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The preparation of some homologues of dinitro ortho and para cresols Briggs, Thomas Irving 1952

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THE PREPARATION OF SOME HOMOLOGUES OF DINITRO ORTHO AND PARA GRESOLS by THOMAS IRVING BRIGGS A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE.. in the Department of Chemistry We accept this thesis as conforming to the standard required from candidates for the degree of MASTER OF SCIENCE Members of the Department of Chemistry. THE UNIVERSITY OF BRITISH COLUMBIA October, 1952 ACKNOWLEDGEMENT Sincere appreciation and gratitude i s extended to my research director, Mr. G. G. S. Dutton, for his patient and helpful super-vision during the course of this project and for his many kindnesses during the d i f f i c u l t days at the end. Many thanks i s extended to Mr. R. K. Powell my hard working co-worker during the summer of 1951 and also to Mr. C. Harris who performed some of the analytical work. II ABSTRACT The ortho and para normal-alkyl-phenols from n-ethyl to n-octyl and ortho and para isobutyl and isoamyl phenols were prepared by the Fries rearrangement method. The para-tertiary-butyl, para-secondary-butyl, para-tertiary-amyl and ortho-tertiary-butyl phenols were pre-pared by miscellaneous methods. A l l the phenols were nitrated to give dinitro derivatives. The cyclohexyl-amine, piperidine and morpholine salts were made for a l l the dinitro-alkyl-phenols prepared. I l l TABLE OF CONTENTS ACKNOWLEDGEMENT I ABSTRACT II INTRODUCTION  The History of the Use of Herbicides and Insecticides 1 Variation of Chemical Structures of Phenols on Toxicity.............. 2 Graph No. I to follow page.. 2 Action of Selective Weedkillers .* 4 Graph No. II to follow page.. A The History of the Preparation of Nitro-Alkyl-Phenols 1. The Preparation of Alkyl-Phenols 7 2. The Preparation of Nitro-Alkyl-Phenols 9 3. The Preparation of the Amine Salts of the Dinitro-Alkyl-Phenols 10 EXPERIMENTAL  THE PREPARATION OF THE DINITRO-ALKYL-PHENOLS 11 I. The Preparation of the Alkyl-Phenols by theo r i e s Rearrangement 11 Table 1 12 Table I I . 12 Table III.... 15 Table IV 16 Table V 17 II . The Preparation of the Dinitro-Alkyl-Phenols 20 Table VI 21 Table VII 22 III. The Salt Formation of the Dinitro-Alkyl-Phenols 23 Table VIII 25 Table IX 26 IV III. The Salt Formation of the Dinitro-Alkyl-Phenols (con't) Table X 27 Table XI 28 Investigation of U.S. Patent 2,385,719... 29 Table XII 29 IV. The Preparation of Alkyl-Phenols by Miscellaneous Methods.... 1. The Preparation of Para-Tert.-Butyl and Para-Tert.-Amyl Phenols 31 Table XIII 32 2. The Preparation of Para-Secondary-Butyl-Phenol 32 3. The Preparation of Ortho-Tertiary-Butyl-Phenol 34 4. Attempted Preparation of Ortho-Tertiary-Amyl-Phenol......37 COMPARISON OF ALKYL-PHENOLS PREPARED BY THE GRIGNARD AND FRIES METHODS 3& Table XIV ,% 39 Table XV .39 A CHECK ON THE PHYSICAL CONSTANTS OF THE INTERMEDIATE COMPOUNDS PREPARED DURING THE SYNTHESIS OF ORTHO AND PARA ISOBUTYL AND ISOAMYL PHENOLS USING THE GRIGNARD METHOD 40 I. The Preparation of Para-Methoxy-Phenyl-Isopropyl-Carbinol......40 II . The Preparation of Para-Methoxy-Phenyl-Isobutene-1......... 41 III. The Preparation of Para-Methoxy-Isobutyl-Eenzene. 41 IV. The Preparation of Ortho-Methoxy-Phenyl-Isopropyl-Carbinol 42 V. The Preparation of Para-Methoxy-Phenyl-Isobutyl-Carbinol 42 VI. The Preparation of Para-Methoxy-Phenyl-Isoamylene-1 43 VII. The Preparation of Para-Methoxy-Isoamyl-Benzene....... ..43 VIII. The Preparation of Ortho-Methoxy-Phenyl-Isoamyl-Carbinol 43 THE PREPARATION OF ORTHO-METHOXY-ACETOPHENONE. 44 DISCUSSION 46 Graph No. I l l . , to follow page... .47 V DISCUSSION (con't) Graph No. IV to follow page..47 BIBLIOGRAPHY 48 INTRODUCTION This thesis describes the preparation of some of the homologues of dinitro ortho and para cresols. The dinitro-alkylrphenols were prepared in order to test and possibly to develop their use as selective herbicides and insecticides. It has been known since 1943 that certain amine salt derivatives of the dinitro-alkyl-phenols are also f a i r l y good selective herbicides.^ Thus three different amine salt derivatives have been made for each dinitro-alkyl-phenol prepared. The History of the Use of Herbicides and Insecticides. The idea of a selective herbicide for weed control i n cereal crops has gradually evolved since Bonnet, i n 1896, showed that when a f i e l d of oats was sprayed with a dilute solution of copper sulfate the oats were unaffected but the weed, the yellow charlock, was destroyed. The next major experiment in selective weedkilling occurred i n 1911 when Rabate sprayed cereal crops with dilute sulfuric acid. A large percentage of dicotyledonous weeds were destroyed but the crops remained practically uninjured. However, the corrosive action of the sulfuric acid on the spraying equipment offered a serious disadvantage. Up to 1933, when Truffaut and Pastac^ discovered the selective action of the nitro-phenol, only a small percentage of the cereal acreage in Great Britain and Europe was treated with sulfuric acid, copper sulfate and similar compounds. Truffaut and Pastac showed that by spraying cereal crops with the dyestuff dinitro-ortho-cresol f a i r l y good control of weeds could be obtained. The advantage of dinitro-phenol over the sulfuric acid was that there was no corrosive action on the spraying equipment. The development of the dinitro-phenols gave rise to a host of organic herbicides. In 1940 Templeman^- discovered that the growth-regulating compound alpha-napthyl acetic acid was toxic to the charlock weed and not to the oats. Since 1940 a large number of substituted phenoxy-acetic acid com-pounds has been developed and tested for use as herbicides. The most well known one i s probably 2:4 dichloro-phenoxy acetic acid used to control the dandelion in gardens and lawns. The development of selective weedkillers has reached the point where tens of millions of acres of cereal crops are sprayed annually. Methods of weed control have been worked out to cover rice, sugar cane, oats, barley, maize, linseed-flax, peas, onions and carrot crops as well as lucerne and grasslands. New developments are in the process of being made for the eradication of mosquitoes, aquatic weeds i n rivers and i r r i -gation channels, weeds i n forest nursery beds and also for the destruction 6 or scrub. The Variation of Chemical Structure of Phenols on Toxicity. The discovery of the selective action of dinitro-phenols by Truffaut and Pastac led to the investigation of the effect of variation 17 in chemical structure of hydroxy compounds on toxicity. Johnson investigated the antiseptic strengths of the homologues of resorcinol where side chains of one to four carbons were inserted into the ring. Johnson found that the antiseptic strength reached a maximum with a four 12 carbon side chain. However, later work by Dohme showed that of the n-propyl to n-octyl and isobutyl, isoamyl and isohexyl derivatives of resorcinol, the compounds with side chains containing six carbon atoms had the highest phenol coefficient. For a graphic i l l u s t r a t i o n of Dohme1s investigations see Graph No. I following page two. Dohme also showed that the phenol coefficients of the iso-alkyl-resorcinols were F i g u r e 1. Phenol C o e f f i c i e n t of 4 - A l k y l r e s o r c i n o l s 2 4 6 8 Number of carbon atoms i n a l k y l group © R - ' n - a l k y l X R « i s o - a l k y l -3-lower than the corresponding normal alkyl-resorcinols. 31 Tattersfield i n his investigations of phenols showed that a nitro group iri the ortho or meta position to the hydroxyl group has l i t t l e affect on the toxicity, but when the nitro group was i n the para position a large increase i n toxicity was obtained. 26 Plantefol found that phenol and i t s nitro derivatives were a l l o toxic to s-fungus nigra but that ortho-nitro-phenol was the least toxic of the mono derivatives and that para-nitro-phenol was the most toxic. Plantefol also found that 2:4 dinitro-phenol was about one hundred times more toxic than phenol and about ten times more toxic than the para-nitro-phenol. 2:4:6 trinitro-phenol had only about the same toxicity as meta-nitro-phenol. Tattersfield carried out tests on insects similar to those tests carried out by Plantefol on fungus and also found maximum toxicity i n the 2:4 dinitro-phenol. The fact that the position of a functional group in the benzene ring i s important to the toxicity of aromatic type herbicides was mentioned by Blackman i n a lecture on selective toxicity. I f three chlorine atoms are attached in the 2, 4» and 5 positions on the benzene ring i n the growth-regulating substance-trichloro-phenoxy acetic acid, then the com-pound i s highly toxicj but i f one atom i s moved from the 5 position to the 6 position the compound exhibits l i t t l e toxicity. Thus i t i s important to test each and every compound in a series i n order to determine maximum activity. Kagy^ investigated the variations i n toxicity with the chemical structures of the 2:4 dinitro-alkyl-phenols varying the side chain structure from two to eight carbons. He found that the maximum ac t i v i t y - 4 -was obtained when the length of a side chain was six or seven carbons. For a graphic i l l u s t r a t i o n of Kagy's investigations see Graph No. II following page four. Kagy also carried out an investigation of the toxicity of certain phenols on the adult female citrus red mite. The results he obtained were as follows: Compound Lethal Deposit of Compound 2:4 dinitro-6-cyclohexyl-phenol 0.40 micrograms/sq. cm. of f r u i t 2:4 dinitro-6-ethyl-phenol 1.20 " n n H n 3:5 dinitro-cresol 1.80 " n n n n 2:4 dinitro-phenol 3.10 " " " " " Dinitro-alpha-naphthol 3.40 w n u n «• g In their work on thio-cyano-acetates Grove and Bovingdon found that the six carbon compound was the most toxic. However, i t i s not a general rule that six carbon side chains i n herbicides and insecticides 7 are the most toxic as Bousquet found that in the alkyl thio-cyanates the lauryl homologue had the maximum toxicity. Action of Selective Weedkillers. The actual operation of the selective mechanism of herbicides i s not f u l l y understood. Certain factors are definitely known to be very important in weed control. One of the most important factors Is the stage of development of the plant i t s e l f . Blackman,^ i n his investigation on the growth-regulating compounds, has shown that while methyl-chloro-phenoxy- acetic acid was toxic to both the charlock and cocksfoot weed in the germination stage i t was toxic only to the charlock weed i n the vegetative phase. Thus, the methyl-chloro-phenoxy-acetic acid was definitely not selective during the germination stage of both plants, but i t definitely was selective during the vegetative stage. Through similar investigations of the relationship between resistance and susceptibility of both weed species and crops i t has been possible to Figure 2. T o x i c i t y of 2:4 Dinitro-o-n-alkylphenols to S i l k Worm Larvae 0 j 2 4 6 8" Number of carbon atoms i n a l k y l group -5-work out methods that offer excellent selective control. Blackman and his team at Oxford have shown that the degree of resistance of a weed species w i l l d i f f e r with different herbicides. In their Investigations of the hoary pepperwort (cardaria draba) they compared the effects of spraying sodium methyl-chloro-phenoxy-acetate and dichloro-phenoxy-acetic acid (2:4 D) during the preflowering stage, the flowering stage and the regeneration stage. Blackman found that during the pre-flowering stage the sodium methyl-chloro-phenoxy-acetate was more toxic than the dichloro-phenoxy-acetic acid. This difference i n toxicity of the two compounds was accentuated in the regeneration stage but i t was reversed during the flowering stage when the dichloro-phenoxy-acetic acid was the most toxic. Similar results were recorded by Holly at Oxford who investigated the control of perennial weeds in grassland. He found that in the spring sodium methyl- chloro-phenoxy-acetate was more toxic to the dandelion than sodium dichloro-phenoxy-acetate, but i n the autumn sodium dichloro-phenoxy-acetate was by far the more toxic of the two compounds. Investigations by numerous workers have shown that the "degree of k i l l " of a weed species does not necessarily increase with concentration of the spray solution. On the contrary, i n many cases the "degree of k i l l " decreased rapidly for large increases i n concentration of the spray. Results of this nature tend to show that the destruction of the roots i s not due to root absorption of the herbicide but i s probably due to the transport of the herbicide from the shoot along to the root. Thus i t may be that a high concentration of a herbicide i n a spray produces a smaller "degree of k i l l " than a less concentrated spray because the transportation system of the plant i s destroyed by concentrated solutions before the herbicide reaches the root in any quantity. This would explain why the low concentrations of the nitro-alkyl-phenols -6-give greater injury than the higher concentrations. Some other important factors are the amount of spray that i s retained by the plant, the amount of herbicide that penetrates into the stem and leaf, and the rate of penetration of the herbicide. Blackman and his workers have shown that certain plants retain more spray when the spray i s an o i l emulsion type. The rate of penetration of a herbi-cide into a plant i s also affected by the o i l . These factors are very important and must be considered when using herbicides that are practically insoluble i n water. These herbicides are usually dissolved in oil-water emulsions. Understanding the above factors has aided workers to develop f a i r l y good weed control of cereal, vegetable and f r u i t crops. However, a serious problem has arisen from the continuous and heavy application of herbicides to crops. Various groups of workers have shown that by heavy and continuous application of herbicides i t i s possible to breed varieties of plants that are resistant to these herbicides. Thus, while i t may be possible to produce food crops that are practically one hundred percent resistant to specific herbicides i t may also be possible to produce weeds that are just as resistant. In the United States very heavy and continuous spraying of areas alongside highways with mineral o i l has destroyed the original undesired vegetation.. However, the original type of undesired vegetation has been replaced by a new type that i s o i l resistant. Similarly the extensive use of 2:4 dichloro-phenoxy-ac'etic acid has kept down the rate of spread of the dicotyledonous weed but i t has increased the spread of the more resistant monocotyledonous weed. Thus i t appears that nature tends to look after her own. This perhaps i s fortunate for the chemist as new effective'herbicides w i l l have to be developed as the old herbicides become Ineffective. -7-The History of the Preparation of Nitro-Alkyl-Phenols. Interest i n the preparation of alkyl phenols was instigated by the works of Johnson and Lane^ 0 i n 1921 and also by Dohme, Cox and 12 Miller i n 1926. These workers introduced the antiseptic hexyl-resorcinol into medicine. They showed that the germicidal value of 4-n-alkyl resorcinol rose to a maximum at 4-n-hexyl resorcinol. 28 In 1928 Rosenmund and Lohfert showed that the alkyl phenols could be prepared by the Clemmensen reduction of the appropriate hydroxy-ketone. In 1930 Coulthard, Marshal and Pyman^using similar procedures as those used by Rosenmund and Lohfert, prepared the alkyl derivatives of phenol, cresol, and guaiacol, and then went on to make a systematic study of the variation of the phenol coefficients of the compounds they had prepared. Coulthard prepared the hydroxy-ketones by the following four methods: (i) the Menchi condensation of acid and phenol using zinc chloride as a catalyst; ( i i ) the Fries isomerization of phenyl esters with aluminum chloride; ( i i i ) the isomerization of phenyl esters using zinc chloride which gave lower yields than the Fries method; (iv) the condensation of acids with phenols by means of phosphorus oxychloride. They reduced the hydroxy-ketones by refluxing the ketones with alcohol, dilute hydrochloric acid and amalgamated zinc for twelve to twenty hours. I t was. found that ortho-hydroxy-ketones took longer to reduce than the para homologues. Coulthard and his fellow workers prepared the ortho and para n-butyl to n-heptyl phenols. Sandulesco and Girard 2^ carried out a project similar to that carried out by Coulthard. Sandulesco and Girard prepared the straight chain alkyl-phenols from methyl to nonyl. They did the preparation of the ester and the Fries rearrangement i n one step by heating phenol, aluminum chloride and the acid chloride up to 130° C. for one hour. I t was found that the hydroxy-ketones were more readily reduced by diluting con-centrated hydrochloric acid with glacial acetic acid instead of diluting i t with water and alcohol. The glacial acetic acid was a better solvent for the ketones than the alcohol. Sandulesco and Girard prepared the phenols with the object of studying the hypnotic properties of these compounds. 13 Farenholt, Harden and Twiss, in 1933 prepared a series of alk y l -phenols using the Fries rearrangement method. In 1935 Bartz, Adams and Miller -^ showed that butyl-phenols could be prepared from the methyl-allyl ethers of phenol. They rearranged the ether compounds by heating the ethers at 245° C. and then reducing the rearranged methyl-allyl-phenols to the saturated butyl-phenols. In 1937 J. B. Niederl and co-workers2^ treated molecular amounts of phenol, acetic acid and various aldehydes at -5° C. with dry hydro-chloric acid for two hours. The resultant material was slowly dried to give mixtures of alkyl-phenols. Pure alkyl-phenols were d i f f i c u l t to obtain by this method. •3/ Tsukervanik and Tambovtseva, in 1937, obtained mixtures of phenols by means of alkylating phenol or anisole with an alkyl chloride. This method gave mostly tertiary-alkyl-phenols. In 1938 Najarova2-^ prepared isoamyl-phenol by a very tedious procedure. He nitrated isoamyl benzene with n i t r i c acid, reduced the nitro compound to the amine, diazotized the amine, and decomposed the diazo compound. 3 Baddely, i n 1938, prepared ortho and para ethyl-phenols by heating phenol, diethyl ether and aluminum chloride at 100° C. -9-Numerous workers have prepared the para-alkyl-phenols by condensing phenol and an alkyl chloride using aluminum chloride as a catalyst. The tertiary-alkyl-phenols are very easily prepared by this method. 2 In 1938 Archer, Simons and Passino showed that i t was possible to prepare tertiary-butyl-phenol by condensing tertiary-butyl chloride and phenol using anhydrous hydrofluoric acid instead of aluminum chloride. Further investigation into the use of hydrofluoric acid as a condensing agent showed that the tertiary-alkyl-phenols could be prepared by condensing secondary or tertiary-alkyl alcohols with phenol using anhydrous hydrofluoric acid as catalyst and as solvent. 15 In 1949 Hart developed a unique method for the preparation of ortho-tertiary-butyl-phenol. He condensed isobutylene with para-bromo-phenol i n toluene using sulfuric acid as the condensing agent. He then removed the bromine from the nucleus by reduction using Raney nickel alloy and dilute sodium hydroxide. In general the Friedel and Craft type reactions already mentioned are best suited for the preparation of para tertiary and para secondary alkyl-phenols. The ortho secondary, iso, and normal alkyl-phenols may be prepared by the Grignard method. Preparation of Nitro-Alkyl-Phenols. Phenols have been nitrated by various procedures. In 1936 Baroni eCnd KLeinau^ nitrated phenols by dissolving the phenol i n chloroform and adding n i t r i c acid at 15° C. At low temperatures monondtro derivatives were formed. The dinitro and t r i n i t r o derivatives were prepared by adding the n i t r i c acid to the phenol i n boiling chloroform. In this way Baroni and Kleinau prepared dinitro derivatives of ortho-methyl-phenol and ortho-cyclohexyl-phenol. In 1938 Ipatieff, Pines and Friedman prepared 2:4 dinitro-6-tert.-butyl-phenol by condensing p-nitro-phenol with isobutene using ninety percent phosphoric acid as a catalyst. The resulting 2-nitro-6-tert.-butyl-phenol was then nitrated by dissolving the mononitro compound in acetic acid and adding n i t r i c acid. 00 o Monti and Cianetti, " i n 1938, nitrated alkyl-phenols at 15-20 C. by passing through their solutions nitrous vapours evolved from a mixture of arsenious oxide and n i t r i c acid. They showed that the choice of solvent for this reaction was important. The dinitro com-pounds were prepared when acetic acid was used as the solvent. Mono-nitro compounds were prepared when petroleum ether (40-70) was used as a solvent. Workers in England nitrated alkyl-phenols by dissolving the phenol in concentrated sulfuric acid and heating the solution at 100° C. for one hour, cooling the solution, and adding i t to n i t r i c acid which had been cooled to -15° C. Preparation of the Amine Salts of the Dinitro-Alkyl-Phenols. In 1943 Coleman and G r i e s s ^ prepared the amine salt deri-vatives of the dinitro-alkyl-phenols by mixing together an aqueous solution of the a l k a l i salt of the dinitro-alkyl-phenol and an aqueous solution of the inorganic salt of the amine. Workers i n England have shown that the amine salt derivative can be prepared by simply mixing the dinitro compound and the amine together and recrystallizing the product from benzene. -11-EXPERIMENTAL A l l boiling points and melting points are uncorrected and measured in °C. Melting points were taken using sealed glass tubes inserted into an e l e c t r i c a l l y heated melting point block. THE PREPARATION OF THE DINITRO-ALKYL -PHENOLS, I. The Preparation of the Alkyl-Phenols by the Fries Rearrangement. A. The Preparation of the Acid Chlorides. The acid chlorides were prepared by the reaction df thionyl chloride on carboxylic acids. The preparation of isobutyryl chloride: Thionyl chloride (1.1) moles was cooled to 0° In a 2-necked 1-litre flask which was f i t t e d with a graduated dropping funnel. Isobutyric acid (1.0 moles) was slowly added over a period of twenty minutes. The flask was frequently shaken during the addition. After the addition of the isobutyric acid was complete the mixture was refluxed for one hour and then the product was d i s t i l l e d through a fractionating column. With the exception of propionyl chloride a l l the acid chlorides were prepared in a similar manner and are recorded i n table I. In the preparation of propionyl chloride the molecular ratio of the acid to the thionyl chloride was reversed, i.e. an excess of propionic acid was used. B. The Preparation of the Phenyl-Esters. The phenyl-esters were prepared by reacting an excess of phenol with the acid chloride. The Preparation of phenyl-isobutyrate: Isobutyryl chloride (180 grams, 2.05 moles) was placed -12-TABLE I PHYSICAL CONSTANTS OF ACID CHLORIDES CHLORIDE YIELD BOILING POINT °C/mm. Obs. L i t . Propionyl 50$ 79-84 80 Butyryl 85% 102 102 ' Isobutyryl 90% 93 92 n-Valeryl 50% 127 128 Isovaleryl 80% 115 115 n-Caproyl 75% 151 153 n-Heptyl 87% 173 176 n-Capryl 80% 194 196 Stearoyl 65% 208-215/15 215/15 TABLE II PHYSICAL CONSTANTS OF PHENYL-ESTERS PHENYL-ESTER YIELD BOILING POINT °C/mm. Obs. L i t . REFRACTIVE INDEX 0bs./25° Lit./20° Phenyl-acetate 85% 192 196 1.5017 1.5038 Phenyl-propionate 80% 206 211 1.5002 1.5011 Phenyl-butyrate 82% 224 227 1.4934 -Phenyl-isobutyrate 82% 209 111/25 1.4919 -Phenyl-valerate 75% 160/14 - 1.4869 -Phenyl-isovalerate 80% 228 224 1.4831 -Phenyl-caproate 75% 260 145/2.5 1.4840 1.4876 Phenyl-heptylate 90% 120/2 282 1.4829 1.4840 Phenyl-caprylate 85% 136/2 300 1.4810 -i n a 1-litre flask. Phenol (200 grams, 2.1 moles) was added in small portions over a period of twenty minutes. A vigorous evolution of hydrogen chloride gas was observed. The ester was then purified by d i s t i l l i n g through a fractionating column. A l l the esters were prepared in a similar manner and are recorded i n table I I . C. The Fries Rearrangement of the Phenyl Esters. The ortho and para hydroxy-ketones were prepared by the Fries rearrangement. The reaction was carried out i n the absence of a solvent as this procedure not only gave good yields but i t was also more convenient to carry out than the usual solvent processes. The temperature of the reaction was adjusted i n order to obtain equi-molecular amounts of the ortho and para forms. The preparation of ortho and para hydroxy-acetophenones: Aluminum chloride (540 grams, 4 moles) was placed i n a 2-necked 2- l i t r e flask and heated to 70°. Phenyl-acetate (360 grams, 2.6 moles) was added to the heated aluminum chloride i n small portions. The temperature of the mixture rose to 100-110° during this addition. The reaction was carried out i n the fume hood because of the vigorous evolution of hydrogen chloride gas. After the addition the temperature of the reaction mixture was brought to 140° and the mixture was maintained at this temperature for three-quarters of an hour. The mixture was i n the form of a soft orange glass. The mixture was cooled to room temperature, and i t was then hydrolysed by pouring very slowly over i t 1500 mis. of 6N hydrochloric acid. In order to complete the hydrolysis the mixture had to be heated to approximately 70° for fifteen minutes. After hydrolysis was complete, -14-a viscous red o i l came to the top of the aqueous layer. The o i l y layer was separated and washed with 200 mis. of 6N hydrochloric acid followed by two 200 ml;, portions of warm water. The o i l was dried by d i s t i l l i n g the water off under water suction. The dry o i l was then vacuum d i s t i l l e d and the fraction was collected i n a Bruel receiver. The ortho-hydroxy-acetophenone was a viscous clear o i l and d i s t i l l e d approximately 70° below the para-hydroxy-acetophenone. On cooling the para-hydroxy-acetophenone was a pink colored solid. Both compounds were then separately r e d i s t i l l e d . The remaining hydroxy-ketones i n this series were prepared i n a similar manner. The particular experimental conditions for each of the hydroxy-ketones prepared are recorded i n table I I I . The physical constants of the hydroxy-ketones prepared are recorded i n table IV. The 2t4 dinitro-phenyl-hydrazone derivatives of the ketones were 25 prepared. The melting points of the derivatives and the nitrogen 25 analysis are recorded i n table V. A few of the semi-carbazon®- J derivatives were prepared and these are also l i s t e d i n table V. -15-TABLE III EXPERIMENTAL CONDITIONS  for the PREPARATION of HYDROXY KETONES ESTER TEMP, of ESTER ADDED °C. TEMP, of AICI3 °C. TEMP. C. MAINTAINED at for 3/4 hr. COLOR of COMPLEX COLOR OF HYDROLYSED OIL Phenyl-Acetate 24 70 135-140 Light Orange Red Phenyl-Propionate 24 70 135-140 Orange Red Phenyl-Butyrate 40 70 135-140 Dark Orange Green Phenyl-Isobuyrate 40 70 135-140 Dark Orange Green Phenyl-Valerate 40 70 145-150 Red Dark Red Phenyl-Isovalerate 40 70 145-150 Red Dark Red Phenyl-Capyroate 60 70 150-160 Dark Red Purple Phenyl-Heptylate 60 80 160 Dark Red Dark Purple Phenyl-Capyrlate 60 80 160-165 Dark Red Dark Purple -16-TABLE IV PHYSICAL CONSTANTS of the HYDROXY-KETONES PHENONES BOILING POINT oc./mm. Hg. Obs. L i t . MELTING POINT °C. Obs. L i t . REFRACTIVE INDEX />C. 0bs./25° L i t . YIELD o-OH-aceto- 44-5/0.1 110/15 1.5570 1.558/21 362 o-OH-propio- 52-6/0.1 115/15 1.5485 1.548/22 48# o-OH-n-butyro- 63-5/0.1 124/15 1.5379 1.5375/21 36^ o-OH-isobutyro- 66-8/0.1 - 1.5360 - 442 o-OH-n-valero- 74-5/0.1 130/10 1.5310 1.5290/21 372 o-OH-isovalero- 72-5/0.1 - 1.5297 - 342 o-OH-capro- 83-5/0.1 145-7/15 1.5262 1.5254/21 452 o-OH-hepto- 93-5/0.1 155/10 1.5211 1.5209/22 512 o-OH-caprjfc- 102-5/0.1 169/11 1.5170 1.5169/22 412 p-OH-aceto- 160/1 190/15 106-7 106-7 502 p-OH-propio- 164/1 191/10 146 148 402 p-OH-n-butyro- 161/1 200/15 89-91 91 342 p-OH-isobutyro- 143/0.6 - 59-60 56 382 p-OH-n-valero- 160-2/0.7 210/15 61-62 62 412 p-OH-isovalero- 162-5/1.5 - 88-89 90 412 p-OH-capro- 172-5/1 207/10 60 63 302 p-OH-hepto- 169-71/0.7 220/15 90 93 342 p-OH-caprjJo- 181-4/0.7' 224/10 58-59 62 342 -17-TABLE V DERIVATIVES OF THE HYDROXY-ALKYL-PHENONES PHENONES MELTING POINT 2:4 Dinitro-Phenyl Hydrazone Obs. °C. L i t . PERCENT Found NITROGEN Calc. MELTING POINT Semi-carbazone ° c Obs. L i t . o-OH-aceto- 210 211 17.53 17.72 218 209-10 o-OH-propio- 189 189 16.80 16.97 214 213 o-OH-n-butyro- 203 202 16.14 16.29 189 192 o-OH-isobutyro- - - - - -o-OH-n-valero- 178* - • 15.38 15.65 202 -o-OH-isovalero- 178*- - 15.74 15.65 - .... -o-OH-capro- 153 ^  154 15.28 15.08 177 179 o-OH-hepto- 153 U - 14.48 14.50 161 162 o-OH-capryfo- 140 - 13.96 14.00 155 157 p-OH-aceto- 255 261 17.22 17.72 198 198 p-OH-propio- 23 2 229 16.50 16.97 168 -p-OH-n-butyro- 215 212 16.11 16.29 - -p-OH-isobutyro- 167 - 16.63 16.29 -p-OH-n-valero- 182 - 15.49 15.65 - -p-OH-isovalero- 201 - 15.71 15.65 - -p-OH-capro- 184 182 14.93 15.08 150 151 p-OH-hepto- 174 - 14.41 14.50 148 -p-OH-capryb- 171 - 13.99 14.00 148 a. Mixed melting point taken of o-OH-n-valero- and o-OH-isovalero gave melting point depression of 8°. Ir Mixed melting point taken of o-OH-capro- and o-OH-hepto- gave melting point depression of 9°. -18-D. The Reduction of the Hydroxy-Ketones. The hydroxy-ketones were reduced to the corresponding phenols by refluxing the compounds with zinc amalgam and f a i r l y con-centrated hydrochloric acid. This method of reduction i s commonly known as the Clemmensen reduction. The ratio of zinc amalgam and hydrochloric acid to the ketonic compound i s not too important provided both the zinc and hydrochloric acid are i n excess of the theoretical amount.^ " The zinc amalgam was prepared by shaking a mixture of 100 grams of mossy zinc, 10 grams of mercuric chloride and 150 mis. of 1 N. hydro-chloric acid for approximately five minutes. The aqueous solution was 21 decanted and the zinc amalgam was washed with hot water. The Clemmensen reduction of o-OH-acetophenone: Zinc amalgam (100 grams) was placed i n a 500-ml. ground-glass flask f i t t e d with a reflux condenser. A mixture of 175 mis. of concentrated hydrochloric acid and 75 mis. of water was added. The keto compound (40 grams) was added. The mixture was refluxed for 2-1/4 hours. It was then cooled and the o i l y layer which floated on the aqueous acid layer was tested with f e r r i c chloride and also with 2:4 dinitro-phenyl-hydrazine. Both tests gave negative results indicating that the keto compound was reduced. The o i l y layer was separated and the aqueous layer was extracted twice with 60 ml. portions of benzene. The benzene extractions were added to the o i l y layer. The benzene-oil layer was then washed twice with cold water and dried over magnesium sulfate. The benzene was d i s t i l l e d off and the product was vacuum d i s t i l l e d . -19-A similar procedure was followed for the reduction of the para and ortho hydroxy-propiophenones and ortho and para hydroxy-butyro-phenones.^ The reflux time for the reduction of ortho-hydroxy-butyro-phenone was fourteen hours. I t was also noticed that the ortho homo-logues required a longer reflux time than the para homologues. The time of reflux also increased with the length of the alkyl chain. Two -ether procedures were tried i n an attempt to reduce reflux time. Method A: Ortho-hydroxy-heptyl-phenone (40 grams) was refluxed with a mixture of 100 grams of zinc amalgam, 175 mis. of concentrated hydrochloric acid and 75 mis. of water. The time of reflux for complete reduction was thirty hours. The yield was seventy-five percent. Method Ortho-hydroxy-heptyl-phenone (40 grams) was refluxed with a mixture of 100 grams of zinc amalgam, 175 mis. of concentrated hydrochloric acid, 75 mis. of water and 200 mis. of ethanol. The time of reflux was twenty-five hours for complete reduction of the keto compound. The yield was seventy-five percent. Method C: Ortho-hydroxy-heptyl-phenone (40 grams) was refluxed with a mixture of 100 grams of zinc amalgam, 160 grams of concentrated 21 hydrochloric acid and 160 grams of glacial acetic acid. The time of reflux for complete reduction was seven hours. The yield was eighty-six percent. Method "C proved to be more efficient than method "A" or "B" and also required the shortest reflux time. Thus the hydroxy-ketones were reduced by method MC" and the physical constants for the resulting phenols are recorded i n table VI. Some of the phenoxy-acetic acid derivatives 2-" of the phenols were prepared with d i f f i c u l t y . The melting points of the phenoxy-acetic acid derivatives are recorded i n table VII. The 3*5 dinitro-benzoate deri-vatives of most of the phenols were prepared and the melting points are •20 recorded i n table VII. I I . The Preparation of the Dinitro-Alkyl-Phenols. Two methods of nitration of phenols were tried on O-isopropyl-phenol S. ' : . •' "\. r'i W „• ." : \x. Method 1: Concentrated sulfuric acid (26 grams) was added to 25 grams of b-isopropyl-phenol with constant s t i r r i n g . The solution was heated on a steam bath for one hour during which time the color of the solution turned to a cherry red. The solution was then cooled and diluted with 25 mis. of water. The temperature rose so the mixture was recooled. Nitric acid (34 grams, density 1.42) was cooled to -15° i n a stainless steel beaker. . Chloroform and dry ice were used for the low temperature bath. The sulfonated material was then added with constant st i r r i n g to the n i t r i c acid. The addition took three hours during which time the temperature was maintained at -15°. The mixture was then allowed to warm slowly to room temperature over a period of sixteen hours. A yellow precipitate had formed during this time. The acid mixture was diluted with three times i t s volume of water. The precipitate was recrystallized from ethyl alcohol. The 2t4 dinitro-ortho-isopropyl-phenol was d i s t i l l e d . The yield was f i f t y - f i v e percent and the boiling point was 132° at 0.15 mm. Method 2: Ortho-isopropyl-phenol (25 grams) was dissolved In 60 mis. of glacial acetic acid and this solution was added dropwise, with constant st i r r i n g , to a solution of 40 mis. of fuming n i t r i c acid and 75 mis. of acetic acid which had been cooled to -15° i n a stainless steel beaker. The addition took about three-quarters of an hour. After this addition the mixture was allowed to come slowly to room temperature over a period of one and one-half hours. The solution was kept at •21-TABLE 71 PHYSICAL CONSTANTS FOR ALKYL-PHENOLS FROM CI-EMMENS6N REDUCTION ALKYL-PHENOL BOILING POINT °C/mra. Obs. L i t . REFRACTIVE Obs. 25° INDEX L i t . 20° YIELD c—ethyl- 64-6/2 101/20 1.5352 1.5348 72% o-propyl- 65-6/1.2 122/20 1.5280 - 60% o-butyl- 69/0.6 109/10 1.5182 1.5180 65% o-isobutyl- 62/0.7 81/6 1.5170 - 55% o-amyl- 82/0.7 122/10 1.5141 1.5132 88% o-isoamyl- 88/1.8 m* 1.5121 - 68% o-caproyl- 121/3.5 135/10 1.5090 1.5089 842 o-heptyl- 105/0.6 147/10 1.5058 1.5058 862 o-capryl- 129/1.5 160/11 1.5052 1.5029 782 p-ethyl- 79/1.6 210-12 MP=45° 1.5239 752 p-propyl- 72/0.7 228-30 1.5220 1.5379 722 p-butyl- 83/0.6 238-42 1.5160 1.5165 672 p-isobutyl- 81-2/0.7 235-9 MP=52° 1.5319 832 p-amyl- 110/3 248-53 1.5107 1.5119 802 p-isoamyl- 102-5/1.5 126/15 1.5100 1.5050 582 p-caproyl- 128/2.5 146/10 1.50 55 - 812 p-heptyl- 142/2.4 271-8 1.5040 1.5090 752 p-capryl- 137-42/1.8 169/10 1.5052 - 632 -22-TABLE VII DERIVATIVES OF ALKYL-PHENOLS ALKYL-PHENOL PHENOXY-ACETIC ACID Melting point °C Obs. L i t . 3:5 DINITRO-BENZOATE Melting Point °C o-ethyl- 135 140 107 o-propyl- 99 99 96 . o-butyl- 103 .97 o-isobutyl- 93 - 93 o-amyl- 76 - 98 o-isoamyl- 58 - 95 o-caproyl- 86 - 95 o-heptyl- 54 - 92 o-capryl- 84 - 93 p-ethyl- 91 90 139 p-propyl- 87 86 123 p-butyl- 80 81 92 p-isobutyl- 106 124 131 p-amyl- 89 90 94 p-isoamyl- 80 128 p-caproyl- - - 87 p-heptyl- - - 97 p-capryl- - 91 -23-room temperature for one-half hour and then i t was poured over a mixture of water and cracked ice. A yellow precipitate settled out. The pre-cipitate was f i l t e r e d , washed, dried and d i s t i l l e d . The yield was sixty-five percent, and the boiling point was 132° at 0.13 mm. Method 1 took twenty-four hours with a yield of f i f t y - f i v e percent while method 2 took three hours with a yield of sixty-five percent. Thus method 2 proved to be the better method, i.e . i t gave slightly better yields and was much quicker to carry out. A l l the phenols were nitrated by the acetic acid method. The majority of the ortho-nitro-alkyl-phenols separated out as o i l s when poured over cracked ice, whereas, the majority of the para compounds precipitated out as yellow solids. The amount of acetic acid used for dissolving the phenol was varied slightly depending on the solubility of the phenols in the acetic acid. The red o i l or yellow precipitate was dissolved in chloroform and the aqueous acid layer was extracted twice with further portions of chloroform which were added to the f i r s t extraction. The chloroform layer was washed with water containing a trace of sodium bicarbonate. The chloroform layer was then dried over magnesium sulfate and the solvent was d i s t i l l e d off. The product was then vacuum d i s t i l l e d . The complete series of dinitro-alkyl-phenols were prepared in this manner and are recorded in table VIII. III. The Salt Formation of the Dinitro-Alkyl-Phenols. Each of the dinitro-alkyl-phenols was characterized by three derivatives, the piperidine salt, the cyclohexyl-amine salt, and the morpholine salt. The preparation of the piperidine salt of DNOC: Dinitro-ortho-cresol (1/2 gram) was placed i n a 25 ml. erlenmeyer and approximately 3/4 gram of piperidine was added. About -24-10 mis. of benzene was then added and the mixture was gently warmed for five minutes. The mixture was cooled and approximately 25 mis. of petroleum ether (30-60) was added. Small colored flakes appeared immediately. The precipitate was fil t e r e d and washed with petroleum ether. The precipitate was recrystallized from a three-solvent solution made up of five parts benzene, one part ethanol and two parts petroleum ether. A l l the salt derivatives of the dinitro-alkyl-phenols, including the cyclohexyl-amine salts and the morpholine salts were prepared by the above procedure. The salts of the 2:4 dinitro-6-alkyl-phenols were recrystallized from a three-solvent solution made up of five parts benzene, one part ethanol and two parts petroleum ether (30-60). The salts of the 2:6 dinitro-4-alkyl-phenols were recrystallized from a two-solvent solution made up of five parts benzene and one part petroleum ether (30-60). The melting points and description of the piperidine, morpholine, and cyclohexyl-amine salts are recorded i n tables IX, X, XI respectively. r25r TABLE VTII PHYSICAL CONSTANTS OF DINITRO-ALKYL-PHENOLS DINITRO-ALKYL-PHENOL BOILING POINT °C/mm. MELTING POINT °C Obs. L i t . YIELD o-methyl- Given o-ethyl- 130/0.5 36 mm 642 o-propyl- 120/0.05 - m* 712 o-isopropyl- 130/0.1 54 - 662 o-butyl- 136/0.05 - - 672 o-isobutyl- 130/0.1 - - 662 o-sec-butyl- Given o-tert-butyl- 120 122 802 o-amyl- 145/0.1 - - 602 o-isoamyl- 135/0.06 - - 572 o-hexyl- 155/0.05 - - 602 o-heptyl- 191/0.4 - - 602 o-octyl- 190/0.4 - - 512 p-methyl- 135/0.1 82 83 602 p-ethyl- 140/0.25 36 - 602 p-propyl- 121/0.03 41 - 502 p-isopropyl- 130/0.2 68 - 652 p-butyl- 152/0.1 47 - 582 p-isobutyl- 121/0.03 - mm 552 p-sec-butyl- 122/0.03 - mm 602 p-tert-butyl- 123/0.05 95 96 802 p-amyl- 156/0.1 - - 612 p-isoamyl- 163/0.3 - - 552 p-tert-amyl- 133/0.05 66 67 502 p-hexyl- 160/0.07 - - 492 p-heptyl- 148/0.02 - - 522 p-octyl- 156/0.02 - - 452 TABLE IX PIPERIDINE SALTS OF DINITRO-ALKYI.**PHENOLS DINITRO-ALKYL-PHENOL MELTING POINT of SALT °G. DESCRIPTION OF CRYSTALLINE SALT o-methyl 157 Small yellow needles o-ethyl 214 Yellow, finely divided o-propyl 186 Yellow flakes o-isopropyl 204 Small yellow needles o-butyl 148 Yellow, finely divided o-isobutyl .187 Yellow needles o-sec-butyl 154 Yellow, finely divided o-tert-butyl 219 Orange, finely divided o-aroyl 138 Yellow needles o-isoamyl 167 Yellow flakes o-hexyl 123 Yellow, finely divided o-heptyl 121 Yellow, finely divided o-octyl 125 Yellow, finely divided p-methyl 195 Small orange needles p-ethyl 234 Orange, finely divided p-prop^rl 193 Small orange flakes p-isopropyl 218 Small orange flakes p-butyl 140 Orange needles p-isobutyl 189 Orange flakes p-sec-butyl 211 Yellow, finely divided p-tert-btityl 232 Orange, finely divided p-arayl 137 Small orange needles p-isoamyl 176 Small orange flakes p-tert-amyl 198 Small orange flakes p-hexyl 154 Large orange flakes p-heptyl 157 Large orange flakes p-octyl 141 Large orange flakes -27-TABLE X MORPHOLINE SALTS OF DINITRO-ALKYL-PHENOLS DINITRO-ALKYL-PHENOL r MELTING POINT of SALT °C. DESCRIPTION OF CRYSTALLINE SALT o-methyl 189 Small red flakes o-ethyl 192 Small orange needles o-propyl 167 Red, f i n e l y divided o-isopropyl 204 Long orange needles o-butyl 169 Large orange flakes o-isobutyl 168 Yellow needles o-sec-butyl 147 Red needles o- t e r t - b u t y l 203 Red needles o-amyl 159 Orange flake s o-isoamyl 190 Orange flake s o-hexyl 155 Orange red flakes o-heptyl 146 Orange flake s o-Qctyl 147 Orange, f i n e l y divided p-methyl 201 Yellow needles p-ethyl 217 Orange flakes p-propyl 165 Yellow, f i n e l y divided p-isopropyl 216 Yellow f l a k e s p-butyl 135 Orange needles p- i s o b u t y l 164 Yellow needles p-sec-butyl 191 Yellow, f i n e l y divided p - t e r t - b u t y l 232 Yellow needles p-amyl 13? Orange flakes p-isoamyl 169 Small orange needles p-tert-amyl 174 Yellow flak e s p-hexyl 150 Orange flakes p-heptyl 148 Yellow, f i n e l y divided p-octyl 135 Yellow flakes -28-T ABLE XI CYCLOHEXYL-AMI NE SALTS OF DINITRO-ALKYL-PHENOLS DINITRO-ALKYL-PHENOL MELTING POINT of SALT°C. DESCRIPTION OF CRYSTALLINE SALT o-methyl 171 Yellow, finely divided o-ethyl 176 Yellow, finely divided o-propyl 185 Yellow, finely divided o-lsopropyl 207 Yellow, finely divided o-btityl 175 Large yellow flakes o-isobutyl 193 Yellow, finely divided o-sec-butyl 210 Yellow, finely divided o-tert-butyl 203 Small orange needles o-amyl 164 Yellow flakes o-isoamyl 188 Yellow flakes o-hexyl 176 Yellow, finely divided o-heptyl 175 large orange flakes o-octyl 158 Small yellow flakes p-methyl 193 Small orange needles p-ethyl 190 Small orange needles p-propyl 178 Small orange needles p-isopropyl 213 Small orange needles p-butyl 148 Orange, finely divided p-isobutyl 192 Small orange needles p-seo-butyl 204 Yellow, finely divided p-tert-butyl 230 Small orange needles p-amyl 154 Yellow, finely divided p-isoamyl 185 Long orange needles p-tert-amyl 219 Small yellow needles p-hexyl 135 Yellow, finely divided p-heptyl 125 Yellow, finely divided p-octyl 120 Orange, finely divided -29-INVESTIGATION OF U.S. PATENT 2.385-719. This patent describes a method of preparing amine salts of nitrated phenolic compounds. These salts were prepared by mixing together an aqueous solution of the a l k a l i salt of the nitrated phenolic compound and an aqueous solution of the inorganic salt of the amine. A comparison of some of the salts mentioned i n this patent with the corresponding salts mentioned i n this thesis i s given i n table XII. TABLE XII A COMPARISON OF PATENT AND THESIS MINE SALTS PIPERIDINE SALT of PATENT THESIS DINITRO-ALKYL-PHENOL M.P. °C. COLOR, M.P. °C, COLOR o-raethyl 140 brown 157 yellow p-tert-butyl 112 yellow 232 orange p-tert-amyl 128 brown 198 orange MORPHOLINE SALT of DINITRO-ALKYL-PHENOL o-methyl 155 red 189 red p-tert-butyl 137 yeilow 232 yellow p-tert-amyl 136 yellow 174 yellow An attempt was made to prepare the above salts by the procedure mentioned i n the patent. The sodium salt of dinitro-ortho-cresol (2.2 grams) was dissolved in 80 mis. of cold water. To this solution was added, with constant sti r r i n g , a solution of 1.6 grams of morpholine-hydrochloride i n 80 mis. of cold water. An orange precipitate settled out of the orange solu-tion. The melting point range of this solid was 168-178°. On close inspection the solid appeared to be made up of a yellow compound and a red compound. -30-The orange precipitate was then recrystallized from a large volume of water. On cooling a yellow precipitate formed. The precipitate was fil t e r e d and the orange solution was boiled down to a smaller volume and cooled. Long red needle crystals settled out. The melting point of the yellow precipitate was the same as the melting point of dinitro-ortho-cresol. When a mixed melting point was carried out with the yellow precipitate and dinitro-ortho-cresol no depression of the melting point of dinitro-ortho-cresol was observed. The melting point of the red crystals was the same as the melting point of the morpholine salt of dinitro-ortho-cresol listed i n table X. When a mixed melting point was carried out with the red crystals and the morpholine salt of the dinitro-ortho-cresol no depression of the melting point of the morpholine salt was observed. It was assumed that the morpholine salt mentioned i n the patent was i n r e a l i t y a mixture of dinitro-ortho-cresol and the morpholine salt of dinitro-ortho-cresol. Various mixtures of the dinitro-ortho-cresol and the morpholine salt of dinitro-ortho-cresol were prepared and the melting points ranged from 150° to 178°. -31-IY. The Preparation of Alkyl-Phenols by Miscellaneous Methods. 1. The Preparation of Para-Tert.-Butyl and Para-Tert.-Amyl Phenols. 35 A. Preparation of tert.-butyl and tert.-amyl chlorides: Tertiary-butyl alcohol (200 grams) was shaken for twenty minutes in a 2 - l i t r e separatory funnel with 650 mis. of con-centrated hydrochloric acid. Two layers were formed. The top layer was separated from the lower layer and washed with a weak solution of sodium bicarbonate, and then with cold water. (Specific gravity of tert.-butyl chloride 0.851/25°.) The crude chloride was dried over magnesium sulfate and i t was then purified by d i s t i l l i n g through an eighteen inch Vigreaux column. The boiling point of tertiary-butyl o 35 chloride was 51 and the yield was ninety-five percent. The reported boiling point was 51°. Tertiary-amyl chloride was prepared i n a similar manner. The boiling point of tertiary-amyl chloride was 86° and the yield was eighty percent. The reported-^ 5 boiling point was 86 . B. Preparation of para-tert.-butyl and para-tert.-amyl phenols: Phenol (103 grams) was added to 100 grams of tertiary-butyl chloride i n a 1-litre flask. Approximately 5 grams of aluminum chloride were added. The mixture was gently heated. Hydrogen chloride gas was given off. The mixture was allowed to stand for sixteen hours. The solid product that formed during this time was f i l t e r e d and washed with cold water. The product was purified by d i s t i l l a t i o n . Para-tertiary-amyl-phenol was prepared i n a similar manner. The physical constants for para-tertiary-butyl-phenol and para-tertiary-amyl-phenol are recorded i n table XIII. -32-TABLE XIII PHYSICAL CONSTANTS of P-TERT-BUTYL and P-TERT-AMYL PHENOLS PHENOL BOILING POINT °C. MELTING POINT °C. YIELD 3:5 DINITRO BENZOATE MELTING POINT Obs. L i t . Obs. L i t . &C. p-tert-butyl- 227-30 237 97 97 10% 158 p-tert-amyl- 240-50 266 92 92 60% 139 2. The Preparation of Para-Secondary-Butyl-Phenol. A. Preparation of secondary-butyl chloride: -^ A mixture of 184 mis. of secondary-butyl alcohol, 544 grams of zinc chloride (anhydrous) and 320 grams of concentrated hydro-chloric acid was refluxed for two hours. The crude chloride was d i s t i l l e d from the reaction mixture. The chloride was washed with a five percent sodium bicarbonate solution followed by cold water and then i t was r e d i s t i l l e d . The boiling point was 67-69° and the yield o 35 was seventy percent. The reported boiling point was 67-69 • B. Preparation of Para-secondary-butyl-phenol: Phenol (62 grams) was added to 60 grams of secondary butyl chloride. Approximately 10 grams of aluminum chloride were added and the mixture was refluxed for three hours. The mixture was cooled and the product was washed with cold water. The product was d i s t i l l e d . No para-secondary-butyl-phenol had formed. Twenty percent of the chloride and f i f t y percent of the phenol were recovered. Using the above specified conditions para-secondary-butyl-phenol could not be prepared. A second attempt to prepare the above phenol was made using hydrogen fluoride. A mixture of 74 grams of secondary-butyl alcohol and 120 grams of phenol was slowly added with constant stirring to 160 grams of anhydrous hydrogen fluoride cooled to 0°. After the addition, which took one-half hour, the mixture was brought to room temperature so that the hydrogen fluoride could evaporate. After the hydrogen fluoride was removed the product was washed with water and distilled. Only phenol was recovered. It was thought that conditions were not drastic enough so another run with hydrogen fluoride was made. This time the temperature of the hydrogen fluoride during the addition was 10°. After the addition the mixture was heated on a steam bath until the hydrogen fluoride had evaporated. The product was washed with cold water and distilled. The para-secondary-butyl-phenol boiled at 235-250°, and the refractive index was 1.5134 at 25°. The yield was thirty-five percent. The 30 o reported constants were boiling point 236 and refractive index 1.5182. It was thought that the hydrogen fluoride method would be more successful i f the reaction could be carried out in a pressure vessel in order to reach a higher temperature. 27 A third method was then tried in order to prepare the para-secondary-butyl-phenol. A mixture of 57 grams of. phenol and 100 grams of zinc chloride was placed in a 3-necked flask fitted with a stirrer, reflux condenser, graduated dropping funnel and thermometer. After the temperature of the mixture was brought to 120° a mixture of 9.4 grams of concentrated hydrochloric acid and 23.5 grams of n-butyl alcohol was added over a period of one hour. During the addition the mixture was vigorously stirred. The temperature of the reaction was raised to approxi-mately 130° and a mixture of 9.4 grams of hydrochloric acid and 71 grams of n-butyl alcohol was added with vigorous stirring over a period of six hours. After this addition the mixture was refluxed for three hours. -34-The mixture was cooled and the o i l y product was washed with cold water and i t was then d i s t i l l e d . The boiling point was 238-246° at atmos-pheric pressure. The refractive index was 1.5114 and the yield was f i f t y percent. 3. The Preparation of Ortho-Tertiary-Butyl-Phenol. The f i r s t step i n the preparation of ortho-tertiary-butyl-phenol was the preparation of para-bromo-phenol. With the para position to the hydroxyl group now blocked a Friedel and Craft type reaction and condensation type reactions were tried i n order to obtain a tertiary-butyl group i n the ortho position to the hydroxyl group. After this was accomplished, the next step was the removal of the bromine from the benzene nucleous to give ortho-tertiary-butyl-phenol. A. Preparation of para-bromo-phenol: Phenol (200 grams) and 200 mis. of carbon disulphide were placed i n a 3-necked 1-litre flask f i t t e d with a reflux condenser, stirr e r and thermometer. The contents of the flask were cooled to approximately 4°» A mixture of 109 mis. of bromine and 100 mis. of carbon disulphide was added with constant s t i r r i n g to the mixture i n the flask. After the addition, which took two hours, the mixture was refluxed for one-half hour. The carbon disulphide was then d i s t i l l e d off and the product was vacuum d i s t i l l e d . The boiling point was 95° at 3 mm. The yield was seventy-five percent. The phenoxy-acetic acid derivative melted at 163°. The reported boiling point was 145-150° at 20-30 mm. and the melting point of the phenoxy-acetic acid derivative was 159°. 35 B. Preparation of ortho-tertiary-butyl-para-bromo-phenol: ( i ) . The aluminum chloride method: Tertiary-butyl chloride (48 grams) was added to 88 grams of para-bromo-phenol. The mixture was heated -35-slightly and approximately 5 grams of aluminum chloride were added to i t . The mixture was maintained at a temperature of 50° for four hours. The mixture was then cooled. The product was washed with water, dried and d i s t i l l e d . Some of the tertiary-butyl chloride and most of the para-bromo-phenol were recovered. It was assumed that ortho-tertiary-butyl-para-bromo-phenol could not be prepared by the above method. ( i i ) . The hydrogen fluoride method: Anhydrous hydrofluoric acid (90 grams) was placed i n a copper beaker. A mixture of 38 grams of tertiary-butyl alcohol and 90 grams of para-bromo-phenol was slowly added to the hydrogen fluoride. During the addition the temperature was main-tained at 5°. The mixture was brought to room temperature and allowed to stand over-night. The product was a tar. No attempt was made to d i s t i l l the tar. The reaction was considered a fai l u r e . 15 ( i i i ) . The Hart Reaction: 35 (a). Preparation of isobutylene: A mixture of 200 mis. of con-centrated sulfuric acid and 400 mis. of water was placed i n a 1-l i t r e flask. Tertiary-butyl alcohol, (177 mis) was added dropwise. The isobutylene was d i s t i l l e d off as i t formed and i t was collected i n an open tube which was immersed in a bath of acetone and dry ice. The crude product was red i s t i l l e d by placing i t i n a flask which was held at room temperature and which was connected to a receiver flask immersed i n a cold bath consisting of dry ice and acetone. (b). Preparation of ortho-tertiary-butyl-p-bromo-phenol: A mixture of 170 grams of para-bromo-phenol, 290 mis. of benzene and 5.8 mis. of concentrated sulfuric acid was placed -36-i n a 1-litre 3-necked flask f i t t e d with a s t i r r e r , Claisen adapter, which held the thermometer, and reflux condenser, and a ; sintered glass gas jet for the introduction of the isobutylene. The mixture was heated to 65° and was vigorously stirred. The isobutylene was then introduced through the scintered glass gas jet which was well below the surface of the l i q u i d . The addition took five hours and during this time the solution turned a dark redish color. The solution was cooled and the acid layer was removed. The benzene layer was washed with cold water four times and i t was then dried over magnesium sulfate. The solvent was removed and the product was o vacuum d i s t i l l e d . The boiling point was 109-116 at 2.6 mm. The phenoxy-acetic acid derivative melting point was 185°. The reported 15 o constants were boiling point 123-31 and the phenoxy-acetic acid derivative melting point 183-184°. C. Preparation of ortho-tertiary-butyl-phenol: A mixture of 80 grams of para-bromo-ortho-tertiary-butyl-phenol, 240 grams of Raney nickel alloy, and400 mis. of ninety-five percent ethyl alcohol was placed i n a 5-litre flask f i t t e d with a reflux condenser an..a graduated dropping funnel. To this mixture 2400 mis. of ten percent sodium hydroxide were added over a period of two hours. After the addition the mixture was refluxed for one hour. The mixture was then f i l t e r e d while hot. The f i l t r a t e was cooled and neutralized with concentrated hydrochloric acid. A yellow o i l appeared on top of the f i l t r a t e . The f i l t r a t e was then extracted with benzene. The benzene layer was washed with cold water and dried over magnesium sulfate. The solvent was d i s t i l l e d off and the product was d i s t i l l e d . The boiling point of the ortho-tertiary-butyl-phenol was 209-213° at atmospheric pressure. The refractive index was 1.5168 at -37-25°. The phenoxy-acetic acid derivative melting point was 147° . The reported constants^ were boiling point 217-220° at atmospheric pressure, refractive index 1.5160 at 20°, and the phenoxy-acetic acid derivative melting point 145-146°. 4. Attempted Preparation of Ortho-Tertiary-Amyl-Phenol. An attempt was made to prepare ortho-tertiary-amyl-phenol using the Hart procedure. A. Preparation of isoamylene: A mixture of 300 mis. of concentrated sulfuric acid and 600 mis. of water was placed i n a 2-li t r e flask f i t t e d with a d i s t i l l a t i o n condenser and a dropping funnel. To this mixture 200 mis. of tertiary-amyl alcohol was added dropwise. The isoamylene was d i s t i l l e d off as i t formed. The isoamylene was purified by r e d i s t i l l a -tion. The boiling point was 38°. Reported boiling point"^ was 38.5°. B. Preparation of ortho-tertiary-amyl-para-bromo-phenol: A mixture of 370 mis. of benzene, 180 grams of para-bromo-phenol and 6 mis. of concentrated sulfuric acid was placed i n a 2-lit r e 3-necked flask f i t t e d with a st i r r e r , a reflux condenser and a dropping funnel. This mixture was stirred and heated to 65°. Iso-amylene (90 grams) was then added over a period of three hours. After the addition the mixture was cooled and washed with cold water to remove the sulfuric acid. The solvent was removed and the product was d i s t i l l e d . The product proved to be recovered para-bromo-phenol. The reaction apparently was not successful. A second attempt was made using 85 grams of para-bromo-phenol, 200 mis. of benzene, 3 mis. of concentrated sulfuric acid and 45 grams of isoamylene. The isoamylene was added as a gas below the surface of the liquid. The temperature of the reaction mixture was raised to approxi--38-mately 80°. The addition of the isoamylene took four hours. The mixture was then cooled and washed with cold water. The solvent was removed and the product was d i s t i l l e d . Only para-bromo-phenol was recovered. It was assumed that ortho-tertiary-amyl-para-bromo-phenol could not be prepared by the Hart procedure as described above. COMPARISON OF ALKYL-PHENOLS PREPARED BY THE GRIGNARD AND FRIES METHODS. As previously shown the ortho and para isobutyl and isoamyl phenols have been prepared by the Fries method. These phenols were also prepared by the Grignard method as part of an undergraduate research project. (A description of the Grignard reaction as used for the preparation of alkyl-phenols may be found i n the following section.) A comparison of the results using both methods i s recorded i n table XIV. The phenols from both methods were nitrated and the three amine salt derivatives were prepared for each dinitro-alkyl-phenol. A comparison of the results obtained i s recorded i n table XV. There i s practically no chance of rearrangement occurring during the preparation of the isobutyl and isoamyl phenols by the Grignard method. The possi b i l i t y of rearrangements occurring during the pre-paration of these phenols by the Fries method always exists. The comparison of the melting points of the amine salts shown i n table XV shows that for the above phenols prepared by the Fries method no rearrangement occurred. Thus, i t may be assumed that no rearrangement occurred during the preparation of the other phenols made by the Fries method using the same experimental conditions. -39-TABLE XIV COMPARISON OF ALKYL-PHENOLS  made by FRIES REARRANGEMENT AND GRIGNARD METHODS ALKYL-PHENOL BOILING POINT REFRACTIVE INDEX o-isobutyl-p-isobutyl-o-isoamyl-p-isoamyl-Fries 62/0.7 81.2/0.7 88/1.8 102.5/1.5 Grig. 101/10 110/10 110-12/10 125-7/8 Fries 25" 1.5170 MP* 52° 1.5121 1.5100 Grig. 18 U 1.5199 1.5104 1.5110 1.5011 TABLE XV COMPARISON OF DERIVATIVES OF THE  DINITRO-ALKYL-PHENOLS made by  FRIES REARRANGEMENT and GRIGNARD METHODS DINITRO- MELTING POINT MELTING POINT MELTING POINT ALKYL-PHENOL °C °C °C MORPHOLINE SALT CYCLOHEXYLi 4MINE SALT PIPERID: [NE SALT Fries Grig. Fries Grig. Fries Grig. o-isobutyl- 168 168 193 193 187 188 p-isobutyl- 164 164 192 192 189 189 0-isoamyl- 190 190 188 188 167 168 p-isoamyl- 169 169 185 184 176 176 -40-A CHECK ON THE PHYSICAL CONSTANTS OF THE INTEPJ»E)IATE COMPOUNDS  PREPARED DURING THE SYNTHESIS OF ORTHO AND PARA ISOBUTYL  AND ISOAMYL PHENOLS USING THE GRIGNARD METHOD. Some of the intermediate compounds prepared during the synthesis of ortho and para isobutyl and isoamyl phenols were tested with quantita-tive 2:4 dinitro-phenylhydrazine reagent. The compounds were found to be contaminated with the aldehydic starting material. I t was thought that there was enough contamination to affect the boiling point and refractive index and that a recheck should be made. The above compounds were prepared as part of an undergraduate research project. A Grignard reaction was carried out i n the normal fashion using equimolecular amounts of benzaldehyde, isopropyl bromide and magnesium. The f i n a l product contained benzaldehyde. It was found that washing with sodium b i s u l f i t e did not take out a l l the benzaldehyde. Further experiments were tried i n which the ratio of alkyl bromide and magnesium to the aldehyde was varied. It was found that to every mole of aromatic aldehyde used two moles of magnesium and alkyl bromide had to be used i n order to give a product free from aldehyde. A typical example i s given in the following section. I. The Preparation of Para-Methoxy-Phenyl-Isopropyl-Carbinol: Magnesium turnings (12 grams) were placed i n a 3-necked flask f i t t e d with a s t i r r e r , a reflux condenser and a dropping funnel. A mixture of 200 mis. of dry ether and 44 mis. of isopropyl bromide was slowly added over a period of twenty minutes. After the addition of the bromide, 200 mis. of dry ether were added to the flask and the contents were refluxed with s t i r r i n g for twenty minutes. The mixture was cooled to 0° and a mixture of 25 grams of para-anisaldehyde and 250 mis. of dry ether was added with vigorous sti r r i n g over a period of thirty minutes. Dry ether (100 mis.) was then added and the mixture was stirred and refluxed for five hours. The mixture was then cooled - A l -and slowly poured into a large beaker containing ice, water and solid ammonium chloride. The ether layer was separated and washed several times with cold water and then i t was dried over magnesium sulfate. The ether was d i s t i l l e d off and the product was tested with quantitative 2:4 dinitro-phenylhydrazine reagent. No anisaldehyde was present. The product was then vacuum d i s t i l l e d . The carbinol product appeared to be partially unstable during the d i s t i l l a t i o n as partial dehydration occurred. The f i r s t fraction contained the dehydrated compound, the middle fraction contained both carbinol and unsaturated compound, and the last fraction contained relatively pure carbinol. The boiling point of para-methoxy-phenyl-isopropyl-carbinol was 105° at 0.6 mm. The refractive index was 1.5220 at 22°. A methoxyl determination was made and i t was found that the percent-age methoxyl was 17.4 percent. The theoretical value was 17.2 percent. I I . The Preparation of Para-Methoxy-Phenyl-Isobutene-1: The para-raethoxy-phenyl-isopropyl-carbinol which had part i a l l y dehydrated was r e d i s t i l l e d . The constants for the para-methoxy-phenyl-isobutene-1 were boiling point 80° at 1 mm. and refractive index 1.5462 at 23°. The reported constant2*"5 for the boiling point was 118° at 15 mm. A methoxyl determination was carried out on the compound and i t was found that the percentage methoxyl was 19.0 percent. The theoretical value was 19.1 percent. II I . The Preparation of Para-Methoxyl-Isobutylr»Benzene: The para-methoxy'-phenyl-isobutene-1 was hydrogenated using ethanol as a solvent and Raney nickel as a catalyst. The boiling point for the para-methoxy-isobutyl-bezene was 70° at 0.8 mm. and the o 9 refractive index was 1.5077 at 21 . The reported constants were boiling -42-point 123° at 15 mm. and refractive index 1.4980 at 25°. A methoxyl determination was carried out on the para-methoxy isobutyl-benzene and i t was found that the percentage methoxyl was 18.9 percent. The theoretical value was 19.0 percent. IV. The Preparation of Ortho-Methoxy-Phenyl-Isopropyl-Carbinol: The preparation was the same as that mentioned i n the preparation of para-methoxy-isopropyl-carbinol except that ortho-anisaldehyde was used i n place of para-anisaldehyde. The ortho-methoxy-phenyl-isopropyl-carbinol was stable to d i s t i l l a t i o n . The boiling point of the ortho-methoxy-phenyl-isopropyl-carbinol was 105° at 1.7 mm. and o 20 the refractive index was 1.5201 at 20 . The reported constants were o boiling point 109 at 14 mm. and the refractive index 1.545 at 17 . It was f e l t that the reported refractive index was incorrect. A methoxyl determination on the carbinol was carried out and i t was found that the percentage methoxyl was 17.2 percent. The theoretical value was 17.2 percent. The phenyl-urethane derivative was made of the carbinol. The melting point was 148°. A methoxyl determination of the urethane derivative was carried out and the percentage methoxyl was found to be 10.4 percent. The theoretical value was 10.4 percent. V. The Preparation of Para-Methoxy-Phenyl-Isobutyl-Carbinolt Para-methoxy-isobutyl-carbinol was prepared i n a similar manner as previously described. The compounds used were para-anis-aldehyde, magnesium turnings, and isobutyl bromide. Some of the para-methoxy-isobutyl-carbinol dehydrated during the d i s t i l l a t i o n . The boiling point of para-methoxy-isobutyl-carbinol was 95° at 0.1 mm. and the refractive index was 1.5203 at 21°. A methoxyl determination was carried out and the percentage methoxyl - 4 3 -was found to be 16.2 percent. The theoretical value was 16.0 percent. VI. The Preparation of Para-Methoxy-Phenyl-Isoamylene-1: The f i r s t fraction obtained during the d i s t i l l a t i o n of the para-methoxy-phenyl-isobutyl-carbinol was placed i n a Dean and Stark apparatus to ensure complete dehydration. The unsaturated compound was vacuum d i s t i l l e d . The boiling point of para-methoxy-phenyl-isoaraylene-1 was 75° at 0.1 mm. and the refractive index was 1.5472 at 20°. A methoxyl determination was carried out and the percentage methoxyl was found to be 17.5 percent. The theoretical value was 17.6 percent. VII. The Preparation of Para-Methoxy-Isoamyl-Benzene: The para-methoxy-phenyl-lsoamylene-l was hydrogenated in a similar method as previously described. The boiling point of para-methoxy-isoarayl-benzene was 87° at 1.2 mm. and the refractive 20 index was 1.5040 at 23°. The reported constants were boiling point 120° at 11 mm. and refractive index 1.4995 at 22°. A methoxyl determination was carried out and the percentage methoxyl was found to be 17.5 percent. The theoretical value was 17.5 percent. VIII. The Preparation of Ortho-Methoxy-Phenyl-Isoamyl-Carbinol: A Grignard reaction was carried out i n a manner similar to that previously described. The compounds used were ortho anis-aldehyde, magnesium turnings and isobutyl bromide. The resulting carbinol was a white solid. It was recrystallized from a mixture of petroleum ether (30-60) and benzene. The melting point was 73°. A methoxyl determination was carried out and the percentage methoxyl was found to be 16.0 percent. The theoretical value was 16.0 percent. The phenyl-urethane derivative was prepared and the melting point was 107°. - 4 4 -THE PREPARATION OF ORTHO-METHOXY-ACETOPHENONE. Ortho-methoxy-acetophenone Is the starting material used i n the synthesis of ortho-secondary-amyl and hexyl phenols by the Grignard method. This compound was prepared by methylating ortho-hydroxy-acetophenone which was made from the Fries isomerization of phenyl-acetate. Ortho-hydroxy-acetophenone (50 grams) was dissolved i n 200 mis. of ethanol i n a 2 - l i t r e round bottom flask f i t t e d with a mechanical stirr e r and a graduated dropping funnel. To this solution was added a mixture of 32 grams of sodium hydroxide and 400 grams of ethanol. The temperature of the contents In the flask was raised to 50° and 104 grams of dimethyl sulfate was slowly added with vigorous s t i r r i n g . The temperature was kept at 50° during the addition. After the addition of the dimethyl sulfate the mixture was stirred and refluxed for twenty hours. During this time the mixture turned a dark brown color. After twenty hours, the mixture was par t i a l l y cooled and then the ethanol was d i s t i l l e d off. The mixture was alkaline. No o i l y layer separated upon cooling which indicated that methylation had not taken place. The mixture was acidified and extracted several times with benzene. Ortho-hydroxy-acetophenone (42 grams) was recovered. The methylation was unsuccessful and another attempt was made. Ortho-hydroxy-acetophenone (100 grams) was dissolved i n a solution of 35 grams of sodium hydroxide and 300 grams of water in a 500 -ml. erlenmeyer. Dimethyl sulfate (126 grams) was added at such a rate o that the temperature of the mixture never went above 50 . After the addition was completed the mixture was allowed to stand for one-half hour. A yellow o i l y layer formed on top of the alkaline solution. -45-The o i l y layer was separated, washed repeatedly with water and vacuum d i s t i l l e d . The boiling point of the ortho-methoxy-acetophenone was 95° at 2 mm. The semi-carbazone derivative was prepared and the 35 melting point was 184°. The reported constants were boiling point 245° at atmospheric pressure and melting point of semi-carbazone derivative 183°. The remaining alkaline solution was acidified and approximately 40 grams of unreacted ortho-hydroxy-acetophenone was recovered. Although the reaction yielded only f i f t y percent of the methylated compound i t was s t i l l of use as most of the unreacted compound could be recovered. -46-DISCUSSION The Fries rearrangement of the esters was found to give satis-factory results. The resulting ortho and para hydroxy-ketones were easily separated because the ortho homologues boiled at • much lower temperatures'than the para homologues. This was probably due to hydrogen bondage between the hydroxy and ketone groups. For the ortho homologues the bondage would be intramolecular and for the para homologues the bondage would be intermolecular. A derivative of ortho-hydroxy-isobutyrophenone could not be made although a derivative was prepared for ortho-hydroxy-valero-phenone. The only explanation offered is that the methyl groups on the end of the alkyl chain of ortho-hydroxy-isobutyrophenone may have offered steric hindrance to the ketone group. In the case of the ortho-hydroxy-valerophenone the methyl groups are more removed from the ketone group. The ortho-hydroxy-ketones were a l l d i s t i l l e d under the same amount of vacuum. For a plot of boiling point versus the length of the alkyl side chain see Graph No. I l l following page 47. A similar plot for the refractive index may be found i n Graph No. TV following page 47. A f a i r l y good correlation was noted between the length of the alkyl side chain and the boiling point and also between the length of the alkyl side chain and the refractive index. The best results for the Clemmensen reduction of the hydroxy-ketones were obtained using glacial acetic acid. The glacial acetic acid was probably a better solvent for the ketones than the water. The preparation of ortho-tertiary-amyl-phenol by the Hart reaction using benzene and sulfuric acid was not successful. I t i s thought that this alkyl-phenol may be made by the Hart reaction i f toluene or -47-xylene were used as the solvent and phosphoric acid used as the catalyst. Time did not permit this investigation. The preparation of the ortho-tertiary-alkyl-phenols has been found to be d i f f i c u l t . It may be possible to prepare the dinitro-ortho-tertiary-alkyl-phenol without having to make the ortho-tertiary-alkyl-phenol * i f the following procedure were to be carried through. (i) Alkylation of para-nitro-anisole with tertiary alcohol using hydrofluoric acid as catalyst to give ortho-tertiary-alkyl-para-nitro-anisole. ( i i ) Demethylation of the above compound using constant boiling hydrobromic acid and glacial acetic acid to give ortho-tertiary-alkyl-para-nitro-phenol. ( i i i ) Nitration of mononitro-phenol to give the desired dinitro-tertiary-alkyl-phenol. The ortho-methoxy-phenyl-isopropyl-carbinol and the ortho-methoxy-phenyl-Isobutyl-carbinol were stable to d i s t i l l a t i o n but the para-methoxy homologues were not. I t i s thought that the intramolecular bondage in the ortho-methoxy homologues was responsible for their greater s t a b i l i t y to heat. The dinitro-alkyl-phenols and their amine salts should be handled with care as these compounds have been shown to be injurious to one's health. Fig. u. Refractive Index of o-Hydroxyketones Number of carbon atoms in alkyl group R. -48-BIBLIOGRAPHY 1. Adams R., "Organic Reactions", Volume I, John Wiley & Sons Inc., New York (1942). 2. Archer S., Simons J., Passino H., " J . Amer. Chem. Soc", 60, 2956 (1938). 3. Baddeley G., " J . Chem. Soc", 330 (1944). 4. Baroni £., KLeinau W., "Monatsh% 68, 251 (1936)j C.A., 30, 7554 (1936). 5. Bartz Q., Adams R., Miller R., " J . Amer. Chem. Soc", 57, 371 (1935). 6. Blackman G., " J . Royal Soc. Arts", XCVIII, 500 (1950). 7. Bousquet A., "Ind. Eng. Chem.", 27, 1342 (1935). 8. Bovingdon H., Grove J., "Ann. App. Biology", 34, 113 (1947). 9. Brazidec Le, " B u l l . Soc. Chim.", 31, 263 (1922). 10. Coleman G. H., Griess G., U.S. Patent 2,365,056 (1943). 11. Coulthard C , Marshall J., Pyman F., " J . Chem. Soc", 280 (1930). 12. Dohme A. R., Cox E. H., Miller E., " J . Amer. Chem. Soc", 48, 1689 (1926). 13. Farenholt L., Harden W., Twiss D., " J . Amer. Chem. Soc", 55, 3383 (1933). 14. Harden W., Rice R., " J . Amer. Pharm. Assoc.", 24, 7 (1936). 15. Hart H., " J . Amer. Chem. Soc", 71, 1966 (1949). 16. Ipatieff I., Pines H., Friedman S., " J . Amer. Chem. Soc", 60, 2495 (1938). 17. Johnson B., Hodge W., " J . Amer. Chem. Soc", 35, 1014 (1913). 18. Johnson B., Lane F. W., " J . Amer. Chem. Soc", 43, 348 (1921). -49-19. Kagy J. P., " J . Ec. Enit.", 34, 660 (1941). 20. Levy J., Tiffeneau M., "Bu l l . Soc. Chim.", 39, 776 (1926). 21. Martin E., " J . Amer. Chem. Soc", 58, 1438 (1936). 22. Monti I., Bianetti E., "Gazz. Chim. i t a l . " , 67, 628 (1937); C.A., 32, 4551 (1938). 23. Najarova Z., " J . Gen. Chem. (U.S.S.R.)", 8, 1336 (1938). C.A., 33, 4214 (1934). 24. Niederl J. B., Niederl V., Shapiro S., McGreal E., " J . Amer. Chem. Soc", 59, 1113 (1937). 25. Openshaw H. I., "A Laboratory Manual of Qualitative Organic Analysis", Cambridge University Press (1946). 26. Plantefol L., "Compt. rend.", CLXXIV, 123 (1922). 27. Read R., U.S. Patent 2,391,798; C.A., 40, 1972 (1946). 28. Rosenmund K., Lohfert H., "Liebig's Annalen de chemie", 56, 460 (1928); C.A., 23, 2161 (1939). 29. Sandulesco G., Girard A., "B u l l . Soc. Chim.", 47, 1300 (1930); .C.A., 25, 1228 (1931). 30. Smith R. A., " J . Amer. Chem. Soc", 55, 3718 (1933). 31. Tattersfield F., "Ann. Appl. Biology", 12, 218 (1941). 32. Templeman W., "Nature", CLV, 497 (1945). 33. Truffant G., Pastac I., French Patent 425,295. 34. Tsukervanik I., Tambovtseva V., "Bu l l . univ. Asie Central" 22, 221 (1938); C.A., 34, 4729 (1940). 35. Vogel A. I., "Practical Organic Chemistry", Logman, Green & Co., New Yor, Toronto (1948). 36. Whaley A. M., Copenhaver J. E., " J . Amer. Chem. Soc", 60, 2495 (1938). 

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