Sept. 20, 1955
PERFLUORO ETHERS: SUBSTITUTION OF a-FLUORINE BY CHLORINE
4837
for three hours yielded the anhydride, 3.2 g., 6.3% yield, m.D. 314-318’. Anal. Calcd. for CeH4BIO: C, 31.36; H , 1.75; I , 55.26; neut. equiv., 229.8. Found: C, 31.27, 31.41; H , 1.74, 1.78; I, 55.19, 55.31; neut. equiv., 229.4. m-Iodobenzeneboronic Acid.-Direct iodination of benzeneboronic acid in sulfuric acid with silver sulfate as a promoter16 could not be used because of hydrolytic cleavage to yield benzene and boric acid. A procedure involving the reaction of the diazonium salt from m-aminobenzeneboronic acid with iodide also proved to be unsuccessful. The method which was successfull6started with m-phenylenediamine which was tetrazotized and converted to mAll melting points are uncorrected. diiodobenzene in 75% yield. A 40% excess of potassium Analyses were performed by Dr. Carl Tiedcke and by the iodide over that necessary for the formation of m-diiodoGalbraith Laboratories. benzene was used in order to ensure destruction of any exp-Iodobenzeneboronic Acid.-The preparation of the p - cess nitrite. When urea or stannous chloride was used exiodo acid has not been described in the literature. p-Dicessive foaming occurred and yields were negligible. Using iodobenzene was prepared by iodination of iod0ben~ene.I~ the same procedure as for p-iodobenzeneboronic acid a yield This compound was converted to the monomagnesium iodide of 5.1% of the m-iodo acid was obtained; m.p. 186.5and added to butyl borate; the product was hydrolyzed 187.5’ (anhydride). to give the acid. Anal. Calcd. for CsH4BOI: neut. equiv., 229.8; I , T o 5.4 g. (0.22 mole) of magnesium turnings in 50 ml. of dry anisole was added dropwise a solution of 73.2 g. (0.22 55.24. Found: neut. equiv., 227.9; I, 54.84. The other boronic acids used have been prepared premole) of p-diiodobenzene in 175 ml. of dry anisole. This solution was kept warm to prevent separation of the diiodo- viously and characteristics of the samples in this investigation are listed in Table 11. benzene. Ethyl iodide was added to start the reaction. As the reaction proceeded the reaction mixture became dark TABLE I1 brown. After the diiodobenzene had all been added and evolution of heat had ceased, stirring was continued for a SUBSTITUTED BENZEXEBORONIC ASHYDRIDES‘ half hour whence only a small amount of magnesium reSuhM.p., OC. Neut. equiv. mained. stituent This paper Lit.0 Obsd. Calcd. This solution was added dropwise to 75 ml. (0.28 mole) 265-266 289-290d 121.1 121.9 P-F of butyl borate in 175 ml. of dry ether cooled in a Dry Ice23 1-232 232-234e 180,6 182.6 acetone bath. After warming to room temperature over- P-CaHb 172.5-175.5 170d 182.6 182.6 night the reaction mixture was poured on 135 g. of ice and 7 m-Br ml. of concd. sulfuric acid. The resulting layers were sepa- m-F 211.5-213.5 22C!-22ld 121.8 121.9 rated and the water layer extracted with three 50-ml. por- m-OCHa 147f 134.4 134.0 158.5-159.5 tions of ether. These were combined with the original exAcids dried to constant weight a t 110’. * Uncorrected. tract and extracted with four 50-ml. portions of 10% sodium Corrected. B. Bettman. G. E. K. Branch and D. L. hydroxide. These latter were combined and acidified with sulfuric acid, yielding a brown resinous material and white Yabroff, THIS JOCRSAL,’56, -1865 (1934). e D . L. W. solid which were filtered off and extracted with portions Yabroff and G. E. K. Branch, zbzd., 56,1850 (1934). of hot dilute sulfuric acid until a precipitate no longer Konig and W. Scharrnbeck, J . firakt. Chem., 128, 153 (1930); C. A . , 25, 927 (1931). appeared in the extract on cooling. The combined precipitates were tan in color, 9.8 g. Crystallization from The kinetic procedure was as previously described.‘ benzene and twice from water (treated with Norite) yielded white needles of the acid which after drying a t 110’ (15) D. H. Derbyshire and W. A. Waters, J . C k e m . Soc., 3694
as these, a whole spectrum of values will be found. Their magnitudes will depend on which part of the Hammett plot is used in estimating rho. Thus the tentative values for electrophilic reactions proposed by Pearson, et aZ.,l3on the basis of data on the Beckmann rearrangement of acetophenone are not applicable to nitration or brominolysis of areneboronic acids, nor are they entirely satisfactory for the pinacol rearrangement. Experimental
(13) D . E.Pearson, J . F. Baxter and J. C. Martin, J. Org. Chem., 17, 1511 (1952). , 293 (14) R. L. D a t t a a n d N. R. Chatterjee, THISJ O U R N A L41, (1919).
[CONTRIBUTION No. 97 FROM
THE
(1950). (16) K.H.Saunders, “The Aromatic Diazo Compounds and Their Technical Applications,” Edward Arnold and Co., London, 1949,p. 25.
DURHAM, N. H
CENTRAL RESEARCH DEPARTMENT, MINNESOTA MININGA N D MANUFACTURING Co.]
The Chemistry of Perfluoro Ethers. I. Substitution of a-Fluorine by Chlorine: The a,a,cr ’-Trichloro Perfluoro Ethers1 BY GEORGEVAN DYKETIERS RECEIVED FEBRUARY 23, 1955 The first chemical reaction of perfluoro ethers is reported. Selective substitution of the a-fluorine atoms by chlorine has been achieved, using aluminum chloride as the exchange agent. Perfluorotetrahydrofurans and tetrahydropyrans bearing a single perfluoroalkyl substituent in the a-position are converted to their a,a,a’-trichloro analogs in good yield. Physical properties are reported for the compounds prepared. Synthesis of a perhalo lactone is described.
Perfluoro ethers are thermally and chemically very stable; indeed, chemical reactions have not hitherto been reported.2 However, researches carried out in this Laboratory have indicated slight (1) Presented a t t h e 126th Annual Meeting of t h e American Chemical Society, New Y o r k , 19%; Abstracts, p . 2 7 M . (2) (a) W. H. Pearlson in J. H. Simons, “Fluorine Chemistry,” Academic Press, Inc., New Y o r k , N. Y., 1950, p . 489; (b) R. N . Haszeldine a n d A. G. Sharpe. “Fluorine and I t s Compounds,” John Wiley a n d Sons, Inc., New Y o r k , N Y . , 1951, p . 144.
but definite activation of the a-fluorine atoms. This communication describes the reaction of aluminum chloride with members of a class of cyclic perfluoro ethers bearing a single perfluoroalkyl substituent in the a - p o ~ i t i o n . ~ ~ ~ The use of aluminum chloride to replace fluorine (3) T. J. Brice a n d R. I. Coon, THISJOURNAL, 75, 2912 (1953). (4) E. A. Kauck a n d J. H. Simons, U. S. Patent 2,644,823,July 7 . 1953.
Vol. 77
GEORGEVAN DYKETIERS by chlorine has been reported previously. Chlorofluorocarbons5and even CF46undergo substitution, the former a t 50-80' and the latter a t 190-260'. The perfluoro ethers used in this research undergo selective reaction with aluminum chloride, the three a-fluorine atoms being replaced by chlorine. The corresponding cyclic a ,a ,a'-trichloro perfluoro ethers are obtained in good yield. The reaction is illustrated by the following equation, in which Rr represents a perfluoroalkyl group and n is 2 or 3. RICF(CF,) nCFz
AlC1,
Rz Ri-0-C-F
I
:A1C13
--+
R3 [R1-O-&R2Ra
R+CCl(CF1)nCClz
-02 For this reaction pressure equipment is necessary, as temperatures of 150 to 200' are required. Best yields were obtained with a 307, excess of aluminum chloride. The use of excessive quantities of aluminum chloride or too-high temperatures leads to extensive decomposition of the product. Low temperatures and short reaction times lower the conversions but do not improve the yields above 607,. The remaining material has not been accounted for completely : some aluminum fluoride and carbonized tars are formed, and distillation residues amount to 3 to 10%. One of the more important decomposition products is hexachloroethane. I t has been isolated from each of the reaction mixtures, roughly 5 g.being formed per 100 g. of perfluoro ether. In no case has carbon tetrachloride been detected, despite infrared analyses of each fraction from the distillations of the reaction products. Monochloro or dichloro fluoro ethers, if present, should have been isolated during these distillations. No such materials were detected even when reactions were stopped a t low conversion. I t follows that these compounds, which probably are actual reaction intermediates, must react appreciably more rapidly than does the perfluoro ether itself. There is no evidence for preferential reaction among isomeric perfluoro ether constituents : unreacted ethers recovered from the reaction mixture were unchanged in refractive index or in infrared spectrum. Both the selectivity in fluorine replacement a t the a-position and the need for a strong Lewis acid suggest a mechanism analogous to that for the acid-catalyzed hydrolysis of acetal^.^ In the latter case the rate-determining step is considered to be dissociation of the conjugate acid (formed by addition of a proton). RZ -O--
I + R~-O-C-OHR
creases in rate of hydrolysis found when Rzand Ra are alkyl groups instead of hydrogen.' A formally similar mechanism may be written for fluorine-chlorine interchange in the perfluoro ethers, if the proton is replaced by the Lewis acid AlC13.
-----f
R8 [ R I - O - ~ R ~ R ~ f3 R~-(;=CRZR~] +
+ ROH
Elimination of the alcohol is facilitated by resonance stabilization of the resulting cation. This mechanism provides an explanation for the tremendous in( 5 ) (a) A. L. Henne a n d 11. s. Piewman, THISJ O U R N A L , 60, 1697 (1938); ( b ) W. T. Miller, Jr., i b i d . , 62, 993 (1940): (c) \V. T. hfiller, Jr., E . U'.Fager a n d P . H . Griswold, i b i d , 72, 705 (1950 ( 6 ) W. C. Schi-mb a n d D. W. Breck, ibid., 74, 1754 (19 (7) C . K . Ingold, "Structure a n d Mechanism in Organic Cornell University Press, I t h a c a , S . I'..1953, p p . 333-333.
tf R1-6=CR2R3]
+
AlCLF-
Exchange is completed by capture of chloride ion from the X1C13F- anion.8 ,ittack by ,41Cl3 is considered to be upon the fluorine atom, with carbonium-oxonium resonance of the resulting cation facilitating its removal.9 If Rzand R3 were powerful electron-attracting perfluoroalkyl groups or fluorine atoms, rather than hydrogen or alkyl groups, a very large decrease in ease of formation of the positive ion (and hence in rate of reaction) would be expected. This provides an attractive explanation for the extremely low reactivity of the perfluoro ethers. This argument implies that the a ,a,a'-trichloro perfluoro ethers should be somewhat more reactive toward strongly acidic reagents than are the perfluoro ethers, since chlorine is less electronegative than fluorine. Such is indeed the case: although without effect upon a perfluoro ether, hot fuming sulfuric acid slowly solvolyzed the corresponding trichloro perfluoro ether. The solvoly&SO4 TZ-C~FSCC~CF~CF~CCL L.-Od
so3
TZ-C~F~CCICF~CF~CO L-0-J
sis product is shown to be a perfluoro-type lactone by the appearance of a single, sharp, intense infrared band a t 5.3.1 p.lO The only other simple carbonyl band found a t this extremely short wave length is that due to acyl fluorides." This possibility is excluded a t once by the observation that aqueous hydrolysis yields one chloride ion per molecule, but no fluoride a t all. By these S O ~ V O H20 n-C4FgCClCF?CFzCO + ~
0---1
HC1
+ (TZ-C~F~COCF~CF~CO~H)
lytic reactions, it is firmly established that the three chlorine atoms are located in the a-positions of the trichloro perfluoro ether. The cyclic cy, a ,a'-trichloro perfluoro ethers show good chemical and thermal stability. However, (8) Radiochemical evidence has been presentedeo which suggests t h e formation of such a re\.rr?ible, metastable complex between AlCli and fluoride ion. (9) Attack upon the oxygen a t o m necessarily would exclude the oxonium resonance f o r m f u r the catinn. and would lead to cleavage with ultimate formation of a n acyl chloride (or ketone). Only traces of such reactive material, insufficient for identification, were found. (IO) RI. Hauptschein a n d A . V. Grosse, THISJ O U R N A L . 7 4 , 1974 (1952), reported t h a t perfluorobt,tyrolactone has a n intense infrared band (due t o carhonylj a t 2.34 p , rather t h a n 3 . 3 t o R.7 p a5 is found for nun-halogenated lactones. we'. 168, 1025 ( I % l ) , a n d K . 1.: Kagarise, (11) K . N. Haszeldine, THISJOURSAL, 7 7 , 1377 !19531, listed 5.30 t o 5 . 1 3 p as the characteristic wave length range for acyl fluorides. Although acid anhydrides have J strong band a t 5 . 3 0 t u . i , 4 5 p , 211 eqlnally intense band invariably uppears at 6.50 t o 5 70 ii due til \.lbratiunal conpling hetwero the t w o carbonyl groui's
TABLE I PROPERTIES, AND YIELDSOF ANALYTICAL DATA,PHYSICAL Trichloro fluoro ether
4839
PERFLUORO ETHERS : SUBSTITUTION OF a-FLUORINE BY CHLORINE
Sept. 20, 1955
B.p., 'C. (760 mm.)
~251)
Carbon, % Calcd. Found
c-CZCIDFIO
114
1.3620
..
c-CsClaFpO c-CsClsFisO C-CioC13Fi70
136 171 20'7
1.3566 1.3491 1.3455
20.6
.
.
21.2
.. , ,
21.2 21.3
Chlorine, % Calcd. Found
THE
~ , ~ , ~ ' - T R I C HFLUORO L O R OETHERS
Fluorine, 7% Calcd. Found
33.8
33.9
42.2
42.1
29.1 22.8 18.8
29.1 23.1 18.8
46.8 53.1 ,57.1
46.9 54.3 X ,0
Pertluoro ether used
c-C~FICO (2-CFsCdF70) c-CeF1PO c-CSFI~O c-CloF2,,0
Amt. Yield not based on recvd., unrecvd. % ether, %
65
40
50 87 81
45 54 00
found.) The filtered solution mas crudely fractionated in a 25-cm. \-igreux column. Only 13 g. of unreacted C-CgFlcO was recovered, and 50 g . of crude c-C~C13F130,b.p. 1671'72", n2% 1.3550 was obtained. The intercut, b.p. 105-167O, weighed onlyd.2 g. and came over almost entirely between 150 and 167 . It solidified t o a slush in the condenser. I t s infrared spectrum indicated the presence of hexachloroethane and C - C S C ~ ~ F but I ~ Oonly , small amounts of other substances. The solid component was recrystallized from C-CSFLGO and showed no depression of melting point upon admixture with an authentic sample of CzC16. The lower b.p. found for the intercut appears t o result from codistillation of the solid C2Cls with the liquid c-CSCI~FI~O. Experimental Some CSClti was present in the crude c-CsCl3F130 and was Perfluoro Ethers.-The perfluoro ethers used in this re- responsible for its high refractive index. The following search were prepared by the Simons electrochemical fluorina- procedure was adopted for purification. Ammonia gas was tion pr0cess.~J3 Boiling points and refractive indices agreed bubbled through the crude c-CsC13F130 t o react with all with previously reported v a l u e ~ , 3arid > ~ imfrared spectra in- acidic materials, then the mixture mas chilled t o -40' or dicated comparable purity. The ethers c-CsF120, clower and filtered centrifugally. The ammonia reaction CsFlaO and c-CloF200, obtained in the fluorination of the products and the C?Cls were removed almost entirely in this acids n-CsHI1C02H, n-C?H16CO2H and n-C9HlsCOzH, re- step: yield 45 g. (54y0), n Z 61.3509. ~ ~ p e c t i v e l y are , ~ known to be mixtures of perfluorinated aFurther purification was desirable t o prepare the sample substituted tetrahydrofuraus and a-substituted tetrahydro- for analysis and determination of physical properties: adpyran^.^ The ether c-CjFloOwas prepared from a-methylsorption fractionation16 has been found satisfactory. A tetrahydrofuran, and was isolated in a state of high purity column of 100 to 200 mesh silica gel 25 cm. long by 2.5 cm. by fractional distillation. Its physical properties have been diameter was used for 50 g. of filtered trichloro ether, with d e ~ c r i b e d and , ~ its infrared spectrum demonstrated the ab- isopropyl alcohol as desorbent. By this procedure there sence of the isomeric c-CjFloO wliich lilrs been prepared was obtained 30 g. (36%) of purified c-CsC13F130, each cut of from tetrahydropyran.3)1i ~ Analytical data are furnished in which had n Z 51.3491. Reactions with Aluminum Chloride.-Similar procedures Table I. If desirable, the rest of the material may be rewere used for all of the A1C13reactions. The perfluoroether covered from the column and the tail fractions. was heated with 1.5 equivalents of AlC1, for 14 hours a t 180' Solvolysis and Proof of Structure of c-CsC13F130.-The ('25and Cc-ethers) or 200--220° (C8- and Clo-ethers). cyclic trichloro perfluoro ether, C - C ~ C I ~ F ~ 46.5 ~ O g. , (0.10 Shorter reaction times may be found satisfactory. An mole), fuming sulfuric acid (20% SOs), 26.1 g., and a trace Aminco rocking autoclave of 43-1111. capacity (IYo. 406- of mercuric sulfate, 0.2 g., contained in a sealed (Carius) 35AX3 j or of 180-ml. capacity (No. 406-35CX3)15 with tube were heated for 15 hours a t 150'. The refractive index automatic temperature control was used. The factor of ~ t o 1.3271. of the ether phase had fallen from n z 5 1.3494 safety provided by this equipment is very large, a s pres- This phase was separated and distilled in a short helixsures usually encountered were only 100 t o 200 p.s.i. HOTV-packed fractionating column. I n addition t o unreacted ever, extensive decomposition, attended by much higher trichloro perfluoro ether and some high-boiling residue, pressures, has been observed upon ovcrheating of the reac- there was obtained the a-chloroperfluorolactone, c-CsC1Frltion mixture t o 280-320'. Sealed (Carius) tubes of '/2" 0 2 , b.p. 14O0, 1.3192, in 70% yield. or 3 / p " 0.d. and l / g " wall thickness also may, with proper Anal. Calcd. for C8C1FlBO2: C1, 8.64; F , 60.1; C1safety precautions, be employed. Properties and yields CJf the trichloro perfluoro ethers are (hydr.), 8.64; F(hydr.), 0.0. Found: C1, 8.50; F, 59.5; Cl(hydr.), 8.20; F(hydr.), 0.0. presented in Table I . The presence of hydrolyzable chlorine, but not fluorine, Preparation of C Y , ~ , ~ ~ ' - C ~ C from ~ ~ F , , C8F160.-The O following is an example of the procedure that was found served to confirm the proposed structure when taken in consuitable for the preparation of the cu,a,a'-trichloro perfluoro junction with the observation of an extremely intense, sharp infrared absorption band a t 5.34 p , assignable t o the perethers. I n a 180-ml. rocking autoclave were placed 88 g. (0.212 fluorohctone carbonyl stretching vibration. mole) of the ether, c-C8Fle0, and 45 g. (0.339 mole) of anPhysical Properties of ~ - C ~ C l ~ F ~ ~ O . - S e v ephysical ral hydrous aluminum chloride. The autoclave was heated for properties not recorded in Table I are listed below, and are 14 hours a t 200°, then after cooling t o room temperature compared with those for the parent perfluoro ether, c~ ~ ~I J ~ ~ ~ 0 . 3 ~ was vented in an efficient hood. Some gases escaped, but the pasty black reaction mixture weighed 121 g. I t was For c-C8Cl8FlsO: d26 1.813, b.p. 171°, m.p. not obsd. mixed with about 60 g. of c-CGFI~O (solvent) and filtered (glass below -loo0), dielectric constant 2.25 i 0.05 under pressure. (CClr is quite satisfactory as a solvent. (1000 cyc.), loss factor less than 0.0005 (1000 cyc.), dielecThe perfluoro ether was used in this experiment as CC14 tric strength about the same as for C-CSF~~O, surface tension might have been formed in a side reaction. None was (dypes/cm., 25') 23.8; viscosity (centipoises) 8.3 ( O O ) , 3.9 (25 ), 1.8 (60'); soliibility, miscible with benzene, benzo(12) J. H. Hildebrand and R. L. Scott. "The Solubility of Rontrifluoride, acetone, heptane, carbon tetrachloride, some-
the presence of chlorine results in marked solubility in organic solvents: qualitative data are given in the Experimental section for c-CSClSF130. The solubility parameter, c?,~? is estimated as 7.2 for this compound, as compared with 5.7 for the perfluoro ether c-C8FI60. Electrical properties, viscosity and surface tension data also are compared for these two ethers. The differences observed can be attributed exclusively to the chlorine atoms, as the ether structure is unchanged.
~~
electrolytes," Reinhold Publi4hing Corp , N. Y . ,3rd B d . , 19.50, p. P,53 seq. (13) J . H. Simons, "Fluorine Cllrnlistrv," . \ c a d e m i r Prew, I n ? . , New York, N.Y . , 1931, p. 414. ( l d j E A . Kauck a n d J H. Siuiurii, 1:. S Paleut 2,594,571'.A p r i l :!9,
I t
1952. (151 hiuerisdu I i i a t r u r u t u t C u . , Silver Spriiig> U d .
(16) €3. J. hlair, T T\'t.\thaver a n d F. D. Rossini, I n d . Eng. Chcm., 42, 1279 (1950). ( I 7 ) 'l'eclinical Bulletin "1;liiorochemical 0-75," Minnesota Mining aiid llanufacturing Co., Fluorochemicnls Department, St. Paul. hlinn., 1952. Other physical properties and exterided, quantitative solubility data are given.
3840
SAFIR,
DALALIAN, FANSHAWE, C Y R , LOPRESTI, !$7ILLIAMS,
what soluble in carbon disulfide and acetonitrile, very slightly soluble in ethanol, insoluble in water, solubilitv parameter12 6 = 7.2 (est.). For t-CgF180: d 2 5 1.7602, b.p. 104', m.p. not obs. (glass below -113') dielectric constant 1.85 zk 0.05 (1000 C V C . ~ . loss factor less than 0.0001 (100 cyc.), dielecthc strehgth 37 kv. (ASTM-D877), surface tension (dynes/cm., 2 5 O ) , 15.2; viscosity (centipoises), 2.41 ( O O ) , 1.45 ( 2 5 O ) , 0.80 (60"); solubility, miscible with benzotrifluoride, somewhat soluble in heptane and carbon tetrachloride, very slightly soluble in benzene, acetone and ethanol, insoluble in water, soluble parameter12 6 = 5.7 (est.). Infrared Spectra of a,a,a'-Trichloro Perfluoro Ethers.These compounds exhibit complex spectra, difficult to interpret. In each case, however, two fairly strong infrared bands were found in the region 10.70-11.10 and 11.2011.55 p, using liquid sample thicknesses of 0.007 mm. These bands. possibly may be attributable to the trichloro ether grouping.
UPHXM, GOLDMAN AND KUSHNERVOl.
77
Other Lewis Acids.-So reaction was observed between the ether c-CaFlsO and the less powerful Lewis acids BCla (230°, 15 hours). The (350°, 24 hours) or iVaCl~AlC1~ ether was recovered quantitatively, with unchanged refractive index and infrared spectrum. Aluminum bromide, however, reacted a t 170' with this ether but produced only aluminum fluoride, carbonized tars and bromine; no impurities were detectable in the recovered ether phase.
Acknowledgment.-The author would like to thank Dr. H. E. Freier for the analytical data, Dr. I\-.E. Keiser and Dr. J. LlcBrady for the infrared spectra, Mr. G. Filipovich for the electrical measurements, Mr. V. Welschinger for the viscosity data, and Mr. J. D. Keating for assistance with the autoclave reactions. ST.PAUL6, MINN. -
[CONTRIBUTION FROM
THE
MEDICINAL CHEMICAL RESEARCH SECTION, RESEARCH DIVISION,LEDERLELABORATORIES, AMERICANCYANAMID Co.]
a-Bromoacid Amides and Ureas as Anticonvulsants BY s. R.SAFIR,H.
DALALIAN,
W. FANSHAWE, K. CYR, R. LOPRESTI,R.WILLIAMS, s. UPHAX, L. GOLDMAN AND S.KUSHNER RECEIVED APRIL8, 1955
A large number of a-bromoacid amides and ureas related t o neuronal and carbromal has been synthesized for anticonvulsant activity. Maximum activity was encountered with compounds in which some branching in the acid chain was coupled with the simpler amide and urea functions.
loss or elimination of anticonvulsant activity. The glycine amide derivatives LII, LIII, LTV, and LV, the amides LI and LVI derived from heterocyclic amines and the isothiuroniutn derivative LIX also proved to be inactive. Compound LVITI, 1,3-bis(2-bromo-%ethylbutyryl)-urea, also was inactive. Thus i t appears that anticonvulsant potency is rctainrd within narrow liniits of substitution among t Iic rlcri \xti\.es of 2-bromo-2-ethylbutyric acid. Sonic lxmcliinf of the acid chain appears to be riecessary for anticonvulsant activity as may be inferred from the high potency shown by cnmpounds XXII, XXV, XXXIII, XXXIl)7, XXXVIII, LX and LXJ and from the virtual absence of anticonvulsant activity among the linear derivatives. Isopropyl groups in particular seem to have a salutary effect. Comparison of the amide derivatives with the R urea derivatives does not permit an unequivocal (C~HJQCCOSH~(C2Hj)zCCOSHCOSHy )CCOR, preference to be made for either group as a strucI RI I I Br I1 Br Br tural requirement for anticonvulsant activity. 111 The amides were prepared by classical procedThe most active group among the compounds ures, namely, reaction between the requisite acid listed in Table I is that derived from 2-bromo-2- chlorides or bromides and ammonia or amines. ethylbutyric acid. The N-methyl (XLI) and 9- Examples of compounds requiring less conventional methylol (XLII) amides of this acid are about as treatment are furnished in the Experimental secactive as neuronal and carbromal. The Ka-methyl tion. "-Ainino--'-ethylbutyramide was prepared analog LVII of carbromal, although active, is some- readily by hydrolysis of the nitrile. The urea derivwhat less potent than carbromal. Alterations in the atives were prepared in fair yields by reaction of alkyl amide group involving increase in the chain the acid chlorides with urea or rnethylurea. Several of the tnost active compounds are preslength, unsaturation or branching, all resulted in ently undergoing a limited clinical trial. ( 1 ) T h e Merck Index, 5 t h ed., Merck Br Co.,Jnc., Kahway, K.J , 1940, p. 196, lists epilepsy as one of t h e uses for neuronal. Sitroux, in an 'I'he pliariiiacological data were secured by Urs. L ~ . Wochschu., 30, 1407 (11)O-L)! commentn early clinical report [ D P ~ ined K. I\-, Cunriinghani and \V. C;ray, assisted by F. on the "extraordinarily favorable effect of neuronal on epilepsy but Smith and C. h u h , and will lw published in full his work was performed on only a few unclassified epileptic patients elsewhere. without benefit of modern, long-range, controlled methods. -1lthough a-bromoamides and ureas have for many years been used in medicine as sedatives and hypnotics, no systematic survey of this class of drugs for anticonvulsant potentiality appears to have been made.' The finding that neuronal (I) and carbromal (11) exhibited a high degree of protection against metrazole-induced seizures in rats gave impetus to the hope that a drug useful in petit mal epilepsy might be found i n the class o f CYbromoamides and ureas. A synthetic prograiii w i t h this goal in niind is the subject of this paper. In the selection of compounds to be syiithesizetl, it was decided to retain the a-bronio atom while varying, on the one hand, the alkyl groups on the acarbon atom and, on the other, the amide or urea function. These features are represented by formula TI1 in which the nitrogen is incorporated into Rz.
~
