THS_ BENZYLATION 0F THYMOL TEESQ 1 EUFT E LEGREE {13’ 31 E 1 33103 d B EVal‘zs 3932 Th F3813 " F‘BH-r 1‘ :- Mun.- 1,. 16:an" it“ 3. .‘" 1 R Y . ,u 1 :1 ;'._.:.:’i.xigr1n Stem: . University _ .fi-‘Ia-z- "a :- -M“4""‘<"~‘~Jl Y“ H)“ A... 17‘. BENZYLATION OF THY¥0L A Thesis Submitted to the Faculty of the Michigan State College of Agriculture and Applied Science in partial fulfillment of the requiremente for the Degree of Hunter of Science by Harold B. Evans July, 1932 1-1144” 9/ ACKNOWLFDGEyFNT I most gladly acknowledge my indebtedness, and express my grat- itude, to Dr. R. c. Hueton, under who-e direction the following page. were written. I attribute whatever measure of eucaeee that has been achieved in this work to hie well timed advice and eympathetic one couragement. flea/.4175, 6W 331828 Contents PREVIOUS YORK AHD CFHYPAL PRINCIPLES Introduction Catalyst used in Organic Condensatione Alkylation of Phenols Benzylation of Phenols Work of Claieen and Followers Nuclear Benzylation Work of Friedel & Craft The Theory of the Action of Aluminum Chloride The Works of Huston Problem Stated EXPERIMENTAL FORK Condensation by the Claisen Method Ethyl and Methyl Ethors of 0- Compound Claieen‘a Ether Preparation of h-Brom Thymol Conionsation of k-Brom Thymol Bramination of 0- Compound Preparation of u-Chloro Thymol Condensation of h-Chloro Thymol Chlorination of o- Benzyl Thymol Aluminum Chloride Condensation Preparation of Z-Brcmo-Thymol Aluminum Chloride Condensation of E-Brom Thymol Bromination of p- Benzyl Thymol Page FNH max 24 3O 33 38 - - - - - - - .pf- BENZYLATIOH OF THYHOL PREVIOUS WORK AND GEH?RAL PRINCIPLFS Introduction Among the thousands of organic syntheses which have been effected during the past decade, not the least inter- esting are those in which hydrogens of the benzene ring have been replaced by aliphatic or aromatic radicals. Every case of substitution is preceded by an elementary addition reaction, that in the course of subsequent de- composition forms a new compound. The new group may occupy the position of the atom or group replaced or may assume a different position. In most condensation re- actions, especially those of Claisen either an acid or salt is split off, ani the substituted alkyl or aryl group occupying a different position than that which the netal took before. A satisfactory theoretical explana- tion for this is still wanted, and new points of view can be expected only from the yield of new experimental facts. In the bensylaticn of thyncl we have constituents present which exert an influence on the entering group; its final position being determined by the group or stem whose influence predominates. Holleman quotes Beilstein's rule: 'If a substituent C enters into a compound Céflnifi. both A and B exert an influence; but the grOup whose in- fluencs predominates directs c to the place it will occupy.' He then lists the groups which direct to para and crtho positions in order of their diminishing velocities. OH 71mg)! >Br 701 are};3 and CooH7So3H >N02 for meta substitution. Catalysts used in Organic Condensations Organic condensations have always been of great historical interest, and such ccndensaticne have been effected since 1870. There are numerous types of con- densations, likewise, numerous catalysts have been used to effect such condensations. Some of these catalysts are sulphuric and acetic acid, phosphoric anhydride, zinc chloride, hydrochloric acid and aluminum chloride. In most ccndensations either a halogen acid or water is split off. It is, therefore, easy to see why dehydrating agents or catalysts have often proved necessary in effecting such syntheses. A mixture of sulphuric and acetic acids was used in 1673 by Meyer & Wuster (Ber. 6, 963) in condensing benzyl alcohol with benzene to form diphenylmethane. Two years later the same catalytic mixture was used by Paterno & Pileti (Gaza. Chin. Ital. 5,361) in condensing benzyl alcohol with phenol to form a benzyl phenol. In 1831 Liebman (Ber. 1h, lSNE) prepared p- Lenzyl phenol from benzyl alcohol and phenol by using zinc chloride as catalyst. He also prepared butyluyhenol condensing isobutyl alcohol and phenol with molten Zn 012. Prepyl and amyl phenols were similarly prepared. Other condense- tions using Zn 012 were performed by Hers & leith (Ber. 1h, 137 eeq;) Auer (Ber. 17, 669); Dennstedt (Ber. 23, 2569) and by Ben: (Ber. 2?, 161a). Phosphoric anhydride was used in lF€6 by Hemilian (Ber. 16, 2360) in forming diphenyl ~p~ xylylmethone from benshydrol and p- xylene. Hydrochloric acid was used in condensing phenols with camphorquinone, by Day and Sen Gupsta (Proc. Chem. Soc. 29, 155). It was also used by Dionin (J. Russ. Ch. Soc. #6, 1310; 191%) in condensing phenols with unsaturated ketones, such as mesityl oxide. Stannic chloride was used by Bistrzyeki (Ber. 37, 659; 190%) in condensing benzhydrol with toluene to form dipnenyl -p- tolylmethane. small quantities of iodine were used as catalyst by Knoll & 00., (Ger. 250, 236, Apr. 23, 1911) in condensing organic compounds with alcohols or ketones. It was found to act as a dehydrating agent. Magnesium chloride was shown by Kazzara (Case. 12, 505; 1882) to have a catalytic effect in condensing K- cresol with proply alcohol. Alkylation of Phenols In lEE9-90 Gatterman, Ehrhardt and Haish (Ber. 22, ll99) prepared condensation products of aniscl, phenetol, etc., by treating them with various acyl chlorides and with benzoyl chloride in the presence of A1013. They expressed their belief that the constitution of the condensation product of anisol and acetyl-chloride is: #3.: 4:: c— 12”, Their proof is the fact that the oxidation of this compound. gives anisic acid. or p- methcxy benzoic acid. The other condensation products which they prepared gave analogous oxidation products. and on these grounds they repeatedly stated (Ber. 23. 1203. 1205. 1208. 1210) that the acyl or bensoyl groups regularly entered the ring in the p- pcsi-— tion. In 1881 Liebman (Ber. 1#,~lSh2) prepared a butyl phenol by condensing phenol and iecbutyl alcohol with the aid of molten Zn Cl . He also prepared propyl phenol and amyl ‘ phenol by the same method. The next year Haszara (Gazz. 12, 505) condensed propyl alcohol and a- cresol with Kg 012, and a year later (Ber. 16, 2U2) he used the same catalyst in preparing methyl butyl phenol. - i In 1891 Lenkowski (Ber. 24. 297%) reported that he had succeeded in alkylating aniline and some other aromatic compounds. He stated that in such reactions the new sub- stituent always takes the p- position, and that the same is true of the higher homologues of phenol, which are prepared 6 by treating a mixture of phenol and the aprroPriate alcohol with Zn 012. He thus extended ani confirmed the theory that was suggested by_Gatterman and his helpers. In 189“ Bauer (Ber. 27, 161%) confisnsed isobutyl alcohol and 0- cresol with the aid of Zn 012 and heat preparatory to the synthesis of nitrated isobutyl 0- crescl. In 1895 Anschuts and Beckerhoff (Ber. 28, has) prepared amyl phenol by condensing both iscamyl alcohol and tertiary amyl alcohol with phenol. The concluded that the two products were the same, citing similarity of melting points, of boil- ;inngoints, and of benzcyl derivatives as proof of identity. In 190# Clemmeneon (Ber. 37, 5h Seq.) prepared ethyl rescrcincl, ethyl hydroquinonc, ethyl pyrocatechol, and both mono-ethyl and di-ethyl pyrcgallol by reducing the apzroDriate ketcnes with zinc amalgam and 1:1 or 1:2 HCL. In 1907 Hersig and Eensel (chatsch 27, 761) stated that they had methylated phenols by treating them with methyl iodide in alkaline solution. In 1913 Johnson and Hodges (J. Am. Ch. Soc. 35, 161“) used Clemmenscn's general method to prepare a few alkyl phenols. They worked With others as well as ketones. The next year Johnson and Kohman (J. Am. on. 800. 36, 1259) crntinued this line of research and succeeded in preparing alkyl phenols with long aliphatic side chains. Benzylation of Phenols Some of the earliest work which has e bearing on the benzylation of phenols was done by Kolleritz and Hertz from 1371-73. (Ztschr. Chem. 1871, 705; Ber. 5,uu7; 6. 4&6) They succeeded in synthesizing diphenyl ketone. and they stated that they had worked according to principles governing the condensation of aldehydes, ketones, and phenols. using phosphoric anhydride as a dehydrating agent. In 1872 E. Paterno prepared benzyl phenol, apysrently the first to do so. (Gaze. Chem. Ital. 2. 1-6). He heated gently a mixture of benzyl chloride and phenol in the pre- sence of zinc dust. It was noted that a reaction started and hydrochloric acid was given off; the liquid entered into ebullition. Later a brown liquid or oil was separated frcn the unchanged zinc, and distilled. The uncombined benzyl chloride and phenol were dis- tilled of! below 260 . The remaining mass was distilled at 6 mm. The main fraction came over at 180 - 19* . This benzyl phenol was soluable in alkaline solutions, but was repreoipitsted by acids. It was insoluable in ammonia. When treated with nitric acid it would form substitution products.' When-treated with sulphuric acid it produced a sulphonic acid with the phenol, the barium salt which was solusble in water. They also found that benzylated anisole treated with hydroiodio-scid, and boiled for 8 haurs at 170 gave methyl iodide, and the sums benzyl phenol as just described. Two years later in 1874 E. Paterno and K. Filetti (Gaza. ), 121-129, 251.25u) gave a further description of possible derivatives of the same benzyl phenol. The action of bromine on benzylated phenol in acetic acid solution gave rise to an unstable oily compound. But they also des- cribed a compound prepared by adding excess bromine to a solution of bensyl phenol in carbon disulrhide which melts at 175 . This remained an amorphorue substance, eoluable in chloroform and carbon disulphide. but insoluable in alcohol‘and ether. They said it 'appears' to be a 'di- bromine”. However, later workers have questioned this compound. In 1890 0. Fisher (Ann. 266, 113) condensed benzyl alcohol and dimethyl aniline with Zn Clg , also benshydrol and dimethyl aniline. He found that he could need either Zn 012 or phosphoric nnhyiride to assist in the reaction. while this was not a case of benzylating a phenol, it is of interest because of the constitutional analOgy between aniline and phenol. Liebmsn (Ber. 1h, lean, 15, 152) prepared a benzyl phenol. Incidentally the question was raised as to whether the zinc used by Paterno was the active catalyst; or whether it was Zn 012 formed from zinc and free HCL always found in benzyl chloride. He referred to some of his own experimental observations as evidence that a very small quanity of Zn 012 cvuld catalyze the reaction. In 1861 Hers and Weith (Ber. 1h, 1&7 seq.) tried the effect of both Zn Cl and A101 on phenol. The result was not a benzyl phenol, but a diphenyl other. Their work is of interest, for it marks one of the first uses of A101 as a catalyst or dehydrating agent in reactions concerning phenol, being either years in sdvance of the work of Gstterman and his associates, who used this catalyst in effect the syntheses already mentioned in connection with their names. ‘ N In 1909 Khotinsky and Patzesitch (Ber. #2, 310d) called attention to the foot that aromatic teritary carbinols may be eesily condensed with meny substances, in- cluding phenol, by the aid of acetic acid to which a little H280“ or Zn 012 has been added. The work of Clsisen and His Followers. In 1923 S. Clsisen published work on the carbon sltyletinn of phenols in the ring. (Z. Angew. Chem. 36, #78-h79). He found that both oxygen and carbon alkyletion of phenols took place, when the reaction between alkyl helices and the sodium derivatives of monchydric phenols of the benzene and nspthnlene series took rises. This was due to the medium in which the reaction was carried out which is the important factor. When a dissociating medium was used such as methyl or ethyl alcohol or acetone, we generally have more oxygen elkylnticn; while in a non- dissociating medium such as benzene and toluene more carbon alkylntion is produced. He further noted that the unsaturated alkyle effect the carbon slkylntion to a greater extent than do saturated alkyle. 3.19. 32.29.23.333 halide 933.12 unsaturated M nermits £13 carbon alkyletion 9i Bhenols WWI-1.23 otherwise‘gg’alkylated. The tendency toward carbon slkylation is still further increased if elkyl phenols be used. The substituent enters into ortno position to the hydroxyl, provided tiis is unsubstituted. Since the work of Claieen is of great importance in connection with this problem, I will give a rather comprehensive review of his work in (Ann. Mal-#32; 210-2h5). 'Among the irregular reactions, 1.6., those wnich run contrnry to the theory and analogous cases, the irregular metal substitutions claim especial interest. Thus those cases when an organic halide reacts in such a way with an inorganic or organic metal compound, the alkyl or acyl takes a different rosition than that which the metal took before. The interest concerning this process may be explained on the one hand by the important roll which they have played, and Which will further play in the history of teutomerism, and on the other hand that a generally fiPPrOVrd theoretical eXplanntion for it is still wanted. It can not be predicted when it occurs or indicated with any certainty the mechanism by which it takes place. Attem;ting to exLIain is not necessary since these were brought together and discussed a short time ago without results. (winlienua) One has the feeling that all that can be acid on the basis of previous material facts has been said and that new points of view can be expected only from the yield of new facts. In the case of phenols, we have no exceptions reecor01nol, orcin, phloroglucinol, anthranol and oxy— nnthranol from which we receive instead of the expected phenol ether the isomer C-elkylphenol. The deviating behavior of the above mentioned phenols can be eleained without tro.ble by tautOmeriem up;enring in these cases. The double nature of these compounds (half phenol and half ketol) apreers also in the alkali salts and causes these to form by reaction with allyl halides both kinds of alkyl derivatives at the same time since they resemble at the eeme time the alkyl phenolate and the Na ketonee. All other [Lenole, however. especially phenols of benzene and nupthylene series were supposed to react in the normal way for euro, thus constantly and exclusively giving the O—elkyl derivatives. When this work was begun not a single contradictory case was known. However, this material, as extensive as it is, has yet its deficiency. At first people corm‘lJe red, in the fewer case-'3 when ulkyl phenol ether was produced an a step in the production of the alkali phenulntcs; especially the possibility of simultaneous resulting of kernnl-derivetivee. However, where this nap one the investigation being specially ll directed to determine in the case of s phenol, the gossi- bility of forming the C-alkyl derivatives, we have as a rule only employed methylation and alkylntion and other alkylstions only rarely. We assumed, as a setter of course that the deficit of the reactions do end mainly on the kind of phenol and much less on the kind of alkyl. Hee- ever, already the w‘rks of Hertzig and Zeisel, referring to the above mentioned phenols, show that there, even be- tween so nearly related substances as methyl and its higher homologues, significant differences. Keufter who likewise has worked on this subject, summnriwed it in this eay:-« that the tendency to enter the nucleus decreases constantly with increveing size and trenching of elirhctic alkyle. In the ease of benzyl it is said by the same author, not th exist at ell. It is strange that the hurt thus given has remained unobserved. If there are elkyls, in the thought we are ownsidering, one Would have to believe that the e must be among the great number of slkyls, especially among these poor in Hz , some that exceed the methyl in. their tendency to penetrate the nucleus. .here are also other conditions to be o-nsidered. If we put tOgether all the factors that are favorable to a transformation of influence, we have the following, in- eluding those already mentioned:-— (1) the kind of phenol (2) the kind of slkyl'(3) the kind of halogen or other component to ehioh the alkyl is bound (for example 804) (4) the kind of natal in the corresponding metal rhenolate, particularly light and heavy metal (5) the medium in which 12 the transformation is being attempted (6) temperature. ‘ Although there has bs.n many interesting and important points in former researches along this line, selecially those of Herzig and Zeisel and their pupils. neverthe- less the actual, systematic procedure, step for step, to prove each separate one of the above mentioned influences is not to be had (or is not given). How profoundly these latter factors, in some very es yet'uncontrollehle way affect the result is seen in Herzigs remarkzn~ 'That the slightest change in the concentration and temperature is of the greatest importance in regard to the nature of the bodies being formed, in spite of the greatest cars to’pre- serve identical conditions, not one errerinont turned nut like any other one.‘ That the medium is of very great consequence spies: from the feet, established by Herzig' and Erthcl, thst in an aqueous solution (made strongly alkaline) the nuclear slkylizstion is more strongly stimulated than in en a100holic solution. Many other observations of the same kind can be made, but they do not ‘ensbleus to form a clear idea of the dependence of the transformation uron the conditions. A complete under~ stending of the whole mst‘er can only be scguired by af careful and minute research into the above mentioned_% facts. - ‘ An excuse for our closer examination of this met‘er vexists in previous studies in the rearrangement of the phenolsllylather, by Claisen, and Cleisen & Eisleh, which are also a question of nuclear slkylizetion, but that here, in contradiction from Herzig & Zeisel reactions, it is accomglished not directly, but in two seperate steps}-- OII oCAh 3 a C3”,' Cub-0K filial-£9 U 4% Now it was observed even then that in the first of those steps, irxthe productions of the yhenolallylsthsr according to the Clsisen-Fieleb method, by boiling the phenols in acetone solution with alkyl bromide and K2003, almost al- ways formed some of the corres:onding ellylptencl. At first it was assumed that this sllyl phenol was due to an insufficient reerrsngcment. However, when it spyesred that the phenol ether did not change in the smallest particular after boiling in an acetone solution, not even if one added to the solution those suhst nose with wzich the ether is in contact with, one could svcii the idea that there was taking place here a direct nuclear slkylizsticn. all eel/o‘OK f C3//s'3r ——--—9 (’qu occurs in two different forms Hp. 21? and hp. 52', which change easily into each other are therefore probably only physical isomers. The tendency to unite with the C is even stronger with the diphenyl methyl ~CH(0535)2 then with benzyl whose bromide transforms itself with Na phenolnte in a bonzol suspension even at room temperature to diphenyl methyl phenol (C635)2-OH-06H5-0H. Even in alcoholic suspension according to Von Busch the transformation tekes place . O. Ch(C6H 5 5’2. According to some authors it can be obtained only by shutting principally in this way; the 0- deriviative, 06H out of all solvrnts and melting tagether the dry materials. In an aqueous alkali it is completely insolusble. It can be removed from benzene solution only by K O H of Clsisen, Lut cannot be remOVed from other solution at all. 20 One difference remains between benzyl end sllyl i.e., the phenol allyl ethers do rearrange themselves with heat but yhenol benzyl others do not. Therefore while one has two ways to nuclear elkylation of an sllyl br0m1d85- the direct method described here and the indirect with the consequent of phenyl ellyl ether and the transformation of them to o-ellyl phenol, one has with benzyl chloride only one. It is noticeable that when as we formerly assumed the rearrangement of the sliyl ether derends entirely upon looseness of bond between ellyl and oxygen. Then this transformation might be obtained also with benzyl ether. The difference might be explained if one assumed that with the rearrangement of phenol ellyl ether the ellyl united not with a carbon atom but with B carbon atom in nucleus. As example:-- -°\ CM; I f'c q - ’60! Q .u" 3 .. cat at y This assumption has recently be=n published by Claieen & Tietze and is suprarted by proof that with phenol cinemyl ether the arrangement takes place like this:- t",/°' ("44.0. c Mt-CII: new, ——-—-+ 0.11., \ eJPeru. cu. It is ;lein that a similar process is not possible with phenyl benzyl ether or at least that it can not lend to en o-benzyl phenol. It ought to be discussed erether the explanation up to present for the mechanism for the anomalous exchange agree With fzcts. These exylenetions may be dividei into two groups. Those which only refer to the one reaction component the metallic connection, and those that refer to two components the metallic and alkyl halide. As an example of first group the View is offered which V. Vielicenus ooneiders the most probable. He assumed that removal of metal by heloren an union of alkyl with oxygen and carbon are not contemporaneous processes. During the short intervals the residue No. 1 arising from removal of metal can remain ovnsietent and will then take up the alkyl uith the oxygen valence. __e,o___> -c'ofl I! II I -—CH ' I _..Q.—-—> It can ho'ever immediately rearrange itself in II. The alkyl will then enter the carbon, in either case whatever happens depends uyon nature of the combination under discussion, which as Wielicenue expresses it depends upon conetiteent influence and partly upon environmental conditions. (Tempt. éOlVLnt and dilntion) At the flame time, however, this is also true of all e1planations of the first method. The destiny of the outcome of the re- action is transferred entirely into the one reaction oomnonent and the alkyl halide is left out of consideration. or course one underetsnds according to this View that of ~t-so different phenols, both treated with same elkyl halide that one forms a prsdominnfiely o-alkyl derivative engagther a carbon, but it is not to be understood why one and the same phenol when treated with two dif? rent elkyl halides 22 under exactly the BPLG conditions sometimes prod cos the O- ond sometiwen the C alhylhtion. This and many similar facts are eX§lhincd only by the explanation of Mecheal which csvumea as a primary process a union of alkyl halide with double bond obtained in metal cerivrtive. 9 _. Q_oNq -—c’—-ON« - c = ' __ ck.) I! + H _______,, “‘1’“ ’ ""4 " -e—u __cun 1~cun .sC-Ofi Here both factors are taken into consideration the Optiwum for tha occuranoe of analomoua transformation must be ob- tained on the one hand from a nfital derivative WJCBG double bond reaniers such a union very easy, and on the other hand if :n alkyl halide which on ECJChnt of very loose union of its halogen is particularly inogincd to duet such a union. The confirmation of this latter state- :ncnt by the present work mu~t in fact be considered 88 a strong argument in favor or Micheal theory. (K. H. Meyhr confirms) At all events the C alkylation is a.process in itself and fioea not stand in any casual relation with the o-alkylfition that ofton t;ko plroe at the same time. Thceefore in no case must a screen alhyl deriv,tivo by a; umed as ncoecrhrily following an o-alkyl derivative. In sodium phenolate, we find the group _.c..,~m_ u ~c-u and benzyl chloride is analogous to an alkyl haliie. We ahouli expect than just such a shift of bonds, a split*ing of bcnzyl chloride into parts which attach themselve to 23 different cnrbon atoms, the elimination of Na Cl, and the final formation of a companni with CH restored and benzyl raiical attached to carbon atom of ring. Probably such a shift oeuld come about only in the case of tee rdjacent carbon atoms which would direct the uenzyl groug to a position 0- to the OH group. Thus we are reasonably certain of obtaining a candenention product With the OH group and entering constituent adjacent to even other. Vs also notice that pure p- compounds are not to be expected as Gnttermen enc‘gthers seem to think, but are likely to produce mixtures of O and P conp0unis, as might be expected from Hollemen's diecueeion of general principles governing suuetitution in benzene ring. (Chem. Rev. July 1924-187 Beg.) it was established of a number of sodium phenoletes (phenol, p creeol, A-B nepthel, quaicol) in checking over the date on hand that the conversion with chloride in nethyl and ethyl alcohol solution produces almost exclusively the benzyl others and a very little or none of nuclear banzyl derivatives. Phenyl benzyl other is entirely un- deoomposed in spite of high B. p 266°- 238., that is it is distillable without rearrangement. The distillate does not leave any alkali hydroxide.' Nuclear Benzylntion 'The experiments were performed upon five above men- tioned phenols and all were capable of nuclear benzylation. It could be proved for phenol and A and B napthol that the benzyl occured in crtho position. (This is a matter of course in p- cresol, but there is no proof in regards to quaiool). The ortho derivative (phenol) up to time of our researches was not known in furs state. According to statement by Rcmmie it arises as a by-product of the con- donsuticn of phenol and benzyl chloride by means of zinc, but could not be separated completely from the p~ derivso tive scouring as chief product. Not until a short time ago did the dye manufacturers E. Byer & 00., succeed in separating the 0~ benzyl phenol from the oil accorued in .crystalline P- ocnpound in the following manner:- The oil is boiled with Ba(OH)2. The P derivative is ppte. partly while still hot and completely uyon cooling as 3 Be salt. From the filtrate the 0- derivative separates in pure sta+e by addition of acid. The sodium phnnolste was'suspended in 1 liter of toluene, and benzyl chloride was salad and allOWCd to st he ever nrght. The e was evidence of a vigorous reaction, the atopprr was found blown out the next morning. It was then heated on an oil bath at 166' for five hours. Using oqueous alkali - get mono bsnzyl and very little or no di- uenzyl compound. After serarsting and redistilling at ljlf~13 min. the oil crystallized, wgich after pre ting 25 out 011 proved to he a pure mono-bonzyl phenol. 0,3H,to. By treatment with Baum)5L it was estnbiished that there was no trace of an isom r. The phenol boiled in the 8‘003 decomposed at 312°._ The e.p. 21'- F.p. 19.. The m.p. and b.p. of p. compound was FE0 and 325 - 320° respectively. The methyl ether obtained by a 2k hr. heating of phenol in acetone with 0331 end (3va5 in a tube to 100° boils at 159-160“ at 12 man. After the m.p. of our product A. hns been determine} to be 2170. we were eurrrieed to hear that the m.p. of the :roduct B obtained at Edler Field dye works by the other nethod was found to be such higher. (52') There was no question of an impurity in our confounds so we asked for a sample of g and were able to deternine very readily that it was merely a question of-two forms of same substance which readily change into each other. Form A-ia more energetic and the efore a modification arising immediately ’in the melted state, which so soon as the change is once started, spontaneously and exothermionlly goes over to final form B which is of lower energy potenial. Outwardly B presented the apyeerance of beautifully glittering crystals more than 1 cm. in 5120 melting quite sharply at 52’. When a little piece of it was put into our form A which has remained unchanged for a ye r, there beg n a . transformation proceeding from of contact and exothcrnio, but without any liquidation of substance tnie change be- gun from A to B involving finally the entire amount. The progress of the change was easily recOgnized by a dunming 26 of crystalline mass something like an efflcrescence. If stable form B is on hand then it is not difficult to get unstable form A since smallest portion of B will initiate change. While formerly as long 23 we did not possess B only A was obtained from melted mass there crystallized now in laboratory traces of B on cooling to about 70 . In general one has the impression that we have here a chemical isomer. ’ I” \ (‘1'7 | ‘7 ”7 Only we have here not a chemical isomer out only a pnysiccl crystallOgraphic isomer, somewhat like the cinsmic acids, the benzoyhenone and the amino krotoscid esters. No case of this latter kind has been observed among phenols up to present. In connection with benzylstion of phenol an effort was made to obtain the corr spending transforma- tion with N-benzyl halides, but this was impossible. By treating p. Nitrc benzyl chloride with Na phenolste a change to resin occured, with the effect of N-nitro benzyl bromide almost nothing was Obtained from an alkaline solution. The chief product (80%) was a thick yellow oil 219-221 -1} mm. whose insolubility in alkali we first ascribed to covering up of its phenol like characters. Since this oil was cenrletely insoluable, not only in Clsisen KOH but even in absolufe methyl alcohol KOH, and since further it did not units with diszo salts it could only of been probably phenol M-nitrc benzyl ether 27 06350 CHZ'C6HN'N02‘ It seems therefore that the nitrc group present in benzyl render d very difficult or entirely prevents the entréps of the residue into nucleue." l. Busch in 1925 working on slkylation of phenols published a very interesting item in Z. Angew. Chem. 38, lth-llh6). He stated that the tendency of benzyl radicals toward carbon slkylation of phenols increased with fine increasing substitution of the methane carbon. It was lossiole to obtain others with benzyl chloride in non- dissociating media, but diphenylmethyl chloride yielisd only the carbon derivatives. Busch had found that diphenyl brow methane with phenol, with or without a solvent, in the presence of heat gave pars hydooxy triphenyl netnnns and with sodium phenolete it gave the ortLo-hydroxy tri- pnenylmethane isomer. . H. Busch and Knoll (Ber. 6GB. 22u3,2257) have been sole to isolate some of these long sought for addition prodncts; claiming the reaction between qSHSOH RX (rschlorine) to proceed as follows: C635 OH+RX ~-: 17- RCGHuOHmX Wit“ 06H50N3 : Congoxa+nx -vc- RCanOHofiX In dissociating solvents partly according to the latter scheme and partly according to the senses: C5H50 NniRX~—»CbH-OR+NaX 5 ‘ (Ann. Mil-4342. BIO-2&5) 28 They also reported that the acmmmlntion of alkyl groups, esfecially those of high molecular weight, on the phenol nucleus materially diminished the ether formation. I. You Auwers, G. Wagoner, and Th. Bahn exylsined the formation of carbon constituents from the salts of ketc- enole and alkyl halides by three hypothesis which had been previously advanced. (Chem. Zentr. I, 2347-23h8 (1926) (i) The initial formation of addition products with subsequent splitting. (Kicheal) (2) 'The initial formation of normal oxygen derivatives. eitn rearrangement of these into carbon derivatives.' (3) “The separating of the metal as a metallic halide, formation of free alkyl and excl radicals, , > u I 0- O and with the slight reactivity of the alkyl group partial or complete rearrangement of the enol to tote radical, and finally union of the radicals.' (Wislicenue) Some recent investigations have shown that the course of the alkylization of a keto-enol deyenis neon its character and upon the elkylization agent. The second hypothesis is inadequate, for it is not comprehensible why an oxygen ether should be transformed into a Carbon derivetive in benzene were easily than in ethyl alcohol. The third hypothesis stated, that the oxygen deriVs- tive shenld be formed with ellyl end with henzyl radicals because of their great reactivity, but this is not the case. 29 However, the formation of radicals and the isomerizstion of anal to tote radicals is necessary to explain the re- actions. We can assume that the greater reactivity indi- cates a large requirement for valence, and vise verse, since allyl and benzyl radicals are diet. guiened by their slight valence requirements and therefore hold oxygen only loosely, they show a preference for combining with carbon to form stable cowhineticns. Clsisen has confirmed these views as already noted (Ann. Rel-4h2), when he stated that un- saturstion results in a comparatively loosely held haIOgen, and furthermore the reaction medium, such as toluene and benzene exert a loosening effect on valence bonds between the alkyl or benzyl radical and the halogen. s. 1. Short reported (J. Chem. Soc. 1. 528 (1928) that when benzyl phenyl other is heated to 225° in the presence of ZnCl . or to lSO'in a stream of H01. 3 2 vigorous reaction occured.‘ The product, on distillation under reduced- gressure, yielded phenol, c-hydroxdiphenyl- methane M.P. 5h’; phenylurethsnc M.P. 180° 5 also p- hydroxydiphenylmethene H.P. Sh’-€h.5‘. The para compound was identified by conversion in p* methoxy benchhenone, H.P. 61{- 62'. Since phenol was formed, it is probable. that the reaction followed a course similar to the hofeenn rearrangement of slkyl-snilines, benzyl chloride being formed as an intermediate. . i G. Vavcn and N. Zehsris (Compt. Bend. 1&7, 3h6-h8) recommended that petroleum other he used for extracting of oxygen derivatives and that an excess of alkali be ewployed. Phenols may be partially extracted from their alkali solutions by means of ethyl ether. The proportion extracted depends on the structure of the phenol. With the introduction of radicals into phenol, the preportion extracted increases, and is greater for ortho-suhstituted phenols than for the meta- or para- isomers. The Work of Friedel and Craft Friedel and Crafts (Compt. rend. eu-1392-1395) in 1876 discovered a new syntheticnl method of producing hydrocarbons. They noted when am;l chloride was treated with small quantities of aluminum chloride there occured a brisk disengagement of hydrochloric acid gas, accompanied by.hydrooarbons which are not absorbed by bromine. when this reaction was made to take place in the presence of a hydrocarbon, it was easy to obtain a connination of the radicle of the organic chloride with_the hydrocarbon, less the hydrogen replaced. Thus they were able to condense amyl chloride with an excess of benzene, and having added aluminun chloride by small quantities at a time they ob- tained by fractionation. a liquid boiling at 185'- 1907 and having the composition and preperties of amyl benzene 663505811. The other halogen salts of aluminum gave re- actions analogous to those of the chloride. They stated (J. Chem. Soc. #1, 115-116) 'we found in general that compounds containing the group OH or OR i.e., alcohols. phenols, acids and their esters undergo decomposition with 31 aluminun chloride. For further references concerning this reaction see articles by J. Boeseken: (Rec. Trev. Chin. 19, 19-26; 20, 102-106; 22, 301-3eu- 22, 315-3173 2}, es (190%). Boesoken stated, (Rec. Trev. Chin. l9, lf-“6 (1900) that in the synthesis of aromatic ketonos and sulphones by means of Friedel-end Crefts' reaction, the condensation takes place in three stageez- . (i) n. 0001 x Alc13 _.——i R -. CoCl, A1013 (2) R. 0001, Alcl3+flR ————r R - COR , AlCl3+Hcl (3) R. con . AlCl mean -—-o~n costlicirnrao The HR represented an eiomatic hydrocarbon or one of its deriVstives. Analogous additive confounds can be isolated when ferric chloride is used instead or aluminum chloride Which has been shown by M. Neneki (Ber. 30, 176641768; 32, Zhlh- 2&19) Boeseken admitted the similarity in (Rev. Trev. Chim. 22. 315-317). , . J. Boeseken (Rev. Tray. Chem. 30, IRS-150) stated that in the case of a typical Priedel and Crafts' reection, in every case the initial reaction is the simple additioxi of two molecules. Three molecules must be present: ’ (a) an unsaturated molecule. (b) a molecule which can be so actiVeted that it can combine with the unsaturated molecule. (c) a catalyst which ec‘intes the molecules (e) and (b). 32 The possibility of the reaction is determined by the loss of free energy. The initial reaction is due to the en— counter of the two molecules with a catalyst; in the case of benzene and other unsaturated cyclic systems the initial additive product, a derivative of dihydrohenzene, etc., cannot be isolafed, because by elimination of hydrOgen chloride or the like it is converted into a system con- taining less free energy. Schasrschmidt (2. Angew. Chem. 37, 286-288) based his theory of the mechanism of Friedel and Crafts re- action on the fact that the aromatic hydrocarbon was activated by aluminum chloride or ferric chloride which is claimed appeared rossible in producing a simultaneous 'locsening' of the bonds of the organic halOgLn campcund. A primary complex was formed, consisting of metallic chloride. hydrocarbon. and addend, in which the metallic Ichloride was held by auxiliary valencies and the addend by ordinary valencies, thus {Ht—'— : :: :(‘uh/R‘ 63 ———-' \R‘ . The stability of this conplex depended upon the division of the inner valenceez and according to the author may pursue one of two courses. a 'molecule course' and the “catalytic course“, of the synthesis. The synthesis may he hindered by substituents in the benzene ring which de- compose the metallic chloride; Other authors who confirm the theory of additive com- 33 pounds of aluminum chloride are Guetnvaon. (Ber. 11, 2151) (Camp. rend; 136, 1365 (1903) Inc, 933 (1905). Schleiehen (J. Pr. Chem. II~105, 355 (1927), Kronberg, (J. Pr. Chem; 11. 61. kgu-u96 (1900). and Menschutkin, (J. Ruse. Pmye. Chem. Soc. #1. 1353-1089 (1909). In 1914. Frankforter and helgere (J. Am. Chem. Soc. 36, 1511-1529; 37, 365) condensed chloral, chloral hydrate, bronal and trioxymethylene with various organic compounds, with the elimination of water. He believed that aluminum chloride, while a catalyst, acts at the same time he a de- hydrating agent, a theory which is now generally accepted. The Theory of the Action of Aluminum Chloride. Friedel & Crafts reaction is connected more particu- larly with the union of aromatic hyirocarbone and their deriVativee with a variety of other organic comrounde, such as alkyl halides, acid chlorides, etc., (Org. Chem.- Cohen 1, 23“). Cohen stated (Organ. Chem.-Cohen I, 3§70 that the results are best explained by assuming the forma— tion of a compound between one or both of the reacting suc- stancee and the aluminum chloride, and by the removal of the letter from the system in combination with the ketone formed. It may be observed that the union tmtween molecules or {arts V! a molecule is nearly always determined by un- eaturation and by a conreguent tendency for the unsaturated to aatur"te themselves. Thus Cohen (Org. Chem. - Cohen, I, 196) divided the condenea+ion proceeeea roughly into two groups: (1) Those in which the combining molecules are induced to units by being rendered, as it were, artifi- cially unsaturated as the result of withdrneing certain elements. (2) Those which, being already unsaturated, combine either spontsneously or with the help of a reagent or catalyst. Sabatier stated (Catalysis in Organic Chemistry, 173) the catalytic activity of annhydrous aluminum chloride in the Friedel & Crnfts' reaction can be explained by the rroduotion of a temporary cembination between the chloride and the organic material. Thus with aromatic hydroceroOns, es would have:-- (C,fl,—-I/ + file/3 —~———+ ”'1 1* l‘?'/:¢Jt QJg- The letter compound would react immediately on the halogen derivative present and we would haves-- ’4"; ”1/ r We! ————r [7,5,3 + “LC“II" e%_ The regenerated aluminum chloride would react again eith the hydrocarbon ani the same reaction would be repeated. The reality of the formation of addition products of the aluminum chloride with the organic compounds hos been established by Guatevmson (Ber. II, 2151 (1878) wno has been able to isolate an addition Iroduct with benzene, an organic colored oil, A1013-30656, decomposable by water, end in the case of the mixture of benzene and ethyl cnloxide, 35 .. , ' . 5.1; - f, x. . . A1013(Ozflu)2 3CbH6, which heat dissoci. ea in o ueneene and 0' m;( Ciliycl)‘ which is stable and serves as a catalyst for the transfor— mation of the mixture. (Compt. rend. 136, lCéS (19e3; inc. 9&0 (1905). The Works of Hueton Huston & Friedmann (J. Am. Chem. Soc. 36, 2527) published the first of a series of papers on the eupyoced dehydrating effect of A1013 on aromatic alcohols and aromatic cempcuflde. The experiment was performed on benzene end benzyl alcohol in the presence of A1013, giv- ing mostly diyhenyl-methnne. Their work ehoeed the forma- tion of an intermediate product which resembles that formed in Friedel & Crefts' reaction. A large portion of A1013 is necessary for the production of a good yield of di- phenylmcthane. (also excess benzene) Primary alcohols were the principal ones need here. Huston & Friedmann (J. Am. Chem. Soc. 40, 785). In this paper works are described using secondary alcohol, benzene and A101}. Three alcohols were used namely methylyhenyl carbinol, ethylphenyl carbinol, and a true aromatic secondary alcohol, benzhylxol, the others being mixed aromatic-elighatic sloonole.' The ethyl and methyl - groups were shown to interfere to some extent with con- densetion of alcohols and benzene; the retarding effect of the ethyl group being greater. The presence of the second phenyl group on the other hand from eXperieental evidence appears to accelerate the reaction. in excess of benzene and a low tempereture (below 10 ) giving from 65%-70% of triphenylmethane. Huston & Sager on the effect of unsaturaticn on the activity of alcoholic hydroxyl, (J. Am. Chem. Soc. 48, 1955) found that of the alcoholic derivatives of aromatic hydrocarbons, only those in which the hydroxyl is on the carbon atom adjacent to ring condense with benzene in the presence of A1013. The saturated aliphatic alcohols up to and including amyl alcohol do not react with benzene in the presence of A1013 to form alkylbenzene. Allyl alcohol (CflésGH-CHOH) reacts with benzene to give a fair yield of allylbenzens. (16%). As compared to 67% for benzyl alconol. The hydroxyl in c adgacent to ring, were only aromatic alcohols found to react. Huston; Louie & Grotemut (J. Am. Chem. Soc. #9, 1365) worked on condensation of methylphenyl oarbinol, ethyl phenyl carbinol and benzhydrol with phenol and A101) . They give additional proof of the effect of unsaturation of the alpha 0 on the reactivity of alcoholic hydroxyl group. Benzhydrcl in which both alpha carbon are members of the unsaturated benzene ring gave a much larger yield of the condensation product. There was also shown the strong tendency of the entering group to be directed para to the hydroxyl. The 0- compound was not precluded, however, the amounts formed were too small for isolation. R. o. Huston & E. F. Eldridge, (J. A. c. s. 53, 2260) printed the first paper dealing with chlorination and the chlorine derivatives of the benzylated phenols. Sentinie made a chloroheneylphcnol by treating (Perntoner & Vitaei Gaza. Chem. Ital. 28, 197) benzyl phenol with 892012. Investigator stated chlorine rrolnbiy entered in ortho position but gave no proof of structure. An attempt by Huston to substitute more than two chlorine into ortho and para benzyl phenols proved un- successful. The AlCl condensation of ('6‘. + cs ”ran. on gave the ether as well as the benzylnted phenol. This be- ing of considerable interest—-the first time an ether has been isolated from AlCl3 condensation. Huston a Lewis (J. Am. Chem. Soc. 53, 2379), condensed Para oresol and benzyl alcohol by both Claisen and A101 methods. An increase in prOportion used (phenol) was found to increase nono-benzylated product.‘ 3s The Problem Steted There are two general methods by which benzyluted thymol may be prepared. Cleieen's method should give an o~ product, which might prorerly be called Immethyl, 2—benzyl. 3-oxy, u-isoprOPyl benzol. The product of the A1013 condeneation, according to Getterman and othera will be a p- product, but if Cleieen and Hollemann are right, it should he a mixture of p and 0 compounds. Our problem, therefore, has been to benzylete tnyunl by two methode mentioned above, and determine producte formed by rroyer means of identification. Condemnation by the Claieen method In the first trial the following 1ortions were uendt- TOl‘ieIie...q........ 0250 000 ThYflOlsssssssssssss 150 gm. BCHZYI Chloride.... 1g6s5 Ems Katallio Na........ 23 gm. Into a one liter 3-way ballon flask fitted with a reflux condenser and an appropirate mercury seal were I placed toluene and small pieces of sodium. This mixture was heated, and before tho toluene began to boil the stirrer was started in order to head the sodium. Thymol was added over a period of one hour. and stirring continued over a moderately warm oil bath. *Benzyl chloride was added to a warm solution (cautiously), and heated over an oil bath at 150-1663 for 8 hours. The temperaturowas brought to the de— sired point very slowly. It was thought that the addition of the benzyl chloride to schot solutign would decrease the amount of residue, however. little variation was noticed. Yst my results can not be considered as conclusive, because of the varying factors. The salt was washed out, and toluene and water were distilled off. I then added 35000. of Clairol'e reagent. (Ann. #42, 22%) Any derivatives with a free jhenolic hydroxyl group would dissolve leaving the ether free ' to be extracted with petroleum ether. The salt was then acidified with 1:1 HCL to liberate the benzylated thymol. During this reaction KCL was precipitated. The benzyleted compound was extracted with ethyl other using 50 cc. portions. From the ethyl ether extract the following fractions were obtained at hmm. - EO'-v95............. 25 gm. 20‘- 13o:........... 25.2 an. 130'- 1601........... 61.? gm. 160'- 1751........... 4.3 gm. residue.. 36 gm. The fraction 8d395' crystallized upon distilli g cver,and upon re-crystallization was found to be thymol. Fractions 1265130‘an3 1305160'also crystallized upon listilling over. After recrystallization it came down in white, needle like crystals having a melting point of 565'- 57.5° and boiling at 157' at 1m. (159'at mm.) Boiling point was determined also at atmospheric pressure (740mm.), and found to be 3333336.. (without decomposi- tion). This compound was assumed to be the henzylated proiuct, and upon analysis this assumption was verified. Analysis: (0173200) .222} gms. gave .6932 gas. 00 and .1665 gme. H O .2195 ' ' .6593 I I I .1525 o o Gale. C........ 85% Rocco's-coo 8.33fi Found c.0000... 85002 HCOOOOOOOOI 6089 . Coocooooo guess 300.0000... 8.3” The yield of orthc product was 36% of theory. The amount of oil recovered from crystals was very small, but was Qound co tound to increase with increased time of heating. From the petroleum ether extract the following fractions were obtained at kma. 80'- 89'......... 1 gm. 120'- 13o:........ 9 - 130'- 160!........ u ' Fraction lZdLlBG'wss found to be the benzyl thymyl ether, as proven by running a Claison in methyl alcohol. Tue boil- ing point was found to be 127' at #mm. Soloninu yrckarcd .tnia other by the action of oenzyl chlorico on thymcl in the presonce_of sodium ethoxida, and the boiling point was 821:823' at 35mm. This pressure was duplicated as near as possible, however, the boiling foint wss much lower than that given by Solonina, being 2051:05' at 36mm. (Solonins Jr. Russ. Chem. Soc; 1907, 39) ' II The same portions wers used as in preceding ex- periment. Bsnzyl chloride was added to a cold solution and allOwed to stand over night before placing on oil bath. The following fractions were collected at 3mm. Ethyl Ether Extract so’- 120’.................... 30 gm. 120’- 1&5'.................... 26.6 ' 1&5‘- 16o”.................... 73.5 ' 160'- 185'.................... 22.7 ' ISBid‘Uficcooo 3"" . Petroleum Ether Extract (3mm.) 100‘- 124’..................... 3 gm. 12t'- 133'.................... 12.3 ' 13o'~ 1ho‘.................... u - 160'- 153‘.................... 6.4 ' Yield of ortho compound was 39% of theory. There was an increase of ortho compound, while the residue remained about the same whether the benzyl chloride see added to a hot or cold solution. The petroleum ether fractions were markedly larger. III The same portions were used as in preceding ex- periment. 100 cc. of toluene was used. Thymol was added over a 2 hr. yerlod. The mixture was hosted on oil bath at 1505166'0. for ten hours. The following fractions were collected at 14mm. from the ethyl ether extract. 100'- 130‘............. 25 gm. 13o'- 17o‘............. 5 ' 180’- 195‘............. 30 ' 185'- 195'............. 3h ' 195‘- 210'............. 15 ' 219‘- 2ho'............. 11 ' refiiduaooo 35 . Fraction 1955-216 did not crystallize upon standing in refrigerator, and had a boiling point much higher than ortho or para benzyl thymol. It was therefore assumed to be the diounzyl product. “3 The test with F6013 further confirmed this belief, how- ever, this is not conclusive for even mintue quantities of the ortho or para compound would give a positive test. A benzoyl ester we: prepared with a melting point of 1921 122.5'. (sufiresting bensoic said) A combustion was run on this sample with the following results. 0 a, Cal. 85.71 6o9b Found ' 7000 701 (Benzcic acid) Cal. > 68.85 4.95 It will be seen that hydrogen checks with the calculated amount for dibenzyl compound, but the carbon checks very close with that of bonsoio acid. The ester was soluvble in dilute NaOH. Th's test for solubility was made before running combustion, however, the melting point for the ester was higher than that for benzoic acid, and the com- hustion was made for further octfirmsti n. Petroleum Ether Extrect (13mm.) 160.- 190 neocoooocoooooooooocoooo 29 gm. 0 “ago. cocooooooooooooot0000600 11 ' residue.... 9 ' Boto:- It will be noticed that most of my bonzOyl esters turned out to be benzcic said. However, Perr lamb and in some cases combustions were made to further prove the solubility test eni in some canes F6013 test. It will be noticed that retroleun ether extrecte were larger. Upon orys+allizing the ortho compouni a consilersble amount of oil was noticed after eve crating the petroleum ether. This oil was found to weigh hf gm. The ortho com- :‘otmd (after being- crystz—zllized) weighed 168.7 gm. “File 011 «as rsfrnctioned and found to have a boiling point of 194 st 1n mm.; a boiling roint which corresyonds very Cloeuly to What is SUPIOSGJ to be the para benzyl thymol. (123. at 13mm.) The yield of ortho compound was out icon to 23?. Attcuits have been made to prepare esters of this oil and compare with pets comycund, however, some difficulty was encountered in crystallization. (They heve not crystallized, as yet.) The ortho compound is eolunble in petroleum ether, ethyl ether, alkali, and sparingly soluabls in ethyl alcahol. Solonina's tcst for benzyl thymol other Isa tried 2nd found to be rositive. Ethyl and Hethyl Ethers of 0- compound. The ethyl and methyl others were prepared as folio;S:—- Using 1/2“ mol. quantities. The sodium was dissolv d in ethyl alcohol end benzyl thymol added slowly. After it has been adled ethyl iodide is adisd from a sep'rstory funnel with stirring. (An ads;uste mechanical stirrer and reflux conuenser are used throughout, with a 500 cc. 3-neck hallon flask.) Temperature 75'0. The ethyl benzyl ether was a straw colored li.uid boiling at 1852-18-6o lemm. The methyl bcnzyl ethrr 13 a liquid boiling at 186- 1?]. lhmm. The methyl thymyl ether was prepared by Paternc (Gaza. 5-15) from thymol and methyl iodide. Behal and Tiffinean (Bl. R3, 732) prepared this other by the reduction of thymol with Na and alcohol. Boiling joint was not yiven 1n Beiletcin. The ethyl ether was prepared from thymol, Czfisl and alcoholic KOH. (Bambuger B. 19, 1620) Claicen'a Ether Using Claiaen’s method the thymyl benzyl etnnr was wrtlur red using mothVI alcohol as the dis ooiatinx: med;um. Same ayyaratue used as in precedin$ experiments nLch Claiso n'a 2 section was mzde use of. 1/10 mol. guanfities aged. Te “pcrature 85-50 C. Hca‘cd 7 hours. 185'~130° ............ 15 gm. 3mm. rrsldue.... 3 ' 11 Same quantities as above. Tempera+ure 951103°O. Hosted for 5 hours. 120. £1.30. .......... 12 gm. 31m. rfffiidueo 2 . Playwretion of 4 Brom Thymol For furtner proof of the ortho compound, it one bromine ed and than h-Brom thymol was condensed with Lenzyl chloride. By such a procedure it was hoped to procure the Same compounds, namely 2 Benzyl, #~Brom thymol. The h—Brom thymol wan prepared by Haz+ara's me‘hod. (Gaza. 1E. 516) taken from Belletein'a Handbuch 7, 540 .eeries “99-605. The terrerature one kart arouni O'C. durf in; the brominetion. Upon the addition of brominetcd mix~ tore to a saturated solution of’(Nflh)209}. there was formed a heavy reddish-brown oil wiioh sinks to botfcm of container. Yieli abcut €T§ of theory. Boiling fOIDt was 117°C. 5t hmm. An oil wra obtained tram crysfala probably 2-3 dibrom thymol. c Condensation of Q-Brom Thymol and Benzyl Chloride. (Olaleen Method) A Claleen reaction was now tried u?ing 1/5 moi. quantities. 61.8 gm. h-Brom Thymol 25.3 ' Benzyl chloride h.6 * Metallic Na 85 cc. Toluene Brcm thymol was adied over an hour period, and stirring continured for 2 heurs. Benzyl chloride was added to a hot solution and the mixture was heated on an 011 bv*h for 7 hours.at lu51150°0. Petroleum Ether Extract (3mm.) 155.- 165.cocoooocooooooooooocoo. 507 gm. “7 Ethyl Ether Extract (3mm.) 90°- 125°................... 19.6 gm. 1ho’- 160‘................... 25.4 ' The fraction lfioLléd'of the ethyl ether extract does not crystallize upon standing or upon plrcing in rsfriger~ star. The third fractionation gene the following results at 3mm. 90'- 125'............. 19.6 gm. 1u5'- 16o’............. 7 ' 160'-17o'............. 16.5 - Fraction lSdLlJO° came over mostly at 166'. and corres.cnds to the product given by bromination of the ortho compound. It refractionsted at lhmm. and found to have a briling point of 2?11223°C. The retroleum ether extract crystallized upon being placed in refrigerator, and was found to have a melting point of “6.5L49'. A Parr Bomb determination for bromine was made on this other with the following results. Sample .2019 Cle.............. 25.05. Found............. 2%.?) ' ............. 2n.69 This h-Brcm benzyl thymyl ether was also prepared in a dissociating medium (alcohol). using Cleisen's method. The same compound was obtained. Temperature was kept around SOLlOd’O., and was heated on oil bath for only 3 hrs. It boiled mostly at 157.. (3mm.) Bromination of 0- Compound The ortho compound was now brominated using the method of Hszssrs. Results probably would have been more eccurste using a calculated amount of bromine instead of adhering to Mazzare's method for preparation of 4-brom thymol, which undoubtedly was figured out on the basis of thymol. The following are the results of the second brominstion of the ortho compound. 25 gm. of ortho compound was dissolved in 50 gm. of glacial acetic acid and placed in s 500 00. round bottom 3-neck ballon flask fitted with an adequate mechanical stirrer. To this mixture was added 26 gm. bromine in 26 gm. glacical acetic acid. The temperature was maintained eroung 0'0. The mixture was poured in a saturated solution of (831‘) 20% , extracted with ethyl ether and frectioned at 3mm. Ethyl Ether Extract 1h0°- 160'.......... 3.2 gm. 160‘- 170'.......... 19 ' Fraction 1603170'csme over mostly at 167'- 3mm. At 13mm. the boiling point was 2231225“. correszonding very closely to the compound obtained by condensation of h-brom thymol and benzyl chloride, which boiled at 22l1223' at lhmm. This compound was somewhat darker in appearance suggesting excess bromine. ‘ The P? tolyl sulfonyl ester was made of these compounds which resulted from condensation and brominetion namely, h-Brom, 2-benzyl thymol. They both had a melting point of “9 1261126.5'C. Parr Bomb determinations for Br gave the following results. Calc....... 16.93 Found...... 15.68 Preparation of H-Chloro-Thymol It was then decided to attach this problem from a difierent angle. namely by chlorination. h-Chloro—thymol was made by method given in J.O.8. 74:641. Bccchl (G. 26 II #03) gives m.p. 58360°. Condcrelli gives a m.p. 621% 3 I found it to be 59.5360'0. Better yields were obtained at a temperature of 80365’0. As in the case of the prep- aration of R-Brom thymol an oil was obtained. No work was done on this oil in either case. It was probably the di or tri substitution product. A 500 cc. roung bottom 3- neck ballon flask was used fitted with a mechanical stirrer, mercury-seal, sepsratory funnel and a trap to catch 80‘ evolved. After SO‘CLa has been added water was added and product was extracted with ethyl ether. Benz’yle tion of 4-Chloro-Thymol * "' The same apparatus used as in preceding Claisen's reactions. One-fourth moi quantities used. Heated for 6 hrs. at 156-160" 0. Ethyl Ether Extract (3rd Fractionation) 105'- 1&5'.............. 6 gm. use. 1A5‘-17o°.............. 26 ' ' 17o'- 195°.............. 6 ' . Fraction 14531}O° boiled mostly at 155'- “mm. It refractioned at 14mm. and the largest fraction (2003210°) came over mostly at 2051206. (lhmm.). It did not crystillize. Chlorination of 0- Benzyl Thymol One-tenth mol nuantities used. The temperature was kept around £0190°C. A very cepiOUs evolution of 802 was noticed. Ethyl Ether Extract (15mm.) 190‘- 200'............... 3 ' gm. 200‘-215‘.............. 15.7 I Fraction 2003215°came over mostly at 2062208‘15mm. Benzoyl esters were preffired of h-chloro, 2-benzyl thymol, and uron analysis was found to be benzoic acid, however, the P- tolyl esters bed a melting reint of 118- 115.8. Parr Bomb determinations confirmed content of chlorine. V Benzoyl, P-tolyl sulfonyl, and benzene eulfonyl esters were prepered of ortLo benzyl thymol. Tne P-tolyl ester salted at 1161116.8°, the benzoyl ester turned out to be benzcio acid; the benzene selfonyl ester did not crystallize. ‘1uminum Chloride Condensation The Bollowing quantities were used:-- 51 33.} gm. 1101J ........... & mol 150.1 gm. Thymol........... 1 ' 300 cc. Petroleum Ether 63.2 gm. Benzyl Chloride -% mol A 500 cc. condensation Jar fitted with a mechanical stirrer was used. The thymol was suspended in the petroleum ether, and to this suspension is ad ed the benzyl chloride folIOWed by A101 . Upon the addition of A101 the solution quickly changed 1: appearance to a dark brown color follOWed by free- evoltuion of BCL gas: A101 was added over an hour period, and stirring continued for 3 hrs. It was tLBU allowed to stand for 3 days. The temperature during the addition of A1013 was maintained at 18.12}. C. The complex molecule was then youred with stirring into a mixture of 500 gm. ice and 500 cc. cono. HCL to accomplish deCOmgosition, after which it was extracted with ethyl ether. The ethyl ether was distilled off and 350 cc. of Claisen’s reagent was added to the residue. Extract with betroleum ether to remove ary ethcrs formed; the mixture is then treated with 1:1 HCL until neutral and extracted with ethyl ether. Both extr~ctions were distilled unier reduced pressure when eth r was removed. Ethyl Ether Extract (3mm.) 85f- 105'............ 97.6 gm. 130'- 155'............ 25.7 - 155'- 165°............ 12.7 - residue.... 15 ' Fraction 1301155° came over mostly at 155°, and was 52 thought to be the para benzyl thymol. It has a boiling point of 196' at 13mm. The boiling point could not be token at atmos;heric pressure, being higher then the thermometer available. From fractions 1301155‘and 1551165’uas isolated a crystalline compound, nhidflrgecryetellizstion was found to have a melting point corresponding to the ortho compound.§ They were also similar in crystalline structure. Upon final {rammionation of these fractions, it came over montly at 196' at 13mm. The ortho compound was isolated from all condensetione using A1013 in a v ry small quantity. The benzoyl, and P-tolyl ester were preysred of the {are compo nd, but bswc not crystallized as yet. In mating the benzoyl es er the first time benzoic acid was obtsired. Petroleum E‘hcr Extract... 3 gm. It does not crystallize. II The following quantities were used for the second condone. 2:10:13 3 112 gm. thymol......... : $01 38 . Alc13coocbooooo 1/365 .01 63.2 ' Benzyl chloride. final 300 cc. Petroleum ether "Bote:- The petroleum ether extract obtained from this condensation was too small to flirt with. As will be noticed there is e m rked percllelism between the boiling paints of product obtained by two methods. Hotc:- All esters were prepared by method given in Porter-Stewsrt-Bronch Methods of Organic Chemistry. (P. 131) Calculated amounts of reagent used for esterificetion. *During the addition of A101 to the condensation mixture a solid mass was formed 0 unknown comprsiticn in- aclusblc in ethyl ether, petroleum ether, acid and alkali. 53 Temperature was maintained from 25130°C. 11013 was added over a 1% hour period. Etlyl Ether Extract (3mm.) 90°~105°............. 63 gm. 115°~145 6.7 - 16o‘- 175°............. 22 . residue.... 24 ' As before a gumy mues was formed. Fraction 1 43175° was refractioned at lhnm. and found to have a boiling point oorree_0nding to the pore ounpound in the preceding con- lensation. I have no plausible rezaon way it enculd come over at a higher tenperature using the szme preeaure (3mm.) unleav it one super-heated. The lower bailing fractions in both oueve, namely 851105. and 903105', were found to be thymol. The a+ruoture of para compound was rroven by brominntion. Mazzera prObably obtvined a different compound than pare benzyl tnymol by his method using zinc filJinge. He obtained a product boiling at 255 6mm. (Berlatein Handbuoh 7, 690) Preparation of Z-Bromothymol E-Brom thymol was made using metood of EngleLerdt and Loteohinoft (J.0.S. 60, 899) with some deviation from their procedure. The following quantities were need:~- 2 mol IKOH 1 ' Thymol 11E ' (oono.) 153m 1 ' Bromine 54 Sulfuric acid was added to thymol and allowed to stand on water Data for 2% hrs. One mol KOH was aided ano allowtd to stand on the water bath for 6 hrs. Anotner mol of KOH was added to make elkaline before brominating. Bromine was ad:ed to the mixture Rearing the temperature around ~5°G. This mixture was allowed to stand until next morning uni then steam distilled over an oil bwth up to 1”3‘C. 300 cc. of conc. 3280‘ wee then adied and tempern+ure was taken up to 19‘° during distillation. More acid W39 added and dis- tillation continued. Not much more was recovered u;on addition of more acid. (1) Before adding acid.. ......... 33 gm oil (2) After adding acid............. 156 ' ' Fractionation (1) 110.(1}-a120. 0.00.006... 3m. 2“ Bl“. Fractionation (2) .(107) o » 95 a 115 .0000 o co... 3 am. 79 gm. (133') 120' - 114.50 0.0.0.0900. . . 76 . After refraction, and Parr Bomb determinations the brominn+ed products were an followe:-- ThYKOlotocoooao-o 2605 gm. Dibrom . 00.0.0.9... 7707 . Kano-brow thYfliOlocoooooo 65 . \31 U} The reaction may bo'rupreeented no follows: us‘s J$ on _. K 3" + “1.5% M w w v OK on c“, CflH «:5 The dibrom product was found to have a boiling point of 1863187‘ at Baum. Corresponding very closely to the boil- _ ing point given by Clonedxraueo (J. Pr. 2 R3, 3h5) which was 1875186°3hmm. The proouot diatillod over before mak- ing acid was found to be dibron thymol. 11613 Condensation of 2—Brom Thymol This 2-br0m thymol tee condensed with benzyl chloride using Hueton'a method. The following quantities were needs- 1/5 nol 2-Bron Thymol 1/8 ' Bonzyl chloride 1/12 ' . _11013 The reaction approaches violence with nuoh HCL given off. Petroleum ether extract was very small. Ethyl Ether Extract (13mm.) 115'- 1350.............. 17.6 gm. 135'. 170'.............. 9 - 170'- 205'.............. 6 ' Fraction 1701205' was assumed to be desired product, for para compound itself has a boiling point above 190‘ at the same pressure used here. Brominotion of p- benzyl Thymol 25 gm. p— benzyl thymol 10.6 ' Bromine Glacial acetic acid used as a medium. Fractionation (13mm.) 170'- 200°........... 3 gm. 200°~>210'........... 22 ' The fraction ZOOLElO‘ was assumed to be desired product. This fraction and frection 1763205° of preced- ing condensation were used to make eetere. The benzoyl esters were made but turned out to be benzoic acid in both cases no product was left to permit the making of this eater again. 57 Sum: an ry l. Thymol was condensed with benzyl chloride by the Huston method, forming an ortho and pars mono benzylsted product. The structure of the ortho compound being defi- nitely proven. Although the para isomer is the expected predominating product to be isolated from this condensa- tion, I have cited no conclusive evidence for this feat. However, test for phenolic groups were positive. Esters have not crystallized as yet. 2. Thymol was condensed with benzyl chloride by the Claisen method, forming orthc and pars mono benzyleted rro- ducts. The pars compound being favored by longer heating and less vigorous stirring. Although giving a test with Fecl3 and having a boiling point similar to the psrs isomer obtained from Huston condensation, evidence is not of such a nature as to establish or assign definitely the pars structure to this oil. Those esters prepared turned out to be benzoic acid, others have not crystallized as yet. 3. The 'Clsisen Ether' was isolated in small amounts using a non dissociating medium, but in much larger amounts using a dissociating medium. (68303) A small ascent of other was isolated {rem Huston condensation, however, to small to conveniently handle. ' k. In the condensation of h-Bromothymol end banzyl chloride by the Cleisen method an other was isolated which proved to be the h-Bromobensyl thymyl ether. This ether was produced also by Clsisen‘s method using a dissociating medium. Although not sent oncd in the c urse of the thesis, an attempt was made to brominnto Claisen’s benzyl thymol ether in an effort to obtain M-bron-benzyl thywol other. The ether was evidently split, for the presence of benzyl bromide was Obvious. Because of Obnoxious odor this ex- periment wss abandoned. William 171’: ME: MIMI; mutifimmn'“ 6 2502