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UBC Theses and Dissertations

The synthesis of some secondary amyl and hexyl homologues of dinitro ortho and para cresols Hillman, Melville Ernest Douglas 1954

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THE SYNTHESIS OF SOME SECONDARY AMYL AND HEXYL HOMOLOGUES OF DINITRO ORTHO AND PARA CRESOLS by MELVILLE ERNEST DOUGLAS HJXLHAN A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE i n the Department of CHEMISTRY Ve accept t h i s thesis as conforming to the standard required from candidates f o r the degree of MASTER OF SCIENCE Members of the Department of Chemistry THE UNIVERSITY OF BRITISH COLUMBIA May, 1954. i ABSTRACT Eight new dinitro secondary amyl and hexylphenols of unequivocal structure were synthesized and characterized by their piperidine, morpholine and cyclohexylamine salts. The f i r s t step in the syntheses was the esterifica-tion of phenol to give phenyl acetate and phenyl propionate. A high temperature Fries rearrangement in the absence of solvent was used to convert the phenyl esters to o- and p-hydroxyaceto- and propiophenones. The alkyl o- and p-hydroxyphenyl ketones were then methylated with dimethyl-sulphate in an alkaline medium. The resulting methoxy-acetophenones and methoxypropiophenones were reacted with Grignard reagents prepared from n- and isopropyl bromides. The tertiary alcohols thus obtained were dehydrated by reflux-ing in toluene, in the presence of iodine. The water in the water-toluene azeotrope was collected in a Dean and Stark tube. Nitrosyl chloride derivatives of the alkenes were prepared whenever possible, and analyzed for nitrogen. The alkenes were dissolved in ethanol and hydrogenated o under 1000 p.s.i. pressure at 50 C. The resulting alkylanisoles were characterized as sulphonamides which were analyzed for both nitrogen and methoxyl content. The para alkylanisoles were demethylated by refluxing o with pyridine hydrobromide at 200 C. The ortho alkyl anisoles were demethylated by refluxing with constant boiling hydriodic acid and phenol. The resulting alkylphenols were characterized as 3,5-dinitrobenzoate derivatives which were analyzed for nitro-gen. The alkylphenols were nitrated to the dinitro derivatives with concentrated n i t r i c acid (density 1.50) in glacial acetic o acid at -15 C. The piperidine, morpholine and cyclohexyl-amine salts were prepared by the addition of the amine to a benzene solution of the nitrophenol. The amine salts were analyzed for nitrogen. The alcohols, alkenes and alkyl-anisoles were analyzed for methoxyl values. Carbon and hydro-gen analyses for the alkylphenols were also obtained. The phenols prepared were: 2-io- and p-hydroxyphenyl)-pentane, 2-(o- and p-hydroxyphenyl)-3-methylbutane, 3-(o-and p-hydroxyphenyl)-hexane, 3-(o- and p-hydroxyphenyl)-2-methylpentane. A sample of "o-sec-amylphenoln obtained from Sharpies Chemicals Inc. was found to consist mainly of 2-(o-hydroxy-phenyl)-pentane. A Fries rearrangement of phenyl trimethyl acetate (phenyl pivalate) gave phenol as the only identifiable pro-duct, together with possible degraded and polysubstituted mixtures. o-Hydroxytrimethylacetophenone (o-hydroxypivalo-phenone) could not be separated or identified in the d i s t i l -late. • • • 1 1 1 ACKNOWLEDGMENTS The writer wishes to express sincere appreciation and gratitude to Mr. G.G.S. Dutton f o r his encouragement and h e l p f u l supervision during the course of t h i s project and f o r his many f r i e n d l y kindnesses. Grateful acknowledgments are also made to Canadian Industries Ltd., to the President of the Uni-v e r s i t y of B r i t i s h Columbia, and to the National Research Council f o r f i n a n c i a l assistance. Acknowledgment i s also extended to the Sharpies Chemicals Inc. f o r a sample of no-sec-amylphenol. n * * * TABLE OF CONTENTS Page ABSTRACT i ACKNOWLEDGMENT i i i INTRODUCTION . . 1 HISTORICAL 1. T o x i c i t y of Nitrophenols 4 2. The Preparation of Alkylphenols by Condensa-t i o n Methods 5 3. The Preparation of Alkylphenols by Molecular Rearrangements • • 16 4. The Preparation of Alkylphenols by Unequivocal Synthesis 18 5. The Preparation and Characterization of Dinitro-alkylphenols 24 DISCUSSION OF REACTIONS 26 EXPERIMENTAL 1. Preparation of Phenyl Acetate 35 2. Preparation of Phenyl Propionate 35 3. Preparation of o- and p-Hydroxyacetophenone . 36 4. Preparation of o- and p-Hydroxypropiophenone. 37 5. Methylation of the Hydroxy-Aceto- and Propiophenones 38 6. Preparation of n-Propyl Bromide 40 7. Preparation of Isopropyl Bromide . . . . . . 40 8. Preparation of Alkyl-Methoxyphenyl Carbinols 41 Preparation of 2-(p-Methoxyphenyl)-pehtanol-2 41 9. Dehydration of the Carbinols 42 10. Hydrogenation of the Alkenes . . . . . . . . 44 Preparation of 2-(p-Methoxyphenyl)-pentane 44 11. Demethylation of the Alkylanisoles 45 (a) Preparation of Pyridine Hydrobromide. . 45 (b) Preparation of 2-(p-Hydroxyphenyl)-pentane 43 (c) Preparation of 2-(o-Hydroxyphenyl)-pentane 46 ( i ) using pyridine hydrobromide . . . 46 ( i i ) using hydriodic acid and phenol . 46 12. N i t r a t i o n of the Alkylphenols 48 Preparation of 2-(4-Hydroxy-3,5-dinitrophenyl) -pentane 48 V Page EXPERIMENTAL (Continued) 13. Preparation of the Piperidine Salt of 3-(4-Hydroxy)- 3,5-dinitrophenyl)-pentane . . 49 14. Attempted Preparation of o-and p-Hydroxy-(trimethylacetophenone) . . . . 49 DISCUSSION OP RESULTS. . 63 APPENDICES I. Yields Obtained in the Methylation of p-Hydroxy-acetophenone • • • • . 75 II. Yields Obtained in the Methylation of o-Hydroxyacetophenone 75 III. Yields Obtained in the Methylation of p-Hydroxypropiophenone . . . . . 75 IV. Yields Obtained in the Methylation of o-Hydroxypropiophenone . . . . 76 V. Melting Points and Mixed Melting Points of the Amine Salts of Nitrated "o-sec-Amyl-phenol" and 2-(Hydroxyphenyl)-pentane. . 76 BIBLIOGRAPHY 77 * * * v i LIST OF TABLES TABLE Page I. Secondary Amyl and Hexylphenols Reported i n the L i t e r a t u r e , Prepared by Condensation Me-thods Using a Straight Chain A l k y l a t i n g Agent 15 I I . Compounds Reported i n the L i t e r a t u r e , Prepared by Unequivocal Syntheses . 20 H I . Alcohols 52 IV. Alkenes • 53 V. N i t r o s y l Chlorides of Alkenes 54 T I . Alkylanisoles . . . . . . . 55 VII. Sulphonamides of Alkylanisoles 56 VIII. Alkylphenols 57 IX. 3, 5 Dinitrobenzoates of Alkylphenols 58 X. Dinitro-alkylphenols 59 XI. Piperidine Salts of Dinitro-alkylphenols . . . . 60 XII. Morpholine Salts of Dinitro-alkylphenols . . . . 61 XIII. Cyclohexylamine Salts of Dinitro-alkylphenols . . 62 * * 1 INTRODUCTION! The synthesis of a wide range of d i n i t r o - o and p-alkylphenols has been undertaken i n t h i s laboratory during the past few years. The alkylphenols previously prepared have included those containing primary, t e r t i a r y (10), i s o (31) and some of the secondary (76) a l k y l groups. This thesis describes the preparation of the res t of the second-ary amyl and four more of the secondary hexylphenols. The only secondary a l k y l phenols of c l e a r l y defined structure that have been prepared through condensations of phenol with the appropriate a l k y l halide, alcohol or o l e f i n are isopropyl and sec-butyl phenols. If an attempt i s made to introduce a large a l k y l group the r e s u l t i n g product i s found to be a mixture of isomeric compounds (42). There are three reasons f o r the synthesis of the phenols and n i t r o phenols prepared i n t h i s laboratory. The f i r s t reason arose from the discovery that 2,4 d i n i t r o -6-sec-butyl phenol was a very toxic n i t r o a l k y l phenol, both as a s e l e c t i v e herbicide and as an i n s e c t i c i d e (25). For many years 2,4-dinitro-6-methyl phenol ( d i n i t r o ortho cresol) (16,102), sold commercially as D N 0 C, has been used as an e f f i c i e n t s e l e c t i v e herbicide. Recent work (24) has shown that secondary a l k y l homologues of d i n i t r o ortho c r e s o l (isopropyl- and sec-butyl-) have enhanced a c t i v i t y . It was therefore decided to prepare the d i n i t r o secondary amyl and 2 hexyl phenols and have them tested f o r h e r b i c i d a l properties. The second reason i s that the compounds described i n t h i s and other theses may be used as reference compounds i n a study of the d i r e c t a l k y l a t i o n of phenol with a l k y l halides, alcohols and alkenes. The t h i r d purpose i s related to the r a p i d l y increas-ing i n d u s t r i a l importance of a l k y l phenols. Hany t e r t i a r y , normal and i s o a l k y l phenols as well as sec-butyl and sec-amyl phenols are sold commercially. Since most of these com-pounds are produced by condensation methods leading to a mix-ture of isomeric products which are not r e a d i l y separated by d i s t i l l a t i o n i t becomes evident that a thorough investigation into the course and mechanism of condensation reactions i s necessary. One of the many uses f o r a l k y l phenols i s i n the plas-t i c s industry. Matsuo (68) i n studying resins made from equimolar quantities of formaldehyde and p - a l k y l phenols, has found that as the number of carbon atoms i n the a l k y l group i s increased the r e s i n f i l m becomes more f l e x i b l e and has better physical properties such as better resistance to s o l -vents. Rostler and Bornstein (95) have found that p - t e r t -arayl phenol when used as an additive to phenol formaldehyde r e s i n , y i e l d s a more transparent product. A l k y l phenols have also been found to be excellent p l a s t i c i z e r s (6). A l k y l phenols have also been used as antioxidant additives i n l u b r i c a t i n g o i l (2) as dye intermediates (17) 3 and as s t a b i l i z e r s against d i s c o l o r a t i o n and v i s c o s i t y degradation i n thermoplastic c e l l u l o s e ether compounds such as e t h y l c e l l u l o s e (59,60). Commercial ortho and para sec amyl phenols pre-pared by condensation methods (88,89,45) have already been used i n the p l a s t i c s industry (59,60) and the para isomer i n the dye industry (17). 4 HISTORICAL 1, T o x i c i t y of Nitrophenols The r e l a t i o n s h i p between t o x i c i t y and chemical st r u c -ture of a l k y l nitrophenols has been discussed i n several review a r t i c l e s (8, 112, 102, 76). The following i s an outline of the t o x i c i t y studies. The most toxic compounds found were the 2,4-dinitro-6-alkylphenols. (25, 119, 69). For st r a i g h t chain a l k y l homo-logues, maximum t o x i c i t y was found f o r s i x or seven carbon atoms i n the side chain.(52). The iso-butyl and iso-amyl com-pounds showed lower t o x i c i t y than t h e i r s t r a i g h t chain isomers and the t e r t i a r y isomers were s t i l l less t o x i c . (8). For-merly i t was thought that increased branching lowered the t o x i c i t y . It was then found by Crafts i n 1946 (24) that 2,4-dinitro-6-sec-butylphenol was more toxic than a l l of the nitrophenols previously tested. This discovery promoted t h i s study of the secondary amyl and secondary hexyl isomers. Dinitro-o-sec-butylphenol, known i n d u s t r i a l l y as D N 0 S B P, has been produced and tested on a commercial scale. (35, 61, 67). Recently o- and p-sec-amyl phenols (45, 88, 89) and t h e i r d i n i t r o derivatives have also been produced commercially. In tests on dinitro-o-sec-amyl phenol (D N 0 S A P), (27, 39) Holmaster and Danielson have demonstrated i t s high t o x i c i t y toward the two spotted spider mite, Tetranychns bimacnlatus. and also toward winter weeds such as henbit and chickweed. Standard A g r i c u l t u r a l Chemi-5 cals Inc. produces a spray concentrate having the trade name Sinox General which contains 75% D N 0 S A P (39). Crafts (25), comparing the relative toxicities of a number of nitro-phenols, assigned the arbitrary value of 100 for dinitro-o-sec-butylphenol, measuring the other phenols as per cent toxicity, compared to D if 0 S B P. Using this system Crafts found a value of ninety for dinitro-o-sec-amyl phenol. The commercial secondary amyl phenols mentioned above were a l l prepared by condensation methods and at best were mixtures of ortho and para secondary and tertiary amyl phenols. 2. The Preparation of Alkylphenols by Condensation Methods To prepare alkylphenols, a direct Priedel-Crafts alkylation (4, 33) could f i r s t be considered. However in most cases this method of synthesis yields mixtures of isomers which w i l l be discussed later. The alkylation reactions were catalyzed by Lewis acids such as aluminum chloride (43, 123) f e r r i c chloride, (103) boron trifluoride (70, 71, 32, 135) zinc chloride (88, 89), hydrofluoric acid (16, 104) sulphuric acid (47, 111) phosphoric acid (118, 48,50) and phosphoric anhydride (122). The alkylating agents included alkenes (105,100), alkylhalides (106), alcohols (127), ketones (126), ethers (3) and esters (9). The mechanism of the Friedel-Crafts reaction appeared to vary with experimental conditions. 6 The nature of the alkylating group and the reaction tempera-ture affected the structure of the products formed. For instance, n-propyl bromide and isopropyl bromide both reacted with benzene in the presence of aluminum chloride to form isopropylbenzene (34, 86), unless the reaction proceeded at a low temperature when no isomerization occurred. (51). CH3-CH-CH3-B r CH3-CH-CH3 A l C l ? CH3-CH2-CH2-Br + AICI3 (Low temp.) If an n-propyl ester was used as an alkylating agent the product was n-propylbenzene. (9). Isomerization did not take place as readily with aluminum chloride as with boron trifluoride or sulphuric acid (51). Hence even the catalyst affected the structure of the reaction products. Among the several mechanisms suggested for the Friedel-Crafts reaction, one postulated by McKenna and Sowa (70, 71) involved an intermediate alkene which could then react at either end of the double bond. Benzyl alcohol and benzhydrol, however, though excellent alkylating reagents are incapable of forming alkenes. 7 In a second mechanism proposed by I p a t i e f f (47) a l k y l a t i o n was thought to occur by means of a complex formed from the a l k y l group and the c a t a l y s t . (123, 124). S3 - C - C I + AlCls.'J-fr R $ - C » C 1 A 1 C 1 S I ' — * . A l k y l a t i o n This mechanism had support from several reactions under mild conditions i n which no isomerization occurred (127, 50) but d i d not o f f e r a s u i t a b l e explanation f o r isomerized products. (125, 128). A t h i r d mechanism involved formation of a carbonium ion which could be followed by an intramolecular migration of a hydrogen atom with bonding electrons to the p o s i t i v e centre, as postulated by Whit more. (132). The r e s u l t i n g carbonium ion attacked the substrate e l e c t r o p h i l i c a l l y to y i e l d isomerized products. CHo^ CH^. _ ^ C CH- CI + A1C1Q > °^C CH + A1C1; / | 2 ^ ^ 3 7 / \ « 2 + -H 3 ^ (alkylated products) This mechanism would explain the formation of a t e r t i a r y butyl compound. Addition of dry hydrogen chloride greatly increased the ease of aluminum chloride catalyzed reactions when an alkene was used as the a l k y l a t i n g agent (7,44), 8 possibly i n d i c a t i n g the formation of carbonium ions. R ^R R + f = C + A1C1 + HCl y C - C -» H + A1C1. / \ 3 / I 4 R R R R Two main e l e c t r o n i c e f f e c t s control the r e l a t i v e s t a b i l i t y of the carbonium ions such as the isobutyl and t e r t - b u t y l ions. The f i r s t e l e c t r o n i c e f f e c t i s induction. C H q CHo \ + \ + C H — • CH« and £c < CH C H 3 " ag* 3 Although the isopropyl group has a greater inductive, and therefore greater s t a b i l i z i n g e f f e c t than the methyl group, the influence of three methyl groups would probably sur-pass the sing l e e f f e c t of the isopropyl group (46). The second e l e c t r o n i c e f f e c t i s hyperconjugation. The i s o b u t y l carbonium ion has only one alpha hydrogen atom, whereas the t e r t i a r y butyl has nine alpha hydrogen atoms with which hyperconjugation can take place. CH„ CHg -C - C H , * C = CH CT3 2 " ^ " w"2 H+ CH_ CHo \ N C - CH2 -i > ^ c = C H2 CH +*-\- CH 3 H 3 H+ 9 Because of extra derealization (resonance) energy of stabi-l i z a t i o n the tertiary carbonium ion would be more stable than the isobutyl carbonium ion. The theory of hyperconjugation assisted i n predicting the type of alkylbenzene or al k y l -phenol that would have resulted from a specific Friedel-Crafts reaction. halides which had beta alkyl substituents invariably yielded tertiary substituted products. Moffatt (76) r e d i s t i l l e d , nitrated and characterized by amine salt formation a sample of Sharpies o-sec-amyl phenol which could have three possible structures. The derivatives were found by the author to be identical with those of 2-(o-hydroxyphenyl)-pentane. Sharpies Chemicals Inc. report (101) that their sec-amyl phenols were produced by condensation of phenol with pentene-2 under acidic condi-tions. An alkene i s a nucleophilic reagent, and may bee: attacked i n i t i a l l y by a proton forming a carbonium ion, which can then react with a molecule of phenol. The proton could have attacked in either of two ways resulting i n two of the isomeric secondary amyl phenols. Huston (43,44) has shown that alcohols or alkyl + CH.-CH = CH-CHA-CH~ + H + CH3-CH2-CH-GH2-CHg I + CH0-CH-CH -CH -CH 3 2 2 II 10 Since the alkylphenol was mainly 2- -hydroxyphenyl)-pentane the most stable carbonium ion should have been I I . This could have been predicted by the theory of hyperconjuga-t i o n , since there are f i v e alpha hydrogen atoms i n carbonium ion U and only four i n carbonium ion I. (44) discovery that on condensation with benzene under the c a t a l y t i c influence of aluminum chl o r i d e , pentanol-3 yielded approximately equal quantities of the two secondary amyl isomers while pentanol-2 gave mostly 2-p-hydroxyphenyl-pentane. attacked, influenced possible isomerization of the a l k y l a t i n g agent. A l k y l a t i o n of benzene with p i n a c o l y l alcohol produced 2,2-dimethyl-3-phenylbutane. However, with phenol the pro-duct was a t e r t i a r y hexylphenol, 2,3-dimetbyl-2-p-hydroxy-phenylbutane. Hustone explained t h i s type of isomerization by the migration of a methyl group during the condensation. This theory was further substantiated by Huston's Huston (42) found that the nature of the molecule OH CH_-C-CH—CH.+ A1C1 k*3 He did not explain why the intramolecular rearrangement did not occur when benzene was alkylated. Although Huston (42) explained the above rearrange-ment by the formation of a carbonium ion, he used the alkene theory to explain other types of isomerization. He found that when 2-methyl-4-pentanol was condensed with phenol under the c a t a l y t i c influence of aluminum chloride the main product was a t e r t i a r y hexylphenol, 2-(p-hydroxyphenyl)-2-methylpentane. He stated that a s h i f t of the double bond i n the alkene produced from 2-methyl-4-pentanol apparently occurred before the main condensation took place. CT3V ° V VCH - C H 0 - C H - C H „ A l C l o ' CH-CH = C H - C H - + H o 0 yS t j 6 6 & ^ 3 OH CH 3 \ C = CH-CH - C H —> condensation y 2 3 CT3 This mechanism might more reasonably involve a double sac-' cessive migration of charge i n a carbonium ion. CH-CH«-CH-CH 0 A l C l o „ , _ " CH / 2 I 3 2 _ » A 1 C 1 3 0 H + 3 ^CH=CH-CH-CH, CT3 OH • C H 3 ^ I 7 3 ^ C - C H - C H g - C H g > ^ C - C H 2 - C H 2 - C H 3 CHg JJ_^ CHg + condensation 12 Degradation of the a l k y l group can occur under the action of a strong acid. Simons (107) has shown that t e r t -butylchloride was obtained in' ten to seventeen per cent y i e l d s by t r e a t i n g tert-amyl chloride with anhydrous hydro-o f l u o r i c a c i d at 0 C. Ether formation and p o l y a l k y l a t i o n also add to the complexity of the reaction mixture (124, 135). Fedoseeva (32) on a l k y l a t i n g phenol with pente.ne-2 under the influence of boron t r i f l u o r i d e , obtained a mixture of sec-amyl phenyl ether, sec-amyl-^ec-amyl phenyl) ether, phenol and sec-amyl phenol. A l k y l a t i o n of toluene (103) or benzene (128) gave mainly the meta-dialkyl benzene with some of the para isomer. Meta s u b s t i t u t i o n could be explained (66) by formation of a charge transfer complex between aluminum chloride and the a l k y l benzene having d i f f e r e n t d i r e c t i n g properties than the free aromatic compound. Several methods f o r converting an alkylbenzene to a p-alkylphenol have been investigated. R e i l l y (92) developed a low temperature n i t r a t i o n of the alkylbenzene to form a para-n i t ro compound which was reduced, diazotized and hydrolyzed. This method has been used extensively by Read (90, 91) and Huston (43, 44) and Najarova (80). Thus Huston has com-pared the phenols obtained by a l k y l a t i n g benzene with those obtained by a l k y l a t i n g phenol using a large number of second-ary and t e r t i a r y alcohols. Bygden (14) produced p-alkyphenols by sulphonation of an alkylbenzene, followed by fusion with moist potassium hydroxide. Jfoyle and Van Duzee (78) converted alkylhalobenzenes to the corresponding alkylphenols by heating 13 i n the presence of sodium hydroxide and cuprous oxide catalyst at 200-300°C. In three hours they produced 2-ethyl-5-sec- amyl phenol and related compounds. Since F r i e d e l - C r a f t s a l k y l a t i o n of phenol usually gives p - a l k y l substituted products, production of ortho alkylphenols has been attempted by blocking the para p o s i -t i o n and removing the blocking group, a f t e r a l k y l a t i o n . Hart (36) prepared pure o-tert-butylphenol°by a l k y l a t i n g p-bromophenol with isobutylene under the influence of sulphuric a c i d , then removing the bromine by the action of Raney nickel-aluminum a l l o y and aqueous a l k a l i (82). Briggs (10) however, found that isoamylene would not condense with p-bromophenol under the same reaction conditions. I p a t i e f f , Pines and Friedman (49) obtained the d i n i t r o derivative of o-tert-butylphenol by condensing p-nitrophenol with i s o -butylene and phosphoric a c i d and n i t r a t i n g the product. Some generalizations can be made about the structure of the a l k y l group following a F r i e d e l - C r a f t s a l k y l a t i o n of phenol. Read (89) found that phenol tended to attach i t s e l f to the most substituted carbon of the a l k y l group. Huston (43, 44) has shown that t e r t i a r y alcohols gave good y i e l d s of pure t e r t alkylphenols. He also showed that beta a l k y l substituted a l k y l a t i n g agents gave t e r t i a r y a l k y l -phenols. When the chain branch was further removed from the functional group, increasing amounts of sec-alkylphenols were formed. 14 The r e s u l t s of condensations using a s t r a i g h t chain a l k y l a t i n g agent are shown i n Table I. Because no derivatives and few r e f r a c t i v e indices were recorded i n the l i t e r a t u r e i t was d i f f i c u l t to compare the compounds having an unequi-vocal structure and those from condensation reactions. Compounds described as the symmetrical p-sec-amyl phenol, 3-(p-hydroxyphenyl)-pentane, gave melting points ranging o from 79 to 86 C. However Moffatt (76) found that t h i s com-o pound melted at 72 C when synthesized by an unequivocal method s t a r t i n g from p-methoxypropiophenone and ethylmagnesium iodide. p-tert-Amyl phenol melts at 92° (100). This sug-gests that the condensation product could contain a large amount of the p-tert-amyl phenol obtained by an intermolecular rearrangement of the carbonium ion. Thus d i e t h y l carbinol and d i e t h y l ketone when used as the a l k y l a t i n g agents gave products having m.p. of 86° and 79° respectively. The a l k y l group was probably less susceptible to isomerization when present as a ketone. The condensation products that should correspond to 3-(p-hydroxyphenyl)-hexane were l i s t e d as being l i q u i d s but t h i s compound when synthesized by an unequivocal method o was a s o l i d melting at 49 C. TABLE I i SECONDARY AMYL AND HEXYLPHENOLS-BY CONDENSATION METHODS USING A STRAIGHT CHAIN ALKYLATING AGENT Compound (as named i n re- A l k y l a t i n g Catalyst B.p T • Refractive Index Ref. ference ) agent n L i t « °C/mm. This lab. °c/mm. L i t This lab n25 sec-amylphenol + phenol Sec-amylphenol p-sec-amyl-phenol Mixture of p-sec-amylphenols pentene-2 pentanol-2 pentanol-2 pentanol-2 BF 3 Z nCl2+Hcl AICI3 A1C1„ + HCl gas 180-204 240-260 150-160/30 90-95/3 84/0.5 84/0.5 84/0.5 84/0.5 — 1.5132 1.5132 1.5132 1.5132 32 88,89 125 42 p-sec-amyl-phenol p-sec-amyl-phenol pentanone-2 pentanol-3 AICI3 Al C l g 245-250 84/0.5 83/0.3 n 1 9=15212 m.p.= 86° v 1.5132 m.p. =72° 126 125 mixture of p-sec-amylphenols sec-amylphenol pentanol-3 AlClo+HCl 0 gas •m mm 90-95/3 238-244 83/0.3 83/0.3 m.p.=85-86° m.p.=85—86° m.p. =72° m.p.=72° 44 45 p-sec-amyl-phenol pentanone-3 AICI3 245-260 83/0.3 m.p. = 79° m.p. =72° 126 o-sec-amyl-phenol sec-hexylphenol pentanol-2 hexene-3 AlClg H 2S0 4 140-150/30 110/3 65/0.1 90/0.03 n 2 0 =1.519 n 2 2 =1.5135 1.5122 m.p.=49° 125 111 sec-hexylphenol sec-hexyl alcohol Z nCl 2+HCl 250-275 90/0.03 mm mm m.p.=49° 88,89 mixture of hexylphenols hexanol-3 A1C1 Q +HC1 gas 252-256 90°/0.03 m.p.=49° 44 mixture of hexylphenols hexanol-2 A1C1.+HC1 3 gas 251-255 80°/0.05 — 1.5110 44 16 3. The Preparation of Alkylphenols by Molecular Rearrangements Alkylphenols have often been prepared by the rear-rangement of alkylphenyl ethers. The a l k y l group was just as susceptible to isomerization i n t h i s reaction as i t was i n the P r i e d e l - C r a f t s condensation. This i s i l l u s t r a t e d by the r e s u l t s of Sowa (110) who reacted isopropylphenyl ether with boron t r i f l u o r i d e producing a wide v a r i e t y of phenols and phenol ethers. Another molecular rearrangement that could have been used to prepare a l k y l phenols was the Claisen rear-rangement of a l l y l ethers of phenols (116, 117). 0CH 2-CHsCH OH This rearrangement was studied to elucidate the mechanism but could be applied to synthesis of ortho substituted amyl and hexyl phenols. The F r i e d e l - C r a f t s and alkylphenyl ether reactions gave predominantly para substituted phenols. Rearrangement of the a l l y l group to the ortho p o s i t i o n has 17 been considered a c y c l i c inversion. Ryan and O'Connor (97) proved t h i s theory by rearranging a l l y l phenyl ether i n which the gamma carbon was tagged with C 1 4 . In the pro-duct the radio-active carbon was attached d i r e c t l y to the ri n g . When the ortho positions were blocked, (79), the a l l y l group migrated to the para p o s i t i o n without inversion. This r e s u l t was explained by Dewar (28) as a // complex mechanism and by Hurd and Pollock (41) as a double c y c l i c inversion. Lauer and co-workers (62) have shown that i n some reactions the beta instead of the gamma carbon of the a l l y l group i s found at the ortho p o s i t i o n . 0CH2-CH-CH CH2 Heat PhNEt 2 6H [3 0-CH-CH=CH Heat PhNEt 2 V C H 3 CH3 0 Both reactions gave about 88% y i e l d of the alkenyl phenol whose structure was determined by i d e n t i f i c a t i o n of the pro-ducts of oxidative degradation. Although no reference to secondary amyl or hexyl-phenols, synthesized by a Claisen rearrangement, could be found i n the l i t e r a t u r e , hydrogenation of the above pro-duct should y i e l d 2-(o-hydroxyphenyl)-pentane. 18 4. The preparation of alkylphenols by uniquivocal synthesis. The alkylphenols of formulas I and I I (n = 0 to 9) have been prepared previously (22, 94, 98, 30). Briggs (10) (CH 2 )n-CH3 I II found the best method of preparation to be a F r i e s rearrange-ment of a phenyl ester, followed by a Clemmensen reduction of the hydroxy-ketone. Dutton, Briggs and Herler (31) prepared o- and p-i s o b u t y l - and isoamylphenols by Grignard reactions of i s o -propyl magnesium bromide and isobutyl magnesium bromide with ortho and para methoxybenzaldehyde, followed by dehydration of the alcohol, hydrogenation of the alkene and replacement of the methoxyl group with hydroxyl. The preparations described i n t h i s thesis were modifications of the above procedure, using a methoxyphenyl ketone instead of a methoxybenzaldehyde. A secondary a l k y l benzene was f i r s t prepared by Elages (54, 55, 57) who reduced with sodium and absolute ethanol (56) the alkene. produced on d i s t i l l a t i o n of the t e r t i a r y a l cohol. Elages (58) obtained the f i r s t secondary amylanisole by reacting ethyl anisate with ethyl magnesium iodide and reducing the r e s u l t i n g alkene with sodium and 19 ethanol. This reaction has been repeated by W e i l l (131), 0-CH3 0-CH3 ^ | EtMgl Na ether |l J EtOH CH3-CH2-C=CH-CH3 CH3-CH2-(J;-CH2-CH3 H Schmitt (99, 64) and Couturier (23). Couturier also obtained the alkene by a Grignard reaction of ethyl magnesium bromide with the d i e t h y l amide of a n i s i c a c i d . 0-CH3 0-CH3 0-CH3 EtMgBr ^ tf*\ HCl ether C=0 Et-C-Et Et-N-Et Et-N-Et Of the secondary amyl and hexylphenols only sym-metrical ones, 3-(o- and p-hydroxyphenyl)-pentane, could have been prepared from an ester or amide. Brown and Voron-kov (11) have prepared the ortho isomer of the alkene by the method of Klages. Recently Brunner (13) has produced the para alkene isomer from p-methoxypropiophenone and ethyl magnesium bromide. Moffatt (76) has prepared both the ortho and para isomers i n t h i s laboratory by Brunner*s method. Table I I l i s t s the phenols 'and intermediates found i n the l i t e r a t u r e which are i d e n t i c a l to the ones prepared i n t h i s project. Smith and co-workers (109) c a r r i e d out the following Claisen rearrangement of # -methyl, oC -ethyl a l l y l phenyl ether. TABLE II COMPOUNDS REPORTED IN THE LITERATURE, (Prepared by Unequivocal Syntheses). Compound B.p.,°C (mm.! Refractive Index L i t . Thesis L i t . Thesis Ref. 2- [o-Me thoxypheny1)-3-me thylbutanol-2 90-91 (1) 68/0.02 — 1.5163 63 2- [o-Methoxyphenyl)-3-methylbutene-2 77-78 (1) 55/0.1 mmmm 1.5204 63 2- (p-Hydroxyphenyl)-pentane 101-103 (2) 84/0.5 — 1.5132 44 3- [o-Methoxyphenyl)-hexene-2 (and 3) 120-125(14) 80/0.05 n20=1.4975 1.5204 109 3- [o-Methoxyphenyl)-hexane 104-105,(9) 58/0.05 1.5022 109 3- [o-Hydroxyphenyl)-hexane 109-111(10) 55/0.01 n20=1.5099 1.5162 109 3- [p-Methoxyphenyl)-hexene-2 (and 3) 125-130(15) 85/0.4 n20=1.5223 1.5260 109 3- [p-Methoxyphenyl)-hexene-2 (and 3) 102-104(0.5) 85/0.4 n 20=i #5302 1.5260 109 3- [p-Methoxyphenyl)-hexane 125 (15) 85/0.1 n20=1.4988 1.4968 109 3- [p-Methoxyphenyl)-hexane 74-75 (0.4) 85/0.1 1.4997 1.4968 76 3- [p- Methoxyphenyl)-hexane 78-80 (0.5) 85/0.1 — 1.4968 96 3- [p-Hydroxyphenyl)-hexane 134-145(14) 90/0.03 m.p.approx. = 25° m.p.=49° 109 3- [p-Hydroxyphenyl)-hexane 116 (2.6) 90/0.03 m.p. = 47° m.p.=49° 76 3- [p-Methoxyphenyl)-2 methylpentene-l (and 3) 122-124(12) 84/0.1 n20=1.5195 1.5240 42 3-1 [p-Methoxyphenyl)- 2 methylpentane 98-99 (3) 74/0.05 n2<>=1.5008 1.5030 42 3-1 [p-Hydroxyphenyl)-2 methylpentane* 108-110(3) 75/0.1 m.p.=33-35° m.p.=29-30° 42 *3;-B dinitrobenzoate m.p. = 118-119° (thesis = 118°) to o 21 0-CH-CH=CH Et Me OH OH Heat I;H-CH=CH \k Me + Small amounts of the indicated products were i s o l a t e d and converted to the sryloxyacetic acids by the reaction of t h e i r sodium s a l t s with ethyl bromoacetate. The r e s u l t i n g aryloxy-a c e t i c acids were hydrogenated i n absolute ether using a platinum oxide c a t a l y s t . To prove the structures of the o- and p-(3-hexyl)-phenoxyacetic acids they synthesized them by an unequivocal procedure. They converted the ortho and para bromoanisoles to Grignard reagents and reacted them with hexanone-3. The t e r t i a r y alcohols were dehydrated by d i s -t i l l i n g with sulphuric a c i d and hydrogenated i n the presence of platinum oxide c a t a l y s t . The a l k y l anisoles were demethy-lated by hydriodic a c i d i n an acetic a c i d , a c e t i c anhydride solvent, then converted to the o- and p-C3-hexyl)-phenoxy-a c e t i c acids. The r e s u l t i n g compounds were compared with the products of the Claisen rearrangement. The synthesis i s i l l u s t r a t e d below: OCH3 0CH3 / V ft f | distilled + CH3-CH2-C-CH2-CH2-CH + CH3-CH=C-CH2-CH2-CH. CH3- CH^ C=CH- CH2-CH. CH3-CH2-CH-CH2-CH2-£E OH . 0CH2-C00H i) CH2Br-C00Et i i ) NaOH  CH3-CH2-CH-CH2-CH2-ch3 22 Host of the r e f r a c t i v e indices and b o i l i n g points reported by Smith agree with those found i n t h i s project. 3-(p-hydroxyphenyl)-hexane however, was reported as tta mushy s o l i d melting s l i g h t l y above room temperature," whereas i t was found i n this laboratory to be a c l e a r l y defined c r y s t a l l i n e s o l i d melting sharply at 49° a f t e r c r y s t a l i z a -t i o n from water. In an undergraduate research problem at t h i s u n i v e r s i t y Harris prepared the same compound and found o i t melted at 47 . Rubin (96) i n attempting to prepare 2- e t h y l - 3 - a n i s y l v a l e r i c acid from the Grignard reagent of 3- anisyl-4-bromohexane obtained a 12$ y i e l d of the desired product and 52# of 3-anisylhexane. i ) C02 i i ) H 20 CH3-CH 2-CH-CH-CH 2-CH3 CH3-CH2-CH-CH-CH-5GH3 C H 3 - C H 2 - C H - C H 2 - C H 2 - C H 3 MgBr COOH 12% 52% Lauer and Hoe (63) i n 1943 with a Claisen rearrange-ment on ethyl p - (V , ¥ - d i m e t h y l a l l y l o x y ) - b e n z o a t e , obtained the normal cleavage products of isoprene and ethyl p-hydroxy-benzoate, plus 2, 2, 3-trimethyl-5-carbethoxycoumaran pro-duced by c y c l i z a t i o n of the abnormal rearrangement product. EtOOC 0CH 2 -CH=C-(CH 3 ) 2 EtOOC OH CH3 V C H 3 EtOOC •(033)2 0H-CH-: 23 To prove the structure of this coumaran derivative they synthesized i t from o-methoxyacetophenone as shown below. O0 0 " 3 (CH3)2CHMgBr |f^V°C H3 H 2 S0 4 ^ |f COCH3 V* > ls^J-9(OH)CH(CH3)2 ^ I •3 HBr HoTc" aQSj-(CH 3) 2 j ) (CH,CO) ?0/AlClq | F ^ V ^ ^ - ( C H 3 ) ; J H - C H 3 i i J N a O a i H O O c J ^ J L-CH3 The compounds obtained by both procedures were identical. Lauer and Moe postulated that in the abnormal rearrangement the beta carbon atom attacks the ring instead of the normal gamma carbon. The physical constants for the second and third compounds in the above equation are l i s t e d in Table II. Huston (44) prepared 2-(p-hydroxyphenyl)-pentane from a Grignard reaction on acetophenone followed by dehydration and reduction. The resulting 2-phenyl-pentane was nitrated to give 2-(p-nitrophenyl)-pentane. The nitro group was ^  reduced to the amine, diazotized and hydrolyzed to give the desired product. None of the intermediates were isolated. The resulting product was compared with that obtained by the condensation of pentanol-2 with phenol under the influence of aluminum chloride and hydrogen chloride gas. (Table I). Huston concluded that the condensation product was a mixture of isomeric compounds. Later Huston and co-workers (42) prepared cKp-hydroxy-phenyl)-2 methylpentane. They condensed anisole with iso-butyryl chloride in the presence of aluminum chloride to get 62$ of p-methoxy isobutyrophenone. The ketone was 24 reacted with ethyl magnesium bromide and the r e s u l t i n g alcohol dehydrated by r e f l u x i n g with iodine. The alkene formed was hydrogenated with a palladium catalyst and demethylated with 48$ hydrobromic acid i n phenol s o l u t i o n . Huston's phy-s i c a l constants f o r the alkene, ether and phenol are shown o i n Table I I . The melting point was reported as 33-35 C. In t h i s laboratory a constant melting point of 29-30°C was obtained a f t e r three f r a c t i o n a l d i s t i l l a t i o n s . A l l attempts to r e -c r y s t a l l i z e t h i s phenol were unsuccessful. 5. The Preparation and Characterization of Dinitro-alkylphenols. Since alkylphenols have activated r i n g s , they are susceptible to mononitration under mild conditions and to d i n i t r a t i o n under more d r a s t i c conditions. Extreme care must be taken i n the l a t t e r case as the side chain could be oxidized by the n i t r a t i n g agent. Several procedures have been developed to minimize the side chain oxidation. P o l l a r d (84) converted a l k y l -phenols to nitro-alkylphenols by sulphonation followed by n i t r a t i o n with concentrated n i t r i c a c i d (density 1.36). The y i e l d s were high but the reaction was time consuming. A second method involved the drop wise addition of an a c e t i c a c i d s o l u t i o n of the alkylphenol to a s o l u t i o n of con-centrated n i t r i c acid and a c e t i c acid at a temperature of -20°C. Briggs (10) compared these two methods, found the l a t t e r gave s l i g h t l y better y i e l d s and required a much shorter reaction time. A modification of t h i s second procedure was 0 25 used by Baroni (5) who added the n i t r i c a c i d i n portions to o an alkylphenol chloroform solu t i o n at 15 C. A t h i r d method (75) involving n i t r a t i o n with nitrous vapours was found to give d i n i t r a t i o n i n g l a c i a l a c e t i c acid solvent and mononitration i n l i g h t petroleum ether. Although alkylphenols have often been characterized by the formation of various benzoates, urethanes and sulphon-ates, these derivatives are d i f f i c u l t or impossible to pre-pare f o r the more a c i d i c dinitrophenols. A procedure has been developed i n t h i s laboratory f o r characterizing n i t r o -phenols by the formation of s a l t s with pip e r i d i n e , morpholine and cyclohexylamine (29). These s a l t s are sharp melting stable c r y s t a l l i n e compounds varying i n color from yellow to red. Previously the use of amine s a l t s of nitrophenols was r e s t r i c t e d to t h e i r a p p l i c a t i o n as i n s e c t i c i d a l and fu n g i -c i d a l sprays and dusts (20). Amines which have been used f o r t h i s purpose are d i a l k y l amines (1), diamines (20, 108) sub-s t i t u t e d cyclohexylamines (18, 19) and dialkyl-benzylamines -(21). It was found (53) that the t o x i c action of the amine s a l t s persisted long a f t e r that of the free nitrophenol, because of the greatly reduced vapour pressure of the s a l t s . 26 DISCUSSION OF REACTIONS A F r i e s rearrangement followed by a Clemmeirsen redac-t i o n was found to be an excellent method f o r preparing normal and iso-alkylphenols (10, 30). Another method which gave the same products was a Grignard reaction on a methoxy sub-s t i t u t e d benzaldehyde (31, 73). Though both of these pro-cedures y i e l d a primary alkylphenol, a F r i e s rearrangement followed by a Grignard reaction should y i e l d the required secondary alkylphenols. This was the procedure adopted i n th i s project. The f i r s t step i n the procedure was the preparation of the phenyl esters. Phenyl acetate was prepared from sodium phenoxide and a c e t i c anhydride (129). CgHg-0Na + (CH 3C0) 2 0 —> CgHg-OOCCHg + CHgCOONa Phenyl propionate was prepared from:phenol and propionic acid by f i r s t converting the ac i d to the acid chloride by means of th i o n y l chloride. CHg-CH— CO OH + S0C1 2-*- CH-CHg-COCl + S0 2 + HCl CHg-CHg-COCl + C 6H 5-0H —CHgCHgCOO-CgHg + HCl A F r i e s rearrangement then converted the phenyl ester to a mixture of ortho and para hydroxyketones which were r e a d i l y separated by vacuum d i s t i l l a t i o n . 27 J - -CH3 O i ) A1C1? i i ) HC1/H20 ? The hydroxyl group was methylated to prevent the sub-sequent Grignard reagents from being decomposed. This was accomplished by the dropwise addition of dimethyl sulphate to the hydroxyketone dissolved i n an excess of potassium hydrox-ide s o l u t i o n . (CR^SC^ > A + KMeSO^  The Grignard reactions were c a r r i e d out under anhy-drous conditions i n an atmosphere of dry nitrogen gas. One ha l f a mole of ketone was added to the Grignard reagent pre-pared from molar quantities of magnesium turnings and a l k y l h a lide, to assure that no contamination of the t e r t i a r y alcohol by unreacted ketone would take place. ? C H3 P*3 <f3 CH3 Cj + CH3-CH2-CK2-Mg-Br ether > r ^ ^ V < ! r ° H The t e r t i a r y alcohols were dehydrated by r e f l u x i n g them i n toluene under the c a t a l y t i c influence of iodine. The water from the toluene-water azeotropic mixture was col l e c t e d i n a Dean and Stark moisture trap (27). OH p- CHgO-C6H4- C- CH2- CH2-CHg I2/Toluene ; > 0-CHgO-C6H5-C=CH-CH2-CH CHg CT3 The alkenes were characterized as n i t r o s y l chloride d e r i -vatives. This procedure which was f i r s t developed by Tilden (120,121) f o r the characterization of terpenes has since been applied to other alkenes (133). The reaction may be considered to be a d i r e c t addition of n i t r o s y l chloride (N0C1) across the double bond, followed by rearrangement of the nitroso group to form an alpha chloro oxime which exists as a dimer. (133). R-CH2-CH=C-(CHg)2 + N0C1—»R-CH 2-CH-C-(CHg) 2 > NO CI R-CU-C —c =(CH ) o — * ( d i m e r ) • II I 3 2 N-OH CI The alkenes were hydrogenated under the c a t a l y t i c influence of Raney n i c k e l . This procedure gave nearly quantitative r e s u l t s i n a l l cases whereas the Elages method (56) of reduction using sodium and alcohol was reported to give low y i e l d s . The r e s u l t i n g a l k y l a n i s o l e s were characterized as sulphon-amides (40) by the action of chlorosulphonic acid followed by addition of concentrated ammonium hydroxide. 29 ?°2 OCH3 R R + HCl :o2 + H-jO ci Demethylation of the alkylanisoles presented con-siderable d i f f i c u l t y in this laboratory before an efficient method was developed. One of the methods f i n a l l y used was a variation of a procedure suggested by Prey (85) who found that most simple ethers could be s p l i t by refluxing for five hours with pyridine hydrochloride. Because presence of water tends to lower the reflux temperature and therefore the yield and because pyridine hydrochloride is very hygroscopic, a procedure using pyridine hydrobromide was developed in this laboratory. This procedure gave excellent results with the para isomers. The ortho isomers were found to react to only a limited extent with the above reagent but a macro scale Zeisel (81) methoxyl type reaction was found adequate. p-CH30-CfiH4-R + Pyridine hydrobromide reflux pH0-CgH4-R The alkylphenols were characterized as their 3, 5-dinitrobenzoates prepared by the pyridine method (134) and + CHgBr + Pyridine purified by recrystallization from petroleum ether (30-60°C.). 30 o r .°*TY4 o^a* N 0 2 N o 2 The alkylphenols were nit r a t e d by a procedure developed i n t h i s laboratory (29) i n which the phenol d i s -solved i n g l a c i a l a c e t i c acid was added dropwise to a solu-t i o n of concentrated n i t r i c a c i d (density 1.5) and a c e t i c o ac i d maintained at a temperature of -15 C. The dinitroalkylphenols were characterized by t h e i r piperidine, morpholine and cyclohexylamine s a l t s . Migr-dichian's (74) method of preparing these s a l t s from the sodium s a l t of the phenol and the amine hydrochloride gave c r y s t a l l i n e mixtures of the nitrophenol and the desired s a l t (29). A procedure was developed (29) i n which the nitrophenol was dissolved i n benzene by warming; a small excess of amine was then added and the s a l t p r e c i p i t a t e d by the addition of petroleum ether (30-60°C.). The s a l t s were r e c r y s t a l l i z e d by dis s o l v i n g them i n benzene followed by the addition of enough petroleum ether to make the so l u -tions saturated. In some cases where the s a l t was only s l i g h t l y soluble i n benzene, a small amount of ethanol was added to e f f e c t s o l u t i o n . This procedure was found to give r e l a t i v e l y pure products a f t e r one r e c r y s t a l l i z a t i o n . o H R H H The structural formulas of the phenols prepared i n this project are ill u s t r a t e d below. H-CH2-CH2 - C H 3 H3 2- (o-hydroxyphe nyl) • pentane C H 3 - C K - C H 2 - C H 2 - C H 3 2- (p-hydroxyphenyl)-pentane 2- (o-hydroxyphe nyl) • 3- methylbutane H — C H p — C H p - C H q H 2 H 3 3-(o-hydroxyphenyl)• hexane C H 3 - C H - C H - C H 0 CH3 J 2^p-hydrox3rphe^yl) -3-methylbutane C H 3 - C H 2 - C H - C H 2 - C H 2 - C H 3 3-(p-hydroxyphenyl)« hexane O H C H 3 CH-CH-CH3 3-(0 «hydroxyphe nyl) • 2-methylpentane C H o - C H p - C H - C H - C H , CH3 i 3-(p-hydroxyphenyl)• 2-methylpentane 32 The other two possible ortho and para secondary amyl phenols and six of the other eight possible hexyl homolognes have recently been prepared in this laboratory by Moffatt. (76). The two hexyl isomers that have not been prepared in this university are compounds I and II, l3 3-(o-hydroxyphenyl)-2:2- 3-(p-hydroxyphenyl)-2:2-dimethylbutane dimethylbutane A report on compound I could not be found in the literature. Huston (44) reports the preparation of compound II by the reaction of tert-butyl magnesium chloride on p-methoxyacetophenone followed by dehydration, reduction and demethylation, however no yields or physical constants of intermediates are recorded. A senior student at this uni-versity in the course of an undergraduate research problem attempted to repeat Huston's work, under the supervision of the author. Even though a large excess of tert-butyl chloride and magnesium were used the yield obtained for the Grignard reaction was less than five per cent. The low yield could be expected since tertiary Grignard reagents are excellent reducing agents (cf. p. 68). In considering 33 other possible syntheses f o r the preparation of compounds I and II Hoffatt (76) suggested a F r i e s rearrangement of phenyl trimethylacetate to give o- and p-hydroxy-(trimethylacetophenone) followed by methylation and a Grig-nard reaction using methyl magnesium iodide. Since no account of t h i s F r i e s rearrangement could be found i n the l i t e r a t u r e , the rearrangement was attempted i n t h i s labora-tory to see whether the ortho hydroxy ketone could be obtained i n s p i t e of s t e r i c hindrance. Trimethylacetic acid was prepared i n t h i s labora-tory by the method of Puntambeker and Zoellner (87) i n which t e r t - b u t y l magnesium chloride was reacted with carbon dioxide. (CH g) g-C-Gl + Hg ether^ (CH 3) 3-C-KgCl (GH«) -CMgCL i ) C ° 2 3*. (CH3)-C-COOH 3 ii)NH 4Cl/H 20 The acid was reacted with two moles of benzoyl chloride and v o l a t i l e trimethylacetyl chloride d i s t i l l e d off as formed. (12). (CH )—C-COOH + C H -C0C1—* (CH )-C-COCl + C H -COOH 3 3 6 5 3 3 6 5 , Phenyl-trimethylacetate was prepared by the method of Han, Swamer and Hauser (65). A mixture of molar quantities of phenol, trimethylacetyl chloride and magnesium were refluxed with benzene f o r three hours. A F r i e s rearrangement was then attempted but no i d e n t i f i a b l e products were obtained except phenol. 35 EXPERIMENTAL 1. Phenyl Acetate (129) Phenol (235 gm., 2.5 moles) was dissolved i n sodium hydroxide s o l u t i o n (1600 ml* of 10%) contained i n a three l i t e r b o t t l e . Crushed ice (1750 gm.) was added, followed by ac e t i c anhydride (325 gm., 3 moles). The bottle was stop-pered and shaken vigorously f o r ten minutes. The r e s u l t i n g emulsion of phenyl acetate was extracted with carbon t e t r a -chloride (100 ml.). The lower carbon te t r a c h l o r i d e layer was separated, washed with saturated sodium bicarbonate u n t i l effervescence stopped, then dried over anhydrous magnesium sulphate. The carbon tetrachloride was removed by d i s t i l l a t i o n and the phenyl acetate was c o l l e c t e d from 192-198°. The ester was r e d i s t i l l e d at atmospheric pres-sure g i v i n g a c o l o r l e s s l i q u i d , b.p. 192-193°, n 2 0 1.5036. Lit e r a t u r e b.p. 195-196°, n 2 0 1.5038. The y i e l d s obtained on three runs were 80%, 92% and 92%. 2. Phenyl Propionate (129). Phenol (375 gm., 4.0 moles) and propionic acid (330 gm., 4.5 moles) were placed i n a two l i t e r ground glass f l a s k f i t t e d with a Claisen adaptor, dropping funnel A l l temperatures are uncorrected and i n degrees Centigrade. K e l t i n g points were determined using an elec-t r i c a l l y heated brass block f i t t e d with a cased thermo-meter, the sample being placed i n an unsealed glass melt-ing point c a p i l l i a r y tube within the block. 36 and r e f l u x condenser. Calcium chloride drying tubes were inserted i n the tops of the condenser and the dropping funnel. Thionyl chloride (490 gm. 4.1 moles) was slowly added through the dropping funnel at such a rate as to keep the evolution of hydrogen chloride and sulphur dioxide under contro l . The mixture was then heated to the b o i l i n g point to drive off the v o l a t i l e gases. The mixture was d i s t i l l e d , the crude ester being c o l l e c t e d from 202-212°. It was then r e d i s t i l l e d through a twelve inch Vigreaux column to give phenyl propionate i n 73% y i e l d as a co l o r l e s s l i q u i d , b.p. 205-208°, n 2 0 1.5007. Lit e r a t u r e b.p. 211°, n 2 G 1.5011. 3. o and p-Hydroxyacetophenone. Freshly powdered anhydrous aluminum chloride (540 gm., 4.0 moles) was warmed up to 70° i n a two l i t e r s t a i n l e s s s t e e l beaker. Phenyl acetate (360 gm., 2.65 moles) was added slowly i n small portions. During the addition the tempera-ture was allowed to r i s e to 120-130° and the r e s u l t i n g red g l a s s - l i k e mixture was constantly s t i r r e d with a s t a i n l e s s s t e e l s t i r r i n g rod. A f t e r the addition was complete the mixture was heated to 150° f o r f o r t y - f i v e minutes and then cooled to room temperature. The beaker was placed i n an ice bath and a mixture of ice and hydrochloric a c i d (1200 ml. of 6 I f .) was added very slowly with constant s t i r r i n g . The mixture was then heated gently to hydrolyze the r e s i d u a l s o l i d material. The red o i l was separated from the lower 37 hydrochloric acid layer i n a separatory funnel while the mixture was s t i l l warm. The o i l was washed with hot d i l u t e hydrochloric acid (150 ml. of 6N.) and twice with hot water (150 ml. each). The re s i d u a l water was removed under water suction and the mixture fractionated under vacuum using a Bruehl receiver as the f r a c t i o n c o l l e c t o r . o-Hydroxyaceto-phenone was obtained i n 35% y i e l d as a c o l o r l e s s l i q u i d , b.p. 63° (1.5 mm.), n 2 1 1.5584. L i t e r a t u r e . (37) b.p. 96° 21 (10 mm.), n 1.558. p-Hydroxyacetophenone was obtained i n o 31% y i e l d as a pink s o l i d , b.p. 154 (2.0 mm.), m.p. 103-106 . Li t e r a t u r e . (37) b.p. 148° (3.0 mm.), m.p. 109°. A second run gave y i e l d s of 35% ortho and 40$ para. 4. o- and p-Hydroxypropiophenone. F i n e l y powdered anhydrous aluminum chloride (540 gm., 4.0 moles) was warmed up to 70° i n a two l i t e r s t a i n l e s s s t e e l beaker. Phenyl propionate (397 gm., 2.65 moles) was added slowly with constant s t i r r i n g and the r e s u l t i n g orange glass was heated to 140° f o r f o r t y - f i v e minutes. The mixture was cooled to room temperature and hydrolyzed with i c e and hydrochloric acid (1000 ml. of 6N.) as described i n the F r i e s rearrangement of phenyl acetate. A f t e r washing the red o i l with hot d i l u t e hydrochloric acid (200 ml.) and hot water (200 ml.) and drying under water suction the mixture was fractionated under vacuum. o-Hydroxypropiophenone was . o obtained i n 30% y i e l d as a col o r l e s s o i l b o i l i n g at 90 (2.0 mm.), n 1.5507. L i t e r a t u r e . (37) b.p. 115 (15 mm.), 22 n 1.548. A f t e r removal of the ortho isomer the still-f>ot r e s i -due was dissolved i n a s o l u t i o n of potassium hydroxide (100 gm.) i n water (800 ml.). This s o l u t i o n was extracted with ether (200 ml.) and the lower aqueous layer was a c i d i -f i e d with concentrated hydrochloric acid. The p r e c i p i t a t e d p-hydroxypropiophenone was f i l t e r e d , washed with water and dried i n a vacuum dessicator over phosphorus pentoxide. The p-hydroxypropiophenone was obtained i n 54$ y i e l d and a sample o r e c r y s t a l l i z e d from ethanol melted at 146-147 . L i t e r a t u r e . (37) m.p. 148°. A second run gave y i e l d s of 42$ ortho and 44$ para. 5. Methylation of the Hydroxy-Aceto- and Propiophenones. p-Hydroxyacetophenone (50 gm., 0.37 moles) was d i s -solved i n a s o l u t i o n of potassium hydroxide (31 gm., 0.55 moles) i n water (250 ml.) contained i n a 500 ml., three necked ground glass f l a s k f i t t e d with a dropping funnel, ground glass thermometer and a very e f f i c i e n t mercury-sealed s t i r r e r . Dimethyl sulphate (70 gm., 0.55 moles) was added through the dropping funnel over a period of twenty minutes. The f l a s k was maintained at a temperature of about 50° f o r three hours with constant vigorous s t i r r i n g . The s o l u t i o n was kept basic by the addition of more potassium hydroxide when needed. The upper o i l y layer was washed with potassium 39 hydroxide solu t i o n (100 ml. of 10$) followed by two washes with water (100 ml.). The o i l was dried under water suction and vacuum d i s t i l l e d . In most cases, considerable unreacted hydroxy alkylphenone was recovered on a c i d i f i c a t i o n of the basic s o l u t i o n . p-Methoxyacetophenone was obtained on d i s t i l l a t i o n as a col o r l e s s l i q u i d which s o l i d i f i e d to give large colorless c r y s t a l s melting at 39°, b.p. 75° (0.08 mm.). L i t e r a t u r e . (37) m.p. 38-39°, b.p. 145 (14 mm.). The re s u l t s of four runs are recorded i n Appendix I. e-Methoxyacetophenone was obtained as a co l o r l e s s l i q u i d b o i l i n g at 75° (0.1 mm.) n 2 5 1.5405. L i t e r a t u r e . (37) o 23 4 b.p. 131 (18 mm.), n * 1.538. The r e s u l t s of f i v e methylations of o-hydroxyacetophenone are recorded i n Appen-dix I I . p-Hethoxypropiophenone was obtained as a co l o r l e s s 0 25 l i q u i d b o i l i n g at 111 (1.77 mm.), n 1.5482. L i t e r a t u r e . (37) 15 b.p. 145 (14 mm.), n 1.5477. The r e s u l t s of four methylations of p-hydroxypropiophenone are recorded i n Appen-dix I I I . o-Hethoxypropiophenone was obtained as a colorless o 25 l i q u i d b o i l i n g at 82 ( o . l mm.), n 1.5336. L i t e r a t u r e . (37) 20 b.p. 137 (165 mm.), n 1.5320. The r e s u l t s of s i x methylations of o-hydroxypropiophenone arerrecorded i n Appen-dix IV. 40 6. n-Propyl Bromide (129). n-Propyl alcohol (90 gm., 1.5 moles) and red phos-phorus (12.4 gm.) were placed i n a 500 ml. ground glass f l a s k f i t t e d with a dropping funnel and e f f i c i e n t condenser. The f l a s k was heated gently and bromine (121 gm.) was added slowly through the dropping funnel. The rate of addition of bromine was controlled so that there was never a large excess of unreacted bromine i n the f l a s k . The mixture was then refluxed f o r t h i r t y minutes a f t e r which most of the bromide was d i s t i l l e d o f f . Water (50 ml.) was then added and the d i s t i l l a t i o n of bromide continued. The crude bromide was separated from the upper water layer then washed successively with water, concentrated hydrochloric a c i d , water, 10 per cent sodium carbonate so l u t i o n , water, and then was dried with anhydrous calcium chloride. n-Propyl bromide was obtained i n 44% y i e l d on d i s t i l l a t i o n as a cle a r c o l o r l e s s l i q u i d o o b o i l i n g at 71-72 . L i t e r a t u r e , b.p. 71-72.5 . A second run using four times the quantities gave a y i e l d of 49$. 7. Isopropyl Bromide (129). Isopropyl alcohol (40 gm., 0.67 moles) and hydro-bromic ac i d (460 gm. of 47%, 2.67 moles) were mixed i n a one l i t e r ground glass d i s t i l l i n g f l a s k . A d i s t i l l i n g head and e f f i c i e n t condenser were attached and the i s o -propyl bromide was slowly d i s t i l l e d (1-2 drops per second) until"about half of the l i q u i d had passed over. The upper aqueous layer was separated and r e d i s t i l l e d to obtain a further portion of crude bromide. The combined lower layers 41 were washed successively with equal volumes of concentrated hydrochloric acid, water, sodium bicarbonate s o l u t i o n (5$), water and dried with anhydrous calcium chloride. On d i s -t i l l a t i o n isopropyl bromide was obtained i n 70# y i e l d as a o o c o l o r l e s s l i q u i d b o i l i n g at 59 . I L i t e r a t u r e , b.p., 60 . On subsequent runs y i e l d s of 56, 79 and 92% were obtained. 8. A l k y l Hethozyphenyl Carbinols. (e.g. Preparation of 2-(p-Methoxyphenyl-pentanol-2). Dry reagent grade magnesium turnings (24.3 gm., 1 mole) were placed i n a dry one l i t e r , three necked, ground glass f l a s k f i t t e d with a mercury sealed s t i r r e r , r e f l u x condenser, and pressure equalizing dropping funnel. The apparatus was assembled to allow the reaction to be ca r r i e d out under a s l i g h t pressure of nitrogen dried by bubbling i t through concentrated sulphuric aci d . Anhydrous, sodium dried ether (180 ml.), was added to the f l a s k , and n-propyl bromide (123 gm., 1 mole) dissolved i n anhydrous ether (250 ml.) placed i n the dropping funnel. Nitrogen was slowly passed through the apparatus f o r t h i r t y minutes to displace a l l oxygen and the flow regulated to maintain a s l i g h t pressure of nitrogen throughout the remaining procedure. The s t i r r e r was started and a small amount of the n-propyl bromide ether s o l u t i o n (about 5 ml.) was added to the reaction f l a s k . A s l i g h t t u r b i d i t y a f t e r about t h i r t y seconds indicated the reaction had started spontaneously. The remaining bromide 42 ether sol u t i o n was added slowly (45 min.) and the black mix-tare reflaxed f o r one hoar and then cooled to -5° i n an ice-rock s a l t bath. While the temperature was maintained below 0°, p-methoxyacetophenone (75 gm., 0.5 moles) d i s -solved i n anhydrous ether (70 ml.) was added through the dropping funnel during one hour. During t h i s addition the mixture turned grey and became f u l l of suspended white s o l i d material. The mixture was then refluxed f o r s i x hours, cooled and added slowly with constant s t i r r i n g to a saturated solu-t i o n of ammonium chloride and cracked ice (1000 ml.). The ether layer was separated, washed with water, and d r i e d over magnesium sulphate. The ether was removed under reduced pressure and a portion (10 gm.) of the crude 2-(p-methoxy-phenyl)-pentanol-2 was d i s t i l l e d under high vacuum i n order to obtain physical constants without spontaneous dehydration. o 25 ^ B.p. 100 (0.05 mm.), n , 1.5308, y i e l d 75$. This procedure was used to prepare eight d i f f e r e n t t e r t i a r y carbinols which are recorded i n Table III with physical constants and analyses. 9. Dehydration of the Carbinols. (e.g. 2-(p-Methoxyphenyl)-pentene-2). Crude 2-(-methoxyphenyl-pentanol-2 (79 gm.) obtained d i r e c t l y from the Grignard reaction was placed i n a 500 ml., ground glass f l a s k f i t t e d with a Dean and Stark tube and r e f l u x condenser. Toluene (150 ml.) and a small c r y s t a l of iodine were added and the mixture refluxed f o r several hours 43 u n t i l no more water was given o f f . The water i n the Dean and Stark tube was found to be 75$ of the t h e o r e t i c a l volume. The toluene was removed under reduced pressure and the alkene vacuum d i s t i l l e d . 2-(p-Methoxyphenyl)-pentene-2 was obtained as a co l o r l e s s o i l , b o i l i n g at 70° (0.1 mm.) and having n 2 5 , 1.5370 Anal. c a l c . f o r c12 H18 0 : 0 C H 3 » 1 7 « 6 1 # « Found: OCHg, 17.62, 17.68$. N i t r o s y l chloride m.p. 84°. Anal. c a l c . f o r H16 C 1 N G 2 :N, 5.80$. Found: N, 5.78$. This procedure was used to prepare eight alkenes, physical constants and analyses of which are recorded i n Tables 17 and V. The n i t r o s y l chloride derivative was prepared from f r e s h l y d i s t i l l e d 2-(p-methoxyphenyl)-pentene-2 (2 ml.) dissolved i n g l a c i a l a c e t i c acid (2 ml.) and isoamyl n i t r a t e (3.4 ml.) by the dropwise addition of a s o l u t i o n of concen-trated hydrochloric acid (2 ml.) and g l a c i a l a c e t i c a c i d (2 ml.). During the addition the mixture was maintained at a temperature of -5° i n an ice-hydrochloric acid bath. The mixture was swirled constantly during the addition which took t h i r t y minutes. Methyl alcohol was added to the green reaction mixture to complete the p r e c i p i t a t i o n of the white s o l i d which was f i l t e r e d o f f and washed repeatedly with methyl alcohol. The s o l i d was dried i n a vacuum d e s i -ccator and the melting point and analysis were done immed-i a t e l y since the n i t r o s y l chloride derivatives were f r e -quently found to be unstable. 44 10. Hydrogenation of the Alkenes (e.g. 2-(p-Kethoxyphenyl)-pentane. 2-(p-Hethoxyphenyl)-pentene-2(49 gms. 0.28 moles) was placed i n a high pressure hydrogenator bomb with Raney n i c k e l (approx. 5 gm.) and ethanol (40 ml. of 95%). The bomb was assembled and hydrogen introduced to a pressure of o 950 p . s . i . The bomb was then shaken at 50 u n t i l no further pressure drop occurred, (approx. two hours). The Raney ni c k e l was f i l t e r e d o f f and washed with 95% ethanol, and the ethanol was removed under reduced pressure. On vacuum d i s t i l l a t i o n 2-(p-methoxyphenyl)-pentane (89%) b o i l i n g at 68°(0.3 mm.) 25 r\ and having n , 1.4970 was obtained. Anal. c a l c . f o r C 1 2 H18 OCHg, 17.4l£.Found: OCHg, 17.44, 17.39. Sulphonamide m.p. 63°. Anal. c a l c . f o r C 1 2H 1 9K0gS:N, 5.44; OCHg, 12.05%. Found: N,5.44; 0CH g, 12.25#. This procedure was used to obtain eight d i f f e r e n t alkenes which are l i s t e d with physical constants and analysis i n Table VI. The sulphonamide derivative (40) was prepared by the dropwise addition of chlorosulphonic a c i d (5.0 gm.) to an ice - c o l d s o l u t i o n of the al k y l a n i s o l e (1 gm.) i n chloro-form (5 ml.). The red viscous reaction mixture was allowed to warm to room temperature, and af t e r standing f o r twenty minutes was slowly added to crushed ice (30 gm.). The chloroform layer was separated, washed with water and the solvent evaporated under reduced pressure. The crude a r y l 45 sulphonyl chloride was boiled f o r ten minutes with concen-trated ammonium hydoxide (10 ml.). A f t e r cooling, water (50 ml.) was added; the s o l i d sulphonamide f i l t e r e d o f f , washed with water, and r e c r y s t a l l i z e d from aqueous alcohol. The sulphonamides are l i s t e d i n Table VII. 11. Demethylation of the A l k y l a n i s o l e s . (a) Pyridine Hydrobromide. Pyridine (80 gm., 1 mole) and hydrobromic ac i d (47$, 192 gm., 1.2 moles) were placed i n a 500 ml. ground glass f l a s k f i t t e d with a d i s t i l l i n g head and ground glass thermometer. Water and excess hydrobromic acid were d i s -o t i l l e d o f f up to 130 . The hot residue was poured into a large mortar and allowed to cool. On s o l i d i f i c a t i o n the residue was ground up to give a cream colored s o l i d which on r e c r y s t a l l i z a t i o n from absolute ethanol gave white c r y s t a l s , o . m.p. 212 . Yi e l d s of 99 and 98% were obtained i n two prepara-tio n s . (b) 2-(p-Hydroxyphenyl)-pentane. 2-(p-£ethoxyphenyl)-pentane (38 gm., 0.21 moles). pyridine hydrobromide (44.5 gm., 0.28 moles) and g l a c i a l a c e t i c a c i d (8.3 gm., 10$ of t o t a l weight) were placed i n a 200 ml. ground glass f l a s k f i t t e d with a r e f l u x condenser. o The mixture, refluxed at 190-200 f o r f i v e hours, became homogeneous and was allowed to cool. Water (100 ml.) and ether (100 ml.) were added and the water la y e r was sep-arated and re-extracted with ether (50 ml.). The combined ether extracts were washed twice with 5% sodium bicarbonate and the phenol was extracted several times with 5% potassium hydroxide. The al k a l i n e extracts were a c i d i f i e d with 6 N. hydrochloric acid and extracted twice with ether. The ether so l u t i o n was dried over anhydrous magnesium sulphate and the solvent was removed under reduced pressure. The phenol was vacuum d i s t i l l e d to give 2-(p-hydroxyphenyl)-pentane i n 68% o y i e l d as a co l o r l e s s o i l b o i l i n g at 84 (0.5 mm.) and hav-ing n 2 5 , 1.5132. Anal. c a l c . f o r 0^^0:0,80.44^,9.82^. Found: C, 80.52, 80.64; H, 9.52, 9.73#. The 3,5- d i n i t r o -benzoate melted at 81°. Anal. c a l c . f o r C^B^NgO^ :N,7.82#. Found N, 7.88%. Four para a l k y l phenols were prepared by th i s method and are l i s t e d i n Table VIII. (c) 2-(o-Hydroxyphenyl)-pentane. ( i ) Pyridine hydrobromide method. 2-(o-Kethoxyphenyl)-pentane (47 gm., 0.26 moles) was refluxed with pyridine hydrobromide (56 gm., 0.35 moles) and g l a c i a l acetic acid (10.3 gm.) as previously described. On a c i d i f i c a t i o n of the potassium hydroxide extracts only 3.8 gm. of crude phenol was recovered. On vacuum d i s t i l -l a t i o n 2-(o-hydroxyphenyl)-pentane was obtained i n 6.2$ o 25 y i e l d (2.7) gm.); b.p. 71 (0.5 mm.); n , 1.5185. The resi d u a l organic phase was dried over anhydrous magnesium sulphate and the unreacted a l k y l a n i s o l e (42 gm., 90%) was recovered by d i s t i l l a t i o n . ( i i ) Eydriodic acid and phenol method. 2-(o-Kethoxyphenyl)-pentane (42 gm.,.24 moles) was refluxed f o r s i x hours with a mixture of hydriodic a c i d (87 47 gm. of 47%, 0.32 moles), and phenol (150 gm.) when the reaction mixture had cooled to room temperature water (100 ml.) and ether (100 ml.) were added and the layers were sep-arated. The ether s o l u t i o n was extracted repeatedly with 5% sodium hydroxide u n t i l a c i d i f i c a t i o n of the extracts gave appreciably no clouding of the so l u t i o n . The ether s o l u t i o n was washed with water and dried over anhydrous magnesium sulphate. The solvent was removed under reduced pressure and the residue was vacuum d i s t i l l e d , g i v i n g a 91% y i e l d of 2-(o-hydroxyphenyl)-pentane as a colo r l e s s o i l b o i l i n g at 65°, 25 (0.1 mm.) and having n , 1.5122. Anal. c a l c . f o r CjjH^gO: C, 80.44; H, 9.82#. Pound: C, 80.20, 80.27; H, 9.74, 9.68. 3:5-Dinitrobenzoate m. p. 85 . Anal. c a l c . f o r Cj^B^gNgOg; N, 7.82%. Pound: N, 7.73%. A l l of the ortho a l k y l phenols l i s t e d i n Table VIII were prepared by t h i s method. The 3,5-dinitrobenzoate derivative (134) was pre-pared by r e f l u x i n g the phenol (1 gm.), pyridine (20 ml.) and 3,5-dinitrobenzoyl chloride (2.5 gm.) f o r one hour. The mixture was then poured into cold sulphuric a c i d s o l u -t i o n (400 ml. of 5%) and the ester was extracted with ether. The ethereal s o l u t i o n was f i r s t washed with sodium hydroxide s o l u t i o n (100 ml. of 5%) then with water, followed by removal of the ether under reduced pressure. The crude 3,5-dinitro-benzoates were r e c r y s t a l l i z e d to constant melting point from aqueous ethanol. The 3,5-dinitrobenzoates and t h e i r analyses are l i s t e d i n Table IX. 48 12. N i t r a t i o n of the Alkylphenols (e.g. 2-(4-Hydroxy-3:5-dinitrophenyl)-pentane). A s o l u t i o n of 2-(p-hydroxyphenyl)-pentane (15 gm., 0.091 moles) and g l a c i a l a c e t i c acid (30 ml.) was added drop-wise with constant s t i r r i n g to a mixture of yellow fuming n i t r i c a c i d (20 ml., density 1.50) and g l a c i a l a c e t i c a c i d (38 ml.). The acid mixture was contained i n a s t a i n l e s s s t e e l beaker and maintained at a temperature of -20 to -15° i n an acetone-dry ice bath. A f t e r the addition which took f o r t y - f i v e minutes, the dark red mixture was allowed to come slowly to room temperature (21.5°) over a period of one hour and maintained at t h i s temperature f o r another hour. The mixture was poured onto crushed ice (200 gm.). The heavy red o i l was extracted three times with 100 ml. por-tions of chloroform. The chloroform extracts were washed eight times with equal portions of water. A f t e r drying over anhydrous magnesium sulphate, the chloroform was removed under reduced pressure. High vacuum d i s t i l l a t i o n gave an 80% y i e l d of 2-(4-hydroxy-3,5-dinitrophenyl)-pentane as a viscous amber colored l i q u i d b o i l i n g at 155° (0.1 mm.) and O K having n , 1.5624. This procedure was used to prepare eight d i n i t r o -alkylphenols which are l i s t e d with t h e i r physical constants i n Table X. 49 13. Amine Salts of Dinitro-alkylphenols. (e.g. The piperidine s a l t of 2-(4-hydroxy-3,5-dinitro-phenyl )-pentane. 2-(4-Hydroxy-3,5-dinitrophenyl)-pentane (1 ml.) was dissolved i n benzene (10 ml.) by warming gently on a hot plate. A f t e r the addition of piperidine the red s o l u t i o n was boiled f o r a few minutes then cooled. The addition of petroleum ether (b.p., 30-60°) prec i p i t a t e d the s a l t i n the form of f i n e orange plates. The c r y s t a l s were f i l t e r e d and r e c r y s t a l l i z e d three times from a benzene-petroleum ether (b.p., 30-60°) solvent p a i r . This procedure gave the piperidine s a l t of 2-(4-hydroxy-3,5-dinitrophenyl)-pentane as orange plates melting sharply at 187°. Anal. c a l c . f o r C 1 6 H 2 5 N 3 G 5 l N * 1 2 ' 3 8 ^ P o u n d : N » 12.39. Tables XI, XII and XIII l i s t the amine s a l t s prepared i n t h i s project. 14. Attempted Preparation of o- and p-Hydroxy-(trimethyl-acetophenone). F i n e l y powdered anhydrous aluminum chloride (200 gm., 1.5 moles) was warmed up to 70° i n a two l i t e r s t a i n l e s s s t e e l beaker. Phenyl trimethylacetate (157 gm., 0.88 moles) was added slowly with constant s t i r r i n g and the red l i q u i d was heated to 150° f o r f o r t y - f i v e minutes. The r e s u l t i n g black mixture was cooled to room temperature and hydrolyzed by the addition of ice and hydrochloric acid (750 ml. of 6N.). The mixture was heated gently to hydrolyze the r e s i d u a l s o l i d material. The black o i l was separated from the lower hydro-c h l o r i c acid layer while the mixture was s t i l l warm and washed with warm d i l u t e hydrochloric acid and twice with warm water. The crude o i l was dried under reduced pressure and vacuum d i s t i l l e d . Two fra c t i o n s were c o l l e c t e d , the f i r s t b o i l i n g at 55° (0.9 mm.) and the second b o i l i n g over the range o o ^ 57 -180 (0.9 mm.). The residue (approximately 35$ of t o t a l ) remained behind as a s o l i d black t a r . Fraction I on o r e d i s t i l l a t i o n gave a co l o r l e s s l i q u i d of b.p. 57 (1.0 mm.) which on cooling gave long co l o r l e s s needles melting at 39-40°. A mixture of t h i s compound with a n a l y t i c a l reagent o grade phenol (m.p., 40 ) gave no v a r i a t i o n of melting point. The 3,5 d i n i t r o benzoate derivatives of the above mentioned o compound and phenol both melted at 144 and a mixed melting point gave no depression. Li t e r a t u r e (129) gives, m.p., 146°. The second f r a c t i o n was dissolved i n potassium hydro* xide s o l u t i o n and washed twice with ether. On separation the r e s u l t i n g aqueous layer was neutralized with hydrochloric acid and the r e s u l t i n g o i l was washed successively with water, sodium bicarbonate solu t i o n and water. The brown o i l was r e d i s t i l l e d to give a small f r a c t i o n of phenol b.p., o 42 (0.5 mm.). The b o i l i n g point of the remaining material o increased over the range 57-160 (0.015 mm.). Of the nine fr a c t i o n s c o l l e c t e d , the l a s t four (b.p., 110-160) were l i g h t yellow very viscous l i q u i d s . The d i s t i l l a t i o n temp-51 erature remained r e l a t i v e l y constant at about 126 (0.015 mm.) which i s about the expected b o i l i n g point of p-hydroxy-(trimethylacetophenone), but no attempt was made to i d e n t i f y t h i s compound. The s o l i d black t a r residue was dissolved i n 10% potassium hydroxide s o l u t i o n and extracted with ether and then with chloroform. On separation of the layers and eva-poration of the organic solvents under reduced pressure i t was found that p r a c t i c a l l y none of the t a r had been extracted into the organic phase. A stream of carbon dioxide was then passed through the alk a l i n e s o l u t i o n f o r two hours. The brown p r e c i p i t a t e was then f i l t e r e d o f f and dried i n a vacuum desiccator and the supernatant s o l u t i o n was c l e a r , c o l o r l e s s and appeared to contain none of the o r i g i n a l t a r . Of the crude product from the Pries rearrangement over 90% was recovered i n the above manner. A l l of the recovered mat-e r i a l was soluble i n potassium hydroxide s o l u t i o n but insoluble i n potassium or sodium bicarbonate s o l u t i o n and was therefore considered to be phenolic i n nature. The amount of phenol recovered accounted f o r decomposition of 28% of the o r i g i n a l ester. TABLE I I I PHYSICAL CONSTANTS OF ALCOHOLS Compound B.p., °C. (mm.) «25 % Methoxyl Found Calc. Y i e l d , % 2-(o-Methoxyphenyl)pentanol-2 85(0.02) 1.5129 15.80,15.83 15.81 80 2-(p-Methoxyphenyl)pentanol-2 100(0.05) 1.5308 15.87,15.75 15.81 75 2-(o-Methoxyphenyl)-3-methylbutanol-2 68(0.02) 1.5163 15.78,15.72 15.81 75 2-(p-Methoxyphenyl)-3-methylbutanol-2 107(0.02) 1.5223 15.98,15.85 15.81 76 3-(o-Methoxyphenyl) hexanol-3 77(0.01) 1.5163 14.95,14.98 14.90 98 3-(p-Methoxyphenyl) hexanol-3 84(0.01) 1.5204 14.97,15.01 14.90 95 3-(o-Me thoxyphenyl)-2-me thylpe ntanol-3 89(0.02) 1.5175 14.89,14.92 14.90 92 3-(p-Methoxyphenyl)-2-methylpentanol-3 82(0.01) 1.5196 14.90,14.92 14.90 97 cn \ to TABLE IV PHYSICAL CONSTANTS OP ALKENES Compound B.p., °C. (mm.) n25 % Methoxyl Found Calc. 2-(o-Methoxyphenyl] i-pentene-2 67(0.4) 1.5229 17.55,17.50 17.61 2-(p-Me thoxyphenyl] l-pentene-2 70(0.1) 1.5370 17.62,17.68 17.61 2-(o-Methoxyphenyl] -3-methylbutene-2 55(0.1) 1.5204 17.60,17.49 17.61 2-(p-Methoxyphenyl] i-3-methylbutene-2 65(0.1) 1.5310 17.55,17;67 17.61 3-(o-Methoxyphenyl] i-hexene-3 80(0.05) 1.5204 16.30,16.37 16.31 3-(p- Me thoxypheny1] '-hexene-3 85(0.4) 1.5260 16.41,16.40 16.31 3-(o-Methoxyphenyl] i-2-methylpentene-2 70(0.05) 1.5228 16.27,16.38 16.31 3-(p-Me thoxyphenyl] i-2-methylpentene-2 84(0.1) 1.5240 16.35,16.31 16.31 CO TABLE V NITROSYL CHLORIDES OP ALKENES Compound if.p., of n i t r o s y l chloride, °C. % Nitrogen Found Calc. 2-(o-Me thoxyphenyl)-pentene-2 93 5.85 5.80 2-(p- Methoxyphenyl)-pentene-2 84 5.78 5.80 2-(o-Methoxyphenyl)-3 methylbutene-2 *m mm — mm mm 2-(p-Methoxyphenyl)-3 methylbutene-2 — — mm mm 3-(o-Methoxyphenyl)-hexene-3 72-73 5.54 5.48 3-(p-Methoxyphenyl)-hexene-3 65-67 5.51 5.48 3-(o-Methoxyphenyl)-2 methylpentene-2 — — mm mm 3-(p-Me thoxyphenyl)-2 me thylpentene-2 cn TABLE VI PHYSICAL CONSTANTS OP ALKYLANISOLES Compound B.p.,°C. (mm.) n25 % Methoxyl Found Calc. 2-(o-Methoxyphenyl)-pentane 62(0.3) 1.4980 17.45,17.36 17.41 100 2-(p-Methoxyphenyl)-pentane 68(0.3) 1.4970 17.44,17.39 17.41 89 2-(o-Methoxyphenyl)-3 methylbutane 58(0.3) 1.5070 17.32,17.39 17.41 94 2-(p-Methoxyphenyl)-3 methylbutane 71(0.5) 1.5011 17.40,17.36 17.41 82 3-(o-Methoxyphenyl)-hexane 58(0.05) 1.5022 16.10,16.02 16.14 92 3-(p-Methoxyphenyl)-hexane 85(0.1) 1.4968 16.18,16.19 16.14 84 3-(o-Methoxyphenyl)-2 methylpentane 56(0.05) 1.5069 16.08,16.11 16.14 90 3-(p-Methoxyphenyl)-2 methylpentane 74(0.05) 1.5030 16.23,16.17 16.14 94 cn TABLE VII SULPHONAMIDES OF ALKYLANISOLES Compound M.p. of Sulphonamide, oC. % Methoxyl Found Calc. % Nitrogen Found Calc. 2-(o-Methoxyphenyl)-pentane 60 11.97 12.06 5.57 5.44 2- (p-Me thoxyphenyl) -pentane 63 12.25 12.06 5.44 5.44 2- (o-Methoxyphenyl)-3-methylbutane 111 12.17 12.06 5.48 5.44 2- (p-Methoxyphenyl)-3-methylbutane 104 12.22 12.06 5.52 5.44 3-(o-Methoxyphenyl)-hexane mm mtt — — -- mm mm 3-(p-Me thoxyphenyl)-hexane 82 11.47 11.44 5.18 5.16 3-(o-Methoxyphenyl)-2 methylpentane — — — — mm mm 3- (p-Methoxyphenyl)-2 methylpentane 69 11.51 11.44 5.19 5.16 cn TABLE VIII PHYSICAL CONSTANTS OP ALKYLPHENOLS B.p., °C. Compound (mm.) M.p., OC. n 2^ % Carbon* Found Calc. % Hydrogen* Found Calc. Y i e l d % 2-(o-Hydroxyphenyl)-pentane 65(0.1) mm mm 1.5122 80.20 80.44 9.74 9.82 91 80.27 9.68 2-(p-Hydroxyphenyl)-pentane 84(0.5) — 1.5132 80.52 80.44 9.52 9.82 68 80.64 9.73 2-(o-Hydroxyphenyl)-3me thylbutane 60(0.25) -- 1.5157 80.78 80.44 9.76 9.82 68 80.96 9.68 2-(p-Hydroxyphenyl)-3-methylbutane 110(0.8) 73 — 80.50 80.44 9.76 9.82 79 80.22 9.34 3-(o-Hydroxyphenyl)-hexane 55(0.01) — 1.5162 80.60 80.85 9.76 10.18 98 80.37 9.64 3-(p-Hydroxyphenyl)-hexane 90(0.03) 49° — 80.91 80.85 10.35 10.18 95 3-(o-Hydroxyphenyl)-2-methylpentane 81.09 10.27 75(0.08) M M 1,5098 80.82 80.85 10.04 10.18 92 3-(p-Hydroxyphenyl)-2-methylpentane 81.01 10.18 75(0.10) 29-30° 1.5170 80.78 80.85 10.06 10.18 97 80.75 10.16 Carbon and hydrogen analyses by Drs. Weiler and Strauss, Oxford. TABLE IX 3,5-DINITROBENZOATES OP ALKYLPHENOLS Compound M.p. of 3,5-dlnitro-benzoate °C % Nitrogen Found Calc. 2-(o-Hydroxyphenyl)-pentane 85 7.73 7.82 2-(p-Hydroxyphenyl)-pentane 81 7.88 7.82 2-(o-Hydroxyphenyl)-3-me thylbutane 72 7.87 7.82 2-(p-Hydroxyphenyl)-3-methylbutane 109 7.76 7.82 3-(o-Hydroxyphenyl)-hexane 61 7.45 7.53 3-(p-Hydroxyphenyl)-hexane 82 7.50 7.53 3-(o-Hydroxyphenyl)-2-methylpentane 70 7.49 7.53 3-(p-Hydroxyphenyl)-2-methylpentane 118 7.55 7.53 cn c o TABLE X PHYSICAL CONSTANTS OF DINITRO-ALKYLPHENOLS .Compound B.p., °C. (mm.) n 2 5 Y i e l d , % 2-(2-Hydroxy-3,5-dinitrophenyl)-pentane 145 (0.05) 1.5686 70 2-(4-Hydroxy-3,5-dinitrophenyl)-pentane 155 (0.1) 1.5624 80 2-(2-Hydroxy-3,5-dinitrophenyl)-3-me thylbutane 140 (0.08) 1.5713 62 2-(4-Hydroxy-3,5-dinitrophenyl-3-methylbutane 155 (0.1) 1.5669 73 3-(2-Hydroxy-3,5-dinitrophenyl)-hexane 150 (0.1) 1.5631 65 3-(4-Hydroxy-3,5-dinitrophenyl)-hexane 155 (0.05) 1.5586 78 3-(2-Hydroxy-3,5-dinitrophenyl)-2-methylpentane 132 (0.1) 1.5710 57 3-(4- Hydroxy-3,5-dinitrophenyl)-2-methylpentane 155 (0.05) 1.5620 65 cn CD TABLE XI PIPERIDINE SALTS OF DINITRO->ALKYLPHENOLS Salt of M.p.,°C. % Nitrogen Found Calc. 2-(2-Hydroxy-3,5-dinitrophenyl)-pentane 140 12.34 12.38 2-(4-Hydroxy-3,5-dinitrophenyl)-pentane 187 12.39 12.38 2-(2-Hydroxy-3;5-dinitrophenyl)-3-methylbutane 145 12.42 12.38 2-(4-Hydroxy-3,5-dinitrophenyl)-3-methyibutane 199 12.36 12.38 3-< 2-Hydroxy-3,5-dlnitrophenyl)-hexane 155 11.96 11.89 3-(4-Hydroxy-3,5-dinitrophenyl)-hexane 192 11.89 11.89 3-(2-Hydroxy-3,5-dinitrophenyl)-2-methylpentane 177 11.87 11.89 3-(2-Hydroxy-3,5-dinitrophenyl)-2-methylpentane 158 11.93 11.89 cn o TABLE XII MORPHOLINE SALTS OP DINITRO-ALKYLPHENOLS o % Nitrogen Salt of M.p.,°C. Found Calc. 2-(2-Hydroxy-3,5-dinitrophenyl)-pentane 146 12.25 12.31 2-(4-Hydroxy-3,5-dinitrophenyl)-pentane 160 12.36 12.31 2-(2-Hydroxy-3,5-dinitrophenyl)-3-methylbutane 153 12.21 12.31 2-(4-Hydroxy-3,5-dinitrophenyl)-3-methylbutane 170 12.32 12.31 3-(2-Hydroxy-3,5-dinitrophenyl)-hexane 157 11.77 11.83 3-(4-Hydroxy-3,5-dinitrophenyl)-hexane 154 11.83 11.83 3-(2-Hydroxy-8,5-dinitrophenyl)-2-methylpentane 166 11.79 11.83 3-(4-Hydroxy-3,5-dinitrophenyl)-2-methylpentane 182 11.86 11.83 TABLE XIII CYCLOHEXYLAMINE SALTS OF DINITRO-ALKYLPHENOLS Salt of M.p.,°( % Nitrogen Found- Calc. 2-(2-Hydroxy-3,5-dinitrophenyl)-pentane 189 11.94 11.89 2-(4-Hydroxy-3,5-dinitrophenyl)-pentane 169 11.91 11.89 2-(2-Hydroxy-3,5-dinitrophenyl)-3-methylbutane 213 d. 11.84 11.89 2-(4-Hydroxy-3,5-dinitropheny1)-3-methylbutane 217 d. 11.82 11.89 3- (2-Hydroxy-3,5-dinltrophenyl)-hexane 160 11.39 11.44 3- (4-Hydroxy-3,5-dinitrophenyl)-hexane 200 11.43 11.44 3- (2-Hydroxy-3,5-dinitrophenyl)-2-methylpentane 179 11.40 11.44 3- (4-Hydroxy-3,5-dinitrophenyl)-2-methylpentane 216 11.46 11.44 cn to 63 DISCUSSION OP RESULTS A Pries rearrangement followed by a Grignard reaction was found to be an excellent method of preparing ortho and para secondary alkylphenols of unequivocal structure. By the correct choice of s t a r t i n g materials almost any desired secondary alkylphenol may be prepared. One of the few l i m i t a -tions which might be encountered i s possible s t e r i c e f f e c t s i n complicated Grignard reactions. S t e r i c hindrance prevent-ing the formation of the ortho isomer during the F r i e s rearrange-ment of phenol esters having highly branched a c i d r a d i c a l s might also be a f a c t o r . The phenol esters were very e a s i l y prepared i n excel-lent y i e l d s . It was found that phenyl acetate could be pre-pared i n high y i e l d (.92%) by the reaction of acetic anhydride on sodium phenoxide. This reaction i s much shorter than the corresponding reaction using a c e t y l chloride and phenol. The most convenient preparation of phenyl propionate involved the r e f l u x i n g of phenol, propionic acid and thionyl chloride rather than the i n i t i a l i s o l a t i o n of propionyl chloride. Briggs (10) has previously shown that approximately equal amounts of the ortho and para isomers were obtained by the F r i e s rearrangement on phenol esters, i f the reaction were conducted without solvent and at a temperature of 140 -o 160 . Since both isomers were required, the above reaction conditions were duplicated. An increase i n the temperature 64 favours the ortho isomer, presumably due to increased s t a b i l i t y r e s u l t i n g from chelation. With pure o-hydroxy-acetophenone the chelation i s due to intramolecular hydrogen bonding (I) whereas under the conditions of the Pries rearrangement the chelation i s probably due to a Lewis acid e f f e c t as depicted i n structure I I . The methylation reaction was e a s i l y performed and gave good y i e l d s . By varying the reaction conditions of the nineteen methylations, the following observations were made. It was found unnecessary to cool the reaction mix-ture during the addition of dimethyl sulphate. A potas-sium hydroxide s o l u t i o n gave better y i e l d s than sodium hydroxide s o l u t i o n due to greater s o l u b i l i t y of the phenol i n potassium hydroxide, a lower reaction temperature (50 -o. 60 ) gave better y i e l d s than the usual r e f l u x temperature, and very e f f i c i e n t mechanical s t i r r i n g was required f o r optimum y i e l d s . The use of bromine and red phosphorus i n the con-version of n-propyl alcohol to i t s bromide appeared to give y i e l d s of only 45-50$ compared with that of 90$ reported by Yogel (129). Moffatt (76) obtained the same r e s u l t when he prepared isobutyl bromide by Vogel's method. The method using hydrobromic a c i d i n the preparation of isopropyl bromide gave excellent r e s u l t s when precautions were taken to condense a l l of the d i s t i l l a t e . A two foot condenser was used and the receiving f l a s k was immersed i n an ice bath. In undertaking the Grignard reactions dry equipment and f r e s h l y d i s t i l l e d reagents were used and the reaction mixture was kept constantly under a s l i g h t pressure of dry nitrogen. In a l l cases a reaction started spontaneously so that seeding with iodine or methyl iodide was unnecessary. The use of two moles of Grignard reagent to one of ketone and the s i x hour r e f l u x period resulted i n a product free of ketone. A mildly a c i d i c agent, ammonium chloride s o l u t i o n , was chosen f o r the hydrolysis because strong mineral acids promote dehydration of the unstable t e r t i a r y alcohols. The bulk of the crude alcohol was dehydrated d i r e c t l y by the Dean and Stark method,, only a small sample being saved f o r d i s t i l l a t i o n . Good y i e l d s were obtained i n a l l cases a f t e r r e f l u x i n g f o r three to f i v e hours. R e d i s t i l l a t i o n of the alkenes, a f t e r standing several weeks, gave a large pot residue i n d i c a t i n g some polymerization. This was expected since the alkenes are substituted styrenes. N i t r o s y l chlorides have proven to be rather unsatis-factory derivatives since many cannot be prepared and those 66 that were prepared were unstable, decomposing a f t e r several months to brown t a r s . When i t was f i r s t r e a l i z e d i n t h i s and previous work (76) that the following alcohols gave alkenes which, on dehydration, would not form n i t r o s y l chloride derivatives, i t was considered that the alkenes might have terminal double bonds since i t has been established that t h i s class of alkenes w i l l not form the de r i v a t i v e . (120). A study of the l i t e r a t u r e showed that Lauer and co-workers prepared the f i r s t of the above alcohols, which they dehydrated by r e f l u x i n g with sulphuric a c i d . By oxidation they proved the double bond was not terminal. 67 The present theory of the n i t r o s y l chloride structure states that there i s a rearrangement of the nitroso group to the oxime group followed by dimerization. (See equation p. 28). It i s immediately seen that an alkene must have a hydrogen at one end of the double bond or no derivative w i l l be formed. Upon reexamination of the above alcohols i t becomes apparent that the most probable alkene on dehydration w i l l be a t e t r a substituted ethylene which therefore cannot form a n i t r o s y l chloride d e r i v a t i v e . Hydrogenation of the alkenes was e a s i l y accomplished using a high pressure hydrogenator and Raney n i c k e l catalyst o at 50 C. Excellent y i e l d s and high standards of p u r i t y were obtained consistently. Demethylation of the alkylanisoles was discussed e a r l i e r i n t h i s t h e s i s . The pyridine hydrobromide method of demethylation gave excellent y i e l d s f o r the para s e r i e s , but not f o r the ortho s e r i e s . Demethylation of the ortho series was accomplished using constant b o i l i n g hydribdic a c i d and phenol. Separation of the ortho alkylphenol from the phenol presented a problem. The method used was based on the smaller s o l u b i l i t y of the ortho alkylphenol i n sodium hydroxide; t h i s method probably resulted i n a considerable loss of product. Attempts to f i n d a better method of separa-t i o n were unsuccessful. The method of n i t r a t i o n , using fuming n i t r i c a c i d i n g l a c i a l a c e t i c acid, was found to give y i e l d s ranging 68 from 57 to 80$. In comparison with other methods of n i t r a -t i o n these y i e l d s can be considered quite high. A so l u t i o n to the problem of characterization of the nitrophenols was found i n the formation of t h e i r s a l t s with piperidine, morpholine and cyclohexylamine. These amines were chosen because they are r e l a t i v e l y strong bases and are commercially available and inexpensive. The amine s a l t s of a ni t r a t e d sample of "o-sec-amyl phenol" obtained from Sharpies Chemi-c a l Company were found to be i d e n t i c a l to the s a l t s of nit r a t e d 2-(o-hydroxyphenyl)-pentane. The melting points and mixed melting points are l i s t e d i n Appendix V. It has previously been noted that the para secondary hexylphenol, which has not yet been prepared i n t h i s labora-tory, could be made from p-methoxyacetophenone and t e r t - b u t y l magnesium chloride i n low y i e l d . A possible means of increasing the y i e l d of a Grignard reagent which i s e a s i l y reduced has recently been suggested by Swain and Boyles (114). They increased the y i e l d of the normal Grignard addition pro-duct, i n the reaction of n-propyl magnesium bromide with d i s -opropyl ketone, from 36 to 65$. This was accomplished by a consideration of the difference between the most probable mechanism of addition of a Grignard reagent to a ketone and the most probable mechanism f o r reduction, the p r i n c i p l e com-peting side reaction. Their mechanism f o r reduction involves an i n t e r n a l c y c l i c rearrangement of a complex formed from a molecule of 69 ketone and a molecule of Grignard reagent. In the following i l l u s t r a t i o n the co-ordinated ether molecules are omitted f o r s i m p l i f i c a t i o n . ;Br It had previously been shown by Swain (113, 115) that the most probable mechanism f o r addition of Grignard reagents to ketones appears to involve reaction of the Grignard-ketone complex with a second molecule of Grignard reagent. B r B r Jfg Me r ^ G ^ ^ ^ ^ g B r ^ G ^ ^ ^ M g B r They predicted that the addition of magnesium bromide should increase the y i e l d i n the Grignard reaction. They reasoned that magnesium bromide was a s l i g h t l y stronger Lewis acid than the Grignard reagent and should complex preferen-t i a l l y with the ketone. The magnesium bromide-ketone complex would be incapable of reduction by intramolecular rearrange-ment, but probably more susceptible to attack by an external molecule of Grignard reagent giving normal addition. The above modification i n procedure could be applied to the reactions of t e r t - b u t y l magnesium chloride with o- and p-methoxyacetophenone, possibly giving much better y i e l d s . 70 The alt e r n a t i v e procedure, to react methyl magnesium iodide with o- and p-methoxy-(trimethylacetophenone) appears to be useless since the s t a r t i n g materials are not r e a d i l y obtained by the conventional methods. Several possible reasons can be given f o r the lack of success i n the preparation of o-hydroxy-(trimethylacetophenone). The f i r s t i s a s t e r i c one, claiming simply that the t e r t -butyl ketone group i s too large to be adjacent to a hydroxy! group on a benzene r i n g . The second reason i s that there i s s t e r i c repulsion between the t e r t - b u t y l group and both the aromatic r i n g and the hydroxyl group, making i t necessary f o r the alpha carbon and oxygen atoms to l i e outside of the plane of the benzene r i n g . This w i l l necessarily increase the energy of the molecule f o r two reasons. The f i r s t i s that d e r e a l i z a t i o n energy due to conjugation of the carbonyl group with the aromatic r i n g w i l l be reduced. The second i s that the p o s s i b i l i t y of intramolecular hydrogen-bonding (chelate r i n g formation) w i l l be d r a s t i c a l l y reduced. Intramolecular hydrogen-bonding i s considered to be the reason why the ortho isomer of a 71 hydroxyphenyl-ketone i s more stable at high temperatures. The generally accepted mechanism of the F r i e s rearrangement involves the primary formation of the para isomer followed by rearrangement to the more stable ortho isomer at high temperatures. If the s t a b i l i z i n g influence i s absent the second rearrangement w i l l not take place to any great extent. The t h i r d reason involves the strong inductive e f f e c t of the t e r t - b u t y l group. OH OH Since much evidence has been found f o r an intermolecular mechanism f o r the F r i e s rearrangement we must consider the p o s s i b i l i t y of polysubstitution. If we consider f i r s t p-hydroxyacetophenone (compound I) we see that since the car-co bonyl group can be/planar with the r i n g and since i t i s con-jugated with the r i n g the aceto group exerts a-K e f f e c t , as depicted by the arrows. Also the aceto group exerts a-I e f f e c t due to the e l e c t r o n e g a t i v i t y of the oxygen atom and the high p o l a r i z a b i l i t y of the carbon-oxygen double bond. This inductive e f f e c t i s shown i n the s t r u c t u r a l formula by I II Symbols f o r e l e c t r o n i c effects are those used by A.E. Remick (93) and C.K. Ingold (46). 72 del t a plus and minus signs. The inductive e f f e c t of the oxygen atom i s counteracted to a s l i g h t extent by the weak + I ef f e c t of the methyl r a d i c a l . The o v e r a l l r e s u l t i s that the aromatic r i n g i s deactivated with respect to e l e c t r o p h i l i c s u b s t i t u t i o n making polysubstitution improbable. In the case of p-hydroxy (trimethylacetophenone) (compound II) the much stronger inductive e f f e c t of the t e r t - b u t y l group would decrease the - I ef f e c t of the keto r a d i c a l , and increase the p o s s i b i l i t y of polysubstitution. In f a c t i f t h i s phenom-enon was very strong i t i s possible that the keto group could have a + I e f f e c t , making p-hydroxy-(trimethylacetophenone) more susceptible to e l e c t r o p h i l i c attack than free phenol. This i s a possible explanation of the mixture of products obtained i n the F r i e s rearrangement. arrangement, Merler (73) reports that phenylisobutyrate on rearrangement gives a small f r a c t i o n of phenol. The s i m i l -a r i t y between phenylisobutyrate (I) and phenyl (trimethyl-acetate) (II) i s evident from t h e i r s t r u c t u r a l formulae. Although the phenol esters of st r a i g h t chain a l i -phatic acids give no i n i t i a l f r a c t i o n of phenol a f t e r r e -I II The preceding arguments apply equally well to phenyliso-butyrate and i t s rearranged products but to a l e s s e r extent. 73 A t h i r d possible synthetic route to 3(o- and p-hydroxyphenyl)2,2-dimethylbutane, would be the method of Smith and co-workers. (109). They reacted hexanone-3 with the Grignard reagents formed from o- and p-bromoanisole. To apply t h e i r procedure to the required synthesis, pina-colone (3,3 dimethylbutanone-2) would be substituted f o r the hexanone-3 giving the following equation f o r the para isomer. 0CH3 OCH3 The t e r t i a r y alcohol would then be dehydrated, hydrogenated and methylated i n the usual manner to give the required secondary alkylphenol. trated i n the i d e n t i f i c a t i o n of the s t r u c t u r a l formula of a commercially synthesized phenol, namely that Sharpie's "o-sec-amyl phenol" i s i d e n t i c a l to 2(o-hydroxyphenyl)-study w i l l f i n d some use i n the other purposes f o r which they were intended, both as s e l e c t i v e herbicides and as reference compounds f o r phenol condensations to be under-taken at t h i s u n i versity. The r e s u l t s of t o x i c i t y studies at Oxford University under the d i r e c t i o n of Professor G. E. Blackman and at the Prevention of Deterioration Centre, l 3 One of the purposes of t h i s project has been i l l u s -pentane. It i s hoped that the r e s u l t s obtained i n t h i s National Research Council, Washington, D. C., under the d i r e c t i o n of Dr. H. G, Shirk are awaited with interest and w i l l be reported at a l a t e r date. 75 APPENDIX I YIELDS OBTAINED IN THE METHYLATION OP p-HYDROXYACETOPHENONE Run No. Y i e l d (based on hydroxy-ketone taken) (%) Y i e l d (based on hydroxy-ketone reacted) (%) 1 88 _ 2 86 89 3 86 90 4* 71 92 Double quantities and less e f f i c i e n t s t i r r i n g used. APPENDIX II YIELDS OBTAINED IN THE HETHYLATION OP o-HYDROXYACETOPHENONE Run No. Y i e l d (based on hydroxy-ketone taken) )• (%) Y i e l d (based on hydroxy-ketone reacted) (%) 1* 56 71 2* 58 76 3* 62 81 4** 79 91 5** 78 92 *Reflux temperature **Temperature 50-60° APPENDIX I I I YIELDS OBTAINED IN THE HETHYLATION OP p-EYDROXYPROPIOPHENONE Run No. Y i e l d (based on hydroxy-ketone -taken) CO Y i e l d (based on hydroxy-ketone reacted (#) 1* 43 88 2 82 88 3 67 86 4 67 89 "Technical grade potassium hydroxide, containing potassium carbonate, used. APPENDIX IV YIELDS OBTAINED IN THE METHYLATION OF o-HYDROXYPROPIOPHENONE Run No. Y i e l d (based on hydroxy-ketone taken) (%) Y i e l d (based on hydroxy-ketone reacted) (%) 1 65 83 2* 37 82 3 62 82 4 62 82 5 60 82 6 61 82 Technical grade potassium hydroxide, containing potas-sium carbonate, used. APPENDIX V MELTING POINTS AND MIXED MELTING POINTS OF THE AMINE SALTS OF NITRATED no-sec-Amylphenol n* and 2-(Hydroxyphenyl)-pentane Dinitro-derivative of-Meltin Z Point of Amine Salt (°C) Piperidine Morpholine Cyc1ohexylamine 2-(Hydroxyphenyl)-pentane 140 146 189 «o-sec-Amylphenol B* 140 146 189 Mixture 140 146 189 Commercial sample, obtained from Sharpies Chemicals Inc. 77 BIBLIOGRAPHY 1. Abbey, A. B r i t . Pat., No. 593, 320 Oct. 14, 1947. (C.A. 42:1702. 1948). 2. Atkins, D.C, Baker, H.R., Murphy, CM. and Zisman, W.A. Ind. Eng. Chem. 39:491. 1947. 3. Baddely, G. J . Chem. Soc. 330. 1944. 4. Balsohn, B u l l . soc. chim. (2) 31:539. 1879. 5. Baroni, E. and Eleinau, W. Monatsh. 68:251. 1936 (C.A. 30:7554. 1936) 6. Berry, B. and Koch, W. Modern P l a s t i c s 25:154 and 246. 1947. (C.A. 42:1435. 1948). 7. Berry, T.M. and Reid, E.E. J . Am. Chem. Soc. 49:3142. 1927. 8. Blackman, G. J . Royal Soc. Art s . 98:500. 1950. 9. Bowden, E. J.Am. Chem. Soc. 60:645. 1938. 10. Briggs, T.I. 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H l L L M A N Reprinted from CANADIAN JOURNAL OF CHEMISTRY 31: 685-687. • 1953 Reprinted from Canadian Journal of Chemistry, 31: 685-687 July, 1953 CHARACTERIZATION OF DINITRO ALKYL PHENOLS1 B Y G . G . S . D U T T O N , T . I . B K I G G S , 2 B . R . B R O W N , 3 A N D M . E . D . H l L L M A N ABSTRACT Amine salts of dinitroalkyl phenols have been suggested as herbicides and insecticides. A selection of such amine salts was examined as to their suitability for characterizing dinitroalkyl phenols. The folowing new salts are described: the piperidine, morpholine, and 'cyclohexylamine salts of each of 2,4-dinitro-phenol, 4,6-dinitro-2-methylphenol, 2,6-dinitro-4-methylphenol, 4,6-dinitro-2-isopropylphenol, 2,6-dinitro-4-isopropylphenol, 4,6-dinitro-2-(sec-butyl)-phenol, 2,6-dinitro-4-(<eri-butyl)-phenol,' and 2,6-dinitro-4-(/er(-amyl)-phenol. In addition, the preparation of 4,6-dinitro-2-isopropylphenol and 2,6-dinitro-4-isopropylphenol does not appear to have been previously described. The use of these salts, and similar ones with other amines, is recommended for the prepa-ration of crystaline derivatives of dinitrophenols. INTRODUCTION Dinitroalkyl phenols have been shown to be effective as insecticides (2, 3) and selective weed killers (6). In connection with a study of such compounds as herbicides a selection of dinitroalkyl phenols has been prepared. The amine salts of these dinitroalkyl phenols were prepared and were found to be excellent derivatives for the characterization of these compounds. The reported method of preparing such amine salts (4) (sodium salt of phenol + amine hydrochloride) has given in our hands crystalline mixtures of the phenol and the desired salt. The discrepancies between the reported melting points of some of these salts (4) and those described here are attributed to this cause. Bell's melting point (1) of 171° C . for piperidinium 2,4-dinitro-phenoxide agrees well with our figure of 172° C . EXPERIMENTAL The phenols selected for nitration were 2-and 4-methylphenol, 2- and 4-iso-propylphenol, 4-(ter/-butyl)-phenol, and 4-(ieri-amyl)-phenol. The latter two were prepared by the method of Putnam (5) and the remainder, together with 2,4-dinitrophenol and 2,4-dinitro-2-(sec-butyl)-phenol, were obtained as com-mercial products. 4,6-Dinitro-2-isopropylphenol 2-IsopropylphenoI (25 gm.) was dissolved in glacial acetic acid (60 cc.) and this solution was added dropwise, with constant stirring, to a solution of nitric acid (40 c c , d = 1.5) and glacial acetic acid (75 cc.) which had been cooled to —15° C . in a stainless steel beaker. The addition took about three quarters of an hour, after which time the mixture was allowed to come slowly to room temperature over a period of one and a half hours. The solution was kept at room temperature for one half hour and then poured onto cracked ice. 1 Manuscript received March 17, 195S. Contribution from the Department of Chemistry, University of British Columbia, Van-couver 8, B.C. 2 Present address, C.I.L., Nylon Division, Maitland, Ontario, Canada. 3 Present address, 45, Myrtle Road, Ipswich, Suffolk, England. 685 686 CANADIAN JOURNAL OF CHEMISTRY. VOL. 31 The yellow precipitate which resulted was filtered off, dissolved in chloroform, and carefully washed to remove all trace of acid. The chloroform solution was then dried over magnesium sulphate and after removal of the solvent, the residual oil was distilled under high vacuum to give the 4,6-dinitro-2-isopropyI-phenol as a clear yellow oil boiling at 132° C . (0.15 mm.). The oil solidified on cooling and on recrystallization from ethanol gave a yellow solid, m.p." 54° C , yield, 65%. In a similar manner all the other dinitrophenols were prepared and the results shown in Table I . TABLE I DlNITROALKYL PHENOLS Phenol M.p., °C. Yield, % 2,4-Dinitro 114 * 4,6-Dinitro-2-methyl 86 67 2,6-Dinitro-4-methyl 82 60 4,6-Dinitro-2-isopropyl 54 66 2,6-Dinitro-4-isopropyl 68 65 4,6-Di ni tro-2- Oec-bu tyl) 42 * 2,6-Dinitro-4-(Jert-butyl) 95 80 2,6-Dinitro-4-(er<-amyl) 66 50 * Commercial sample. . Piperidine Salt of Jh,6-Dinilro-2-methylphenol 4,6-Dinitro-2-methylphenol (0.5 gm.) was placed in an Erlenmeyer flask and a small excess of piperidine (0.75 gm.) was added. Benzene (10 cc.) was then added and the mixture gently warmed for five minutes. Petroleum ether (25 c c , 3 0 - 6 0 ° C.) was then added when the salt crystallized as colored flakes. The precipitate was filtered off, washed with petroleum ether, and recrystal-lized from a mixture of benzene (five parts), ethanol (one part), and petroleum ether (two parts).% In a similar way the piperidine, morpholine, and cyclohexylamine salts of all the dinitrophenols were prepared and these are listed in Tables II, III, and IV. TABLE 1 1 PIPERIDINE SALTS OF DlNITROALKYL PHENOLS Phenol Formula M.p., °C. Nitrogen, % Description Calc. Found 2,4-Dinitro 4,6-Dinitro-2-methyl 2,6-Dinitro-4-methyl 4,6-Dinitro-2-isopropyl 2,6-Dinitro-4-isopropyl 4,6-Dini tro-2-(sec-butyl) 2,6-Dinitro-4-(tert-butyl) 2,6-Dinitro-4-(>rt-amyl) C„H1SN306 CJHIJNJOS Cr.H17N3Os Ci4H2IN306 diHnNaO* CJHONJOS CiiH23N306 CjoI-htNuOt 172* 157 195 204 218 154 232 198 15.61 14.83 14.83 13.50 13.50 12.92 12.92 12.39 15.54 14.93 14.86 13.52 13.44 12.93 12.92 12.54 Orange needles Yelow needles Orange needles Yelow needles Orange plates Yelow needles Orange needles Orange plates * Ref.(,l). DUTTON ET AL.: PHENOLS , 6 8 7 TABLE III M O R P H O L I N E SALTS O F D I N I T R O A L K Y L P H E N O L S Phenol Formula M.p., °C. Nitrogen, % Description Calc. Found 2,4-Dinitro CibHiaNsOe 169 1 5 . 4 9 1 5 . 3 6 Yelow needles 4,6-Dinitro-2-methyl C„HI6N306 189 1 4 . 7 4 1 4 . 7 6 Red plates 2,6-Dinitro-4-methyI CiHuNjO, 217 1 4 . 7 4 1 4 . 7 3 Orange plates 4,6-Dinitro-2-isopropyl 1 3 H 1 9 3 C 204 1 3 . 4 2 1 3 . 5 4 Orange needles 2,6-Dinitro-4-isopropyl C.jHi.N.Oe 216 1 3 . 4 2 1 3 . 5 5 Yelow flakes 4,6-Dinitro-2-(sec-butyl) H M N J O . 147 1 2 . 8 4 1 2 . 8 9 Red needles 2,6-Dinitro-4-(ter2-butyI) CnH;iNS06 2 3 2 1 2 . 8 4 1 2 . 9 2 Orange needles 2,6-Dinitro-4-(ter/-amyl) ClsH23N30„ 174 1 2 . 3 2 1 2 . 2 2 Yelow plates TABLE IV C Y C L O H E X Y L A M I N E SALTS O F D I N I T R O A L K Y L P H E N O L S Phenol Formula M.p., °C. Nitrogen, % Description Calc. Found 2,4-Dinitro C12H17N3O5 158 1 4 . 8 3 1 4 . 8 5 Yelow needles 4,6-Dinitro-2-methyl C13HI9NA, 171 1 4 . 1 3 1 4 . 2 3 Yelow needles 2,6-Dinitro-4-methyl 13 10 3O5 193 1 4 . 1 3 1 4 . 1 6 Orange needles 4,6-Dinitro-2-isopropyl C16H23N3O5 207 1 2 . 9 2 1 2 . 9 5 Yelow needles 2,6-Dinitro-4-isopropyl C,5HaN306 213 1 2 . 9 2 1 2 . 9 9 Orange needles 4,6-Dinitro-2-(sec-butyl) IO MNJOB 210 1 2 . 3 8 1 2 . 4 4 Yelow needles 2,6-Dinitro-4-(ter<-butyl) CicHssNsOfi 2 3 0 1 2 . 3 8 1 2 . 3 9 Orange needles 2,6-Dinitro-4-(ter/-amyl) Cl7H27N30fi 219 1 1 . 9 0 1 1 . 9 3 Yelow needles ACKNOWLEDGMENTS Our thanks are due to the National Research Council and to the University of British Columbia for financial support. We are also grateful to Dow Chem-icals of Canada Limited, and to Koppers Company Incorporated, for gifts of materials, and to M r . C . K . Harris for assistance with the analyses. REFERENCES 1. B E L L , F. J . Chem. Soc. 609. 1931. 2. C R A F T S , A. S. Science, 101:417. 1945. 3. K A G Y , J . F. J . Econ. Entomol. 3 4 : 660. 1941. 4. M I G R D I C H I A N , V. U.S. Pat. No. 2,385,719. 1945. 5. P U T N A M , M. E. U.S. Pat. No. 2,039,044. 1936. 6. W E S T G A T E , W. A. and R A Y N O R , R. N. Calif. Dept. Agr. Bull. No. 634. 1940. 

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