IHII \lliIIIIWIHIHTWill, lHiNllllH ( 104 922 .THS_ SOME CHLo‘Ro DERWATIVES CF O-CRESOL THESE-FOB THE DEGREE UP M.Sx Wilbur S. Claus 1n/ :9jq ‘1. t ‘ .545: iww, [1.4 r .. . ‘krmfvitlf; . w .. ,4 . .\ :{nn pert/A: SOME GHLORO DERIVATIVES 0F o-CRESOL Theeie Submitted to the Faculty of Michigan State College of Agriculture and Applied Science in partial fulfillment of the requirement: for the Master of Science Degree. by Wilbur 8. Glen- July 193‘ ACKNOYV LEJD‘IR‘TT The writer wishes to express to Dr. R. C. Huston hie sincere appreciation for assistance and inspiration received during this work. I. II. III. IV. 7. CONTENTS Introduction. Historical. 1. Preparation of the monochloro-o-creeole. e. d chloro-o.ereeol. b. d chloro-o-creeol. 8. Preparation of 4, O dichlcro-o-cresol. Diecueeion 1. Sulronetion of o-creeol. I. Nitro-o-creeole. 3. Statement of problem. Eacperimental. 1. Preparation of 4 chloro-o-creeol. 8. Preparation of 6 chloro-cc-creaol from 6 chime-coerced. 3. 6 chloro-o-creeol by the fuming sulfuric acid method. d. The method reported by HuetOn and Ballard. 8. Derivatives and enelyeee of derivatives. Summary. 331619 Page 5-4 6-8 9.10 11 DITRODUCTION In the subsequent investigation or the chlcro derivatives or o-cresol. it was noticed that there is seemingly some confusion in the nomenclature of these derivatives. The 4 chloro-o-cresol is often labela ed as B ehlcro-c-cresolg 5 chloro-o-cresol as e chloro-o-cresolg 8. 8 dichloro-o-cresol as 4. dedichloro-o-cresol. This is due to the fact that some investigators use the methyl group as number one, while others use the hydroxyl group as number one in their system of nomenclature. H lac/{5 This work uses the hydroxyl group as the ordinal group in all of the compounds listed, as shown above. HISTORICAL i Chlorc-Oooresol Some of the early workers in this field were Claus and Jackson (J. prakt. chem, (2) 38. 328 (1888) ) who prepared a chloro-o-creeol by the action of chlorine in an acetic acid solution in the presence or iron. They give the (Impound a melting point of 53°; boiling point, aso°. In 1898, Peratcner and Condorelli (Gaza. chem. Ital.. 88 I. 211) prepared the eompmmd by the action or sulfuryl chloride on e-cresel. It was in 1919 that Bette and Hitter (I. Am. Chan. See... a. DO“ - 58) again prepared it by chlorinating the aqueous solution of the 4 - suin- i'bnie acid derivative. They state that the chlorine replaces the sultonio acid group with the formation of mineral acids. Their product melted at «7°. (This .111 he discussed in detail in Section III (Discussion) or on. thesis.) Morgan and Burstall (J. Chem. 800., London 1928. 3860-70) obtain. ed, by the interaction of selenium oxychloride on o-cresol in chloroform solution with progressive halogenation, this derivative as one of the many and varied products. Their compound method at 48°. Th. de Crauw (Rec. Trev. Chem. Pays-Bee 50, 183-92: 0. 1931. 4766) prepared a chloro-o-cresol by treating 2, - 5 dichlorotoluene with sodiu- asthylat which gave an impure product along with its leaner, 3 - methyl .. 4| chloro phenol . ' _6_ Chloro-o-cresol The literature reveals meager and conflicting information concernp ing the preparation, properties, and proof of structure of this compound. This derivative with the chlorine atom ortho to the hydroxyl group is often confused with the derivative in which the chlorine atom is ortho to the .nethyl group (a chloro-o-cresol). 'i‘wo - methyl .. 6 - chlorOphenol was first prepared, and then patented by Raschig (C. 1905 I. 1448: D. R. P. 160504). He states that by drying at 1000 the o-chorbo-oresol . p-sulfonic acid, the desired product is obtained. ‘ 1 It was also prepared and patented by Fahlberg. List a 00.. (D. R. P. 256345; C 1913 I. 866: Frdl. 8. 138: 11, 191). They give a boil- ing point of 185° (uncorr.). Bures (Chen. Litay, 81.82. 108, 143, 822, 261, (1927) ) stated that ortho chloro and orthc bronco-o- and n-crceols are prepared by direet halogen- ation at 80°C. by slow addition of molar quantities of halogen to molar quantities of the usual. The reaction is carried out without the aid of a catalyst. He, however, reports no preperties or proof of structure of the desired compound. Other references are Th. de Crauw (loo. sit.) and Anwers and Wittig (Born 67 B. 127045 (193!) ) . neither of which give the method of prepar- ation or preperties of the listed o-chlor-o-cresol. Many of the references in the literature pertaining to the I chloro- c-sresol deal with the preparation of the 3-chloro~o-crssol. It can be seen from the above that the information concerning the O-ehloro-o-cresol is un- Itisfaetory and incomplete, as revealed in the literature. _4_, 6—di chloro-o-cresol Zinloe (A. 417, 206) prepared this compound by passing chlorine in- to a cold solution of c—cresol in carbon tetrachloride. He gives a melt- ing point of 55° (out of benzene). Claus and Riemen (Ben, 16, 1601) and Claus and Schweitzer (Ben. 19, 98'!) prepared the 4, 6 dichloro derivative by passing chlorine gas into a vigorous boiling solution of cacresol. Their product melted at 55°. Martini (Gaza. chem. Ita1., 29 II, 60) obtained the desired product by the use of sulfuryl chloride on c-cresol. Euros (loc. cit.) in his extensive survey of the chloro~ and bronc- derivatives of c- and p - n 4- eresol gives a yield of 95 «- 97%: mp. of 56°, and bp. of 226.50. ' Morikawa and Sakamoto (.1. Chem. Soc., Japan 51, 275-7) (1930) s C. A. 86, 706 (1932) report that they were able to prepare the 4, Michloro compound by passing chlorine into c-cresol in the presence of Pail.a under direct sunlight and high temperature. A recent patented procedure, Farbenind, (Fr. 724, 779 (Oct. 80, 1931) t C. A. 1932, 4827) stated that ”cresols containing 5 cl atms are prepared by treating a mixture of chlorotoluenes containing (11 - 1) 01 atoms and ohlerotoluenes containing _n_ Cl atoms (the former largely preda- inating) with an alcoholic or aqueous alcoholi alkali hydroxide under pressure and at a temperature at which only the (:1 ~ 1) .. chlorotoluene reacts. The amount of alkali hydroxide is calculated with respect to the (n - 1) ‘- chlorotoluene". w’IJ‘LI-l " ' DISCUSSION me Sulfonation £1: c-Cresol During the last few years a great deal of work has been done in this laboratory with the halogenation of phenol and phenolic compounds. Some of this investigation has been done by the method of sulfonation. However, some difficulty has been encountered in obtaining crtho halogen substitution. In most cases this has been done by protecting the para position or the para and one ortho position with sulfonic acid groups. Sue of the important papers related to this problem are those of Peterson (Master's Thesis, 1933); Chen (J. Am. Chem. Soc" 55, 4814 (1933) )3 But- chinscn (J. Am. Chem. 300., 54, 1504 (1932); and Ballard (Master‘s Thesis, 1938). The halogenation of sulfonated phenol has been quite thoroughly discussed in Ballard' s work. No attempt will be made to review that phase of sulphonation except inasmuch as it concerns ”meal. The more impor- tant references are ll. Tanaka and K. J‘utani (J. Pharm. Soc., Japan 617, 847.2523 0. A. 20, 2669): Datta and Bhoumick (J. Am. Chem. Soc., 43, 303, (1921) ); Obermiller (Ber., 40, 6631, 6640) and Merck (Ben, 87, R 96?). Campbell (J'. Chem. 800., 181, 647-57 (1922) ) stated in his study on the sulfonation of o-cresol that the speed of sulfonation is retarded by the methyl group to the hydroxyl group to the least extent at 80° (approximately one-third the degree of the para methyl group) and that as the temperature of sulfonstion increases the retarding influence of the o- .thyl group diminishes saneshat rapidly up to about 60°. Above this tu- perature the influence is only very slightly progressive. Bette and Hitter (loc. sit.) stated that chlorine replaces the sulfonic acid group, wherein an aqueous solution, with the production of armatic halogen derivatives. later Bette and Bhoumick (loo. cit.) stated that frequently halogens not only replace the sulfonic acid groups, but that usually more halOgens enter the ring with the formation of higher halogen derivatives. They believed this to be a good general method of preparation of halogen derivatives of pheolic compounds since they found that replacement of the sulfonic acid groups (-8035) takes place readily at ordinary temperatures in the case of compounds having one or more hydroxyl groups attached to the nucleus. Claus and Jackson (loo. cit.) found that by heating one part of o-creeol with one and one-half parts of concentrated sulfuric acid for d to 8 hours on a steam.bath that the p~sulfonic acid derivative was prepared. Engehardt and Latechinow (s. 1869, 621): Eeutke, (Ber., 80, 3810): Neville and Winther'(Ber., 13, 1946); Gerver (Ann. 169, 385)):aeyduek (Ann. 172, 213); BASE, (D. R. P. 265, e15: c. 1913 II 150; incl 11, 189); and Datta and hitter (loo. cit.) have also prepared the posulfonie acid derive ative in similar'waye. The last two named authors stated that they were able to separate the insoluble o-sulfonic acid derivative from.the soluble p—eulfonic acid derivative by pouring a cold sulfonated mixture of o-cresol into water. In repetition of this work, an innumerable number of trials failed to duplicate the results of these authors. To explain this discrepancy, it was assumed that the accresol used by the author was more pure (i.e. less contamination with the p-isomer) or that some important condition of the process as previously carried out had not been noticed or recorded. The d, d-dieulfonic acid derivative was prepared by the action of tuning sulfuric acid on o-cresol and heating on the steam.bath by Claus and Jackson (ibid p. 334). Hesse (Ann. 230, 293): and Zehenter CKonatsh., 33, 345) also pre- pared the d, d-disulfonic acid derivatives from.eimilar related compounds. Probably the.most complete discussion of sulfonation, in general, with methods, examples, and procedures is given by Lesser-Cebu (Arboitslflethoden fur Organische Chemische Laborataorien, 5th ed., Git-980, (1923) )o Nitro-oc-cresols The nitro derivatives of o-creeol have been studied by a amber of investigators. Those nitro derivatives especially related to this study are the d «- nitro -, 6 nitro -, and the d, 6-dinitro-o-cresols. Of the three mentioned nitro deriVatives, the 4 nitro compound has a recorded melting point range of 79 to 95°. Some interesting facts were observed concerning these nitro compounds as prepared as intemediates of the chloro-o-oresols. Schulta (Ben, 1907, 40, 4319) has reported one of the best pro- ccdures for nononitration. He records a 25 - 25,% yield of the 6 nitro with about 75% formation of the 4 nitro-oecresol by nitrating in the presence of benzene at 80°. Neville and Winther (Ben, 1882, 15, 8978) reported that the 4 nitro derivative exists in either the anhydrous or the sonohydrate form. They record the melting point of only the monohydrate as ranging from so «- 40°. Gibson (J. Chem. 300., 127, 488) (1925) ) stated that the 4 nitro derivative, when formed by action of 131103 on e-oresol in glacial acetic acid at 15°, and when recrystallised frcn hot benzene solution was deposit- ed in fine yellow needles, which when touched or pressed became a powder. He fives a melting point of 96° of the anhydrous powder 4 - nitro deriv- stivs, stating that it melts as low as 76°, but depends upon the rapidity of heating. In repeating Gibson's work we obtained after my recrystal- lisations fran hot benzene, the 4 nitro compound in light brown needles without the fomation of the powder, having a constant melting: point of 92 - 93.o°. The 6 nitro—o-creaol used in the preparation of the 6 chloro-o~ cresol was prepared by Gibson's method (loo. cit.), having a boiling point of 103 - 1030/9 mm. and.melting point of 69.6 - 70°. He records a yield of 35% crude product. Koetachet and Koetschet (Helv. Chemi. Acta 13, 474 - 82 (1950): C 1930 II, 1368) prepared it from o-toluidine. They give their maximum yield as 3%. Mp. co ~ 70°. Veibo1 (Ber., 63, 2074-82 (1930) ) has reported an exhaustive quantitative study of the preparation of the 6 nitro and 4 nitro compounds by using a mixture of fines and 11:102. ‘ The d, d-dinitro-o-cresol has been formed by the action of nitric acid on related compounds by Ullman and Sane (Ber., 1911, id, 4730); Cain and Simonsen (3., 1914, 105, 156) Spiegel, Munblit, and Kaufmann (Ber., 1906, 39, 3240)] Herman and Millar (Ber., 1881, M, 568); Rapp (Ann, 1884, 884, 175); Wieland (Ber., 1921, 54, 1776): Hesse (Ber., 52, 1173)) Pensio (0., 46 II, 60): Robinson (J. Chem. Soc., London, 109, 1086): Kehrmann (Ber., 48, N36): Datta and Vanna (I. Am. Chem. 300., 41, 9041); Frische (Ann., 884, 138): Oliveri-Fortorie (6., 28 I, 50?); Noelting and Kohn (Ber., 17, 3'71) Noelting and De Salis (B., 14, 987); Claus and Jackson (loo. cit.“ and Neville and Winther (Ber., 13, 1946). Statement 21:. Problmn This problem may be briefly stated as follows: 1. 3. d. To prepare, identify and study the preperties of some of the chloro derivatives of o-cresol. a. d chloro-o-cresol. b. d chloro-uo-cresol. c. d, 6 diohloro-o-cresol. To determine the preperties and characteristics of the compounds formed. To increase the yields of the e chloro-o-oresol. To prepare their ester derivatives. FJCPERI} {3"le 18 The Preparation 3; g. Ovhlorooo-creso; In the preliminary work with the chloro-o-cresole, consider- able difficulty was encountered in repeating Bette and mtter's work (loo. cit.). They state that cold concentrated sulfuric acid was added to the o-cresol, care being taken to keep it cold, and then allowed to stand for "smxetimefl 'Ihe whole of the syrupy liquid was then poured into water and the soluble portion containing the d-eulfonic acid was separated from the insoluble oily d-euli‘onic acid derivative. The ‘- sulfonic acid derivative was then diluted "with water" and chlorinated un- til the heavy oil which settles out was no longer formed. The oil was then separated by a separatory funnel and recrystallised from glacial acetic acid. 0n cooling and stirring, it yielded a white crystalline product melting at 47°. After mm repeated failures to prepare the 4-Ohloro-Oc-oreeol by their method. it was decided to prepare it by Claus and Jackson's proced- ure (loo. cit.) as modified by Milligan (Master's Thesis. 1933). One modification was mde in preparing the compound by his method; via. the solution was cooled to 0° and below, by an ice and salt bath mixture. Milligan reported a yield never exceeding 303% while we obtained a yield of 40 «- 48%. me procedure is as follows: One hundred grams of freshly distilled o-cresol was dissolved in 300 grams of glacial acetic acid in a 500 ml. three-necked flask fitted with a mechanical stirrer, aspirator and thermometer. The solution was cooled below 0° in a ice and salt mixture into which dry chlorine gas was 13 admitted at such a rate that the temperature did not exceed 6° above aero. When the theoretical amount of chlorine (by weight) was added, the acetic acid was removed by distillation at atmospheric pressure, and the remaind- er fractionated under reduced pressure. The product came over at 106-109/14 as. pressure, and recrystallized frmn petroleum ether. It crystal- lised in the form of long, white needles. melting at 47.60 o (8.60. Anal. Calcd. for cgnqo c1. cl. 24.89. Found: c1. 24.13. Since halogenated phenolic compounds had been prepared in this laboratory by the finding sulfuric acid method, it was suggested that this method be applied to the chlorination of o-crescl. Many preliminary runs were attempted, using mnell quantities of o-cresol, with variations in pro- portions of acid to o-cresol and conditions, in order to determine the Optimum procedure for preparing these chlore derivatives. Below are listed the attempts as made: e-Oresol Inning Condition 0 Observation Used 11330., Used A W Ad ed 80 cs. 20 so. (20%) Room temp. Very little Viscous mass. 10 so. 20 so. (80%) Room temp. None " * 18 ee. 72 cc. (2035) Room temp. Very little " " 13 ee. 72 cc. (20:3) o°(4o cc. Some .. . H o) 8 100 so. 80 cc. (20:3) 0° Very little * w 10 ee. 20 cc. (48%) Room temp. None " " as so. 25 cc. (48%) 0° None - . M as. 25 so. (48%) 00(50 ec. Theo. am't. Likely 330) Iron the results as observed above, it was noticed that in many 14 cases sulfonation completely blocked halogenation. From the work of Datta and Hitter (loo. cit.) suggesting that chlorination takes place best in the cold or at ordinary temperatures, no preliminary attempts were made to determine the effect of heating the sulfonated cresols before chlor- ination. However, this Was attempted and will be described in a latter part of this paper. It was noticed from the last preliminary attempt that dilution by water undoubtedly decreased the concentration of the acid enough to allow for chlorination. On this basis other attempts were made using those preportions and conditions. A typical run is as follows: Fifty cc. of fuming sulfuric acid (49% 803) was placed in a three liter, three~neclned,,flask fitted with a mechanical st'rrcr and thermometer and cooled by an ice-salt mixture. To the acid was added 1 mode (108 Gfld 103 cc.) of c-eresol thread: a separated-y funnel during 1 . 0 hours with constant stirring. care was taken to keep the reacting mixture as close to care as possible (allowing; it to rise to 30° for the initial reaction). It was stirred for two more additional hours and then allowed to stand for 84 hours in the refrigerator. It was again placed in an ice-salt mixture and to it added 100 cc. of'rater during 1 hour, keeping the temperatur. below 10°. After stirring the mixture for 5 hours at room temperature, it was hydrolysed by super-heated steam on an oil bath at 190 - 210°. The first portion of the distillate crystallized which was later found to be the d. d dichloro derivative. 'ihe last. portion of the distillate came over as a red oil, which was extracted with ethyl ether. The oil after five or more repeated fractionations gave the following fractions: 15 up to ec°/c m. 2 go. as - 72°/c m. 14.5 em. 72 - 97°/9 m. 29.0 911. 97 - 1029/9 mm. 7.0 gm. Residue about 3.0 gm. The fraction between 06 «- 720/9 m. was later found to be the 6 chlorc isomer, while the 97 e 102°/9 m. fraction, when cooled and seeded with 4 chlorc needles prepared by the acetic acid method, proved to be 4 chlorc product. The crystalline product (36 grams of crude product) when recrystallized from petroleum ether gave a constant melt- ing point of 54.5 - 55° E. Bures (loo. cit.) gives a mp. of 56° for the d, d dichloro derivative. One similar run using the mole quantities gave an increased yield of the d chlorc fraction (19.0%) with practically the same yield of the d chlorc product (7:3). He attempts were made to increase the yield of the d chlorc product, for the main objective in using: this fuming tulfuric acid method was to prepare the o-chloro-o-crssol derivative. 16 Preparation 2!. 0 Chloro-owresol from _6_ __Amino-o-cresol The 6 chlorO-o~cresol was prepared by the following series of reactions: 0H Q” C ”5 It” CH5 C! Q”; ———6 ————-:7 For the preparation of the d-nitrm—o-cresol, the method of Gib-v son (loo. cit.) was used. A mixture or 107 cc. 0:12:02 (d. 1.42) and 300 cc. of glacial acetic acid was placed in a three liter three-necked flask, fitted with a.mechanicel stirrer and thermometer and cooled in an ice-salt bath mixture to «15°. To this solution was added 100 grams of accresol dissolved in 100 so. of glacial acetic acid during; a period of two hours. It was then allowed to stand for three hours in the freesing mixture after which it was poured into 6000 so. or cold water and allowed to stand overnight. The product was filtered off at the suction pump and steam distilled. The distillate, while being collected in ice water. crystallized in yellow plates which was the crude d-nitro product. Upon separation and fractionation it boiled at 102 «- 3°/9 m. and melted at 69 - ?O°. Gibson reported a melting point of 70° and a yield of 35,4 of the crude d-nitro product. By using double amounts of the above and keeping' the temperature bola! 0° during the addition of the o-cresol-acetio acid mixture during a . 3 hours, an increased yield of the crude product was obtained. The average yields with these modifications were 39 - 403% of the theoretical. 17 An attempt was made to prepare the 6 nitro product by using I’cterson's method for obtaining sonitro-n-cresol (J’. Am. Chem. Soc" 06, 3879 (1935); Gibson. J. Chan. Soc.. 123, 12693 Hodgson and Beard, J. Chem. Soc.. 12?. 4.98 (1925) ). To a cold solution of 108 grams of o-cresol in 400 cc. of f.- ing sulfuric acid (20% 803), a mixture or 100 cc. of Mine 3280‘ (203’. 803) and as cc. of cone. nitric acid (d. 1.5) was gradually added during one and one-half hours. The mixture was thus allowed to stand overnight. (A characteristic yellow nitro color was obsemd at the completion of the addition of the nitric acid solution, but a black colored solution was observed in the moraine.) 'ihe liquid was diluted with 600 cc. of water and then steam distilled with super-heated steam. Only a mall amount of product was collected in the distillate which when recrystallised true hot gasoline had a melting point or 85.5 - 8§.5°o That this product was the d. d di-nitro-o-crcsol was proven by a mixed melting point with the d, d div-nitro product produced by Gibson's method (p. 16). One other attempt was me using a 1:1 ratio or o—crcsol to twins 3830‘. but with similar re. sults. It was damned inadvisable to continue with this method for swidonte ly both of the suli‘enic acid groups were replaced by the nitro groups. {the yields were too small to determine the presence or any of the 6 nitro product. The 0 nitro was reduced to the 6 animo by the method of Pmskonriakofl and Titherington (I. An. Chem. 800.. 88. W8 «- cc (1930) ). fifty grams of the 6 nitro product was dissolved in 1000 cc. of 35 tm solution and placed in a 2 1. three-necked flask equipped with a mechanical stirrer and theme-star. ins solution was heated to 90° wherewith the host was discontinued while about 100 mm of sodium hydrosuli’ite (Na‘sgo‘) were added with constant stirring. (Care must be taken to keep the temperature below 100°.) Invariably, the reduction was completed when a straw-colored solution was obtained on the addition of the soditm hydrosulfitc. Ten grams of norit were added and the tadperature maintain- ed at 90 . 95°. ihc solution was filtered while hot and the filtrate cooled at the tap. The crystallized product was filtered and dried in an mn at 40°. The crude dry product was recrystallized from hot 001‘ which gave a constant melting point of 88 - 89°. ('Ihe yield averaged 40 ~ “3% of the theoretical.) The 6 animo~o-creeol wae treated with hydrochloric acid, diago- tined and converted into the corresponding chlorine compound as modified by MarVel and Lichlvain for the preparation of o- and po chlorotoluene (Organic mtheses, Wiley and (Bone, Vol. III . 53). The cuprous chloride solution was prepared by dissolving 156 grass of crystallised cepper sulfate and 40.5 grams of sodium chloride in 600 cc. of water to which was added a solution of 33 grams of sodium sul- fite and 21.8 'grams of New dissolved in 150 cc. of water. The mixture was stirred continually during the addition of the sodium aulfite solution and was then allowed to cool to room temperature. The solution was de- canted and washed seVeral times with cold water; after w: 1011 it was dis- solved with 165 cc. of 1101 (d. 1.15). Sixty-too and one-half grams of the Mine product was dis- solved in 200 cc. of nci (d. 1.14). care being taken to insure complete salt formation. The mixture was cooled to 0° by adding cracked ice. to which was added a solution of sodim nitrite (55 grams dissolved in loo cc. 19 water) keeping the temperature at 0°. The diagotissd solution was then poured into the well stirred cold cuprous chloride solution (0°). The solution‘becsme somewhat thick due to the separation of the addition product between the diagoniun salt and the cuprous chloride. Stirring was continued for two hours after which it was allowed to warm up to room temperature by standing overnight. (When warned on the steam.beth, no escaping nitrogen was observed.) With the addition of steam, during steam distillation, an oily layer separated on tap which volatised with the steam. The light brown oil in the distillate was extracted with petroleum ether and dried over anhydrous 08612. The ether was distilled off and the oil fractionated three times under reduced pressure. The fraction between 66 0 68°79 mm. (37.5 grams) was the desired product. The almost colorless oil failed to crystallize. The proof of its structure was identified by chlorinating this fraction of c chlorc-o-cresol in a cold chloroform solution with one mole of chlorine. up. 54 - 55°. The analysis of the liquid was as follows: We Cal-Ode for CMUJJ Cl. usage Found: 01. 24.54. 80 _6_ Chloro-tcrocol E; the Fusing Sulfuric Acid Method. It has been reported (Peterson and Chen, loc. cit.) that ortho halogenated phenolic compounds can be prepared directly by halogenation in timing sulfuric acid. This method, previously mentioned (p. 15), had as its objective the preparation or this o-chlor—o-creeol. By sulfonating and ohlorinating in the cold (p. 13) a maxim yield or 195% was obtained for the 6 chlorc derivative. Sulfomtion was then attempted at room temperature with the subsequent procedure the seas as in above case. The yield of the o-chloro product was 21.0 grime for the one mole quantity used (yield 14.87.). Another suli‘onaticm carried out this tires by heating the cooresol and fining sulfuric acid (in the same proportions as above) with the cane subsequent procedure gave a yield of only 5.0%. No duplicate results were made as checks since the procedure was carefully adhered to in each trial run. It is generally believed that by heating a eulroneted mixture that some or the o-mli‘onic acid is chmged to the p—sulronic isomer. If this be true, then with heating there should be an increased amount of p-- sul- fonic acid fanned and an increased amount of the 6 chlorc product famed. However. it was noticed in the above runs that there was a decrease in the mount of the d chlorc formed by hosting the sulfonated mixtures and a corresponding increase in the amount or the 4, 6 dichloro product formed. The explanation or this phenanenon is largely conjectured. Chlorination or the d chlorc fraction (66 . 720/9 m.) in a cold chloroform solution with one mole of chlorine gave a dichloro product (-9. 54 «- 66°) which gave a mixed melting point of the same with the 4. 6 dichloro product formed from 6 ant-no o-cresol. Anal. 39.106. far C7H603L2: Cl. 40.08. Found : Cl, 39091. 22 The method Imported 1.1 Huston and Ballard A series of attempts were made to prepare the 6 ohloro derive- tive by the method reported by Huston end Ballerd (Organic Syntheses, Wiley and Sons, Vol. XIV. 14) for the preparation of o—brunophenolc Since Claus end J’nokson (loo. cit.) reported that the p. sulfonic seid derivetive as prepared by hosting one pert of cresol to one end one-half psrts of cone. sulfuric acid for 6 . 8 hours on the steam bath. it seemed reasonable that with the fonnstion of the sodium salt of this p- sulfonio said, that on chlorination, chlorine should enter the ortho position, giving then on neutrelizstion, acidification end hydrolysis, the desired 6 chloro—o-cresol. The shove euthors' method Ins followed rigorously using the above method for the preparation of the p- sulfonic scid derit‘etive. The amount of Real necessary for this method see calculated to be four moles (Ballard, Manter's Thesis. 1932. p. 27). It we necoosrzry to omit one step of their procedure; vim. the concentration and evaporation of the solution on es 011 both. which grestly interfered with the subsequent ecidifying end ste- distillstion. If the solution was concentrated and ”sported. there was ucessive foaming up end chem-ring of the product during the steen distill- ation. A typical run is es follo's: One pert of o-cresol end one and one-half pert of cone. sulfuric seid sore pieced in s one liter three-necked flask end heated on the stone both for 6 hours. When cooled to roan temperature, the calculated snout of film as edded with stirring and the temperature kept below 400, m. solution see then chlorinated (below 40°) till the theoretical emotmt, by my“, had been ebsorbed. (The solution must be slimline after chlorin- stion.) The product was then transferred to a 5 1. round bottomed fleck to which was edded 550 so. of cone. sulfuric acid with frequent cooling and shaking. (Excessive ecid caused decomposition and cherries.) The flesh was then fitted for steam distillation, which was carefully controlled to prevent some foaming up due to an excess of the liberated hydrogen chloride. Steam distillation required about an hour, after which the product was ex- tracted with ethyl ether. The oil obtained was then slowly frectioneted in s one end one-belt foot small side are meisen flask, collecting the free- tion between 60 e 92°/9 In. es the 6 chlorc product. A series of such we were made using varying percentege strength of New solution, with ell other conditions ramming the sens. Tubulnted below ere the results, using 11 1:1} ratio of eresol to ecid (hosting on steam bath for 6 hours) in one-half mole quantities of the creeol: 6; ham am. of Ram/on. Proctgon: 79 Yield Used i 01;sz A 66-72 je 31.3. 30 80 3/267 co. 6.0 gm. 7 eo" so g/soc on. 10.0 - i4. 50 80 3/160 cc. 10.0 " 14 60* 80 3/133 cc. . 8.0 " 11.8 70 80 3/114 cc. 8.0 " 11.3 80 80 3/100 cs. 9.5 " 18.4 Tameka weri made witfpracticflly identical yields. A series of runs were else made using s 1:2 ratio of meal to cone. sulfuric scid and heating on the steam bath for 5 hours. The emount of Head was calculated to be 5 moles. The tabulated results ere as follows: (The yields ere based on 1/2. mole quantities used.) $3 ‘Xa Nail-I an. of iu'uCii/cc. Fra cti'rn: 7'5 Yield Use! _ -M.2£1€.Q..i.--.-l,.i_--....<1§.:7a‘.’12.ua- : mm 40 100 {3/350 Cos 5e5 Kris 7.3 60 100 g/BOO cc. 8.0 ” 11.8 60 100 3/100 cc. 6.0 c 0.4 70* 100 3/140 cc. 5.5 n 7.8 80 100 3/125 cc. Solidified before corplete chlorination. __' v.“ mfimmmumnarmarvm“ It appears from the above results that an excess of cone. sulfur- is acid on sulfonation partially blocks c.10rinution, nhiie with an inn crease in the concentration of the Nada solution beyond 50% causes a de- crease in the amount of the 6 chlorc formed. The best yields were obtainp ed by using a 111% ratio of cresol to acid, and e 40 or 502 Neda solution for the formation of the sodium salt. DeriVativso end analyses of D€”5V8t1793 w—NC-W new" dew—m l--.-. "~m—‘n- a“ 4 3h1