A;, .C - w l.‘\ u‘ ‘ u L p m. r . _ _ . , 4 . 1 .- _ 1.. .. . _ 2 .1: - .. - . r M _. M . 9 ,s < _u a L a ,I V: 0 A L m M w . r. m L ‘5 y‘. 20“. I 1’ l‘t’gn‘nt... .. t O 0.1. I‘ u‘. . o q A .. u .n a I . , w.______________ ., I‘m. ‘ ’ _’Oh% 1”. I .a. - ’ . .. fl. alll‘li‘lil. 1 .' III!!!‘ § Il" ' \' r ... ' .ll' . vier 'A‘. ’..bl.| I x ‘ l...l."..r . University é LIBRARY I mg... I MichiganStatc ‘— Benzylation of Pare.Cresol Thesis Submitted to the Faculty of Michigan State College in partial ful- fillment of the requirements fit the degree or Master of Science. 37 ‘7 Wilfred C. LBWIB 1929 Acknowledgment To Dr. R. C. Huston, the author exPressee his thanks for generous aid and kindly guidance in accomplishing thie work. 102368 Table of Contents Historical- Early work with Aromatic compounde,........... Use of Aluminum Chloride as a catalyst,....... (Work of Huston and others) Benzylation of cresols, o..................... The prOblGM, eeeeeeeeeeeeeoeeeeeebeeeeeeeeeeee Experimental - Part I Condensation by the Claieen.method,........... Preparation of 2-benzyl 4-methyl phenol,... Preparation of 2-benzyl 4-methyl phenyl benzoate,............................... Preparation of 2-benzyl 4-methyl 6-brom phenol, ...............................¢ Preparation of 2-6 dibenzyl 4-methyl phenol Preparation of 2-6 dibenzyl 4-methyl phenyl benzoate) Ooeeeeeeeeeeeeeeeeeeeeeeeeeeee Part II Condensation by the Huston Method Y181d’, eeeeeeeeeeeoeeeeeeeeeooeeeeeeeeeeeee Summary, eooooeeeeeeeeeeeeeeeeeoeeeeeeeeeeio Page 10 ll 13 14 15 16 21 22 Oo-ooeec .yoeee-e 0.000... 'OQeaae. .OOUQOOOOOI... I .ee-eeeeeeeneoeueeeeeeooo 0"... 00.... .000000900 oeuveeeeeeeeOOCDOOIOe .o.ees.eoO.eOOeOoue .0000! :- .JO 1. Part I Condensation may be defined as, ”A reaction between two or more molecules of the same or different substances with or without the elimination of water or some other inorganic compound". In this work our chief interest lies in those types of condensations in which water or a halogen acid are eliminated under the influence of a catalyst that may also act as a dehydrating agent. Reaction between Aliphatic or Aromatic alcohols or haliies and benzene or its derivatives are promoted by a catalyst of this type. Some of'them.that have been used are: Zn, ZnCla,,MgClg, SnCl., P205, P015, HCl, I and A101.. A search of the literature discloses many instances of the use of'Aromatic Alcohols or Halides and benzene or its derivatives in condensation reactions, and as such, have a most direct bearing on this problem, a few will be g1! en. Historical In 1872 Paterno (Gazz. chim. ital. 2, 20) prepared benzyl phenol from.benzyl alcohol and phenol, using zinc as the catalyst. O. Fischer (Ann. 206, 113-1880) condensed benzyl alcohol with dimethyl aniline using ZnClg. Lieb- mann (Ber. 14, 1842) in 1881 prepared benzyl phenol from benzyl alcohol and phenol using the same catalyst. In 1881 Merz and Wirth (Ber. 14, 187) prepared diphenyl other from phenol by the use of ZhClg. Meyer and wurster (Ber. o, 963) in 1873 used a mixture of 3330. and 01130003 in preparing diphenyl methane from benzyl alcohol and benzene. Paterno and Fileti (Gazz. chim. ital. 5, 381) in 1875 used the suns catalytic mixture in preparing benzyl phenol from benzyl alcohol and phenol. Hemiliam.(Ber. 18, 2360) in 1888 used P305 to form.diphenyl p. xylyl methane from benzhydrol and p. xylene. Bistryzcki (Ber. 37, 679) in 1904 used SnCl. in condensing benzhydrol with toluene to florm.diphenyl p. tolyl methane. Hahn (J. Am. Chem. Soc. 43, 175) in 1921 «Ju- densed 4-methyl benzophenone chloride with phenol with the aid of'P01so The use of A101. as'a catalyst began with the work of Friedel and Crafts (Comp. Bend. 84, 1392) in 1878. They condensed amyl alcohol with various hydrocarbons to form emyl hydrocarbons. Their work was solely with aliphatic 5. compounds and they stated that A101. would not bring about condensation with Aromatic compounds. Hewever, subsequent work has disproved this. Merz and Weith (Ber. 14, 187 - 1881) treated phenol with A101. and obtained diphenyl ether. Gustavson (Ber. 15,157 and Bull, Chem. 42, 525 - 1880 and 1884) develOped the theory that the A101. formed an addition product in the reaction, which prod- uct subsequently broke down and regenerated the AlCla. This theory was confirmed by Schliechen and by Buttgenbach (J. Prokt. Chem. 105, 355 - 1925). ' That the A101. may also act as a dehydrant is shown by Jaubert (Compt. rend. 152, 184 - 1901) who pre- pared aniline and p. toluidine from.hydroxy1 amine hydro- chloride and benzene. ' In 1916 Huston and Friedeman (J. Am. Chem. Soc. 58, 2527) showed that benzyl alcohol when treated with benzene in the presence of A101. would condense to form diphsnyl methane as thejprinciple product. Small amounts of ortho and para dibenzyl benzene and anthracene were turned at the same time. Two years later they described (J. Am. Chem. Soc. 40, 785) the condensation.of certain secondary alcohols with benzene. Methyl phenyl carbinol, ethyl phamyl carb incl and benzhydrol were used to prepare diphenyl ethane, diphenyl prOpane and triphenyl methane, A101. being the catalyst. It was found that the yiehdwas greatest where the alcohol was entirely aromatic. The 4. presence of the alkyl group had a retarding effect upon the reaction but ethyl decreased the yield more than.methyl. In 1920 Huston (Science 52, 206-7) condensed benzyl alcohol and phenol using A101. at comparatively low temperatures, forming p. benzyl phenol. Aniscl and phonetol with benzyl alcohol gave better yiehis of the respective ethers. Again in 1924 (J. Am. Chem. Soc. 46, 2775) Huston has shown that temperature has a marked effect on the yield of p. benzyl phenol. Also that in- creasing the amount of A101. above one half mol. did not increase the yield. Huston and Sager (J. Am. Chem. Soc. 48, 1955- 1926) found that the normal aliphatic alcohols up to anyl would not condense with benzene in the presence of A101., but that allyl alcohol gave a small yield of allyl benzene. 0f the aromatic alcohols, only those in which the hydroxyl is attached to a carbon atom.adjacent to the ring, will condense with benzene. The hypothesis was advanced that tnsaturation increased the activity of the alcoholic hydnaxyl. In 1926 Huston and Bartlett condensed phenyl butyl carbinol with phenol using A101. and obtained p. hydroxy l, 1 diphenyl pentane. Huston and Strickler in 1927 prepared p. hydroxy l, l diphenyl butane from pr0pyl phenyl carbinol and phenol by the same method. Huston, Lewis and Grotemut (J. Am. Chem. Soc. 49, 1565) in 1927 condensed methylphenyl carbinol, ethyl phenyl carbinol and benzhydrol with phenol, using AlCl., u: farm. 5. p. hydroxy 1, 1 diphenyl ethane, p. hydroxy l, l diphenyl prepane and p. hydroxy triphenyl methane respectively. Additional evidence was obtained showing that the alkyl group of the carbinol had a retarding effect on the react- ion, ethyl having the greater effect, but benzhydroxy1,which is purely aromatic, gave the largest yield. The tendency of the phenolic hydrcxyl to direct the entering group to the para position was noted. Additional evidence of the effect of unsaturation of carbon adjacent to the alcoholic hydroxyl upon its activity was obtained. 6. Benzylation of Cresols When introducing benzyl radicals into the cresol nucleus, a number of possibilities exist. The groups already substituted in the ring will have a directing influence upon groups which are subsequently introduced.. According t) Holleman (Chem. Rev. 1, 202‘ - 1924) the groups which direct to the para and ortho positions are OH; NH., I, Br, C1, CH., arranged in the diminishing order of their activity. The hydroxyl group of a cresol, then, will have the greater influence over entering groups and the methyl group practically none. In the case of ortho cresol, one position, - ortho to the hydroxyl and the para position,are Open. Hence two mono benzylated o. creSOls and one dibenzylated o. cresol are theoretically possible. 6 Huston and Swartout in 1927 carried out the benzylat— ion of c. crescl by the use of A101. on o. cresol and benzyl alcohol and obtained mostly 2-methy1, 4-benzyl phenol and a small amount of 2-methy1, 6-benzyl phenol. About ninetem percent of theoretical of 2-methyl, 4-6 dibenzyl phenol was obtained. In order to distinguish between the two isomeric mono-benzyl derivatives, the investigatdrshenzyla ted o. cresol by the method of Claisen. In this process (Ann. 442, 210-1925) the phenol dissolved in toluene is treated with an equivahit of sodium which forms the sodium salt of the Phenol. This when treated with benzyl chloride first forms an addition. compound attach- ing at the double bond adjacent to the O-Na, the halogen going to the carbon.atom.holding the O-Na and the benzyl radical .r. 7. to the adjacent carbon. This compound then splits off the sodium.halide and forming a double bond between carbon and oxygen. Rearrangement then occurs in which the hydrogen on the carbon atom holding the benzyl group shifts to hydroxyl position and the double bond is reestablished between carbon atoms. It is evident that by this means only ortln substitut- ion products can be formed. This ring substitution is not what one would ex- pect, but rather the formation of an Ether. It is found that when a dissociating medium such as alcohol is used in which to dissolve the reactants, the Ether is the principle product. But when a non dissociating medium.such as toluene is used, "ring alkylation" or anamolous metal substitutionfi,/fi%§%£g, formation of the ortho substitution product. Claisen and Tietze (Ber. 588, 275-81, 1925) have shown that when alkali phenolates in non dissociating media are treated with unsaturated alkyl halides only ortho alkyl phenols are Obtained instead of phenol ethers. And also that the alkyl is attached to the nucleus by the same carbon atom as it is in Ethers. Shorigin (Ber. 588, 2028-56; 1925) states that benzyl ethers such as PhCHgOR under the influence of sodium, rearrange to form carb inols - PhCH(0H)R, where R is para tolyl, cyclohexyl and benzyl. But ortho cresyl benzyl ether gave a Phenol in which the benzyl radieal was substituted in the side chain. Phenyl and ethyl ethers of ortho cresal are stable towards sodium,and when heated give the Phenol and Alcohol as decomposition products. This shows that the 8. benzyl group must be present to permit of rearranganent. Claisen and Tietze (Ann. 449, 81; 1926) treated 2-4 dimethyl phenol with allyl bromide in the presence of K200. and obtained the allyl ether which when heated gave almost quantitatively the 2-4 dimethyl 6-a11y1 phenol. In 1928 Huston and Honk benzylated meta crescl using A101. as the catalyst. In this Phenol both orth) positions are open as well as the para. Hence the possib- ilities for substitution are greater. They secured 5- methyl, 4-benzyl phenol; 5-methyl 4-6 dibenzyl phenol and 5-methyl 6-benzyl phenol. The compounds were identified by combustion analysis, and by the preparation and analysis of branine derivativds and benzoyl esters. They also benzylated meta crescl by the Claie en method and 5-methyl 6-benzyl phenol,agreeing in propertl as with that prepared by the A101. method, was obtained. Also 5-methyl 4-6 dibenzyl phenol which was identical wi th ttat prepared by the A101. method. And in addition, a 2-6 di- benzyl 5-methy1 phenol, which was not obtained by the A101. condensation, as well as 2-benzyl 5-methy1 phenol. 9. Benzylation of Para Cresol This reaction employing A101. as the catalyst was first carried out by Huston in 1920. The work was repeated in 1925 by the author. After the publication of the work of Claisen in 1925, it was deemed necessary to check the products obtained by the two methods to see if they were the same. Part of the problem also is t: prepare bromine and benzoyl derivatives of the condensat- ion products and determine their properties. Ala: to . discover the best prOportions of reactants to secure maximum yields by the A101. method. Since in para crescl only the ortho positions to the hydroxyl are Open, the Huston method and the Claism should both give a mono and a di-benzylated product. 10. Experimental - Part I Condensation of p. crescl with benzyl chloride. Claisen's method. 54 g. crescl (1/2 mol) 11.5 s sodium (1/2 mol) 64 " benzyl chloride (1/2 mol) 125 " toluene The finely chipped sodium was suspended in the toluene and the p. crescl added forming the white solid salt of the crescl. The flask was heated on an oil bath for half an hour and cooled. Upon adding the benzyl chloride much heat was liberated. The mixture was allcw ed to stand over night and then heated on the oil bath for five hours at 150 - 160°. After cooling the produst was washed twice with water to remove the sodium chloride, separated from the water and the red liquid heated on the oil bath to remove the toluene. The residue was dismlved in 250 cc. of Claisen's methyl alcoholic potadi solution (Ann. 442, 224) and extracted with 200 cc. pet- roleum ether in 50 cc. portions to remove the small amount of benzyl crescl ether, the potassium salt of the benzylated p. crescl not being soluble. This potassium salt was acid- ified with H01 to liberate the benzylated p. crawl and washed with water to remove the K01. From this mixture tln desired product was extracted with 150 cc. of sulfuric ether in three portions. After removing the other on the stem bath the residue was fractionally distilled. ll. 1,. —— CHsCeHB 11:10 O ONa + 2010H203Hs——->H30 0 0-11 and H30 0 O-CH2CsHs + NaCl 1st fractionation. (5 mm) up to 140 8.7 s The temperature rose rapidly to 170° 170 - 180 (mostly 170-175) 51.4 g 180 - 255 (mostly 225-250) 11.8 g 2nd fractionation (6 mm) Up to 140 8.0 g 140 - 162 (mostly 160-161) 48.0 g 162 - 24c (mostly 210-220)_ 15.5 g The second fraction crystallized immedh tely i when seeded with a crystal of 2-benzy1 4-methyl phenol which had been prepared by another method. A second coniensaticn using the same quantities of'materials gave: gave: 12. 2nd fractionation (5 m) up to 140 o g. 140 - 165 (mostly 160-162) 30.0 g. 165 - 240 (mostly 200-220) 2.6 g. A third condensation using the same quantities 2nd fractionation (5 mm) Up to 140 3.0 g. 140 - 160 42.0 8. 1‘0 " 280 10.0 80 The three middle fractions were combined and purified by recrystallization from petroleum ether in th ice box. The crystals were tramparent prisms and melt ed at 35 - 56°. Combustion analysis of 2-benzyl 4-methy1 phmol. (By Huston) .1508 g. substance gave .0980 g. H20 am .4695 g. 00.. Calculated for Cl‘Hl‘O; 0 .. 84.8%, H . 7.12% Found 0 - 64.954, H - 7.274 18. Preparation of the Benzoyl Ester 21 g. of the 2-benzyl 4-methyl phenol 6.97 g. KOH 14.82 " benzoyl chloride The phenol was dissolved in the potassium hydroxide in about 20 cc. water and the benzoyl chloriie added. After shaking together for an hour a white oily liquid was formed which did not crystallize. This was “cl-with ether and drhd over calcium chloride. After distilling off the ether the residue on fractionating at 5 mm. practically all came over at 205-206. After stand- ing at room temperature for about five months, it cry- stallized. It was purified by recrystallization from alcohol forming large transparent plates. Melting point was 42-42.5. ' 0 1' HsC/\ O - K + CsHsCOCl—>Hsc O O'C'CQHs 4 4 HSCCHS ' CHBCBHB Combustion analysis of the 2-benzyl 4-methyl phenyl benzoate - 1.008 g. gave .5056 g. 00. and .0541 3. H20 Calculated for C2IH18°2 : 0 . 85.4%, H a 6.0% Found 0 - 85.55%, H .. 6.05% 14. Preparation of the mono brom derivative: 15 g. 2-benzyl, 4-methyl phenol 12 g. bromine 50 cc . chloroform The Phenol was dissolved in the chloroform and the bromine added slowly. A rap id evolution of hydrogen bromide and much heat was observed. The chloroform was allowed to evaporate at room temperature and the residue was fractionally distilled at 10 mm. After two fractionat- ions a portion boiling at 177-178 was obtained which cry- stallized after standing more than two months. When cry- stallized from about 85% alcohol the crystals were a white (4’ silky felt. The melting point was 43-45°. ’ ‘Br H300 0 - H + Bra—$330< >0 - H + HBr CH203H5 w, Cflgc 3H5 Analysis of 2-benzyl, 4-methyl, 6-brom phenol. The Parr bomb was used. .1 g. substance gave .028771 3. Br. Calculated for 014111303r : Br - 28.84%. Found Br - 28.7'Il%. In the formation of the 2-benzy1, 4-methyl, 6- brom phmol, the location of the bromine was assumed t) be ortho to the hydroxyl. In order to obtain additional evidence, 6-bran para cresol was prepared by treating p. cresol in chloroform with the calculated amount of bromine to produce the mono brom derivative. The temperature was 15. kept below 10°. This was condensed with benzyl chloride accord- ing to the Ulaisen method as outlined in the first part of this discussion of the experimentalpart. Using half molar quantities in two condensations rather poor yields were obtained of fractions which boiled at 177-1780 (10 mm) and which crystallized immediately when seeded with a crystal of B-benzyl, 4-methyl, 6-brom.phenol which was prepared by brominating the 2-benzyl, 4-methyl phenol. Upon purifying by recrystallization from.alcohol the melt- ing point was 43-450. 1‘ H.011 + Brg———+Hs $03 + am ___4/ H20 OHS Ha<‘j >ON8 + Cefiscflch——)Hs OH + No.0]. 1' 1‘ Preparation of 2-6 dibenzyl, 4-methyl phenol. In all the preceding condensations a small fract- ion of'high boiling range was obtained. To secure a sufficient amount for investigation, three more condensations using half molar quantities were made. From.the 170-250o fractions (6-10 mm) there was obtained 15 g. of liquid that boiled at 256-238° (8 mm). This agrees with the boiling point at 2-6 dibenzyl, 4-msthyl phenol which was prepared by another method. I. 16. /‘.\ 320e38 Ha Bib-Na + 203H50H201—4Hs€\ H + 2Na01 CflecsHS Combustion analysis of 2-6 dibenzyl, 4-methyl phenol: .1752 g. sample gave .5555 g. 002, and .1068 g. 820. Calculated for 0218200; 0 - 87.45%, H n 6.99% Found c a 87.41%, H - 6.65% Preparation of the benzoyl ester of 2-6 dibenzyl, 4-methyl phenol. (By Huston). It was anticipated that it would be difficult to form the ester because of steric hindrance of the tw: benzyl group ortho to the hydroxyl. A sample of 2-6 di benzyl, 4- methyl phenol was treated with strong potassimn hydroxide solution. It did not dissolve, but solidified. Wren treat- ed with the calculated amount of benzoyl chloride heat was liberated and an oily liquid formed. After extracting with ether, drying and distilling a viscous yellowish red liquid was obtained. It did not solidify. CH2CeHs CHaCsHs .0 a. 0K + 0.350001% -0 - cm. + KCl CHgCaHG CHaCeHS . 0 v - . 7 . 1' .. , . ~ ‘ i . ,l ‘ . I ' ' .‘ ' . a ' I“ ~_ . 1. , ' I .1 . . u 4 , . . __ A . . e ‘ > ‘ — - I .7 V ‘ V . ‘E s; . I 17. Combustion analysis of the benzoyl ester of 2-6 dibenzyl, 4—methyl phenol. (Lewis). .250 g. substance gave .72 g. 009 and .1542 g. H20. Calculated for C H 03; G . 85.67%, H - 6.168% 28 24 Found » C I 85.55%, HI- 6.43% Experimental - Part II Condensation of p. cresol with benzyl alcohol. Huston's method. 108 g. p. cresol ( 1 mol ) 54 g. benzyl alcohol ( 1/2 mol ) 55 g. alundnum.chloride ( 1]! mol ) 75 g. petroleum.ether The p. cresol and benzyl alcohol were dis solved 18. in the petroleum.ether and stirred mechanically while adding the aluminum. chloride in small portions during the course of one hour. The temperature was kept below 25°. Hydrogen chloride gas was evolved most freely after about two thirds of the aluminum.chloride had been added. Stirring was cone tinned for another hour and the reaction product allowed to stand over night. The dark red viscous liquid was de- composed with ice and hydrochloric acid yielding a white oily liquid which was extracted with sulfuric ether. After recovering the ether the residue was fractionated. Preliminary fractionation Up to 225° without vacuum. 68.0 g. 140 - 190° (10 mm) 45.5 g. 190 - 250° n - 14.0 g. Residue 9.5 g. ,- 6- Second fractionation 19. Up to 140° (10 mm) 02.0 g. The temperamure rose rapidly to l67o 167 - 190 (10 mm) 55.0 g. 190 "' 250 n w 15.0 go Residue 5.0 g. Third fractionation Up to 100 (7 - 8 mm) 61.5 g. 165 - 185 " 54.0 8. 185 - 250 ' 85.5 8. Residue none The 165-1850 fraction crystallized immediately when seeded with a crystal of 2-benzyl, 4-methyl phenol, which had been prepared by Claisen's method, and placed in the ice box. With the intention of finding the-best proportions of reagents to use to obtain.maximum.yield, a second condem- sation.was made using the ingredients in the ratio of 5 mole of the Phenol to one mol of the Alcohol. aluminum chloride was not changed. 162 g. p. cresol 55 3. aluminum chloride 54 g. benzyl alcohol 75 g. petroleum.ether The anount of 20. Fourth fractionation Up to 100 105.5 8. 150 - 190 65.5 g. 190 - 250 21.5 So Residue .5 6. The 150-190 fraction was again distilled. (10 min) Up to 150 9.0 g. 150 - 180 502x30 180 - 250 .5 6. Residue .5 3. The 150 - 1800 fraction crystallized when seeded and placed in the cold. A third condensation using the same quantities as in the first was made. Third fractionation (8 mm) Up to 140 57.5 g. 150 - 190 54.5 g. 190 " 250 19.5 8. The 150 - 190 fraction crystallized when seeded and placed in the cold. 21. Yields The theoretical yield from half a mol of benzyl alcohol is 99 g. of the mono derivative or 72 g. of the di derivative. A101. " HsC-O-H + oicH.c.H.————. 3.0 First Condensation 54 - 55% of the mono derivative 35 - 56% n " di * Second Condensation 52 - 55% of the.mono derivative 29 - 50% ” " d1 ' Third Condensation 54 - 55% of the mono derivative 27 f 28% " " d1 " CH2C3HS and 330‘; >O-H + HCl CH2C6H5 22. Summary Para cresol was benzylated by the methods of Huston and Claisen. The products Obtained by both methods were shown to be the same. A bromine derivat- ive of themono benzylated para cresol was prepared and identified, as well as the benzoyl ester. The benzoyl ester ef’di benzylated para cresol was prepared and identified. It was found that using the Phenol and Alcohol in the molecular ratio of three to one increased the yield. ”1.59.. .115.» 9 '49 Who. I: 13"; T547 L677 . 102368 Lewis