Science, Faculty of
Chemistry, Department of
DSpace
UBCV
Moffatt, John Gilbert
Master of Science - MSc
University of British Columbia
Eight new dinitro-sec.-amyl and hexylphenols of unequivocal structure were synthesized and characterized by their piperidine, morpholine and cyclohexylamine salts. The synthetic route followed involves the Fries rearrangement, of phenyl acetate and phenyl propionate to give the easily separated isomers o- and p-hydroxyacetophenone and o- and p-hydrcocypropiophenone. These compounds were then methylated to give the corresponding methoxyacetophenones and methoxypropiophenones. The methylated aryl-alkyl ketones were condensed through a Grignard reaction with various alkyl bromides to give tertiary alcohols which were dehydrated by the Dean and Stark method to the corresponding olefins and then hydrogenated to alkylanisoles. Demethylation was effected through the use of pyridine hydrobrondde for the p-alkylphenols, or 47% hydriodic acid and phenol for the o-alkylphenols. The alkyl phenols were then nitrated with fuming nitric acid in glacial acetic acid at -15⁰C., and the resulting dinitro-alkylphenols characterized as amine salts. The phenols prepared were: 3-(o- and p-hydroxyphenyl)-pentane, 2-(o- and p-hydroxyphenyl)-hexane, 2-(o- and p-hydroxyphenyl)-3-methylpentane, 2-(o- and p-hydroxyphenyl)-4-methylpentane. Of these, only 2-(p-methoxyphenyl)-3-mathylpentane has been reported prepared by an unequivocal synthesis. All other phenols, their intermediates and derivatives, and their dinitro derivatives, are previously unreported except in odd cases through questionable condensation methods.
THE SYNTHESIS OF SOME SECONDARY AMYL AND HEXYL HOMOLOGUES OF DDJITRO ORTHO AND PARA CRESOLS by JOHN GILBERT MDFFATT A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF THE -REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE IN THE DEPARTMENT OF CHEMISTRY. Me 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 July, 3953. ABSTRACT Eight new dinitro-sec.-amyl and hexylphenols of unequivocal structure were synthesized and characterized by their piperidine, morpholine and cyclohexylamine salts* The synthetic route followed involves the Fries rearrangement, of phenyl acetate and phenyl propionate to give the easily separated isomers o- and p-hydroxyacetophenone and o- and p-hydrcocypropiophenone. These compounds were then methylated to give the corresponding methoxyaceto-phenones and methoxypropiophenones. The methylated aryl-alkyl ketones were condensed through a Grignard reaction with various alkyl bromides to give tertiary alcohols which were dehydrated by the Dean and Stark method to the corresponding olefins and then hydrogenated to alkylanisoles. Demethylation was effected through the use of pyridine hydrobrondde for the p~alkylphen ols, or 47$ hydriodic acid and phenol for the o-alkylphenols. The alkyl phenols were then nitrated with fuming nitric acid in glacial acetic acid at -15°<'&-, and the resulting dinitro-alkylphenols characterized as amine salts. The phenols prepared were; 3-(o- and p-hydroxyphenyl)-pentane, 2-(o- and p-hydroxyphenyl)-hexane, 2-(o- and p-hydroxyphenyl)-3-methylpen-tane, 2-(o- and p-hydroxyphenyl)-4-methylpentane. Of these, only 2-(p-methoxyphenyl)-3-mathylpentane has been reported prepared by an unequivocal synthesis. A l l other phenols,. their intermediates and derivatives, and their dinitro derivatives, are previously unreported except in odd cases through questionable condensation methods. ACKNOWLEDGMENT Sincerest thanks is extended to my Research Director, Mr. G.G.S. Dutton, for his ever ready assistance, interest, and friendship throughout the work on this project. I should also like to express appreciation to the National Research Council and to the Standard Oil Company of British Columbia, for financial aid, and to the Sharpies Chemical Company for samples of o-sec«-amylphenol, o-fcert.-amylphenol, and p-sec.-amylphenol. TABLE OF CONTENTS. Page No. I. INTRODUCTION 1 H. HISTORICAL - . • 1. The Development of Selective Herbicides 4 2. The Relationship of Structure to Toxicity 9 3. The Preparation of n- and iso-Alkylphenols 23 4. The Preparation of Secondary Alkylphenols by Synthesis 33 5. Secondary and Tertiary Alkylphenols by Condensation Methods 45 6. The Preparation and Characterization of Dinitro Alkylphenols .... 51 HI. EXPERIMENTAL • * 1. Preparation of Phenyl Acetate (a) Sodium Phenate-Aeetic Anhydride Method ....... 53 (b) Phenol-Acetyl Chloride Method 53 2. Preparation of Phenyl Propionate 54 3. Preparation of o- and p-Hydroxyacetophenone 54 4. Preparation of o- and p-Bydroxypropiophenone 55 5. Methylation of the Bydroxy-Aceto- and Propiophenones 56 6. Preparation of Isobutyl Bromide ... 57 7. Preparation of Alkyl-Methoxyphenyl Carbinols (a) Preparation of 3-(p-Methoxyphenyl)-pentanol-3 .. 58 8. Dehydration of the Carbinols (a) Preparation of 3-(p-Methoxyphenyl)-pentene-2 ... 59 9. Hydrogenation of the Alkenes (a) Preparation of 3-(p-Methoxyphenyl)-pentane .... 60 10. Demethylation of the Alkylanisoles (a) Preparation of lyridine Bydrobromide 61 (b) Preparation of 3-(p-Hydroxyphenyl)-pentane .... 62 (c) Preparation of 2-(o-Bydroxyphenyl)-4-methylpentane (i) using pyridine hydrobromide 62 (li)using hydriodic acid and phenol 63 11. Nitration of the Alkylphenols (a) Preparation of 3-(4-Hydroxy-3;5-dinitrophenyl)-pentane 63 12. Preparation of Amine Salts' of the Dinitro-alkylphenols (a) Preparation of the Piperidine Sal$ of 3-(4-Rydroxy)-3:5-dinitrophenyl)-pentane 64 IV. DISCUSSION OF RESULTS , ... 77 V. APPENDIX 85 VI. BIBLIOGRAPHY 86 LIST OF TABLES. Page No. Table I. Physical Constants of Carbinols . 65 Table I I . Physical Constants of Alkenes.. 66 Table I I I . Nitrosyl Chlorides of Alkenes 67 Table IV. Physical Constants of Alkanes 68 Table V. Sulphonand.des of Alkanes ".. ... 69 Table VI. Physical Constants of Alkylphenols ... 70 Table VII. 3:5-Dinitrobenzoates of Alkylphenols 71 Table Vrn. Physical Constants of Iftriitro-alkylphenols. ...... 72 Table IX. Piperidine Salts of Dinitro-alkylphenols 73 Table X. Morpholine Salts of Dinitro-alkylphenols. .*'.' 74 Table XI. Cyclohexylamine Salts of Dinitro-alkylphenols .... 75 Ta^ >le XII. Compounds Previously Reported i n the Literature ... 76 LIST OF FIGURES. Figure 1. Phenol Coefficients of 4-alkylresorcinols to B. typhosus.. 12 Figure 2. Toxicity of 2-n-alkylpyridines to Red Spider... ... 15 Figure 3. Phenol Coefficients of p-alkylphenols to B. typhosus 16 Figure 4* Toxicity of 2:4-Dinitro-6-alkylphenols to Silk worm larvae ... 20 Figure 5« Toxicity of Dinitro-alkylphenols to Tricoderma viride 21 Figure 6, Toxicity of Dihitroralkylphenols to Brassica~aXba.. 22 LIST OF APPENDICES. Appendix'I. Yields i n the Fries Rearrangement of Phenyl Acetate 85 Appendix II.Results of Methylations of p-Hydroxyacetophenone... 85 Appendix III. Results of Methylations of o-Hydrocyacetophenone... 85 I. INTRODUCTION. The synthesis of a wide range of dinitro-o and p^alkylphenols has been undertaken in this laboratory during the past few years. Previously the alkylphenols prepared have a i l been those containing primary normal and isoalkyl groups. This thesis represents the first attempt to prepare phenols containing secondary alkyl groupings. Previously isopropyl and sec.«*>utyl phenols of clearly defined structure have been prepared through various condensations of phenol with the appropriate alkyl halide, alcohol or olefin, but beyond this point isomerization occurs during condensation and the exact nature of the product i s uncertain, we have, therefore, developed a synthesis for dinitro-o and p-alkylphenols i n which each step can proceed, in only one direction, giving as a final product a compound of unequivocal structure. There are two distinct reasons for the preparation of these compounds. Firstly, i t has long been known that 2s4-dinitrophenol and the dinitrocresols, especially dinitro-o-cresol or D.N.O.C., as i t is known commercially, are potent insecticides and herbicides, their particular interest lying in their selective action which allows them to destroy undesirable weeds while leaving the main crop unharmed. Button and his co-workers at both Sir John Cass College, London, and the University of British Columbia^), have extended this knowledge by preparing and testing twenty-two different dinitro-o and p-primary-alkylphenols where the alkyl group is either normal or iso and varies in length from ethyl to octyl, and also dinitro-o and p-tert.«*utyl, and dirdtro-p-tert.-amylFhenols. These investigations have shown that maximum toxicity towards several test - 2 -organisms occurs at the o-ethyl or propyl homologues (see Figures 5 and 6) and that the other members of the series are less toxic. Chain branching appears to decrease toxicity as shown by those phenols containing tertiary and isoalkyl groups. Dinitro-o-sec.^3utylphenol, - however, shows anamol-ously high toxicity in comparison with a l l others tested, and this has led to the present study of other dinitro-sec.-alkylphenols. 2s4-dinitro-6-sec.-butylphenol has become well known as a herbicide and is marketed by Dow Chemicals under the trade name "Dow General1*. None of the other sec.«*alkyl compounds' have been tested and reported. The second reason for this work involves the considerable industrial importance that alkylphenols and their derivatives have achieved during the last twenty y e a r s ^ ' ^ ' ) . Their chief use is as nondis colour ing antioxi-dants in the synthetic rubber and other industries^ 8), in which case it has been found that polyalkylphenols, especially those containing bulky tertiary groups ortho to the phenolic centre, are most•.• efficient and desirable'. Other uses which alkylphenols have found are as" intermediate s in the production of synthetic resins, as polymerization inhibitors for gasoline, paints, and varnishes, as dye intermediates, as insecticides, as photographic developers (especially in the case of p-tert.-oetylphenol), and as water-in-oil emulsion breakers. Some p-sec. and tert.-amyl and hexylphenols prepared through condensation methods have proved to be especially valuable in this latter class. Various simple derivatives of alkylphenols have also found their place in industry. Bydrogenated alkylphenols with fairly long side chains are useful as perfume bases and modifiers in lubricating o i l S < n ) . Their esters and ethers are used in plastics, paints, and waxes, and their sulphonates in detergents, emulsifying agents, textile finishing agents, and high pressure lubricants. This rather long l i s t shows the importance of alkylphenols to modern l i f e , and when i t i s realized that nearly a l l these compounds are prepared through condensations giving mixtures of products, the exact structure of which are not conclusively known, i t becomes obvious that once an extensive series of alkylphenols has been synthesized in such a way that their structures are definite, then the exact natures of these condensation products can be determined. A future project is planned at this university dealing with various phenol condensations, using the phenols prepared and characterized during the present study as reference compounds. Nearly al l the intermediates in the syntheses described, are also previously unreported, and have been characterized as well as possible through physical constants, derivatives and analyses. IT. HISTORICAL. 1« The Development of Selective Herbicides. Since man first took an economic interest in the cultivation of land, he has been faced with a retaliation by nature in the form of weeds which threaten his crops and cost him millions of dollars a year in damage and control measures. Through the years a great deal of work has gone into the development of various chemical agents which have the ability to combat the ever present weeds. Obviously, the most desirable compounds are those which may be applied to a cultivated field without damage to the desired crop, but at the same time destroying the unwanted weeds. Such compounds are described as "selective" herbicides, and many have been suggested from time to time. t The fi r s t true selective weed killer to be tested extensively was a dilute solution of copper sulphate which Bonnet discovered; in 1896. By spraying a field of oats with this solution, Bonnet found that the oats were largely unharmed, but that yellow charlock, a very troublesome weed, was killed. The significance of this work did not seem to be realized, for very l i t t l e work i s reported along these lines for some years. In 1911, however, Rabate^96) showed that as a general rule, spray-ing with dilute sulphuric acid would k i l l dicotyledonous weeds with very l i t t l e injury to the desired crop. This agent was found to be efficient against a wide range of weeds, but i t suffered from the obvious drawback of its corrosive action on equipment and the resulting difficulty in handling. There was then another lapse of achievement f o r a number of years, broken i n 1933 when Truffant and Pastac found that nitrophenols and cresols, particularly dinitro-o-cresol or D.N.O.C., as i t became known, have very definite selective actions against various cereal crop weeds^). The toxic nature of phenols and nitrophenols against insect pests had long been known, and, as early as 1868, the use of soapy water and cresylic acid was reported in the Gardener *s Monthly as being an efficient i n s e c t i -cideC116). In 1892 a German company marketed the potassium salt of 3s5-dinitro-o-cresol as a stomach poison for the housefly and louse but this did not seem to have been accepted with much acclaim^33) # j^e compound i t s e l f had been known since 1866 and had found i t s chief use as a yellow dye which was even used i n various foodstuffs u n t i l i t s toxic nature was discovered. With the discovery that certain phenols and nitrophenols possessed selective properties towards weeds as well as insects, considerable interest i n these compounds was aroused and i n i t i a l l y centred on D.N.O.C. i t s e l f . Until the middle 1930 's, the vast majority of a l l herbicides and insecticides used were those based on various arsenic compounds, most commonly acid lead arsenate (PbHAsO^ .) and arsenious oxide ( A S 2 O 3 ) . These T agents had to be handled with great caution due to t h e i r t o x i c i t y towards mammals and certain trees and plants. The very significant discovery was made by Kagy in 1936 that inorganic salts of both D.N.O.C. and 2s4«dinitro-6-cyclohexylphenol were more toxic than the most efficient arsenic sprays marketed at the t i m e t 6 2 ) . The calcium salt of D.N.O.C. was on the average four times as potent against several test organisms. With this discovery came a surge of research on the agricultural use of D.N.O.C. and dinitro-o-cyclohexylphenol. The results were promising and showed excellent control of both plant and insect pests using very dilate sprays or dusts. Cockchaffers were found to be controllable to an extent of 90$ using sprays containing only 0.2-0.5$ while they were almost impervious to arsenic preparations( 8 "0. Very similar results were shown in the control of grasshoppers^ 3 3^, blowflyC-1-3 )^, and coddling moth larvae (-^J. These compounds, however, have a tendency to damage foliage to a certain extent and so are not too suitable for use on f r u i t trees. Field crops, oh the other hand, suffer very l i t t l e damage and are highly suited to pest control with D.N.O.C. Fortunately, i t has been found that while nitrophenols are highly toxic towards insects, they" are not overly toxic to animals. Controlled experiments on rabbits and rats show that they are not appreciably i r r i t a t i n g to the skin and that rats maintained on a diet containing 0.05$ D.N.O.C., or related compounds, for six months, showed n o * i l l e f f e c t s ( ^ ) . These compounds^ however, have the undesirable property of staining everything they touch a vivid yellow or orange. » It i s interesting to note that certain dinitrophenols, especially 2j4-dinitro-6«cyclohexylphenol, 2;4-dinitro-6-hexylphenol, and their dicyclohexylamine salts, can be used as "safeners" i n arsenic sprays to minimize damage to trees and p l a n t s ^ 5 0 ) . The addition.of from 0.5-6.0 oz. of the nitrophenol to 100 gallons of the parent spray, produces this effect. * . . . . The actual application of these compounds falls into two distinct classes - as .sprays, and as .dusts. There seems to be some evidence that sprays are most effective in cold weather, and dusts i n hot weather, but both are used extensively. For sprays, i t is generally found convenient to use the simple inorganic salts of the acidic dinitropnenols as a means of increasing their solubility. Unfortunately, the ammonium salt of D.N.O.C, which is the most toxic of the salts, also has a very limited solubility in water and so the somewhat less, toxic sodium or potassium .salts are usually preferred^ 3). The use of various amine salts appears to offer a solution to this problem since the ethylamine salt of D.NiO.G.,. has the toxicity of the ammonium salt, but is many times more soluble. „. The direct suspending of nitrophenols over some carrier such as redwood bark flour( 4 1) or diatomaceous earth^ 8^, gives good control of a wide range of insects and weeds, but since most of the dinitro-alkylphenols are liquids, this procedure is rather difficult. The solution here also seems to be the use of amine, salts since these are well defined crystalline compounds and can easily be mixed homogeneously with the carrier. A further advantage of the amine salts is their greatly reduced vapour pressure and volatility as compared with the parent nitroFbenol. The toxicities- seem to be comparable, but the -toxic action of the amine salts persists long after that of the free nitrophenol^). This factor of volatility must be carefully considered .in testing any new herbicide . since some of our mast toxic agents are impractical due to. high vapour pressure. Thus 4-bromoacetophenone, which is exceptionally toxic, is found to have completely disappeared within five days of application^ 1 3 1). - 8 -Moore and QrahamC®), have studied the physical properties of efficient herbicides and insecticides by the addition of a non-toxic dye such as Trypan Blue and determination of the degree of penetration, and have concluded that, as a general rule, compounds with a viscosity greater than castor oil, or a volatility greater thanxylene, are of little use. Those soluble an chloroform and other fat solvents have the highest penetrating power. The principle of selective herbicides is admirably shown by a comparison of the actions of D.N.O.C. and of 2«4-dinitro-6-sec.-*utylphenol. The latter proves to be over four times as toxic as D.N.O.C. towards mustard ^Iri. peas, but only 0.55 times as toxic towards the peas, therefore, making it roughly eight times as selective in its action(9). It must be remembered, however, that repeated use of one chemical agent will eventually sort out resistant strains within the weed popula-tion. In this, way roadsides which have been repeatedly sprayed with oil which originally killed a l l the vegetation have appeared with new oil -resistant types of weed. Also, repeated use of 2j4-dichlorophenoxyacetic acid or 2»4D, has destroyed many dicotyledonous weeds but the resistant monocotyledenous varieties have increased in number. The only remedy for this is carefully arranged herbicide rotation. There are many aspects of the action of herbicides and insecticides which are not yet fully understood, such as the reason why certain concen-trations of growth regulating substances such as alpha-*iaphtbylacetic acid, and certain substituted phenoxy and naphthoxyacetic acids, selectively J destroy yellow charlock and do not affect cereal crops. This investigation has been undertaken by Slade and Templeman(122*9) commencing in 1940 and promises to give us some interesting information. The concentrations and rates at which other agents are applied are also c r i t i c a l since for sprays that are absorbed into the plant and translocated to a c r i t i c a l area.,, the spray must not be too concentrated or the foliage w i l l simply die where the droplets touch and the translocation w i l l not occur, fhusj certain tests with nitroalkylphenols show greatest t o x i c i t y at low concentrations. These facts clearly point out that weed and pest control i s no longer i n the hands of the ordinary farmer, but i s the job of a trained specialist, i f optimum results are to be obtained. . . . 2, The Relationship of Structure to, Toxicity. It i s always of interest to correlate the properties of a homolo-gous series of compounds with the nature of the individual molecule. Toxicity tests on homologous and isomeric series of compounds possessing herbicidal or insecticidal properties provide an interesting experiment of this type and are certainly of economic importance in the development of the most efficient and practical agents for agricultural use. Quite a number of such correlative studies have been carried out since chemical interest in pest control has been aroused, and the most significant of these are described in this paper. It was realized as early as 1665 by Li s t e r that phenol i s an effective germicidal agent, but a systematic study of other phenolic compounds does not seem to have been started u n t i l 1306 at which time Ehrlick found that polyhalogenated phenols have high t o x i c i t i e s towards - 10 -certain organisms( 1 3 0). Thus, pentabromophenol i s five hundred times as toxic as phenol for the case tested. Strangely enough, following this discovery, there seems to be a lapse in the study of phenols which lasted fo r some fifteen years and did not become really active again u n t i l Johnson and Lane's work on a l k y l r e s o r c i n o l s ^ ) . In the meantime a certain amount of work on the germicidal properties of alkyl alcohols and amines was undertaken by Morgan and CooperC8^). Alcohols were found to be considerably less active than phenol and so i t was concluded that the aromatic nucleus i n some way gave the added toxicity. Chain branching was found to reduce the a c t i v i t y and thus n-butanol i s more powerful than tert.-butanol with sec.-butanol hold-ing an intermediate position. As w i l l be shown later, this effect i s usually also found in the alkylphenols. The alkylamines are better germi-cides than the alcohols, and their toxicity increases as the chain length becomes longer to a maximum value at n-heptylamine. While the aliphatic amines are stronger than the alcohols i t i s found that aniline i s consider-ably weaker than phenol. In 1921, Johnson and Lane^ 6 1) started the f i r s t organized study of the relationship of tox i c i t y to structure, by preparing the 4-*i-alkylre-sorcinols from methyl to butyl and doing standardized t o x i c i t y tests. Their method of synthesis was the Nencki condensation of resoreinol with a fatty acid in the presence of zinc chloride to give an acylresorcinol, followed by a Clemmensen type reduction using zinc amalgam and hydro-chloric acid. Their results showed that the t o x i c i t y steadily increased with the length of the alkyl side chain. - 11 -Five years later, Dohme, Cox, and Miller, extended t h i s work by the preparation and testing of a l l the 4^-alkylresorcinols up to n-octyl and also several isoalkyl derivatives. The results of their tests were very interesting and are shown in Figure 1. It can be seen that the toxicity, as measured by the phenol coefficient towards B. typhosus, rises to a maximum value for the 4-n-hexyl derivative and f a l l s off for both higher and lower homologues, reaching a value of zero for the n-octyl and higher derivatives. - 12 -Figure 1.-Phenol Coefficients of 4-Alkylresorcinols to B. typhosus. 0 L. i i i i i : 1 :—I & L 2 4 6 8 Number of Carbon Atoms . in Alkyl Group. . 0 R - n-alkyl. x. R - iso-al'kyl. I t i s to be noted that the standard of efficiency used here and in many other studies i s the phenol coefficient which i s merely a comparison of the germicidal action of a compound to that of phenol as unity* Since the coefficient varies with the test organism and also with the tempera-ture, care i s to be taken i n drawing comparisons, and several different tests are desirable. Thus, while the phenol coefficient of 4-n-alkylre-sorcinols i s at a maximum at the hexyl homologue in tests against B. typhosus, the same compounds tested against Staph, aureus have progressively increas-ing coefficients as far as have been i n v e s t i g a t e d ^ ^ . Leonard(77) realized the significance of Dohme's work and showed that 4^-hexylresorcinol possesses the properties of an Meal internal urinary antiseptic, a use which i t s t i l l finds. Dohma used the same synthetic method as Johnson and Lane, i . e . , a Nencki condensation and Clemmensen reduction, but i n 1931 Cox showed that the same compounds may be prepared in equally good yields by the condensa-tion of the acid chlorides with resorcinol at 900,€. without any catalyst. This method i s to be preferred in that i t does not require the use of a large excess of acid which must be removed as i n the Nencki condensation. Cox also showed that reduction of the acylresorcinols may also be effected using clean, mossy zinc and hydrochloric acid rather than zinc amalgam. The next development was a study of the monoalkylresorcinol ethers by Klarmann et a l ^ ^ . Once again the hexyl homologue showed maximum toxicity, with chain branching leading to lower values. The phenol coefficients seem approximately the same whether the alkyl group ;is attached to a carbon or to an oxygen atom. Dialkylresorcinols show an increased toxicity when at least one of the alkyl groups is of greater than three carbon a t o m s t but no quantitative results are shown. Of a l l the primary amines tested, cyclohexylamine i s the most toxic, and by the addition of n-alkyl groups the t o x i c i t y is increased steadily as far as tests have been made^3^. It i s interesting to note thai; in the case of cyclohexylamine, substitution in the ring reduces toxic i t y sharply as contrasted with most other types of compound tested. Pyridine i s not a particularly active fumigant, but alkylpyridines once more show considerable a c t i o n ^ ) , Figure 2 shows the results of tests using 2-alkylpyridines against the red spider, and i t can be seen that i n this case the maximum does not occur at the hexyl derivative, but rather at the n-butyl homologue* The more d i f f i c u l t l y obtained 4-alkyl -pyridines appear to be more toxic than their 2-alkyl isomers. For short side chains the iso compounds are less toxic, but for isohexyl and higher they are more toxic. The alkylpiperidines have not been carefully studied but appear to be slightly more efficient than the corresponding pyridines. Fused ring systems such asquMoline and acridine are among the most toxic insecticides known(^). The studies of the greatest interest to the present work are those concerned with alkylphenols and nitrophenols and these w i l l now be considered. The alkylphenols themselves show a maximum phenol coefficient for n-amylphenol, there being very l i t t l e difference between the ortho, meta and para isomers. The primary alkyl derivatives are more toxic than the secondary and tertiary isomers as shown in Figure 3 by the work of - 15 -' Figure 2. Toxicity of 2-n-alkylpyridines to Red Spider. 2 4 6 " 8 Number of Carbon Atoms in Alkyl Group. . - 16 -Figure 3. Phenol Coefficients of. p-Alkylphenols to B. typhosus. •H O •rH «M «H <D O O H O C 0) .c a, 2 4 6 8 Number of Carbon Atoms in Alkyl Group. © R •= n-alkyl. R -• sec.-alkyl. G3 R •= t e r t . - a l k y l . - 17 -CouTbhard, Marshall and Pyman^26*-1-03). These workers have also shown the high toxicity of the amyl homologues of the four alkylcresols, and the 4-alkylguaiacols, all these compounds being prepared by one of the four following methods, followed by Clemmensen reduction 1. Nencki condensation of acid and phenol with zinc chloride* 2. Fries rearrangement of phenol esters with aluminum chloride. 3« Isomerization of phenol esters with zinc chloride. 4. Phenol-acid condensations using phosphorus oxychloride. These studies show that the presence of a second alkyl group greatly increases the phenol coefficients of both alkylphenols and alkylresorcinols. Thus, the n-amylcresols show high values in the range 250-300. The introduction of halogens into the alkylphenol nucleus, causes increased toxicity, the 2-chloro-4-alkylphenols reaching their peak at the hexyl homologue and the isomers containing the halide para to the phenolic centre being more toxic yet. Fluorophenols, however, show no increased toxicity (75 ) # The introduction of nitro groups into the phenol nucleus is the point of chief interest in this study. Mazetti^8-*-) has shown that nitrophenols have much higher phenol coefficients than phenol itself, with the p-nitro isomer, the most toxic of the mononitro derivatives being a hundred times more toxic than phenol(92). The dinitrophenols are more potent yet, by .a factor of about ten, and Tattersfield 0-33) w a s the first to show that the introduction of alkyl groups caused a sharp rise in toxicity. Thus dinitro-o-cresol was found to be far superior to dinitrophenol. It appears that a nitro group para to the phenolic centre is necessary for maximum toxicity and thus the dinitro-o-alkylphenols are the compounds of chief interest rather than the p-alkyl series. The introduction of a third nitro group, however, reduces the toxicity to about that of the mononitro derivatives. The f i r s t study of the toxic powers of 2:4-dinitro-6-n-alkylphenols was made by Kagy( 6 5), and the results of his work against silkworm larvae are shown in Figure 4« Maximum toxicity is once more found between the hexyl and heptyl homologues. Al l these compounds are powerful metabolic stimulants to man and D.N.O.C. has been used in slimming p i l l s with some success. Fortunately, the order of toxicity of the dinitro-n-alkylphenols towards man i s exactly opposite to that towards insects and this offers seme added protection to the spray operator. An extension of this work by Simon(H?) against the fungus Tricoderma viride and the mustard Brass!ca alba i s illustrated in Figures 5 and 6. In these cases the maximum toxicity is found with the compounds containing o—propyl and o-ethyl side chains respectively. In a l l cases the dinitro-o-alkylphenols are more toxic than their p-isomers, and the reduced toxicity accompanying iso and tertiary" alkyl groups i s admirably shown. The point of real interest is the anomolously high toxicity of 2i4-o^initro-o-sec,-butylphenol which would be expected to f a l l somewhere between the values for the primary and tertiary isomers. It is this unexpectedly high toxicity which has prompted the present work involving other dinitro-sec.-alkylphenols and i t will be very inter-esting to see whether or not the o-sec.-butyl homologue is unique in this property. The only other reference that could be found dealing with toxicity tests on other sec.-alkylphenols merely showed that compounds that are presumably "di-sec-hexy!" and wdi-sec.-heptyl B resorcinols formed by resorcinol-alcohol condensations with zinc chloride, are extremely toxic and have coefficients of the order of 1GOO-1350 For an excellent account of the toxic action of many series of polysubstituted phenols, the reader is referred to a review by - 20 - • Figure 4. Toxicity of 2:4-Dinitro-6-alkylphenols to Silk'Worin Larvae, IT) t o & e s • IP <D CO •a 2 4 6 8 Number of Carbon Atoms in Alkyl Group O R - n-alkyl. <2> R cyclohexyl. • Acid lead arsenate. - 21 -Figure 5« Toxicity of Dinitro-alkylphenols to Trijooderraa v i r i d e . Number of Carbon Atoms in Alkyl Crcup ® *=• 2:4-dinitro-6-*i->alkylphenols. A «= 2:6-dinitro-4-n-alkylphenols. • - 2:6-dinitro-4-tert.-alkylphenols . • - 2:4-dinitro-6-sec.-alkylphenols. - 2 2 -Figure 6. Toxicity of Dinitro-alkylphenols to Brassica alba. .« o l f \ u o c o •rl -p n) u -p c (D O c c o o to o 0 1 2 3 4 5 Nu.-aber of Carbon Atoms in Alkyl Group © = 2:4-dinitro-6-n-alkylphenols. * . = 2 :6-dinitro-4-n -alkylphenols. • = 2:6-dinitro-4-ter.t. -alkylphenols. • - 2:4-dinitro-6-sec.-alkyl phenols. - 23 -3. The Preparation of n- and iso-alkylphenols. Primary alkylphenols have been prepared by quite a number of different methods. The more significant of these methods w i l l be described in this section. The problem confronting the chemist is either one of the introduc-tion of an alkyl side chain into a phenolic nucleus, or of introducing a hydrozyl group into the nucleus of an alkyl benzene* The second case is somewhat tr i v i a l since i t f i r s t requires the introduction of an alkyl group to benzene and this i s essentially the same problem found in the fir s t case. We shall then first of a l l consider the introduction of a side chain into the phenolic nucleus* The f i r s t idea which meets the eye i s a directcondensation of an alkyl halide, say, with phenol by a Friedel-Crafts type reaction(*°»95). This possibility is immediately ruled out for two reasons. Firstly, the Friedel-Crafts reaction is known to give a mixture of isomerization products in nearly a l l cases using alkyl halides. Thus the alkylation of phenol, say, with both n-propyl bromide and isopropyl bromide, both give isopropylphenol. This isomerization effect w i l l be discussed in greater detail in a later section of this thesis. The second disadvantage is that the Friedel-erafts type condensation gives almost exclusively para substitution and thus a different method of approach is desirable for the synthesis of o-alkylphenols. The f i r s t difficulty* may.be- surmounted by using the Friedel-Crafts ketone synthesis in which case an acid chloride is used instead of an alkyl halide, and the resulting aryl-alkyl ketone is reduced, usually by a Clemmensen type reduction. - 24 -ow ,c«3 oU H CI 9—> o c«z-c(/r-cH3 Unfortunately, the para isomer once more predominates in most cases, but the structure of the resulting phenol is unambiguous* Ralston^ 8) has studied the acylation of phenol with acid chlorides and aluminum chloride, and claims that excess aluminum chloride favours para substitution while equimolecular amounts favour ortho substitution, presumably due to the directive influence of the aluminum complex that can form with both reactants and products. The use of low temperatures also increases the yield of ortho acylpbenols* . One of the CO.emmensen's earliest papers reports the use of his new reduction of aryl-alkyl ketones to produce p-ethyl and p-n-propyl-phenols obtained from a Friedel-Crafts reaction^). In 1931, Beranger(5) made a careful study of this method of synthesis and prepared a l l the para-primary acyl and alkyl derivatives of phenol and anisole from ethyl to heptyl. The anisoles were also demethylated to the corresponding phenols by the use of gaseous hydrobromic acid in glacial,acetic acid. Some years previous to this work, Skraup^ 0) had prepared and character-ized the p-n-alkylanisoles from propyl to nonyl, by the Friedel-Crafts and Clenmensen reactions, as part of an investigation of the mechanism of the cracking process. On heating to 320°C. Skraup found that those compounds with an even number of carbons in the side chain split off the terminal methyl group while those with an odd number were stable. The anisoles were characterized as their sulphonamide derivatives. This general method of synthesis has also been extended to the preparation of long chain o—alkylphenols such as o-dodecylphenol by both Friedel-Crafts condensation of fatty acid chlorides with anisole in nitrobenzene followed by Clemmensen reduction and demethylation using hydrobromic and glacial acetic acids, and by Nencki condensation of the fatty acid with phenol^ 9 1). The use of different condensation catalysts such as anhydrous (14) hydrofluoric acid x ' boron trifluoride, etc., for Friedel-Crafts type . condensations, shows definite promise of reducing side reactions, isomerization and migration to a minimum, but need not be discussed here. In 1908, Fries discovered that on heating phenol esters with anhydrous aluminum chloride, and hydrolysing the resulting complex, a r>n mixture of isomeric ortho and para hydroxy alkylphenones are formed (6). This reaction became known as the Fries Rearrangement and provides a very satisfactory route by which to obtain both ortho and para alkylphenols with none of the complications described above for the Friedel-Crafts method. By adjusting the temperature and the solvent used (if any), the - 26 -relative amounts of the two isomers may be altered to a considerable degree* It has been found in this laboratory that a temperature of 145-I60°e. without solvent, gives roughly equimolecular amounts of the o- and p-hydroxy-alkylphenones, which may be cleanly separated by fractionation since, due to chelation of the o—hydroxy ketones, their boiling points are reduced some sixty degrees below those of the para isomers* This chelation i s also demonstrated in the steam volatility of the ortho isomers, and their much increased solubility in ligroin. The para isomers are also found to be solids and the ortho isomers liquids 0 Varying the length of the alkyl group in the phenol esters does not appear to effect the para to ortho ratio of the rearrangement products in any consistant way, the ratio varying between 1-1.6 for phenol esters from phenyl caprylate to phenyl stearate^ 9 8). The use of nitrobenzene, as a solvent, favours the para isomer in a 3:1 ratio, while carbon disulphide only slightly favours the para isomer. Experiments by Ralston^ 9 8), have shown that the hydroxy ketones themselves are stable to heating with two moles of aluminum chloride at 100°e» for six hours, and 90-98$ of the unchanged hydroxy, phenone may be recovered. If, however, three moles of aluminum chloride are used, decomposition results and only 35$ of the reactants may be recovered. On the other hand, i f only half a mole of aluminum chloride i s used, the phenones are apt to condense with themselves. Thus, acetophenone heated with one-half a mole of aluminum chloride gives a 73$ yield of dypnone05). 2G6H5'C0.GH5 A l c 1 3 CgHtj-GCGHj JsGH-GO-GgHg - 27 -With g r e a t e r t h a n o n e m o l e o f a l u m i n u m c h l o r i d e , h o w e v e r , i t h i s c o n d e n s a t i o n d o e s n o t t a k e p l a c e * These r e a c t i o n s a r e n o t a p t t o t a k e p l a c e d u r i n g a Fries r e a r r a n g e -m e n t , b u t o n l y i l l u s t r a t e t h e f a c t t h a t t h e a l k y l p h e n o n e s a r e s t a b l e s t r u c t u r e s a n d a r e n o t p r o n e t o i s o m e r i z a t i o n , t h e r e f o r e g i v i n g r i s e t o c o m p o u n d s o f p o s i t i v e s t r u c t u r e * i There h a v e b e e n q u i t e a n u m b e r o f w a y s d e v e l o p e d f o r t h e r e d u c t i o n o f k e t o n e s t o h y d r o c a r b o n s , t h i s b e i n g t h e r e a c t i o n c a l l e d f o r i n o r d e r t o c o n v e r t t h e h y d r o x y a l k y l p h e n o n e s t o a l k y l p h e n o l s ( 6 0 ) , A v e r y e a r l y m e t h o d c o n s i s t e d o f h e a t i n g t h e k e t o n e w i t h h y d r i o d i c a c i d a n d r e d p h o s -p h o r u s , a n d t h i s w a s f o u n d t o w o r k i n q u i t e a f e w c a s e s * Other w o r k e r s h a d s h o w n t h a t z i n c a n d s u l p h u r i c a c i d , o r z i n c a l o n e , w o u l d w o r k i n c e r t a i n c a s e s a n d n o t i n o t h e r s . In 1898, KLages p u b l i s h e d t h e f i r s t o f a s e r i e s o f p a p e r s o n t h e u s e o f s o d i u m a n d e t h a n o l i n t h e r e d u c t i o n o f a r o m a t i c k e t o n e s , b u t t h i s m e t h o d w a s a l s o f o u n d t o b e u n r e l i a b l e f o r m i x e d a r y l - a l k y l k e t o n e s . Shortly l a t e r , Darzens^29) s h o w e d t h a t t h i s t y p e o f k e t o n e c o u l d b e r e d u c e d t o t h e h y d r o c a r b o n b y h e a t i n g t o 190°e, i n t h e p r e s e n c e o f h y d r o g e n a n d a s p e c i a l l y r e d u c e d n i c k e l c a t a l y s t , a n d i n 1942, Ipatieff (5?) r e o p e n e d t h i s s t u d y a n d f o u n d t h a t b y u s i n g a c o p p e r o x i d e - a l u m i n u m o x i d e c a t a l y s t , a t e m p e r a t u r e o f 100°IC*, a n d a h y d r o g e n p r e s s u r e o f 120 a t m o s p h e r e s , a l k y l p h e n o n e s w e r e r e d u c e d t o c a r b i n o l s , b u t t h a t a t 150-180°G, t h e p r o d u c t w a s t h e c o r r e s p o n d i n g a l k y l b e n z e n e ; The m o s t e f f i c i e n t m e t h o d f o r t h i s t y p e o f r e d u c t i o n i s , h o w e v e r , t h e d e m m e n -s e n r e d u c t i o n u s i n g z i n c a m a l g a m a n d h y d r o c h l o r i c a c i d f 8 0 * 2 0 ) . Clemmensen's e a r l y w o r k d i d n o t i n v o l v e a r o m a t i c k e t o n e s , a n d V o s w i n k e l ^ - O , i n 1909, iras the first person to use this reaction for the reduction of hydroxy-alkylphenones to alkylphenols* The Fries rearrangement followed by GLemmensenl reductions was* the method used in this laboratory for the preparation of eighteen normal and iso-alkylphenols with the side chain varying from ethyl to octy l ^ 3 7 ) . The phenol esters were readily prepared from the corresponding acid chloride by reflux!ng with phenol, and fractionation. This method of synthesis has also been used by Sandulesco and GirardO°7) f o r the preparation of o- and p-acyl and alkylphenols with normal side chains from butyl to nonyl in an investigation of the hypnotic properties of these compounds. These workers showed that for the ortho series the reduction could be carried out by simply refluxing with equal volumes of glacial acetic acid and fuming hydrochloric acid. It may also be extended to the preparation of di and trialkylphenols by the Fries rearrangement by alkylphenol e s t e r s ^ 3 ' 3 9 ) . A third general method of synthesis involves the introduction of an alkyl side chain through a Grignard reaction between an alkyl halide and a methoxy benzaldehyde: to give a secondary carbinol which may be dehydrated to an olefin, hydrogenated to an alkylanisole, and demethylated to an alkylphenol. This synthesis i s very general and can be extended to the preparation of secondary alkylphenols by the use of the appropriate methoxy-alkylphenone. This is the method used in the experimental section of this paper and discussion w i l l be withheld until the section on the synthesis of secondary alkylphenols. - 29 - : The ortho and para isobutyl and isoamyl phenols have been prepared by Button by this method, and found to be identical with those by the Fries method(57). The general method of this synthesis was originated by ELages in 1902 and was used by this worker to prepare various alkylanisoles, alkylphenatoles, and alkylbenzenes, with side chains varying from ethyl to heptyl( 6 9' 7 0 , 7 1» 7 2» 7 3). However, he never attempted demethylation of the anisoles to give the corresponding alkylphenols, A typical Klages synthesis is shown as follows: c«3 S»3 HCI ocU3 A OCH3 - 30 -The general plan of the series of reactions i s the same as that used in this laboratory, but the procedures used in going from one step to the next have been altered* Thus, while KLages dehydrates his carbinol by f i r s t converting i t to the chloride by treatment with concentrated hydrochloric acid and then dehydrohalogenates by refluxing with pyridine, i t has been found more convenient to use the method of Dean and Stark(32) of refluxing the carbinol in an inert solvent such as toluene in the presence of a catalytic amount of iodine* Also, where KLages reduced his olefin to a saturated alkylanisole by treatment with metallic sodium and alcohol, the more recently developed catalytic methods of hydrogenation using Raney nickel as a catalyst have been found to be much easier, and infinitely more successful. Another group of workers in France have also followed this synthesis for several steps in the synthesis of various unsaturated and saturated alkylanisoles as part of a very extensive programme of investiga-tion of "affinity capacities and migration tendencies"03*), This group, under the direction of Tiffeneau, has produced a great deal of published material, but while they report many of the intermediates in the synthesis of the normal and iso-alkylphenols prepared in this laboratory, none of the secondary alkylphenols described in this paper are reported* Davies, Dixon and Jones(51) have also used the Grignard method for the preparation of several unsaturated hexylbenzenes and anisoles, using the KLages method of dehydration* A more recent synthesis of alkylphenols by the Grignard method i s reported by Alles^ 2) who, during work on the synthesis of cannabinol derivatives, prepared m-n-amylphenol by the action of nBuMgCl on m-MeO»C6H4»CHO to give 1-(m-methoxyphenyl)-pentanol-l which was dehydrated by heating for one hour at 150°C. with potassium bisulphate, to give l-(m-methoxyphenyl)-pentene-l. This compound was then hydrogenated to m-n-amylanisole using palladium oxide and hydrogen at 25°G., and then demethylated both by using 30% hydrobromic acid in glacial acetic acid, and by constant boiling hydriodic acid in glacial acetic acid* Alles also prepared m-n-amylphenol from m-methoxybenzyl chloride and n-butyl-magnesium chloride in rather poor yield* The compounds were identical, however, and were characterized by their 3i5-dinitrobenzoates, and, with difficulty, by analysis since they tended to explode on combustion. These have been the three most important syntheses of normal and iso-alkylphenols, but there have also been several other methods of less general nature proposed which will be briefly described* The first of these is the Claisen rearrangement of allylphenol ethers( 1 8). The commonest example of this reaction is in the rearrangement of the a l l y l ether of phenol, prepared by the action of a l l y l bromide on phenol in the presence of potassium carbonate* If this ether is refluxed for six hours i t slowly rearranges to o-allylphenol which may then be reduced to o-propylphenol* A , Qrtbo-isobutylphenol was f i r s t reported by the rearrangement of the methallyl ether of phenol prepared in a similar way to the allyl ether (4). These rearrangements must be carefully controlled, however, or cyclization will take place to give substituted coumarans. This cyclization can be smoothly accomplished by the addition of pyridine-hydrochloride(4), or hydrobromic acid in acetic acid(76,19)# The rearrangement always goes to the ortho position i f i t is open, and otherwise para. The Claisen rearrangement i s even more pronounced in the case of the a l l y l ethers of alkylphenols. During the alkylation of phenols with a l l y l halides, the solvent i s the determining factor which determines whether 0- or C-alkylation will result 0-7) # Alcohol promotes the formation of ethers, while non-dissociating solvents, such as benzene, favour C-alkylation. Very limited use has been made of the lurtz reaction to prepare alkyl phenols. Radcliffe(97) ^ as obtained p-n-araylphenol in 25% yield by the action of butyl bromide on benzyl bromide in the presence of sodium wire, and, in somewhat better yield from bromobenzene and n-amyl bromide, followed by monosulphonation and alkali fusion. The usual side reaction makes the Wurtz reaction of l i t t l e value when other methods are available. Niederl and co-workerst88) in 1937 prepared a series of p-n-alkyl-phenols from ethyl to heptyl by condensation of equimolecular amounts of phenol and the appropriate aldehyde in glacial acetic acid at -5°C in the presence of hydrochloric acid gas. A polymer resulted which, on distillation at atmospheric pressure, decomposed to give roughly 40$ yields of the corresponding alkylphenols. The physical constants of these compounds, however, do not agree well with those obtained in this, and other, laboratories by other methods of synthesis. In general, i t seems possible to prepare almost any desired alkylphenol by application of one of the Friedel-Crafts, Fries, or Grignard methods, and the latter two have been extensively studied in this laboratory. 4. The Preparation of Secondary Alkylphenols by Synthesis. The methods described in the last section for the synthesis of primary alkylphenols are, in general, not applicable to the preparation of secondary alkylphenols. Condensations of the Friedel-Crafts type have been used rather extensively in the preparation of secondary and tertiary alkylphenols, but while these methods are adequate for the latter compounds isomer!zations occur almost inevitably during condensations of sec.-alkyl halides and alcohols, or olefins with phenol or i t s derivatives. The applications and limitations of condensation methods of this sort w i l l be discussed separately in Section 5 of this paper. For the moment i t is sufficient to say that secondary alkylphenols of an unequivocal structure cannot be generally prepared through condensation methods of the Friedel-Crafts type. - 34 -The Pries rearrangement method is obviously limited by its nature to the preparation of primary alkylphenols since i t involves rearrangement to a phenone which can only be primary. The Claisen rearrangement of tf-ethylallyl-phenyl ether has been reported to give a mixture of 3-(o-hydroxyphenyl)-pentene-l and 2-(o-hydroxyphenyl)-pentene-3^^), but isomerization i s inevitably encountered and the method seems most unsatisfactory. The Grignard method, however, provides a highly specific and very general synthetic route by which almost any primary or secondary alkyl-phenol of unambiguous structure can be prepared by a correct choice of starting materials* It i s this method that has been used for the preparation of the eight dinitro-sec*-alkylphenols described in this paper. The complete synthesis maybe summarized by the following example, namely, the preparation of 2-(2-hydroxy-3:5-dinitrophenyl)-3-methylpentane: o - 35 -Orl Gt-*)c/fit- H&c /VO; CI/3 The synthesis i s not a new one although the procedure has been developed i n this laboratory from basic principles, and i t has only been after an exhaustive literature survey that references have been found to workers who have carried i t to completion by synthesis of secondary a l k y l -phenols. Of the phenols described, only 2-(p-bydroxyphenyl)-3-methylpentane has been previously reported by an unequivocal synthesis, that being the Grignard method, and even i n this case, no intermediates are l istedX56). As previously mentioned, the general method was f i r s t developed by KLages, and this worker has prepared both primary and some secondary alkylanisoles. Table XLT shows a comparison of the physical constants of a l l compounds described i n this paper that have been previously reported by reliable syntheses. KLages also prepared a series of primary and secondary alkylbenzenes with side chains ranging from ethyl to heptyl, by Grignard reactions between benzaldehyde or acetophenone and the appro-priate a l k y l h a l i d e ( 7 1 > 6 9 ) . The only compounds which KLages has reported that duplicate those prepared for this paper were obtained by a Grignard reaction between ethyl anisate and ethyl magnesium iodide, the product - 36 -spontaneously dehydrating to 3-(p-methoxyphenyl)-pentene-2. Attempted reduction of this compound using sodium and ethanol proved very difficult, and after three attempts, the constants were s t i l l quite different from those obtained in this laboratory. The next use of a Grignard method to produce a secondary alkylphenol was in connection with Smith and Ungnade's work on the structure of Vitamin E ^ - 2 ^ . As part of a synthetic proof of structure, these workers prepared both 3-(o- and p-hydroxyphenyl )-hexane by Grignard reactions between o- and p-bromoanisole and hexanone-3. The resulting carbinols dehydrated spontaneously to the corresponding olefins which were hydro-genated, using a palladium catalyst, to the alkylanisoles. These compounds were demethylated by refluxing for two hours with hydriodic acid in glacial acetic acid. The phenols were characterized as their phenoxyacetic acid derivatives. 3-(pOHydroxyphenyl)-hexane has been prepared by G.K. Harris at this university as part of an unpublished undergraduate research problem, and both this compound and i t s ortho isomer are soon to be reported in final form as part of the present study. There appears to be considerable deviations between the physical constants of some of the intermediates reported by Smith and those found in the undergraduate.: study previously mentioned. These constants are as follows:-Compound b.p. n2U Smith Harris Smith Harris 3-(p-Methoxyphenyl)-hexene-2 (and 3) 3- (p-Methoxyphenyl )-hexane 3- (p-Hydroxyphenyl )-hexane 125-3©°A5 125%5 134-45° A4 102-4°A>.5 74-50/0.4 116°/2.6 1.5223 1.4988 m.p.approx. 250 1.5302 1.4997 m.p.s 47° - 37 -As part of a very lengthy study on Friedel-Crafts type condensations between various aromatic compounds and aliphatic alcohols, Huston^ 3), in 1945, reported the synthesis of 3-(p-hydroxypheny])-2-methylpentane and its intermediates as a proof of structure of the condensation product of phenol and 2-methyl-pentanol-4. Bis synthesis, involved a Grignard reaction between ethylmagnesium bromide and p-methoxy-isobutyrophenone prepared by a Friedel-Crafts ketone synthesis. The resulting carbinol was found to spontaneously dehydrate to 3-(p-methoxyphenyl)-2-methyl-pentene-2 which was hydrogenated using a palladium catalyst, and demethylated by refluxing with 47$ hydrobromic acid and phenol for four hours. This compound will also shortly be reported from this laboratory starting from p-methoxypropiophenone and isopropyl bromide. In a later paper, Huston has reported the synthesis of nine p-sec-hexyl and heptylphenols starting from p-methoxyacetophenone and p-methoxy-propiophenone^). unfortunately, no Intermediates are listed and only boiling points and melting points of the alpha naphthylurethan derivatives of the phenols are given. Of these phenols, only 2-(p-hydroxyphenyl)-3-methylpentane duplicates the compounds reported in the experimental section of this paper, the constants being shown in Table XL I. One other use of this synthesis has been in the preparation of m-cyclohexylphenol from m-methoxybromobenzene and cyclohexanone^) using catalytic hydrogenation and demethylation in 95$ yield with hydrobromic and glacial acetic acids. A rather difficult approach to the Grignard synthesis has been studied by Couturier(2?) who reacted two moles of ethyl magnesium bromide with N,N-diethylanisamide to produce 3-(p-methoxyphenyl)-3-diethylamino-- 38 -pentane which was decomposed i n dilute hydrochloric acid to give 3-(p-methoxyphenyl)-pentene-2 which he also obtained from ethyl anisate and ethyl magnesium bromide. Experimentally i t has been found i n this laboratory that excellent yields of the phenol esters may be obtained by merely refluxing the appropriate acid chloride with phenol for an hour, washing the reaction mixture with dilute sodium hydroxide, and fractionation. For the case of phenyl propionate i t i s convenient' to add thionyl chloride gradually to a slowly refluxing mixture of phenol and propionic acid, followed by fractionation(43,139) # ^ s satisfactory than f i r s t preparing the propionyl chloride since this compound boils at 80°C, and thionyl chloride at 77°C, Alternatively the chloride may be prepared by the action of phosphorus trichloride on propionic acid. I t has been reported that theesterification of phenols proceeds i n exceptionally high yields i f ten grams of magnesium per mole of phenol i s added to the reaction mixture (126). The conditions required for optimum yields i n the Fries rearrangement have previously been described, and i t i s sufficient to say that i f , on addition of the phenol ester to anhydrous aluminum chloride preheated to 70°C«, the temperature i s allowed to rise to 145°C. and held at this point for a short while before cooling to room temperature and slow hydrolysis - 39 -with dilute hydrochloric acid and ice, that roughly equimolecular proportions of the ortho and para hydroxyalkylphenones result i n an overall y i e l d of 75-80$, the isomers being easily and cleanly separated by fractionation under reduced pressure. Since the next step i n the synthesis involves a Grignard reaction, i t i s necessary to protect the phenolic group as Grignard reagents are decomposed by acidic hydrogens. Methylation has been chosen as the means of accomplishing this masking since i t provides a very stable group that w i l l not decompose i n either acidic or basic solutions under ordinary conditions. Methylation also provides an opportunity to follow the subsequent reactions by means of the simple and accurate Zeisel technique of methoxyl determination. A l l intermediates and derivatives reported i n this paper have been analysed for methoxyl content and the method has been found to be most successful. Use of the classical methylation procedure using dimethyl sulphate i n alkaline solution has been found to be just as efficient and consider-ably less trouble'than the more specialized methods using diazomethane or methyl iodine and silve r oxide. Yields of 60-80$ were obtained i n most cases and i t was found that recovery of much of the unreacted phenol could be made by alkaline extraction of the reaction mixture. I t was found to be preferable to use potassium hydroxide rather than the more common sodium hydroxide during methylation due to the greater solubility of the potassium phenates i n water. - 40 -I t has been shown by Lewis and Treischmann(79) that -toe presence of a l k a l i i s necessary, and that no methylation occurs i n neutral or acidic solutions, the amount of methylation being roughly of the same order as the ratio of a l k a l i to phenol. With excess dimethyl sulphate i t has been shown that only the f i r s t methyl group enters the reaction, but under forcing conditions treatment of one mole of phenol with 0.5 moles of dimethyl sulphate and 1.5 moles of sodium hydroxide, a 70% y i e l d of anisole may be obtained. The Grignard reaction i s done by conventional methods using great care that a l l reagents and apparatus are scrupulously dry and that the reaction flask i s kept under a slight pressure of dried nitrogen at a l l times. I t has been found i n this laboratory that the reaction mixture, after the addition of the carbonyl compound at -5°C., should be refluxed for from fiv e to six hours i n order to prevent contamination of the product with unreacted carbonyl. The use of two moles of Grignard reagent also opposes this contamination, and, i f on completion of the reaction, the products shows the presence of a carbonyl group on testing with 2:4-dinitrophenyl-hydrazine, i t should be carefully dried and treated with a further amount of Grignard reagent. The tertiary carbinol formed by the Grignard reaction may be dehydrated by either of two ways. F i r s t l y , i t may be refluxed i n an inert solvent such as toluene or xylene with a catalytic amount of iodine, the water which s p l i t s off being azeotropically d i s t i l l e d and collected i n a Dean and Stark t u b e ( 3 2 ) . Alternatively, the dehydration may be effected by refluxing with ten percent sulphuric acid, or with sulphuric acid i n - 41 -glacial acetic acid(? 6). The former method i s to be preferred whenever possible since the reaction may be followed to completion by merely measuring the amount of water s p l i t off, and also i t avoids the use of a mineral acid which frequently causes polymerization of ole f i n i c compounds. The Dean and Stark method was t r i e d i n a l l cases i n the present work, but i n several instances no water was collected and the compound was refluxed with sulphuric a d d for two hours to ensure complete dehydration. I t i s during this dehydration that the only possible isomerization might occur since i n most cases i t i s possible for water to be s p l i t out i n either of two directions, although one probably predominates. This problem w i l l , however, be circumvented during the hydrogenation step to follow. ! h i l e alcohols such as (CHj^C'GR^OH containing f u l l y substituted carbons adjacent to the carbinol group are known to undergo the Wagner-Meerwein rearrangement to a mixture of (CHJ^C^CHCHJ and CHg^CHjJCR^CHj on dehydration, there appears to be no evidence of rearrangement occurring i n carbinols of the type produced i n this work, and such a rearrangement would certainly seem energetically improbable. The alkenes were characterized as their nitrosyl chloride derivatives which, unfortunately, proved to be quite unstable i n most cases and had to be prepared immediately prior to analysis. This derivative was f i r s t developed by Tilden055,47) f 0 r the characterization of terpenes, and i t has been found that a nitrosyl chloride w i l l not form from a terminal ethylenic bond i n a carbon chain. Their formation may be represented as a direct addition of N 0 C 1 to the ethylenic bond and the derivatives were - 42 -originally formulated as nitroso compounds. It now appears that a further rearrangement takes place to give a colourless, oxime-like compound which occurs as a dimer. Thus R-GH2-CH^-(CH3)2+N0C1 f R-CHg-CH-C- (CHj^ f N=0 CI R-GHg-C-TC^ - (CH^ ) g N-OH CI Nitrosyl chlorides of olefins containing no hydrogens on the unsaturated carbons cannot isomerize i n this way and are blue i n colour. The olefins were very easily reduced by pressure hydrogenation i n the presence of Raney nickel. Almost quantitative yields were obtained i n a l l cases and the alkylanisoles were characterized as their sulphon-amide derivatives (144,50) by treatment with chlorosulphonic acid at -15° G. followed by the addition of ammonium hydroxide. The use of this derivative was f i r s t reported by Skraup(- L 2 1) i n 1924, but at this time the use of chlorosulphonic acid had not been developed and the derivative was prepared by treatment of the anisole with concentrated sulphuric acid, and conversion to the chloride by treatment with sodium or barium chloride, followed by addition to ammonium hydroxide. The catalytic method of reduction i s vastly sup r i o r to KLages method using sodium and alcohol which has been previously described. The f i n a l step i n the preparation of alkylphenols by the Grignard method i s demethylation of the alkylanisoles, and this presented consider-able d i f f i c u l t y i n this laboratory before an efficient method was developed. The method most frequently mentioned in the literature consists of reflux-ing the anisole with 47$ hydrobromic acid i n glacial acetic a c i d ^ 0 * 2 ? ) and this procedure has met with very varied success by different workers. The addition of gaseous hydrogen bromide during the f i r s t few hours of the reaction seems to materially improve the y i e l d s ( 2 2 ) . The use of hydrobromic acid and phenol followed by steam d i s t i l l a t i o n of the phenol has also been suggested^ 3), as have the use of various aluminum s a l t s ( 2 ? ) , quaternary ammonium salts and potassium hydroxide i n ethanol at 200°C. In general, however, the methods involve the use of mineral acids, especially hydrogen halides, under temperature and usually pressure. The use of bound halides such aniline hydrochloride was then found to give f a i r l y good results at 200°C, especially when the ether link was weakened by nuclear substituents. Anlsole i t s e l f could not be demethylated i n this way even on long heating. In 1941, however, Prey suggested the use of pyridine hydrochloride(94) y found that most simple ethers could be s p l i t i n five hourd at 200°C. The most important factor i n this type of reaction i s homogenization of the reaction mixture, and the addition of 5-15% of the tota l weight of glacial acetic acid was found to give optimum results. The presence of any water i n the reaction i s to be avoided since the reflux temperature of the mixture w i l l be lowered, and as pyridine hydrochloride Is"quite hygroscopic, the use of non-delequescent - pyridine hydrobromide has been developed i n this laboratory. This compound i s a stable salt which melts and boils without decomposition and may be stored easily. The use of 1.5 equivalents of pyridine hydrobromide to 1.0 equivalents of the alkylanisole plus 10$ of the total weight of glacial-acetic acid heated under reflux to 185-195°C. for five hours, provides a clean demethylation of para alkylanisoles i n excellent yields. The yields for primary a l k y l -anisoles are nearly quantitative while those for secondaryalkylanisoles are roughly 70-90$. This method, however, does not provide a means of demethylation for ortho-secondary alkylanisoles i n greater than a few percent y i e l d . In a search for a method for these compounds, the use of a macro scale Zeisel methoxyl determination type reaction was found to be adequate. The anisole was refluxed for three hours with an excess of constant boiling hydriqdic acid and enough phenol to provide a homogeneous mixture. For the separation of the alkylphenol from the phenol solvent, use' was made of the ins o l u b i l i t y of higher sec.-alkylphenols i n dilute sodium (12' hydroxide, a phenomenon more frequently associated with polyalkylphenols v Since the same reagents provide a quantitative estimation on a semimicro scale, i t was assumed that the reaction was nearly quantitative and the free alkylphenol was purified by d i s t i l l a t i o n under reduced pressure. Yields of 70-85$ were obtained i n this way. jMl the alkylphenols were characterized as their 3:5-dinitrobenzoates prepared by the pyridine 'method^8) purified by recrystallization from light petroleum ether. The use of alpha-naphthylisocyanate to give alpha-naphthylurethans also provides an adequate method of characterization^ 9^. In passing i t i s worth noting that alkylbenzenes may be converted to the corresponding p-alkylphenols either by sulphonation followed by fusion with moist potassium hydroxide^ 3), or by the use of a rather tedious synthesis developed by Reill y and HIckenbottom(105A02,104). This method calls for mononitration of the alkylbenzene using either mixed sulphuric and n i t r i c acids at -5°0. or fuming n i t r i c and gl a c i a l acetic acids at -I0°e., both of which give exclusively p-nitro-alkylbenzenes, followed by reduction to the amine with t i n and hydrochloric acid. - 45 -The amine is then diazotized and the diazo compound decomposed to a phenol by boiling. This method has been used quite extensively by Huston as a "proof of structure w of alkylphenols prepared through condensation methods. 5. Secondary and Tertiary Alkylphenols by Condensation Methods. While i t can be seen that the preparation of secondary and tertiary alkylphenols by true synthetic methods has been q#ite limited, there has been rather a l o t of work done on the preparation of these compounds through direct condensation reactions between phenol and various active alkyl compounds. Unfortunately, much of this work has been of a purely industrial nature, and as long as compounds possessing the desired properties were obtained, l i t t l e work was done on determining the exact nature of these products and the mechanism of their production. As previously mentioned, nearly a l l condensations of the Friedel-Craf ts hydrocarbon synthesis type result i n isdmerization and a mixture of products. Huston has spent some thirty-five years studying condensa-tions of this type and has written many, papers on the subject, but s t i l l even he has to admit that the exact nature of the products cannot be accurately predicted, nor can a single, pure product be obtained i n most cases(56). In general, the aromatic nucleus may be condensed with an alcohol, a halide or an olefin, but i n certain cases use may be made of ketonesO'8), aldehydesC88), sulphates(38), and other compounds with variable success. Sulphuric acid and anhydrous aluminum chloride are by f a r the most commonly used catalysts, but the use of many other agents including hetero-polyacids such as phosphotungstic a c i d ^ 2 0 ) , perchloric acid^- 1- 2), zinc phosphate;-.0-09)t and others have been reported but need not be discussed further i n a paper of this sort. ' In general, the function of these catalysts may be exemplified by aluminum chloride which promotes condensation due to i t s electrophilic nature which allows.; i t to capture electrons from an alkyl halide. to leave a carbonium ion which may then condense with a point of high electron density i n the aromatic nucleus. I t has been suggested by Skraup (120) that alkylations of this type proceed i n i t i a l l y through the formation of O-alkyl derivatives which then rearrange i n the presence of excess catalyst to the isomeric C-alkyl derivatives. By heating various phenol ethers with different'J catalysts, especially phosphotungstic acid, Skraup has shown that rearrangement of this type does occur, but this mechanism i s not widely accepted today. There are, however, certain amounts of phenol ethers produced during alkylation, and these have been shown to isomerize to alkylphenols on treatment with aluminum chlorideO 2^). At low temperatures, ethers may be obtained as the sole reaction product of phenol alkylation using the more recently developed catalyst boron t r i f l u o r i d e ^ 8 ) , but at 40°G. there i s no evidence of ether formation. During his lengthy work on condensation reactions using aluminum chloride, Huston has shown that as a rule the condensation of phenol with primary alcohols gives, with d i f f i c u l t y , a mixture of primary and secondary alkylphenols, those with secondary alcohols give a mixture of secondary and tertiary alkylphenols, and those with tertiary alcohols give mainly the corresponding p-tertiary alkylphenol^ 2,54). These isomerizations may be looked upon as being due to migration of the carbonium ion charge to a position of maximum s t a b i l i t y or to dehydration or tiehydrohalogena-tion of the alcohol or halide i n either of two directions. Almost inevitably i f the functional group i s adjacent to a chain branching, then the tertiary alkylphenol w i l l result i n great excess(53,55,56)# j n u s b o t n tert.-amyl alcohol and 2-methylbutanol-3 both gives p-tert.-amylphenol on condensation with phenol. OH 3 OH > 4-This phenomenon i s explained by the great s t a b i l i t y of tertiary carbonium ions. The only secondary alcohols of those tested that do not isomerize were isopropyl, secondary butyl, and pinaccyl alcohols. Obviously the f i r s t two cannot give rise to more than one secondary carbonium ion without rearrangement of the carbon chain, and pinacoyl alcohol, (2:2-dimethylbutanol-3), because of the tertiary carbon atom adjacent to the carbinol group, also has but one choice. Huston has attempted to prove the structures of his various reaction products by two different synthetic routes. F i r s t l y he has used the Grignard synthesis to prepare ten different para secondary hexyl and heptyl phenols, only one of which duplicates those reported i n this paper, and secondly he has alkylated benzene and introduced a para hydroxy group by mononitration, reduction and diazotization according to the method of R e i l l y ( 1 0 5 ) . This second method does not appear to offer very conclusive proof of structure, since isomerization i s just as apt to occur during the benzene alkylation, but Huston claims to have identified these alkylbenzenes by molar refraction, parachor, density, and molecular volume determinations. These same general tendencies have also been found by Read^00*-*-0-'-)* using zinc chloride and hydrochloric acid, and i n a much more indefinite way be several groups of Russian workers working with phenol and anisole (132,136,137,139) Thege -workers, however, often only refer to n s e c -amylphenoln, etc., and i n general their physical constants seem to be somewhat irregular and not to be trusted. For example, Tsukervanik and NazarovaO 3?) report o-ethylphenol as a s o l i d melting at 137°G., this compound now being recognized as a l i q u i d at room temperature. Their results for the preparation of tertiary alkylphenols, however, seem to agree favourably with others reported. These Russian workers found the presence of considerable amounts of phenol ethers and dialkylphenols during aluminum chloride catalysed re-actions and showed that these side reactions could be minimized by the use of excess catalyst. Their proposed mechanism of the alkylation reaction i s as follows: ROH PhOH A1C12(0R) 2PhOR The alkylphenol i s then obtained by the action of excess aluminum chloride i n a manner not described. By the action of pentanol-2 on phenol, Tsukervanik reports 3-(p-hydroxyphenyl)-pentanel as a crystalline solid of melting poiJnt 86°e«, accompanied by both o- and p-(2-hydroxyphenyl)-pentane. ,In this laboratory 3-(p-hydroxyphenyl)-pentane was found to melt at 72°c., and a purified commercial sample of 2-(o-hydroxyphenyl)-pentane was found to have a refractive index of 1.5154 compared to the value of 1.519 reported. In a later paper Tsukervanik reports the preparation of 3-(p-nyroxy-phenyl)-pentane from diethyl ketone and phenol with a melting point of 79°C, and a twenty degree boiling range, along with another np-secondary amyl-phen©l w which must be 2-(p-hydroxyphenyl)-pentane, this time with a refractive index of 1.5215 at 20°C. These s t a t i s t i c s are meant merely to point out the d i f f i c u l t i e s which have been found i n attempting to isolate pure compounds by condensation methods. The use of aluminum chloride as the condensation catalyst causes less isomerization than does sulphuric acid(59.) the effect being most f e l t i n the case of halide condensations. While using olefins and sulphuric A1C13 ^ A1C12(0R) 4 HCl A1C13 ^ PhOAlCl 2 4 HCl PhOAlCl 2 H C 1 ;> PhOR 4 A l C l j • AlClgOH A1C13 ^ RPhOR 4 PhOH acid, the isomerization i s caused by i n i t i a l addition to the ethylenic bond followed by removal of sulphuric acid, thust (CH5)2-CH2-CH=CH2+H2S04 k (CH3)2-CH-CH-CH5 (CH5)2-C-CH2-CH3 — * H^O^CCH^^C^H-CR^ OSO3H The use of anhydrous hydrofluoric a c i d ^ 1 4 * 1 1 8 * 1 1 9 ) as a condensation catalyst shows considerable promise i n reducing side reactions to a minimum, but only rather limited use has been made of this reagent for phenol condensations other than those leading to p-tert.-butylphenol. Boron t r i f l u o r i d e ^ 8 > i 4 8 ) s o m e other fluorine containing compounds (128) also appear to be effective i n producing high yields and pure products. I t i s to be noted that substitution i s almost invariably i n the para position and only by blocking this position can ortho substitution-be induced. A very elegant synthesis of o-tert.-butylphenol was introduced by Hart< 4 6) i n 1949 involving the condensation of p-bromophenol with iso-butylene followed by removal of the halogen by treatment with Raney Ni-Al alloy inaqueus a l k a l i according to the method of Papa^ 9 0)' Dinitro-o-tert.-butylphenol has also been prepared by condensation of isobutylene with p-nitrophenol followed by nitration(58). From this account i t can be seen that apart from the preparation of p-tert.-alkylphenols, condensation methods do not provide a very reliable synthetic route to alkylphenols of unambiguous structure, but at the same time i t i s f e l t that for most commercial purposes at the present time, the condensation processes provide satisfactory products, and that with the development of definitely known reference substances, such as those prepared i n this laboratory, the quality of these compounds may be materially improved. 6. The Preparation and Characterization of Dinitro-alkylphenols. Phenols, being activated ring systems, are very easily nitrated using dilute n i t r i c acid to give both o- and p-nitrophenols. In order to introduce a second nitro group, i t i s necessary to use slightly more severed conditions and on applying these procedures to alkylphenols, care must be exercised to prevent oxidation of the side chain which i s quite susceptible to attack by oxidizing agents, such as n i t r i c acid. To counter-act this oxidation, there have been two general methods developed for the dinitration of alkylphenols. The f i r s t of these involves an i n i t i a l sulphonation using concentrated sulphuric acid followed by conversion of the sulphonic groups to nitro groups by the action of concentrated n i t r i c acid (density 1.36) i n i t i a l l y at -1G°C» Unfortunately, this procedure(93), while giving quite good yields, requires rather a long reaction time to give optimum results. The second method makesuse of the powerful nitrating agent fuming n i t r i c acid (density 1.50) at a low temperature using gl a c i a l acetic acid as a solvent. The phenol dissolved i n glacial acetic acid i s slowly dropped, with constant s t i r r i n g , into a mixture of fuming n i t r i c acid and glacial acetic acid, the reaction mixture being maintained at a temperature of -20°G» throughout the addition. The mixture i s then allowed to come to room temperature during two to three hours and i s poured over crushed i c e . The resulting o i l or solid i s extracted i n chloroform, carefully washed free of excess acid, dried and d i s t i l l e d under high vacuum. - 51a-Both procedures have been used i n this laboratory and both give roughly the same yields on .the order of 60-80$. However, the second method requires much less time to complete and i s somewhat easier, there-fore making i t the preferred procedure, and the one used i n the experimental section of this paper. Great care must be taken i n seeing that the crude nitrophenol i s washed free of excess n i t r i c acid since, i f any remains, decomposition w i l l result on d i s t i l l a t i o n . A somewhat similar procedure has been used by Baroni^ 3) i n the dinitration of various simply alkylphenols. This involves the use of concentrated n i t r i c acid (density 1.45) i n a large excess of chloroform at 15°C and i s reported to give excellent yields. A rather interesting method of nitration i s by the use of nitrous vapours evolved from a mixture of arsenious oxide and n i t r i c a c i d ^ 8 2 ) . The choice of solvent i s very important i n this reaction and determines whether mono or dinitration w i l l result. The use of glacial acetic acid favours dinitration while light petroleum ether gives mononitration. By the use of concentrated n i t r i c acid (density 1.36) i n glacial acetic acid at -20°$., mononitration results and this i s the method most frequently used i n the conversion of alkylbenzenes to alkylphenols by nitration, reduction and diazotization. I h i l e phenols and alkylphenols are easily characterized as benzoates, urethans, p-toluenesulphonates, etc., these reagents are nearly useless when applied to the more acidic dinitrophenols. The use of various amine salts of dinitrophenols have been suggested as suitable derivatives for - 52 -these compounds, and at the same time are of interest because of their insecticidal and herbicidal nature and their a b i l i t y to render dinitro-phenols water soluble. Almost any amine may be used provided i t s bacisity i s sufficient to enable salt formation, and a wide variety has been suggested including diethylaminet 2^), benzylamine^) and various diamines( 2 5» 1 2 5). A l l the dinitrophenols prepared i n this laboratory have been characterized as their piperidine, morpholine and cyclohexylamine salts a l l of which are easily purified red, orange, or yellow crystalline compounds ranging i n melting point from 120-234°G« for those tested to date. These salts are especially valuable as derivatives since isomeric compounds di f f e r widely i n their melting points. For example, the piper-idine salts of 2-(2-hydroxy-3:5-dinitrophenyl)-pentane and 3-(2-hydroxy-3:5-dinitrophenyl)-pentane melt at 141°C. and 173°e. respectively. This characteristic seems to be quite general and isomeric compounds may be easily identified as their amine salts. The salts are sharp melting and relatively pure after one recrystallization from benzene-petroleum ether, The experimental section of this paper describes i n detail the conditions found to be optimum i n a l l the steps involved i n the synthesis of dinitro-sec.-amyl and hexylphenols. - 53 -III EXPERIMENTAL. NOTE: A l l temperatures are uncorrected and in degrees Centigrade. Melting points are determined using an electrically heated copper block fitted with a cased thermometer, the sample being placed in a sealed glass tube within the block. 1. Preparation of Phenyl Acetate. a. Sodium Phenate - Acetic Anhydride Methodfc^l). Phenol (230 gms., 2.4 moles) was dissolved in sodium hydroxide solution (1600 mis. of 10$) contained i n a three li t e r , wide necked bottle. Crushed ice (1750 gms.) was added, followed by acetic anhydride (325 gms., 3*2 moles). The bottle was stoppered and shaken vigorously for five minutes. Carbon tetrachloride (150 mis.) was added and the lower layer separated, washed with saturated sodium bicarbonate until effervescence stopped, and dried over magnesium sulphate. The carbon tetrachloride was removed by distillation and the phenyl acetate collected from 193-200°. The ester was redistilled at atmospheric pressure, giving a colourless liquid of b.p. 193-4°, n 2 0 =1.5037. Literature gives b.p. - 195-6°, n 20« 1.5038. The yields obtained on three runs were 80$, 90$ and'90$. b. Phenol - Acetyl Chloride Method. Phenol (385 gms., 4.1 moles) was placed in a one l i t e r ground glass flask fitted with a dropping funnel and reflux condenser. Acetyl chloride (314 gms., 4.0 moles) was added slowly through the dropping funnel at such a rate as to keep the evolution of hydrogen chloride under control. The mixture was refluxed gently for thirty minutes and distilled through a - 54 -twelve inch Tigreaux column as a colourless l i q u i d boiling at 192-4°, n 2 0 =1,5037. Literature gives b.p. = 195-6°, n20« 1.5038, Yields 93$. Because of i t s good y i e l d and simplicity, the phenol-acetyl chloride method i s to be preferred* 2 # Preparation of Phenyl Propionate(141). Phenol (300 gms,, 3.2 moles) and propionic acid (264 gms,, 3.5 moles) were placed i n a one l i t e r ground glass flask f i t t e d with a dropping funnel and reflux condenser, Thionyl chloride (398 gms,, 3,5 moles) was slowly added through the dropping funnel at such a rate as to keep the evolution of hydrogen chloride and sulphur dioxide under control. The mixture was refluxed for.one hour to drive off these volatile gases, and d i s t i l l e d , the crude ester being collected from 203-212°, It was then r e d i s t i l l e d through a twelve inch Vigreaux column to give phenyl propionate as a colourless l i q u i d of b,p.= 206-8°, n21= 1,5010, Literature gives b.p,= 211°, n2°= 1,5011. The yields on two runs were 75$ and 76$. 3. Preparation of o- and p-Hydroxyacetophenone. Finely powdered anhydrous aluminum chloride (540 gms., 4.6 moles) was warmed up to 70° i n a two l i t e r , two necked flask. Phenyl acetate (360 gms., 2.7 moles) was added very slowly with constant s t i r r i n g . During this addition the temperature rose to 120° and the mixture became an orange-red glass. The mixture was heated to 140° for forty-five minutes and then cooled to room temperature. The flask was f i t t e d with a reflux condenser and placed i n an ice bath. Ice cold hydrochloric acid (1500 mis. of 6N) was added very slowly with swirling. On hydrolysis a dark red o i l formed as an upper layer and was separated by decantation. The residual solid material and acid was refluxed for thirt y minutes and the oil'once more removed. This procedure was continued u n t i l no s o l i d material remained. The red o i l was washed with dilute hydrochloric acid (2G0 mis. of 6N) and twice with water (200 mis.). The water was removed under water suction and the residual mixture fractionated under vacuum using a Bruel receiver and passing steam through the condenser-while the solid p-hydroxyacetophenone fraction was collected. o-Bydroxyacetophenone was obtained i n 41$ y i e l d as a colourless l i q u i d o f b.p.= 75°/ 2»4 mm., n 2 1 = 1.5588. Literature gives b.p.= 96°/l0 mm., n 2 1= 1.558. Semicarbazone m.p,= 215-6°, 2:4-dinitrophenylhydrazone m.p.* 212-3°• - Literature gives semicarbazone m.p.* 209-10°, 2:4-dinitrophenylhydrazone m.p,- 211°. p-Hydroxyacetophenone was obtained i n 39$ y i e l d as a red so l i d of b.p.= 160G/4 ufflu, a sample of which on recrystallization from ethanol melted at 106-7°. Literature gives b.p. = l48°/3.0 mm., m.p.* 109°. Sendcarbazohe m.p.= 203-4°i 2x4-dinitrophenylhydrazone m.p.= 258-60°. Literature gives semicarbazoner:-:.c\:\t m.p. = 198°, 2:4-dinitrophenylhydrazone m.p.™ 261°. The percentage yields of a series of duplicate runs are given i n Appendix I. 4. Preparation of o- and p-Bydroxypropiophenone. Anhydrous aluminum chloride (555 gms., 4.1 moles) was placed i n a two l i t e r , two necked flask and warmed to 70°. Phenyl propionate (400 gms., 2.7 moles) was added with constant sti r r i n g and the mixture heated to 140° for one hour, then cooled to room temperature and hydrolysed by the slow addition of concentrated hydrochloric acid (750 mis.) and water (250 mis.) as described i n the Fries rearrangement of phenyl acetate. Hot water (500 mis.) was added to the mixture to dissolve a l l the aluminum chloride, the pinkish p-hydroxypropiophenone removed by f i l t r a t i o n and dried. The o-hydroxypropiophenone appeared as a black o i l i n the f i l t r a t e and Was separated. Both fractions were dried under water suction and fractionated under vacuum using a Bruel receiver. o-Hydroxypropiophenone was thus obtained i n 44$ yi e l d as a colourless o i l boiling at 79°A8 mm., n 2 2= 1.5498, semicarbazone m.p, = 214-5°» Literature gives b.p.= 115°A5 mm n22s 1.548, semicarbazone m.p.» 213°. p-Hydroxypropiophenone was obtained i n 22$ y i e l d as a light pink solid of b.p.= l8l°/5 mm., which on recryst-a l l i z a t i o n from ethanol gave colourless plates melting at 147-8°. Semi-carbazone m.p. = 167-8°. Literature gives b.p. s 191°A° mm., m.p. = 148°, semicarbazone m.p.*168°. 5. Methylation of the Hydroxy-Aceto- and Propbphenones. p-Hydroxyacetophenone(50 gms., 0.37 moles)owas dissolved i n a solution of potassium hydroxide (40 gms.) i n water (250 mis.) contained i n a 500 ml., three necked ground glass flask f i t t e d with a dropping funnel and a very efficient mechanical s t i r r e r . The flask was cooled i n an ice back to 9 ° and dimethyl sulphate (90 gms., 0.71 moles) added through the dropping funnel over a period of twenty minutes. The ice bath was then removed and the flask warmed to about 50° for two hours with constant,:vigorous sti r r i n g throughout. More potassium hydroxide was added, i f necessary, to keep the solution basic. The mixture was allowed to settle and the o i l y upper layer separated. A further portion of dimethyl sulphate (10 gms.) and sufficient potassium hydroxide, to ensure basicity, was added to the residual l i q u i d and s t i r r i n g continued for half an hour. This procedure was continued u n t i l no more o i l y layer formed. The combined upper layers were washed with 10$ potassium hydroxide u n t i l no cloudiness resulted on acidification of the washings, then with water, the o i l dried under water suction and d i s t i l l e d under vacuum. In a l l cases, considerable unreacted hydroxy alkylphenone was recovered on acidification of the remaining basic solution. p-Methoxyacetophenone was obtained on d i s t i l l a t i o n as a colourless l i q u i d of b.p.= 97°/0.7 nun., which s o l i d i f i e d on standing to give large colourless plates of m.p.* 36-7°. Semicarbazone m.p. = 198-9°. Literature gives b.p.» 145°/14 mm., m.p.= 38^9°, semicarbazone m.p.= 197°. The results of seven duplicate runs are recorded i n Appendix I I . o-Methoxyacetophenone was obtained as a colourless l i q u i d of b.p.= 85°/0.7 mm., n 2 0= 1.5390, semicarbazone m.p. = 184-5°. Literature gives b.p. * 131°/18 mm., n 2 5 • -> = 1.538, semicarbazone m.p. • 182-3° • The results of nine methylations of o-hydroxyacetophenone are recorded i n Appendix I I . p-Methoxypropiophenone resulted i n 56$ y i e l d as a colourless l i q u i d of b.p.»97°/0.4 mm., n 2 0 - 1.5460, semicarbazone m.p. = 177°. Literature gives b.p.= 145°/l4 mm., n!5» 1.5477, semicarbazone m.p. = 172-3°, 177°. An almost quantitative recovery of unreacted starting material was achieved. o-Methoxypropiophenone was obtained i n 72$ y i e l d as a colourless liquid of p.p..=; 86°/0.4 mm., n 2 0 * 1.5320, semicarbazone m.p. = 156°. Literature gives b.p.= 137°/16.5 mm., semicarbazone m.p.= 154°. 6. Preparation of Isobutyl Bromide (140). Isobutyl alcohol (277.5 gms.) and red phosphorus (25.6 gms.) were placed i n a one l i t e r ground glass flask f i t t e d with a dropping funnel and reflux condenser. Bromine (315 gms.) was slowly added through the - - 5 8 -dropping runnel while the flask was gently warmed. On completion of the addition the mixture was refluxed for one hour, the reflux condenser removed and the majority of the bromide d i s t i l l e d off. Water (100 mis.) was added to the residue and d i s t i l l a t i o n continued u n t i l no more heavy o i l appeared i n the d i s t i l l a t e . The lower layer was separated, washed twice with equal volumes of concentrated hydrochloric acid, water, 10$ sodium carbonate, water, and dried over calcium chloride. The bromide was then d i s t i l l e d and collected as a heavy, very pale yellow l i q u i d boiling at 90 -92 ° , and having n 25= 1.4330. Literature gives b.p.= 9 1 ° , n 2 0s 1.436. Yields of 44$ and 49$ were obtained i n two preparations. 7. Preparation of Alkyl-Methoxyphenyl Carbinols. (e.g. 3-(p-Methoxyphenyl)-pentanol-3) Magnesium turnings (24.3 gms.i 1 mole) were placed i n a scrupulously dried one l i t e r , three necked, ground glass flask f i t t e d with an effici e n t , y mercury sealed s t i r r e r , pressure equalizing dropping funnel, and reflux condenser. The whole apparatus was f i t t e d so as to allow i t to be kept under a slight pressure of nitrogen dried by bubbling i t through concen-t r a t e d sulphuric acid. Anhydrous, sodium dried ether (180 mis.) was added to the flask, and ethyl bromide (109 gms., 1 mole) dissolved i n anhydrous ether (250 mis.) placed i n the dropping funnel. Nitrogen was passed through the apparatus for ten minutes to displace a l l a i r , and then flow regulated so as to keep a slight pressure of nitrogen throughout the remaining procedure. The s t i r r e r was started and the ethyl bromide and ether added very slowly. A reaction started after the addition of a few mis. The remaining bromide was added over forty-five minutes, the black mixture refluxed for one hour and then cooled to - 5 ° i n an ice-rock salt - 59 -bath. With the temperature kept at about 0°, p-methoxypropiophenone (82 gms., 0.5 mis.) dissolved i n anhydrous ether (70 mis.) was added through the dropping funnel during forty-five minutes. The mixture was then refluxed for f i v e or six hours during which time i t turned grey and became f u l l of suspended solid material. The mixture was then added very slowly and with constant sti r r i n g to a saturated solution (1 l i t e r ) of ammonium chloride and cracked ice. When the layers cleared the ether layer was separated, washed with water, and dried over magnesium sulphate. The ether was removed under reduced pressure and a small amount of the remaining 3-(p-methoxyphenyl)-pentanol-3 d i s t i l l e d under mercury diffusion i n order to attempt to obtain physical constants without spontaneous dehydration. B.p.= 67°/0»005 mm., n 25» 1.5278, y i e l d * 88$. Calculated for G^HisOgxMeO, 15.81$. Pound: MeO, 15.93, 16.09$. This procedure was applied to obtain eight different tertiary carbinols, physical constants and-analyses of which are shown i n Table I . 8. Dehydration of the Carbinols. (e.g. The Preparation of 3-(p-Methoxyphenyl)-pentene-2) Crude 3-p-methoxyphenyl-pentanol-3 (92.5 gms.) obtained directly from the Grignard reaction was placed i n a 500 ml., ground glass flask f i t t e d with a reflux condenser and Dean and Stark tube. Toluene (150 mis.) and a very small crystal of iodine were added and the mixture refluxed for several hours u n t i l no more water was collected. Very close to the theoretical volume of water was collected i n the Dean and Stark tube. The toluene was then removed under reduced pressure and the remaining alkene vacuum d i s t i l l e d . 3-(p-Methoxyphenyl)-pentene-2 was obtained as a colour-less, somewhat o i l y l i q u i d of b.p.= 58°/0.03, n 2 5 a» 1.5310. Calculated for ej£H1^0.'lfeO,17*61$. Found: lieO, 17*52, 17.55$. Nitrosyl chloride m.p. = 76°(d.). Calculated for C12H1602NCl:MeO, 12.84; N, 5.80$. Found: N, , This method was used to prepare eight alkenes, physical constants and analyses of which are recorded i n Tables n and ILT. The nitrosyl chloride derivatives (135,47) were prepared by adding dropwise a mixture of glacial acetic acid (2 mis.) and concentrated hydro-chloric acid (2 mis.) to the alkene (2 mis.) dissolved i n glacial acetic m acid (2 mis.) and isoamyl n i t r i t e (3*3 mis.) contained i n a small Erlenmeyer flask chilled to -5° i n an ice-hydrochloric acid bath. The mixture was stirred constantly during the addition which took thir t y minutes. The mixture was green and eventually threw, out of solution a white solid which was f i l t e r e d off and washed repeatedly with methyl alcohol. I t was then dried i n a vacuum desslcator and melting points, analyses, etc., done immediately since the nitrosyl chlorides were frequently found to be unstable. 9* Hydrogenation of the Alkenes. (e*g* The Preparation of 3-(p-MBthoxyphenyl)-pentane)• 3-(p-Methoxyphenyl)-pentene-2 (63 gms*, 6.36 moles) was placed i n the glass l i n e r of the hydrogenatbr along with Raney nickel (approx* 2 gms.) and ethanol (10 mis*). The li n e r was placed i n the bomb and hydrogen introduced to a pressure of 750 p . s . i * The bomb was then shaken at 50° un t i l no further pressure drop occurred (approx. one hour). The Raney nickel was then f i l t e r e d off, washed with ethanol, and the ethanol removed under reduced pressure. The alkane was then vacuum d i s t i l l e d , giving 3-(p-fflethGxyphenyl)-pentane i n 90$ yie l d as a colourless o i l of b.p.= 56°/0.02, n 25= 1.5030. Calculated for C12H180:MeO, 17-4135- Found:-MeO, 17.40,17.47. Sulphonamide m.p.-107°. Calculated for Ci^gOjNSjMeO, 12.11$ N,5.49$. Found :MeO, 12.28j N, 5.52$. Eight alkanes were prepared i n this way and their physical constants are reported i n Tables IV and V. The sulphonamide d e r i v a t i v e ^ 4 3 ) w a g prepared by dissolving the phenol ether (1 gm.) i n chloroform (5 mis.) contained i n a 25 ml., Erlenmeyer flask. Chlorosulphonic acid (7 mis.) was added dropwise to the mixture kept at -15° i n an ice-hydrochloric acid bath. The mixture, which turned red and became somewhat viscous, was then added slowly to crushed ice (30 gms.). The chloroform layer was separated, the chloroform evaporated under reduced pressure, the residue added to concentrated ammonium hydoxide (10 mis.) and boiled for fifteen minutes. Water (50-100 mis.) was added, the so l i d f i l t e r e d off and recrystallized from petroleum ether. 10. Demethylation of the Alkylanisoles. (a) The Preparation of Pyridine Rydrobromide. Pyridine (80 gms., 1 mole) was placed i n a 500 ml., 3 necked ground glass flask f i t t e d with a reflux condenser and dropping funnel. Hydro-bromic acid (47$, 192 gms., 1.2 moles) was slowly added through the dropping funnel and the mixture refluxed for thirty minutes. The reflux condenser was replaced by a d i s t i l l i n g head and the water and excess hydrobromic acid d i s t i l l e d off up to 130°. The residue was poured into a large mortar while s t i l l hot, allowed to cool, and ground up. Pyridine hydrobron&de was obtained a slightly pink solid or, on recrystaliization from ethanol, as white crystals of m.p.= 214-5°• Literature m.p.= 213°. Yields of 9% 34% and 96$ were obtained i n three preparations, (b) The Preparation of 3-(p-Hydroxyphenyl)-pentane. 3-(p-Methoxyphenyl)-pentane (45.5 gms., 0.25 moles) was placed i n a 100 ml., ground glass flask f i t t e d with a reflux condenser. Pyridine hydrobromide (53«5 gms., 0.325 moles) and gla c i a l acetic acid (9.8 gms., 10$ of t o t a l weight) were added and #he mixture refluxed at 190-200°"over-night, the temperature being controlled by a Variac and a thermometer hung down the reflux condenser with i t s bulb i n the l i q u i d . The mixture was cooled, water (50 mis.) added and the mixture extracted with ether. The ether extracts were washed twice with 10$ sodium bicarbonate, and the phenol extracted several times with 10$ potassium hydroxide. The alkaline solution was then acidified with hydrochloric acid at which point the phenol appeared as an o i l which was extracted i n ether, dried over magnesium sulphate, the ether removed under reduced pressure, and the phenol vacuum d i s t i l l e d . 3-(p-Bydroxyphenyl)pentane was obtained i n 68$ y i e l d as a colourless o i l boiling at 83°/0»3 mm., which s o l i d i f i e d on cooling to a white solid of m.p.-71-2°. Calculated for CnHi60:C, 80.44; H, 9.82$. Found: C, 80.26j H, 9.44$. 3:5-Binitrobenzoate m.p.* 92-3°. Calculated for CigB^gNgOsxN, 7.82$. Founds,7.92$. (c) The Preparation of 2-(o-Hydroxyphenyl)-4-methylpentane. (i) Using pyridine hydrobromide. 2-(o-Methoxyphenyl-4-methylpentane (37.6 gms.) was refluxed with pyridine hydrobromide (41 gms.), and glacial acetic acid (7.9 gms.) as - 63 -previously described. On extraction with 10$ potassium hydroxide and acidification, only approximately 0.5. gms., of a brown o i l was liberated. The demethylation was considered to be a failure and the residual organic phase was dried and d i s t i l l e d to recover 30 gms. of the unreacted phenol ether. ( i i ) Using hydriodic acid and phenol. 2- (o-Methoxyphenyl)-4-methylpentane (35.5 gms.) was refluxed f o r three hours with a mixture of 40$ hydriodic a d d (175 gms.), and phenol (175 gms.). At the end of this time the reaction mixture was cooled to room temperature, dissolved i n ether, and extracted repeatedly with 5$ sodium hydroxide u n t i l acifidication of the extracts gave almost no clouding of the solution. The ether solution was then washed with water, dried over magnesium sulphate and d i s t i l l e d under reduced pressure, giving a 76$ yie l d of 2-(o-hydroxyphenyl)-4Hnethylpentane as a colourless viscous li q u i d of b.p.* 59°/0«03 mm., n25 = 1.5077. Calculated for C-j_|H180: C,80.85j H, 10,18; MeO. 0.0$. Found: C, 81.055 H, 10.17$ OCH3, 0.30$. The product was only very sparingly soluble i n dilute sodium hydroxide. This method of demethylation was used for a l l the ortho alkylphenols reported. . . . I I . Nitration of the Alkylphenols. (e.g. The Preparation of 3-(4-Hydroxy-3:5-dinitrophenyl)-pentane). 3- (p-Rydroxyphenyl)-pentane (24 gms.) was mixed with gla c i a l acetic acid (60 mis.) and added dropwise, with constant mechanical s t i r r i n g , to a mixture of yellow fuming n i t r i c (density 1.50, 40 mis.) and gla c i a l acetic acids(75 mis.) contained i n a stainless steel beaker and cooled to -20° i n an acetone-dry ice bath. The temperature was kept at -20° - 64 -throughout the addition which took forty-five minutes. On addition of the phenol the mixture became a dark red colour. The beaker was removed from the cooling bath and allowed to come slowly to room temperature. I t was then allowed to stand for two hours and poured onto crushed ice (200 gms.) whereupon a red o i l sank to the bottom. The ice was allowed to melt slowly and the mixture extracted three times with 100 ml. portions of chloroform. The chloroform extracts were then carefully washed with warm water u n t i l neutral to congo red indicator paper. This usually -required about ten washings. The solution was then dried over anhydrous magnesium sulphate, the solvent removed under reduced pressure, and the remaining red l i q u i d d i s t i l l e d under high vacuum, to give a 75$ y i e l d of 3-(4-bydroxy-3*5-dinitrophenyl)-pentane as a viscous amber coloured l i q u i d of b»p.= 149°/ 0.03 mm., n 2^- 1.5664. This technique was used i n the preparation of ten dinitrophenols, physical constants of which are l i s t e d i n Table VIII. 12. Preparation of jamine Salts of Dinitro-alkylphenols. (e.g. The Preparation of the piperidine salt of 3-(4-hydroxy-3i5-dinitrophenyl)-pentane• 3-(4-hydroxy-3t5-dinitrophenyl)-pentane (1 ml.) was dissolved i n benzene (5 mis.) contained i n a small Erlenmeyer flask. Piperidine (1 ml.) was added to this mixture which immediately turned red, and the solution was boiled for a few minutes on a hot plate. On cooling and addition of low boiling petroleum ether (b.p.= 30-60°) a solid mass of orange crystals was deposited which was f i l t e r e d and recrystallized twice from a benzene-pabroleum ether (b.p. 65-100°) solvent pair. The product was easily purified i n this way giving small orange plates melting at 213o. - 64a-Calculated for G^H^N^: N, 12.38$. Found: N, 12.36$. Piperidine, morpholine and cyclohexylamine salts of the eight dinitroalkylphenols were prepared in this way and their melting points and analyses are recorded in Tables IX, X and XI. TABLE 1. PHYSICAL CONSTANTS OF CARBINOLS Compound b.p. n 25 Found : % Methoxyl Calculated % Yield* 2-(p-Methoxyphenyl)-hexanol-2 2-( p-Methoxyphenyl)-4-methylpentanol-2 2- ( p-Methoxyphenyl) -3-methylpentanol-2 3- (p-Methoxyphenyl)-pentanol-3 2-(o-Methoxyphenyl)-hexano1-2 2-( o-Met hoxyphenyi)-4-me thylpent anol-2 2- (o-Methoxyphenyl)-3-methylpentanol-3 3- (o-Methoxyphenyl)-pentanol-3 68%.oo5 63%. 005 1.5285 1.5128 .14.92, 14.82 15.06, 15.11 Dehydrated spontaneously 87%. 005 1.5278 16.09, 15.93 79%.005 1.5095 14.78, 14.77 68%. 005 1.5260 15.20, 15.26 73%. 005 1.5170 16.18, 16.14 76%.005 1.5160 15.96, 15.90 14.90 14.90 14.90 15.81 14.90 14.90 14.90 15.81 85 84 81 88 79 85 84 95 •» Based on amount of water s p l i t off during dehydration whenever possible. Apparently dehydrated spontaneously on d i s t i l l a t i o n . Methoxyl determinations high i n most cases indicating partial dehydration. TABLE II. PHYSICAL CONSTANTS OF ALKENES. n 25 % Methoxyl Compound . . * b.p. Found Calculated 2-( 'p-Methoxyphenyl)-hexene-2 70°/0.0l 1.5329 16.15, 16.25 16.31 2H [p-Methoxyphenyl)-4-methylpentene-2 68%.04 1.5290 16.22, 16.26 16.31 2-[p-Methoxyphenyl)-3-methylpentene-2 6 3 % . 04 1.5260 (17.45, (17.45, 17.45) 17.40) .16.31 3-< [p-Methoxyphenyl)-pentene-2 58%.03 1.5310 17.52, 17.55 17.61 •2-[o»Methoxyphenyl)-hexene*2 64%.04 . 1.5199 16.34 .16.31 2-[o-Methoxyphenyl)-4-methylpentene-2 59°/0.0l 1.5134 16.16, 16.21 16.31 2-1 [o-Methoxyphenyl)-3-methylpentane-2 5 7 % . 04 1.5170 16.60, 16.53 16.31 3- 'o-Methoxyphenyl)-pentene-2 7 0 % . 03 1.5220 17.54, 17.52 17.a • TABLE III. NITROSYL CHLORIDES OF ALKENES. Compound m.p. of nitrosyl chloride % Nitrogen Found Calculated 2-(p-Methoxyphenyl)-hexene-2 86 5.48 5.48 2-(p-Methoxyphenyl)-4-me thylpent ene-2 104 5.53 5.48 2-( p-Methoxyphenyl)-3-methylpent ene-2 - - 5.48 3-(p-Methoxyphenyl)pentene-2 79 5.83 5.80 2- ( o-Methoxyphenyl) -hexene-2 103 5.45 5.48 2-(o-Methoxyphenyl)-4-methyl pentene-2 - - 5.48 2-(o-Methoxyphenyl)-3-methylpe nt ene-2 - 5.48 3-(o-Methoxyphenyl)-pentene-2 97 5.81 5.80 TABLE IV. PHYSICAL CONSTANTS OF ALKANES. n25 % Methoxyl Compound b.p. Found Calculated % Yield 2-[p-Methoxyphenyl)-hexane 6 0 % . 03 1.5012 16.26, 16.30 16.14 100 2-[ p-Methoxyphenyl) -4-methylpentane 54%.04 1.4930 16,28, 16.16 16.14 80 2- /P-Methoxyphenyl)-3-methylpentane 60%.03 1.5060 (16.88, (16.89, 16.90) 16.92) 16.14 67 3-[p-Methoxyphenyl)-pentane 56%.02 1.5030 17.40, 17.47 17.41 90 2- [ o-Methoxyphenyl)-hexane 59%.02 1.5045 15.96, 16.01 35.14 91 2-1 [ o -Me thoxyphenyl) -4-methylpent ane 54%.04 1.4951 15.99, 16.15 16.14 94 2-[o-Methoxyphenyl) -3-methylpentane 5 2 % . 0 l 1.5070 16.22, 16.25 16.14 96 3-[o-Methoxyphenyl)-pe nt ane 5 0 % . 01 1.5010 17.20, 17.24 17.41 93 TABLE V. SULFONAMIDES OF ALKANES. m.p. of % Methoxyl % Nitrogen Compound sulphonamide Found Jalculated Found Calculated 2-( p-Methoxyphenyl) -hex an e 79 11.59 [ 11.44 5.18 5.16 2-( p-Methoxyphenyl) -4-methylpentane 92 11.43 11.44 5.10 5.16 . 2-(p-Methoxyphenyl)-3-methylpentane 100 11.44, 11.48 11.44 5.16 5.16 3-( p-Methoxyphenyl)-pent ane 107 12.28 12.11 5.52 5.49 2-( o-Methoxyphenyl) -hexane - - 11.44 5.16 2-( o-Methoxyphenyl) -4-methylpentane 103 11.47, 11.51 , 11.44 5.13 5.16 2-(o-Methoxyphenyl)-3-me thylpentane - - 11.44 5.16 3-(o-Methoxyphenyl)-pentane 71 crud^ 12.11 5.49 TABLE VI. PHYSICAL CONSTANTS OF ALKYLPHENOLS. n25 % Carbon* % Hydrogen* Compound. b.p. m.p. Found Calculated Found Calculated % Yield 2-( p-Hydroxyphenyl) -hexane 8 0 % . 05 - 1.5110 80.37 80.85 9.93 10.18 68 2-(p-Hydroxyphenyl) -4-methylpentane 8 0 % . 1 - 1.5082 80.69 80.85 10.21 10.18 89 2-( p-Hydroxyphenyl) -3-methylpentane. 8 7 % . 09 - 1.5210 80.60 80.85 10.01 10.18 56 3-( p-Hydroxyphenyl) -pent ane 83%.3 72° mm 80.26 80,44 9.44 9.82 68 2-(o-Hydroxyphenyl)-hexane 6 0 % . 0 l - 1.5160 80.99 80.85 10.12 10.18 81 2-(o-Hydroxyphenyl)-4-methylpentane 59%.03 ma 1.5077 80.38 80.85 10.17 10.18 76 2-(o-Hydroxyphenyl)-3° methylpentane 53%.02 - 1.5074 81.05 80.85 10.00 10.18 81 3-(o-Bydroxyphenyl) -pentane 6 1 % . l 64° - 79.93 80.44 9.78 9.82 71 2-( o-Hydroxyphenyl).-pentane 2-(o-Hydroxyphenyl)-2-methylbutane. 6 8 % . 05 6 5 % . 03 1.5154) ) 1.5208) Conn e r c i a l Samp les. * Carbon and hydrogen analyses by Drs. Weiler and Strauss, Oxford. TABLE VII. 35-DINITROBENZOATES OF ALKYLPHENOLS. Compound m.p. oi' 3:5-dinitro-benzoate % Nitrogen Found Calculated 2-< [p-Hydroxyphenyl)-hexane 92 7.66 " 7.53 2-( [ p-Hydroxyphenyl) -4 -diethyl pent ane 93 7.57 7.53 2-1 [p-Hydroxyphenyl) -3-methylpentane 103 7.64 7.53 3-1 [ p-Hydroxyphenyl) -pent an e 92 7.92 7.82 2-( [o-Hydroxyphenyl)-hexane 94 7.60 7.53 2-< [o-Hydroxyphenyl) -4-methylpentane 95 7.49 7.53 12-( ' o-Hydroxyphenyl)-3-met hylpent an e 94 7.57 7.53 3-( ' o-Hydroxyphenyl)-pentane 87 7.67 7.82 2-( [o-Hydroxyphenyl) -2-methylbutane* 154 7.92 7.82 2-( [ o-Hydroxyphenyl) -pentane*"' 96 7.75 7.82 it Sharpies o-tert.-amylphenol. •fKf Sharpies o-sec.-amylphenol. TABLE VIII. PHYSICAL CONSTANTS OF DINITRO-ALKYLPHENOLS. Compound b.p. n 25 % Yield 2- (4-Hydr cxy-3 s 5 -dinit r o phenyl) -hexane 160%.02 1.5574 71 2-(4-Hydroxy-3;5-dinitro phenyl)-4-methylpentane 147%.01 1.5562 74 2-(4-Hydroxy-3:5-dinitrophenyl)-3-methylpentane 157%.03 1.5648 60 3-(4-Hydr oxy-3i5-dinitrophenyl)-pentane 149%.03 1.5664 75 2-( 2-Hydroxy-3; 5-dihitro phenyl) -hexane 145%.05 1.5636 66 , 2-( 2-Hydroxy-3:5-dinitrophenyl) -4-methylpent ane 14 2%.04 1.5589 63 3-( 2-Hydroxy-3; 5-dinitrophenyl) -pentane 2-(2-Hydroxy-3:5-dinitrophenyl)-3-methylpent an 2-(2-Hydroxy-315-dinitrdphenyl)-2-methylbutane^ 138°/0.007 3 1 3 7 % . 05 158%.3 1.5668 1.5520 (m.p.*53°) 1.5770 55 62 58 2-( 2-Hydrcxy-315-dinitrophenyl} -pentane4*" 132%.03 1.5698 63 •«• Phenol obtained from Sharpies Chemical Company. TABJE IX. PI PERU) INE SALTS OF DHJITRO-ALKYLPHENGLS. % Nitrogen Salt of M.P. Found Calculated 2-(4-Hydroxy-3:5-dinitrophenyl) -hexane 150 11.84 11.89 2-( 4-Hydroxy-3:5-din i t ro phenyl) -4-methylpentane 186 11.87 11.89 2-( 4-Hydroxy-3 j 5niinitrophenyl) -3-methylpentane 160 11.80 31.89 3-(4-Hydroxy-3:5-dinitroph eny 1)-pent ane 213 12.36 12.38 2-(2-Bydroxy-3 s 5-dinitrophenyl)-hexane - - -2-(2-Hydroxy-3:5-dinitrophenyl)-4-met hylpent ane 136 11.83 11.89 2-( 2-Hydroxy-3 s 5-<iinit rophenyl) -3-methylpent ane 187 11.89 11.89 3-( 2-Hydroxy-3 s 5-dinitro phenyl) -pent ane 173 12.33 12.38 2-(2-Hydroxy-3$5-dinitro phenyl) -2-methylbutane 164 12.29 12.38 2-(2-Hydroxy-3:5-dinitrophenyl)-pent ane 141 12.22 1 12.38 TABLE X. "MORPHDLINE SALTS OF DINITRO-ALKYLPHENOLS. ! • % Nitrogen Salt^ of nup. i?'ouna Calculated 2-( 4-Hydroxy-3:5-dinitrophenyl) -. hexane' 145 11.73 11.83 2-( 4-Hydr oxy-3 j 5-dinitrophenyl) -4-methy:lpentane 168 11.75 11.83 2- (4~Hydrpxy-3s5-dinitrophenyl)-3-me tby/lpent an e 113 12.15 11.83 3-( 4-Hydroxy-3; 5-dinitrophenyl)-pentane 185 12.17 12.31 2-(2-Hydroxy-3:5-dinitrophenyl)-hexane 133 12.81 11.83 2-( 2-Hydr oxy-315-<iinitro phenyl) -4-jaethylpentane 144 11.78 11.83 2- ( 2-^ydroxy-3s 5-dinitrophenyl) -3-methylpentane *• - - 11.83 3-( 2-Hydroxy-3j 5-dinitrophenyl) -pentane • - 157 11.84 12.31 2-(2-Hydroxy-3;5-dinitrophenyl)-2-methylbutane 154 11.84 12.31 2-( 2-Hydroxy-3s 5-3initrophenyl)-pentane . , 147 - 12.22 12.31 TABLE XI. CYCLOHEXYLAMINE SALTS OF DIN3TRO-AIKYLPHENOLS. 1 % Nitrogen | Salt of m.p* . Found Calculated | 2-(4-Hydroxy-3:5-dinitro phenyl)-hexane 138 11.32 11.44 2-( 4-Hydroxy-3s 5-dinitrophenyl) -4-methylpentane 165 11.34 11.44 2- ( 4-Hydr oxy-3 j 5-dinitrophenyl) -3-me thylperitane 163 11.36 11.44 3-( 4-Hydroxy-3:5-dinit rophenyl) -pentane 217 11.77 11.89 2-( 2-Hydr oxy-3 s 5-dinitrophenyl) -hexane 173 11.48 11.44 2-(2-Hydroxy-3$ 5-dinitrophenyl)-4-methylpentane 193 11.3.7 11.44 2- ( 2-Hydroxy-3s 5-dinitrophenyl) -3-methylpentane 207 U.42 11.44 3-(2-Hydroxy-3s5-din itrophenyl)-pentane 192 ll. V80 11.89 2-( 2-Hydr oxy-315-<iinitro phenyl) -2-methylbutane 205 11.74 11.89 2-(2-Hydr oxy-3:5-dinitrophenyl)-pentane 190 11.84 11.89 TABLE XII. , COMPOUNDS .PREVIOUSLY REPORTED IN THE LITERATURE. Refract: Lve Index Compound Ref. Method l i t . thesis n 2 1 l i t . n 25 thesis • 3 - (• p-Methoxyphen yl) -pentanol-3 27 p-Med4C6H4-C0OEt 4 EtMgBr 120°/3 8 7 % . 005 - 1.5278 3-(p-Me t hoxyph enyl) -pentene-2 27 p-MeO'C6H4-CO'N(Et)2 + EtMgBr 117°/8 5 8 % . 03 - 1.5310 ,3- (p-Methoxyphenyl) -pentene-2 72 • p-Ke0«C6H4»CO0Et + EtMgl 129°/17 5 8 % . 03 1.5395 1.5310 3-(p-Methoxyphenyl)-pentane 72 Above olefin 4 Na/EtOK 5 6 % . 02 1.5276 1.5030 2- (p-Hydroxyphenyl)-3-methylpentane 56 p-Me0'C6H4*C0.CH3 •* 2° BuMgBr 120°/3 8 7 % . 09 - 1.5210 3-(p-Hydroxyphenyl)-pentane 56 Condensation 108-17°/2 83%.03 - m.p. =72° 2-(p-Hydroxyphenyl)-hexane 56 Condensation H0°/2 8 0 % . 05 — 1.5110 2- (p-Hydroxyphenyl)-3- methylpentane 56 Condensation 120°/3 87%.09 - 1.5210 2-(p-Hydroxyphenyl)-4-methylpentane' 56 Condensation 109°/2 8 0 % . 1 1.5082 -77-IV. DISCUSSION OF RESULTS. The Grignard method of synthesis of both ortho and para secondary alkylphenols described i n this paper appears to provide the only complete synthesis of these compounds i n such a way that their structures are unequivocal 0 By a judicious choice of the correct starting materials, almost any desired phenol may be prepared. The only limitations which might be imposed are those due to steric effects during more complicated Grignard reactions, and possibly steric hindrance preventing the formation of the ortho isomer during the Fries Rearrangement of highly branched phenol esters. I t was originally thought i n this laboratory that a Grignard reaction between tert.-butylmagnesium chloride and the methoxyaeetophenones i n the syntheses of 2-(o- and p-hydroxyphenyl)-3»3ScJiinetnylbutane would be a fa i l u r e due to the rather limited a b i l i t y of tertiary Grignard reagents to react without reduction. Huston and Kaye^6) have, however, reported the synthesis of the para isomer of this phenol by the Grignard method, and therefore i t appears that even tertiary halides may be used i n certain cases. An alternative synthesis of these phenols i s planned i n this labloratory starting with a Fries Rearrangement of phenyl pivalate (phenyl trimethylacetate) to give o- and p-hydroxyphenyl-tertiary butyl ketone which may then be methylated and treated i n the usual way with methyl magnesium iodide. I t w i l l be interesting to see whether the ortho hydroxy ketone may be obtained i n spite of steric hindrance» Yet another route to these phenols was considered but found to be impractical. This involved a Grignard reaction between o- andp-bromo-- 78 -anisole and pivaldebyde (trimethylacetaldehyde), but the aldehyde could not be obtained i n sufficiently large yields and proved to be most unstable, being oxidized i n a i r to pivali c acid* The method of synthesis attempted was that using an anomalous Grignard reaction between tert.-butyl magnesium chloride and methyl formate at -50°C* as suggested by wbitmore^ 1 4^* The phenol esters were very easily prepared i n high yields and i n the case of phenyl acetate i t was found to be more efficient to use acetyl chloride rather than acetic anhydride and sodium hydroxide as suggested by Vogel0*1 ) # Phenyl propionate was best prepared by refluxing a mixture of phenol, propionic acid, and thionyl chloride rather than attempting to isolate propionyl chloride f i r s t * I t i s to be noted that almost equimolecular amounts of the ortho and para isomers were obtained by the Fries Rearrangement of phenyl acetate under the reported conditions. By increasing the temperature;; of reaction, the ortho isomer i s obtained i n larger amounts, presumably due to the greater s t a b i l i t y of this compound due to chelation* The low y i e l d (22$) of p-hydroxypropiophenone obtained by the Fries Rearrangement of phenyl propionate i s unfortunate since a quite pure crude product'was obtained i n almost 50$ y i e l d . However, during d i s t i l l a t i o n of this compound trouble was encountered with the laboratory plumbing and the d i s t i l l a t i o n had to be stopped and started several times, resulting i n some decomposition and a large pot residue. The methylation procedure described seems to be quite satisfactory and very easily executed. I t appears that excessive caution i n cooling the reaction mixture during addition of the dimethyl sulphate i s - 79 -unnecessary provided the addition i s made slowly and the temperature kept under control* The use of potassium hydroxide i n salt formation of the phenol i s to be preferred over sodium hydroxide due to the much greater solubility of the potassium salt and the resulting smaller volume of reaction mixture which may be more efficiently stirred. Very efficient mechanical s t i r r i n g was found to be necessary i f good yields are to be obtained. The methylation of a 100 gram batch of p-hydroxy-acetophenone rather than the usual 50 grams was found to give only a 50$ yield, some 20-30$ lower than those obtained with the small batch. This i s presumably due to the less efficient s t i r r i n g possible with the larger volume of reaction mixture. The use of red phosphorus and bromine i n the preparation of primary alkyl bromides from the corresponding alcohols appears to give only 45-50$ yields compared with that of 90$ reported by Vogel0-4°). These yields, however, are for the twice d i s t i l l e d product, a crude y i e l d at 71$being obtained, „ The Grignard reactions were carried out using the usual precautions with regard to dry equipment and freshly d i s t i l l e d reagents, the reaction mixture being kept constantly under a slight pressure of dried nitrogen throughout the reaction. *n a l l cases a reaction started almost immed-iate l y on the addition of the halide to clean magnesium turnings and i n no case was i t found necessary to resort to, seeding the mixture with iodine or methyl iodide. The lengthy f i v e hour refluxing has been found to effectively eliminate the presence of unreacted ketone which has a tendency to c o d i s t i l with the reaction product. The use of two moles - 80 -of Grignard reagent also favours complete reaction. Once again, very efficient, mechanical s t i r r i n g i s required, especially during the addition of the ketone at -5°C. at which point a sol i d material i s sometimes thrown out of solution. The hydrolysis i s best carried out using a very mildly acidic agent such as ammonium chloride rather than a mineral acid which would promote dehydration of the unstable tertiary carbinols. Even using ammonium chloride, 2-(p-methoxyphenyl)~3~methylpentanol-2 was found to dehydrate spontaneously, and the slig h t l y high methoxyl content of nearly a l l the other carbinols indicates pa r t i a l hydrolysis during dehydration or during d i s t i l l a t i o n under high vacuum. The crude carbinols were dehydrated directly by the Dean and Stark method and only a small portion was d i s t i l l e d to obtain constants. Alpha-naphthylurethan derivatives were attempted, but i n no case was any product other than dinaphthylurea (m.p. 296°G.) obtained. Alphaj-naphthylisocyanate i s , i n general, a much more satisfactory reagent than phenylisocyanate due to i t s much greater s t a b i l i t y towards water. Urethans are the only standard derivatives which have been used for tertiary alcohols, but only very few cases have been reported and i n general they are considered to be of use for only primary and secondary alcohols. Ordinary alcohol derivatives, such as benzoates, p-toluenesulphonates, etc.j cannot be prepared for tertiary alcohols since they require acidic reagents which cause dehydration to occur. In the few cases where no water was collected during Dean and Stark dehydration, i t was necessary to reflux the carbinol with 10$ sulphuric acid to ensure complete dehydration. This measure was, however, avoided i f at a l l possible, since sulphuric acid i s known to induce polymerization of olefins, and, indeed, when i t was used a considerable high boiling residue was l e f t which undoubtedly consisted of polymeric material. Once again the problem of preparing a derivative was encountered, but the use of nitrosyl chlorides seems to have provided an answer* These compounds do not seem capable of recrystallization without a large loss occurring and since the nitrosyl chlorides are frequently only obtained i n very small yie l d , i t has been found more convenient to merely wash the derivatives repeatedly with absolute methanol to remove any impurities. In this way the nitrosyl chlorides were obtained as f i n e l y divided white powders which started to darken i n colour within twenty-four hours and eventually became black tars. Because of this i n s t a b i l i t y (which seems to be absent i n the nitrosyl chlorides of lower primary alkylanisoles), the derivatives were prepared immediately prior to analysis and dried under vacuum at room temperature. Hydrogenation of the alkenes was very easily accomplished using a pressure hydrogenator and a Raney nickel catalyst at 50°e. No refinements i n this procedure are desirable or necessary, high yields and standards of purity being obtained.consistently. Sulphonamides provide a satisfactory, but sometimes d i f f i c u l t to obtain, derivative for alkylanisoles, the procedure using chlorosulphonic acid being i n f i n i t e l y more successful than that using sulphuric acid and barium chloride previously described. Only o i l s could be obtained from two of the eight anisoles prepared, and i n most other cases the y i e l d of purified sulphonamide was small. The problems related to demethylation of the alkylanisoles have been described earlier i n this paper. The use of pyridine hydrobromide appears to be suitable for the para series, but not for the ortho series. "The use of constant boiling hydriodic acid and phenol certainly provides demethylation i n quite good yields, and while the reaction i s probably quantitative, considerable losses are bound to occur during separation of the alkylphenol from the solvent on the basis of the smaller s o l u b i l i t y of the o-alkylphenol i n sodium hydroxide. Considerable thought has been devoted to finding another solvent, but a l l seem to have a disadvantage. Glacial acetic acid would be ideal but does not appear to work, even on long refluxing. Hydrobromic acid and phenol, and hydrobromic acid and acetic acid have both been attempted at this university, but with only moderate success. Hydriodic acid and acetic acid suffers from the added drawback that some decomposition to free iodine occurs and the alkylphenol i s d i f f i c u l t to isolate free from the colour of iodine* Further investiga-tion of the use of 47$ hydrobromic acid g l a c i a l acetic acid plus gaseous hydrogen bromide might provide satisfactory results. Pyridine hydriodide suffers i n the same way as the hydrochloride i n being hygroscopic and carrying water of hydration with i t . Nitrations are best carried out using the fuming n i t r i c - g l a c i a l acetic acid method which gives yields of 55-75$ i n a l l cases tested. The use of a longer period of standing after the addition of the phenol to the acid, might increase the yields somewhat but was not considered to be worth the extra time required. I t is interesting to note that the percentage y i e l d varies according to the amount of reactants, being highest when a large batch of phenol i s nitrated. This i s presumably due to the relatively smaller amount of dinitrophenol l o s t during extraction of the excess n i t r i c acid with water. Usually the dinitrophenol was obtained as the sole reaction product but i n a few cases a very small amount of a yellow solid was obtained boiling at a lower temperature. This was appa-rently a mononitro derivative but only 0.5-1.0 grams were ever obtained. Salt formation of the dinitrophenols proved very easy except f o r two piperidine and one morpholine salts which could only be obtained as viscous o i l s on repeated attempts. The cyclohexylamine salts were a l l easily obtained. A l l the amine salts were readily recrystaliized from a mixture of petroleum ether, benzene, and ethanol as required i n the individual cases. Nitration and salt formation of a sample of no-see.-amylphenolM obtained from the Sharpies Chemical Company proved this compound to be different from 3-(o-hydroxyphenyl)-pentane prepared i n this laboratory, and thus i t i s to be assumed that i t was 2-(o-hydroxyphenyl)-pentane. This compound i s being prepared i n t h i s laboratory and w i l l be described shortly. No explanation can be given for the anomalous methoxyl analyses shown for 2-(p-methoxyphenyl)-3-methylpentene-2 and 2-(p-methoxypheny])-3-methylpentane, both of which showed reproducable determinations respectively 1.1 and 0.3$ higher than the theoretical. Carbon and hydrogen analysis of the resulting phenol indicates a relatively puie compound, both being within 0.2$ of the theoretical values. Analyses of the derivatives of these compounds are very close to the theoretical. - 84 -It i s hoped that the experimental results obtained i n this study w i l l f i nd some use i n the dual purpose for which they were intended -both as selective herbicides or Insecticides and as reference compounds i n further studies of phenol condensations to be undertaken at this university. The results of toxicity tests being undertaken at Oxford university under the direction of Professor G.E. Blackman are eagerly awaited and w i l l be reported at a later date. - 85 -APPENDIX I. YIELDS IN THE FRIES REARRANGEMENT OF PHENYL ACETATE. % Yield o-Hydroxy- % Yield p-Hydroxy- Overall Run No. aeetophenone acetophenone Yield 1 28 35 63 2 33 36 69 3 33 38 71 4 41 39 80 APPENDIX II. RESULTS OF METHILATIONS OF p-HYDROXYACETOPHENONE. Run No. Percentage Y i e l d 0 B.P. l a 2 k 5 b 6 7 50 60 73 50 48 78 75 134°/5o0 mm. 114°/3.0 mm. 108°/2.5 mm. l00°/0.9 mm. 98°/0.9 mm. 97°/0.7 mm. 96°/0.7 mm. (a) Sodium hydroxide used instead of potassium hydroxide. Phenol found d i f f i c u l t to dissolve. (b) Double quantities used and s t i r r i n g not as efficient due to larger volume. (c) Yields are based on reactants and do not take into account recovered unreacted material. APPENDIX III. RESULTS OF METHYLATIONS OF o-HYDROXYACETOPHENONE. Percentage Yield Run No. B.P. n 20 1 2 3 4 5 6 7 8 9 a 36 47 65 60 65 69 46 64 40 88°/l>0 mm. 82°/0.4 mm. 85°/0.5 mm. 86°/0.8 mm. 85°/0.7 mm. 8l°/0.6 mm. 89°A»2 mm. 82%>.7 mm. 82°/0.7 mm. 1.5390 1.5390 1.5391 1.5388 1.5391 1.5391 1.5391 1.5390 1.5390 (a) Methylation of crude, recovered o-hydroxyacetophenone. - 86 -VI. BIBLIOGRAPHY. 1. Abbey, A. British Patent 593,320. 1941. (C.A. 42:1702). 2. Alles, G.A., Icke, R.N., Feigen, G.A. J. Am. Chem. Soc. 64:2031. 1942. 3. Baroni, £., KLeinau, W. Monatsh, 68:251. 1936. (C.A. 30:7754). 4. Bartz, Q.R., Miller, R.F., Adams, R. J. Am. Chem. Soc. 57:371. 1935. 5. Beranger, P.M. Bull. soc. chim. 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Thesis/Dissertation
eng
Chemistry
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Graduate
The synthesis of some secondary amyl and hexyl homologues of dinitro ortho and paracresols
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