?-tribromoethyl 4'-nitrocarboxylic acids in general undergo cleavage in benzoates were only partly cleaved in 1 0 0 ~ osulsulfuric acid and the free acids can be recovered furic acid and, in an extreme case, 2,4,6-trichIoro3',5'-dinitrobenzoate was almost comby pouring the reaction solutions into ~ a t e r . ~ phenyl -~ (1) Presented i n part before the Organic Division, 131st National A.C.S. Meeting, Miami, Fla., April, 1957. ( l a ) Stanford Research Institute, Menlo Park, California. (2) For a good review of organic bases in sulfuric acid see J. R. Gillrspie and J. A. Lristen, Qunrf. R Z U S8. ,, 40 (1951).
(3) hi. S . Newman, R . A. Craig and A. B. Garrett, THISJOURNAL,?^, 809 (1944). (4) (a) Id. S. Newman, H. G. Kuivila and A. B. Garrett, ibid., 67, 704 (1945): (b) L. P. K u h n a n d A. H. Corwin, ibid., 10, 3370 (1948): (c) A . Bradley and M. E. H i l l , ;hid., 77. 1575 (195.5).
2807
TRANSESTERIFICATION IN SULFURIC ACID
June 5, 1960
TABLE I TRANSESTERIFICATION IN SULFURIC ACID Product 2,4,6-TrichlorophenyI 3’,5‘-dinitrobenzoateh
4’-Nitrobenzoate
?.P., C. 162-163
Z’-Methylbenzoate 2,2,2-Trifluoroethyl 4‘-Nitrobenzoate Tereohthalate 2,2,3,3-Tetrafluoropropyl I’-Nitrobenzoate*
concn., method 4% fuming, AC 4 % fuming, B
171-172 92.5-93 62-62.5 190-191 197-198
1-3. acid-alcohol acetate
4% fuming, E
55
43.32
43.12
1.21
177-178
1-1, methyl ester-alcohol
4% fuming, B
40
29.74
29.76
100-101 54-54.5
2-1, 2-1, 2-1, 2-1.
2 5 . 7 2 25.98
135-135.5
2’-Nitrobenzoateb 4‘-Chlorobenzoate 2’-Chlorobenzoate Terephthalateb 1’,3’,5’-Ben~ene-~ tricarboxylate 2,4,6-Tribromophenyl 3’,5’-Dinitrobenzoateb 2,2,2-Tribromoethyl 4’-Nitrobenzoate Z’-Chlorobenzoate
Ratio, reactants
7 Composition,” $&------Other--Yield, --Cart.onHydrogen Ele70 Calrd. Found Calca. Found ment Calcd. Found
1-1, methyl ester-alcohol 1-1, acid-alcohol acetate 1-1, methyl ester-alcohol acetate 1-1, methyl ester-alcohol 1-1, methyl ester-alcohol 1-1, acid-alcohol acetate 2-1, acid-alcohol acetate 2-1, acid-alcohol acetate 2-1, acid-alcohol acetate 2-1, methyl ester-alcohol acetate 2-1, acid-alcohol acetate 2-1, acid-alcohol acetate 2-1, acid-alcohol acetate 2-1, methyl ester-alcohol 2-1, acid-alcohol acetate 1-2, acid-alcohol acetate
105-106
3’-Nitrobenzoate
H2S04
64.5-65
methyl ester-alcohol acid-alcohol acetate acid-alcohol acetate acid-alcohol acetate
4% 4% 4% 4% 4%
fuming, A fuming, fuming, B fuming, A fuming, A
loo%, A 96%, A
55 80 70 42 40 46 73 44 5
4% fuming, A 4% fuming, B loo%, B loo%, A 4 % fuming, A loo%, A 4% fuming, A
72 45 16 60 20 10 53
4 5 . 0 1 45.12 46.46 4 6 . 3 1 46.46 46.60 45.76 46.00
1.73 1.93 1.80 2.00 1.80 2.11 1.54 1.70
C1 CI C1
loo%, loo%, 96%, loo%,
B A A A
33 41 58 15
C1
30.72 42.21 42.21 40.52
30.90 42.42 42.50 40.70
1.38
CI
42.64
42.69
0.96
1.26
N
5.34
5.53
1.53
1.70
30.00 3 0 . 1 3 2 . 2 6
2.23
Br
59.79
59.46
47-48 112-113
1-3, methyl ester-alcohol 1-3, acid-alcohol acetate
loo%, A loo%, A
32 12
43.80 43.78 4 3 . 6 5 43.75
2.46 2.45
2.62 2.65
N
5.68
5.85
43-44
2-1, acid-alcohol acetate
loo%, A
45
42.70
2.49
2.66
N
4.98
5.20
42.75
Analyses by Dr. Mary Aldridge, American University, Washington, D. C. * Product precipitated from solution. 407, recovery after hydrolysis of this ester under e I n 100% sulfuric acid, no yield; in 10% fuming HaSon, 10% yield. the same conditions. a 2,2,3,3-Tetrafluoropropanol was furnished by E. I. du Pont de Nernours and Co. (1
pletely unaffected by 470 fuming sulfuric acid. The cleavage of the corresponding methyl esters, on the other hand, was more easily achieved and, if carried out in the presence of a negatively substituted phenol such a s 2,4,6-trichlorophenol or a polyhalogenated alcohol, a new ester was formed in situ. These findings prompted a study of the equilibria involved in sulfuric acid solutions of esters negatively substituted in the acid and alcohol portions.
Discussion and Results The transesterification procedure consisted simply of heating a nearly saturated solution of the ester to be transesterified and the reaction component in anhydrous or fuming sulfuric acid a t 70’ until cleavage of the starting ester and establishment of a new equilibrium system had occurred. After completion of the reaction, the product was isolated by pouring the reaction mixture into ice and water and followed by purification. As indicated in Table I , nearly the same yields were obtained in comparable systems by alcoholysis of a methyl ester. acidolysis of an alcohol acetate or ester interchange of a methyl ester and alcohol acetate. Of the three transesterification procedures studied, the reaction of acids with alcohol acetates proceeded a t the highest rate, requiring less than an hour in comparison to six hours or more when methyl esters were used as starting esters. The strength of sulfuric acid required for optimum yield varied markedly with the extent of
negative substitution in the reactants. The acetates of halogen-substituted aliphatic alcohols transesterified readily in 100% sulfuric acid, but optimum reaction in the preparation of derivatives of 2,4,6-trichlorophenol required 470 fuming sulfuric acid. The latter was necessary in order t o obtain any yield a t all in the preparation of 2,4,6trichlorophenyl 3’,5‘-dinitrobenzoate, but no advantage was gained by using lOy0fuming sulfuric acid containing more than an equimolar amount of sulfur trioxide. In a series of trichlorophenyl benzoate preparations under standard conditions varying only the substituent group and ring position, nitro and carboxyl groups in the p-position were effective in enhancing product formation, but chlorine was much less so. For the mono-0-substituted benzoates in which a limited degree of steric hindrance was involved, the reaction proceeded well, as in the case of 2,4,6-trichlorophenyl 2’-nitrobenzoate. In comparing the effect of halogens in the alcohol portion, not much variance was observed in the results of the 2,2,2-tribromoethanol and fluoroalcohol 4-nitrobenzoate preparations. The existence of an equilibrium was demonstrated by comparison of the preparation and cleavage reactions of 2,4,6-trichlorophenyl 4’nitrobenzoate in which the 40% yield realized in the preparation of the ester was the same as the amount of uncleaved ester remaining after its hydrolysis under the same conditions in a separate experiment. Alternatively, the same equilibrium
~ I U K R AHAUPTSCHEIN Y AND ROBERTE. OESTERLING
"6s
point was r e x h e d by first cleaving the starting ester aiid then adding the reactant. Although the yields of the acid-soluble esters were limited by the equilibrium degree of conversion of the intermediates to product and varied from 3-73$,, in some cases the equilibrium was upset by the precipitation of the product from solution. Esters such as ?,-I,G-trichlorophenyl 3',5'-dinitrobenzoate and terephthalate were insoluble t o the extent that very little remained dissolved in the reaction solution. Introducing an excess of one reactant forced the reactiori toward higher conversion t o product in the normal itt:uiner of an equilibrium process. I n considering a mechanism for the transesteriLcation reaction, experimental results do not indicate the actual reacting species in sulfuric acid solutions since there are a number of possible ionic reactants from the starting ester equilibrium and from the equilibria resulting from the introduced reactants possible mode of reaction involves an initial cleavage of the starting ester followed by formation of a new equilibrium system which favors the product ester, summarized in equations 1-4 for the alcoholysis reaction. IICOOCHJ
+ I-I:S'14 c,
+ iisoi-
[KcoociiJ1ir
[KCOOCH,]II
+ H?SOI f_
[IICOOHJH'
+ R'OII [ R C O O R ' ] I I + + HSOr-
[ K c o o I r J I i'
+ CHaOSOjlI + I120
[IICOOIC']H
+
RCOOR' f IIaSOi
(1) (2)
(3) (4)
These equations are in agreement with the forrnation of product ester by either alcohol-ester, acidester or ester-ester interchange in which the coiillimn reactants are some form of the negatively substituted acid and alcohol. X principal factor which influences the extent of reaction is the weak basicity of the product ester relative to sulfuric acid, with the forward reaction represented in equation 3 favored. The protonation equilibrium of the product with sulfuric acid, equation 4, accounts for the forniation of the un-ionized form which may or may not precipitate froin solution.
[COSTRIUUTION FROM
Vel. Y%
Otherwise tlie reaction would not proceed beyond ester cleavage represented by equations 1 and 2. This interpretation is consistent with the effect of electron-withdrawing substituents in the reactants, naniely a decrease in basicity of the ester grouping with concomitant increase in stability toward sulfuric acid. Acknowledgment.- -U'e wish to acknowledge our indebtedness to Dr. J. I. Conley, whose work in a related reaction inspired this project, and to Dr. D. IT. Sickman for many helpful suggestions. Experimental T h e preparation of 2,~,B-trichloroplieii~-l 4'-nitrobenzoate by alcoholysis of methyl 4-nitrobenzoate exemplifies the geiieral method used for the ester interchange reactions in sulfuric acid solution: Method A.--A solution of 1.81 g . (0.010 mole) of methyl 4-nitrobenzoate and 1.97 g. (0.010 mole) of 2,4,6-trichlorophenol in 16 g . of fuming sulfuric acid containing 0.008 mole of sulfur trioxide was heated 6 hours at 70". (Alternatively, 2,4,6-trichlorophenyl acetate was heated for 30 minutes with 4-nitrobenzoic acid or for 6 hours with methyl 4-nitrobenzoate.) ilfter cooling, the solution was poured onto ice aiid filtered. T h e crude wet product mixture was slurried with sodium carbonate solution for several hours, filtcred, dried, and recrystallized from aqueous methanol. There was obtained 1.45 g., 42y6, o f 2,4,6-trichlorophenyl 4 ' - n i t r ~ benzoate, 1n.p. 105-106'. This product proved t o be idcntical t o t h e ester obtained by metal halide catalysis of the reaction t ) f 4-nitrobcnzoyl chloride with 2,4,6-trichlorophenol5 by lack of reductioii in meltiug point when mixed and by identical infrared traces. T h e same cxperiment w a s rut1 using 32 g. of 494 fuming sulfuric acid instead of 16 g . The yield was reduced t o 24%. Method B.--iI solution o f 1.81 g. (0.010 mole) of methyl 4-nitrobenzoatc in 16 g. o f fuming sulfuric acid containing 0.008 mule of sulfur trinxidc was heated at 70' for 6 hours, the required period for crirnplete cleavage of tlie metlip1 4-i~itrohcnzoatc. To this solution was added 1.97 g . (0.010 niole) ( J f 2,4,6-trichlorop11eiiol and the resulting reaction solution was heated a n additional 30 minutes. (Alternatively 2,4,6. trichloropheriyl acetate was heated 5 minutes, :ti1 acid added and the solution heated for 1 hour.) After cooling, the product was isolated as in method A. A yield of 1.38 g., 40?&, of 2,4,6-trichlorophenyl 4'-nitrobenzoate, m . p . 105-106O, was obtained. T h e results of other reactions arc summarized in Table I Lvliich a h coiitains elemental analyses of new compounds.
T I E I < h S E A K C I I A S D n E V I 3 L O P M E N T I)EPAKTMENT, PESSSALl C I i E M I C A L S
CORP.]
Novel Elimination Reactions of Telomer Iodides of 1,l-Difluoroethylene' WEIN ANI)
1vau
ROBERT E. 0
OC?'OIlEK
5, 1959
pteferentially whet1 'Icloiiicr iritlitlch 11;ivitig CI'2C)i-1,Cl'nl cnti griitips Iiavc becli friuiitl t o uiidergo dcliydriri~Jdill~ttiol1 trcnted with ii widc variety o f strong aiid wcdi bases and i~t~clcnphiles.Only the relatively noti-basic halide ion nuclew philcs Iinvc liecii sliowii t(J produce the dehydroioditlatiotl product --C1FaCH==CF2 exclusively. Lithium chloride in diiiictliylfornlair~itic.in particular, gave high collversions it1 a rapid and selective elirninntiou reaction, and the syiithesis of a series of the olefins R,(CHaCF2),CH=CFn is described. T h e preparations of some of the related chlorides and fluorides I
