2,4,6-Tris-(trifluoromethyl)-styrene

[CONTRIBUTION FROM THE I)EPARTMENT O F CHEMISTRY A N D THE PURDUE RESEARCH FI)LIVIJA I'IOY, P U R D U E UNIVERSITY] 2,4,6-Tris- (trifluoromethy1)-styrene' Downloaded by HENKEL KGAA on August 18, 2009 Published on December 1, 1950 on http://pubs.acs.org | doi: 10.1021/ja01168a058 RP EARL' R ~ C R E F ROBERTA. SANFOKD' 1 ANI) This investigation was conducted to determine but it1 general, the reaction requires that the whether a styrene monomer with both ortho halogen being exchanged be either bromine or positions substituted with trifluorornethyl groups iodine.i In fact, it is possible to exchange selecwould undergo polymerization. Mesitylene was tively a bromine in a bromochlorobenzene.a -111 attempts to polymerize 2,4,6-tris-(trifluorochlorinated photochemically in a single step to give chloro-2,4,6-tris-(trichloromethyl)-benzene methyl)-styrene were unsuccessful. Apparently, which was purified by recrystallization from a the steric effect of two ortho trifluoromethyl mixture of benzene and methanol. This chloro groups is sufficient to prevent polymerization. compound was fluorinated with anhydrous hy- In fact, this compound seemed to inhibit the drogen fluoride in the presence of antimony(V) polymerization of vinyl acetate when copolychloride a t atmospheric pressure to yield chloro- merization experiments were attempted. How2,4,6-tris-(trifluoromethyl)-benzene.The latter ever, this latter observation may be attributed in compound failed to yield a Grignard reagent, but, part to dilution of the vinyl acetate. 3-Nitrowhen i t was subjected to a n exchange reacticln styrene is the only other styrene known to the with butyllithium, i t yielded 2,4,6-tris-(trifluoro- authors which has failed to undergo polymerizamethyl)-phenyllithium. The addition compound tion.9 Tn dti attempt to prepare 2,4,6-tris-(trifluoroof this lithium derivative and acetaldehyde was hydrolyzed to 2,4,6 - tris - (trifluoromethyl) - a- methyl) - a: - methylstyrene, 2,4,6 - tris - (trifluoromethylbenzyl alcohol which was dehydrated a t methyl)-phenyllithium was treated with dry ' room temperature with phosphorus(V) oxide in 1 acetone in ether. Apparently steric factors interbenzene medium yielding 4,3,li-tris-!trifluc,ro- fere with the reaction of the carbonyl group in acetone with the organometallic compound, since methyl)-styrene . The following series of reactions show the i t failed to give an addition complex after refluxing sequence involved in the synthesis of 2,i,6- for twelve hours. tris-(trifluoromethy1)-styrene starting with mesiAcknowledgment.-The authors are indebted tvlene. to Westinghouse Electric Company for the CH? C ! C1 financial support which made this investigation possible P ;zv C11c/2 CCI 111: I' C A C F 3 Experimental --+ > SbCI Mesitylene .-Mesitylene, obtained from the University H I C ,\,,CH, cl/' of Illinois, was rectified through a Podbielniak colum; CCI c I:, "' Y (Hyper-Cal) . The fraction boiling between 162-163 (uncor.) a t atmospheric pressure, was used in further synthesis. Chloro-2,4,6-tris-( trichloromethyl) -benzene .-MesitylIIC =C?I, I-IC-CH3 Li ene was chlorinated photochemically using carbon tetra1 chloride as a solvent following the general procedure of F J C O C F ~P206 F X / j C F 3 CHZCHO F z c P s McBee and Leech.lo t t - By removing the solvent and increasing the reaction H + , H?O CBHB temperature t o 130 a substantially quantitative conversion to chloro-2,4,6-tris-( trichloromethyl) -benzene wa5 CF3 CF, CR obtained. It should be noted that no attempt was made The structure of 2,4,6-tris-(trifluoromethyl)- to make the equipment and chlorine lines iron free. Chloro-2,4,6-tris-(triffuoromethy~) -benzene .-Fluopheny€lithium by its hydrolysis to rination of -benzene was 1,3,5-tris- (tri -benzene. This dis- conducted chloro-2,4,6-tris-(trichloromethyl) successive a t atmospheric pressure.ll Two counted the possibility that butyllithium reacted fluorinations, at 70 and IO", required to produce were with fluorine present in the trifluoromethyl the desired product. Over-all yields of 70-8137~ were obtained. groups. 2,4,6-Tris - (trifluoromethyl) e-methylb enzyl Alcohol.-4 metal-halogen exchange involving chlorine The reaction was conducted under an atmosphere of nitroattached to an-aromatic r h g is an uncommon gen in a 3-necked round-bottom flask, fitted with a separaA few examples have been reported tory funnel, an efficient stirrer and a condenser. Lithium (2.8 in which chlorine was exchanged for l i t h i ~ r n , ~ , ~ J g., 0.50 mole) was cut into small pieces and dropped into the reaction flask containing about 300 ml. of anhy(1) Abstracted from doctoral thesis of Robert A. Sanford drous ether. The n-butyl bromide (27.0 g., 0.20 mole) OH n-BuLi /, CI (2) Sinclair Research Laboratories, Harvey, Illinois. (3) H Gtlniari, \' 1.nnghdm .md F Moore, THISJOURNAL, 6'2, I 2 127 (1940) ( 4 ) S M Spatz, l o u d .%ale Cull J Scr.. 17, 129 (1942). ( 5 ) G Wittig, G Harborth and W. Merkle, Brr , 77B, 315 (19441 (6) D S Melstrom, Iowa Sfale Coli J . Scr , 18, 65 7 ) A 1-1 Haubern rbrd , 18, 48 (19411 (A) H. Gilmso and S. Spatz, TmS JOURNAL, 98, 621 (1944). (9) C,S . Marvel, C. G. Overbergcr, R . E. Allen and J. H. Saunders, ibid., 68, 736 (1448). 10' 12. 'r I f c R c r . i i i d K 13, T.cech, f i d Enp. C h c m , 99, 394 1947:. 1 1 ' R . T. McBee and 0. R. Pirrce, i b i d . , 89, 397 (1947). Downloaded by HENKEL KGAA on August 18, 2009 Published on December 1, 1950 on http://pubs.acs.org | doi: 10.1021/ja01168a058 Dec., 1950 O-BENZYLPHENOL DERIVATIVES : QUATERNARY AMMONIUM HALIDES was mixed with an equal volume of ether and added slowly to the reaction flask. The rate of reaction was controlled by the rate of addition of the butyl bromide. Vigorous stirring was used throughout both this step and those following. Lithium bromide precipitated from the ether solution q a chalky white solid. After the formation of the butyllithium was complete, 47.5 g. (0.150 mole) of chloro-2,4,6-tris-(trifluoromethyl)benzene, mixed with an equal volume of ether, was added slowly. An exothermic reaction occurred throughout the addition. When no further reaction was apparent, the mixture was refluxed for 0.5 hour and then cooled in an ice-bath. Acetaldehyde (8.8 g., 0.20 mole) was mixed with an equal quantity of ether and added to the solution of organometallic compound. No apparent reaction occurred on mixing. However, on refluxing for 0.5 hour the mixture changed from a pale yellow to a bright orange color. The mixture was hydrolyzed with a saturated solution of ammonium chloride and the ether layer separated, dried, and the ether removed by distillation. Rectification of the remaining organic material yielded 26.4 g. (55.0%) of 2,4,6-tris-(trifluoromethyl) -a-methylbenzyl alcohol, b. p. 71-72' (4 mm.), m. p. 56-56.5", n% 1.4092. Anal. Calcd. for CllH,FgO: F, 52.4. Found: F, 51.9. A small quantity of 2,4,6-tris-(trifluoromethyl) -phenyllithium was prepared as above and hydrolyzed with a saturated solution of ammonium chloride. No unreacted chloro-2,4,6-tris-(trifluoromethyl) -benzene was observed and an 89% yield of 1,3,5-tris-(trifluoromethyl) -benzene was obtained. This discounted the possibility that the butyllithium had attacked fluorine present in the trifluoromethyl groups. The exchange reaction with lithium goes very well, but the reaction of the organometallic compound with the carbonyl compound seems t o be a limiting factor in the preparation of 2,4,6-tris-(trifluoromethyl) a-methylbenzyl alcohol. 2,4,6-Tris- (trifluoromethyl) -styrene .-2,4,6-Tris- (trifluoromethyl) a-methylbenzyl alcohol (10.0 g., 0.031 mole) was dissolved in 100 ml. of dry benzene contained in a small round-bottom flask and 7.1 g. (0.05mole) of phosphorus(V) oxide was added as a suspension in benzene. A trace of hydroquinone was added as a polymerization inhibitor and the mixture was shaken vigorously for thirty minutes. The benzene solution was then decanted from the partially hydrated phosphorus(V) oxide and distilled. After the benzene had been removed at atmospheric pressure, the product was rectified under reduced pressure to give 3.4 g. (56.670) of 2,4,6-tris-(trifluoromethyl) -styrene, b . p. 59' (20mm.), n z 7 1.3900, d24r1.4540. ~ [COXTRIBUTION FROM THE 5575 Anal. Calcd. for C11H6Fe: F, 55.6: Found: F, 52.6. The Attempted Polymerization of 2,4,6-Tris-(trifluoromethyl) -styrene.-Four tests were conducted in sealed tubes. Two were activated with a trace of benzoyl peroxide and two with ultraviolet radiation. They may be summarized as follows: 1. Activated with benzoyl peroxide a t 70" for 48 hours: (a) 1 g. of substituted styrene; (b) 1 g. of substituted styrene and 1 g. of vinyl acetate. 2. Activated with ultraviolet radiation a t 30' for 70 hours: (a) 1 g. of substituted styrene; (b) 1 g. of substituted styrene and 1 g. of vinyl acetate. In tests la, 2a and 2b, no apparent polymerizatio oc curred. The mobility of each sample remained unaiered throughout the test. Sample l b , however, polymerized to a highly viscous material. After removal of the volatile starting materials, the sample was analyzed for fluorine. Since none was found, it appears that no copolymerization took place. Rather, the styrene may have exerted a hindering effect upon the polymerization of vinyl acetate as apparently was the case in sample 2b. The inability of 2,4,6-tris-(trifluoromethyl) -styrene to polymerize is not surprising, since it is sterically hindered with two ortho trifluoromethyl substituents. Attempted Preparation of 2,4,6-Tris-(trifluoromethyl) a,a-dimethylbenzyl Alcohol.-2,4,6-Tris-(trifluoromethy1)-phenyllithium, 28.8 g., was prepared in an ether solution by means of a butyllithium exchange as discussed previously. Dry acetone, 7 g., was introduced with no evolution of heat or apparent reaction. The mixture was refluxed for five hours, but no color change occurred as in the previously condensation with acetaldehyde. After hydrolysis and isolation of the ether layer, and removal of the ether by distillation, the remaining organic material was distilled. None of the desired product was formed, but due to the hydrolysis of the organometallic compound, 24 g. of 1,3,5-tris-(trifluoromethyl)-benzene,b. p. 118119' (750 mm.), was obtained. Apparently, the carbonyl group in acetone is unable to react with 2,4,6-tris(trifluoromethyl) -phenyllithium because of steric effects. - Summary 1. The synthesis and the attempted polymerization of 2,4,6-tris-(trifluoromethyl)-styrene are described. 2. An attempt to prepare 2,4,6-tris-(trifluoromethyl)-a-methylstyrene was unsuccessful. LAFAYETTE, IND. RECEIVED APRIL 1, 1950 RESEARCH DIVISION, BRISTOL LABORATORIES, INC.] o-Benzylphenol Derivatives. VI. Quaternary Ammonium Halides2" BY WILLIAM ~VHEATLEY, B. WILLIAM FITZGIBBON, E. WILLIAM MINOR,RICHARD SMITH, F. R. LEE C. CHENEY AND S. B. B I N K L E Y ~ ~ The discovery that dialkylaminoalkyl ethers of o-benzylphenol (and substituted o-benzylphenols) exhibit potent antihistaminic activities3 made it worth while to prepare further related compounds. One type which came to mind was the quaternary ammonium halides derived from (1) For paper V in this series, see Wheatley, Cheney, Pitzgibbon JOURNAL, 12, 4443 (1950) and Binkley, THIS (2) (a) Presented before the Division of Medicinal Chemistry of the American Chemical Society, Chicago, September 3-8, 1950. (b) University of Illinois College of Medicine, Chicago, Ill. (3) (a) Cheney, Smith and Binkley, THIS JOURNAL, 71, 60 (1949); (b) Wheatley, Cheney and Binkley, ibid., 71, 64, 3795 (1949); ( c ) Mills, Rohrmann, Dinwiddie and Lee, Arch. internal. pharmacodyn., 80, 119 (1949). the tertiary aminoethers. Accordingly, a series of quaternaries has been prepared and evaluated for possible physiological activity. The majority of the quaternary halides prepared were those derived from substituted N,N-dimethyl o-benzylphenoxyethylamines, and thus constitute a new class of choline ethers. It is not surprising, therefore, that quaternization was attended by a profound change in physiological behavior. Antihistaminic activity is present in the quaternaries, but to a lesser degree than in the tertiary amines. A noteworthy fact is that the quaternaries possess a high degree of vasopressor activity. A report