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

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THE PREPARATION OF SOME HOMOLOGUES OF DINITRO ORTHO AND PARA GRESOLS by THOMAS IRVING BRIGGS  A THESIS SUBMITTED IN PARTIAL FULFILMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE.. i n the Department of Chemistry  We accept t h i s t h e s i s as conforming t o 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 October, 1952  ACKNOWLEDGEMENT  Sincere appreciation and gratitude i s extended to my research d i r e c t o r , Mr. G. G. S. Dutton, f o r h i s patient and h e l p f u l superv i s i o n during the course of t h i s project and f o r h i s many kindnesses during the d i f f i c u l t days at the end. Many thanks i s extended to Mr. R. K. Powell my hard working co-worker during the summer of 1951 and also to Mr. C. Harris who performed some of the a n a l y t i c a l work.  II ABSTRACT  The ortho and para normal-alkyl-phenols from n-ethyl to n-octyl and ortho and para i s o b u t y l and isoamyl phenols were prepared by the F r i e s rearrangement method.  The para-tertiary-butyl,  para-secondary-  b u t y l , para-tertiary-amyl and ortho-tertiary-butyl phenols were prepared by miscellaneous methods. give d i n i t r o d e r i v a t i v e s .  A l l the phenols were nitrated to  The cyclohexyl-amine, piperidine and  morpholine s a l t s were made f o r a l l the dinitro-alkyl-phenols  prepared.  Ill TABLE OF CONTENTS ACKNOWLEDGEMENT  I  ABSTRACT  II  INTRODUCTION The History of the Use of Herbicides and Insecticides  1  V a r i a t i o n of Chemical Structures of Phenols on T o x i c i t y . . . . . . . . . . . . . . 2 Graph No. I  t o follow page.. 2  Action of Selective Weedkillers Graph No. I I  .* 4 to follow page.. A  The History of the Preparation of Nitro-Alkyl-Phenols 1.  The Preparation of Alkyl-Phenols  7  2.  The Preparation of Nitro-Alkyl-Phenols  9  3.  The Preparation of the Amine S a l t s of the Dinitro-Alkyl-Phenols  10  EXPERIMENTAL THE PREPARATION OF THE DINITRO-ALKYL-PHENOLS I.  The Preparation of the Alkyl-Phenols by t h e o r i e s Rearrangement  II.  III.  11  11  Table 1  12  Table I I .  12  Table I I I . . . .  15  Table IV  16  Table V  17  The Preparation of the Dinitro-Alkyl-Phenols  20  Table VI  21  Table VII  22  The S a l t Formation of the Dinitro-Alkyl-Phenols  23  Table VIII  25  Table IX  26  IV III.  The S a l t Formation of the Dinitro-Alkyl-Phenols (con't) Table X  27  Table XI  28  Investigation of U.S. Patent 2,385,719...  29 29  Table XII IV.  The Preparation of Alkyl-Phenols by Miscellaneous Methods.... 1.  The Preparation of Para-Tert.-Butyl and Para-Tert.Amyl Phenols  31  Table XIII  32  2.  The Preparation of Para-Secondary-Butyl-Phenol  32  3.  The Preparation of Ortho-Tertiary-Butyl-Phenol  34  4.  Attempted Preparation of  Ortho-Tertiary-Amyl-Phenol......37  COMPARISON OF ALKYL-PHENOLS PREPARED BY THE GRIGNARD AND FRIES METHODS  3&  Table XIV  ,  %  Table XV A CHECK ON THE PHYSICAL CONSTANTS OF THE INTERMEDIATE COMPOUNDS PREPARED DURING THE SYNTHESIS OF ORTHO AND PARA ISOBUTYL AND ISOAMYL PHENOLS USING THE GRIGNARD METHOD I . The Preparation of  39 .39  40  Para-Methoxy-Phenyl-Isopropyl-Carbinol......40  I I . The Preparation of Para-Methoxy-Phenyl-Isobutene-1......... I I I . The Preparation of Para-Methoxy-Isobutyl-Eenzene.  41 41  IV. The Preparation of Ortho-Methoxy-Phenyl-Isopropyl-Carbinol  42  V. The Preparation of Para-Methoxy-Phenyl-Isobutyl-Carbinol  42  VI. The Preparation of Para-Methoxy-Phenyl-Isoamylene-1 VII. The Preparation of Para-Methoxy-Isoamyl-Benzene.......  43 ..43  VIII. The Preparation of Ortho-Methoxy-Phenyl-Isoamyl-Carbinol  43  THE PREPARATION OF ORTHO-METHOXY-ACETOPHENONE.  44  DISCUSSION Graph No. I l l . ,  46 to follow page... .47  V DISCUSSION (con't) Graph No. IV BIBLIOGRAPHY  to follow page..47 48  INTRODUCTION This thesis describes the preparation of some of the homologues of d i n i t r o ortho and para cresols.  The dinitro-alkylrphenols were prepared  i n order to t e s t and possibly to develop t h e i r use as selective herbicides and i n s e c t i c i d e s .  I t has been known since 1943  that certain amine s a l t  derivatives of the dinitro-alkyl-phenols are also f a i r l y good s e l e c t i v e h e r b i c i d e s . ^ Thus three d i f f e r e n t amine s a l t derivatives have been made f o r each dinitro-alkyl-phenol prepared.  The History of the Use of Herbicides The  and I n s e c t i c i d e s .  idea of a s e l e c t i v e herbicide f o r weed control i n cereal  crops has gradually evolved since Bonnet, i n 1896, of oats was unaffected  showed that when a f i e l d  sprayed with a d i l u t e solution of copper sulfate the oats were but the weed, the yellow charlock, was  destroyed.  major experiment i n selective weedkilling occurred i n 1911 sprayed cereal crops with d i l u t e s u l f u r i c a c i d .  The next  when Rabate  A large percentage of  dicotyledonous weeds were destroyed but the crops remained p r a c t i c a l l y uninjured.  However, the corrosive action of the s u l f u r i c acid on the  spraying equipment offered a serious disadvantage. Up to 1933,  when Truffaut and P a s t a c ^ discovered  the s e l e c t i v e  action of the nitro-phenol, only a small percentage of the cereal acreage i n Great B r i t a i n and Europe was and s i m i l a r compounds.  treated with s u l f u r i c a c i d , copper sulfate  Truffaut and Pastac showed that by  spraying  cereal crops with the dyestuff d i n i t r o - o r t h o - c r e s o l f a i r l y good control of weeds could be obtained. s u l f u r i c acid was equipment.  The advantage of dinitro-phenol over the  that there was  no corrosive action on the  The development of the dinitro-phenols  of organic herbicides.  spraying  gave r i s e to a host  In 1940 alpha-napthyl oats.  Templeman^- discovered that the growth-regulating a c e t i c acid was  Since 1940  compound  t o x i c to the charlock weed and not to the  a large number of substituted phenoxy-acetic acid com-  pounds has been developed and tested f o r use as herbicides.  The most  well known one i s probably 2:4 dichloro-phenoxy a c e t i c acid used to control the dandelion i n gardens and lawns. The development of s e l e c t i v e weedkillers has reached the point where tens of m i l l i o n s of acres of cereal crops are sprayed annually.  Methods  of weed control have been worked out to cover r i c e , sugar cane, oats, barley, maize, l i n s e e d - f l a x , peas, onions and carrot crops as well as lucerne and grasslands.  New  developments are i n the process of being  made for the eradication of mosquitoes, aquatic weeds i n r i v e r s and  irri-  gation channels, weeds i n f o r e s t nursery beds and also f o r the destruction or  6 scrub. The V a r i a t i o n of Chemical Structure of Phenols on T o x i c i t y . The discovery of the s e l e c t i v e action of dinitro-phenols by  Truffaut and Pastac led to the i n v e s t i g a t i o n of the e f f e c t of v a r i a t i o n 17 i n chemical structure of hydroxy compounds on t o x i c i t y .  Johnson  investigated the a n t i s e p t i c strengths of the homologues of r e s o r c i n o l where side chains of one to four carbons were inserted i n t o the r i n g . Johnson found that the a n t i s e p t i c strength reached a maximum with a four 12 carbon side chain.  However, l a t e r work by Dohme  showed that of the  n-propyl to n-octyl and i s o b u t y l , isoamyl and isohexyl derivatives of r e s o r c i n o l , the compounds with side chains containing s i x carbon atoms had the highest phenol c o e f f i c i e n t .  For a graphic i l l u s t r a t i o n of  Dohme s investigations see Graph No. I following page two. 1  Dohme also  showed that the phenol c o e f f i c i e n t s of the i s o - a l k y l - r e s o r c i n o l s were  Figure Phenol  C o e f f i c i e n t of  2  4  1.  4-Alkylresorcinols  6  Number o f c a r b o n atoms i n a l k y l  ©  R -'n-alkyl  X  R «  iso-alkyl  8 group  -3-  lower than the corresponding normal a l k y l - r e s o r c i n o l s .  31 Tattersfield  i n his investigations of phenols showed that a n i t r o  group iri the ortho or meta p o s i t i o n to the hydroxyl group has a f f e c t on the t o x i c i t y , but when the n i t r o group was a large increase i n t o x i c i t y was 26 Plantefol  i n the para p o s i t i o n  obtained.  found that phenol and  i t s n i t r o derivatives were a l l o  t o x i c to s-fungus nigra but that ortho-nitro-phenol was of the mono derivatives and that para-nitro-phenol was P l a n t e f o l also found that 2:4  little  dinitro-phenol  was  the l e a s t toxic the most t o x i c .  about one hundred times  more toxic than phenol and about ten times more toxic than the paranitro-phenol.  2:4:6  t r i n i t r o - p h e n o l had only about the same t o x i c i t y  as meta-nitro-phenol.  T a t t e r s f i e l d carried out t e s t s on insects s i m i l a r  to those tests carried out by P l a n t e f o l on fungus and also found maximum t o x i c i t y i n the 2:4  dinitro-phenol.  The f a c t that the position of a functional group i n the benzene r i n g i s important to the t o x i c i t y of aromatic type herbicides by Blackman  i n a lecture on s e l e c t i v e t o x i c i t y .  are attached i n the 2, 4» and  was mentioned  I f three chlorine atoms  5 positions on the benzene r i n g i n the  growth-regulating substance-trichloro-phenoxy a c e t i c acid, then the compound i s highly t o x i c j but i f one atom i s moved from the 5 p o s i t i o n to the 6 p o s i t i o n the compound exhibits l i t t l e t o x i c i t y . important to test each and  Thus i t i s  every compound i n a series i n order to  determine maximum a c t i v i t y . K a g y ^ investigated structures  of the 2:4  structure from two  the variations i n t o x i c i t y with the chemical  dinitro-alkyl-phenols  to eight carbons.  varying the side chain  He found that the maximum a c t i v i t y  -4was  obtained when the length of a side chain was  s i x or seven carbons.  For a graphic i l l u s t r a t i o n of Kagy's investigations see Graph No. II following page four. Kagy also carried out an i n v e s t i g a t i o n of phenols  on the adult female c i t r u s red mite.  the t o x i c i t y of c e r t a i n The r e s u l t s he  obtained  were as follows: Compound  Lethal Deposit of Compound  2:4 dinitro-6-cyclohexyl-phenol 2:4 dinitro-6-ethyl-phenol 3:5 d i n i t r o - c r e s o l 2:4 dinitro-phenol Dinitro-alpha-naphthol  0.40 micrograms/sq. 1.20 " n 1.80 " n 3.10 " " 3.40 n u  In t h e i r work on thio-cyano-acetates that the six carbon compound was  w  cm. of f r u i t n H n n n n " " " n «• g  Grove and Bovingdon  the most t o x i c .  found  However, i t i s not a  general r u l e that s i x carbon side chains i n herbicides and i n s e c t i c i d e s  7 are the most t o x i c as Bousquet  found that i n the a l k y l  thio-cyanates  the l a u r y l homologue had the maximum t o x i c i t y . Action of Selective Weedkillers. The actual operation of the s e l e c t i v e mechanism of herbicides i s not f u l l y understood.  Certain factors are d e f i n i t e l y known to be  important i n weed control.  One of the most important factors Is the  stage of development of the plant i t s e l f . on the growth-regulating  very  Blackman,^ i n his i n v e s t i g a t i o n  compounds, has shown that while methyl-chloro-  phenoxy- a c e t i c acid was t o x i c to both the charlock and cocksfoot weed i n the germination stage i t was t o x i c only to the charlock weed i n the vegetative phase.  Thus, the methyl-chloro-phenoxy-acetic acid  was  d e f i n i t e l y not s e l e c t i v e during the germination stage of both plants, but i t d e f i n i t e l y was  s e l e c t i v e during the vegetative stage.  Through  similar investigations of the r e l a t i o n s h i p between resistance and s u s c e p t i b i l i t y of both weed species and crops i t has been possible to  Figure T o x i c i t y of 2:4  2.  Dinitro-o-n-alkylphenols  t o S i l k Worm Larvae  0  j 2  4  6  Number o f carbon atoms i n a l k y l  8"  group  -5work out methods  that o f f e r excellent selective c o n t r o l .  Blackman and h i s team at Oxford have shown that the degree of resistance of a weed species w i l l d i f f e r with d i f f e r e n t herbicides.  In  t h e i r Investigations of the hoary pepperwort (cardaria draba) they compared the effects of spraying sodium methyl-chloro-phenoxy-acetate and d i c h l o r o phenoxy-acetic  acid (2:4 D) during the preflowering stage, the flowering  stage and the regeneration stage.  Blackman found that during the pre-  flowering stage the sodium methyl-chloro-phenoxy-acetate was more t o x i c than the dichloro-phenoxy-acetic a c i d . compounds was accentuated  This difference i n t o x i c i t y of the  i n the regeneration stage  but i t was  reversed  during the flowering stage when the dichloro-phenoxy-acetic acid was most t o x i c .  S i m i l a r r e s u l t s were recorded by H o l l y at Oxford  investigated the control of perennial weeds i n grassland. i n the spring sodium methyl- chloro-phenoxy-acetate dandelion than sodium dichloro-phenoxy-acetate, dichloro-phenoxy-acetate  two  the  who  He found that  was more t o x i c to the  but i n the autumn sodium  was by f a r the more t o x i c of the two compounds.  Investigations by numerous workers have shown that the "degree of kill"  of a weed species does not necessarily increase with concentration  of the spray s o l u t i o n . On the contrary, i n many cases the "degree of k i l l " decreased  r a p i d l y f o r large increases i n concentration of the  spray.  Results of t h i s nature tend to show that the destruction of the roots i s not due to root absorption of the herbicide but i s probably due to the transport of the herbicide from the shoot along to the root.  Thus i t  may be that a high concentration of a herbicide i n a spray produces a smaller "degree of k i l l "  than a l e s s concentrated  transportation system of the plant i s destroyed by  spray because the concentrated  solutions before the herbicide reaches the root i n any quantity.  This  would explain why the low concentrations of the nitro-alkyl-phenols  -6-  give greater i n j u r y than the higher  concentrations.  Some other important factors are the amount of spray that i s retained by the plant, the amount of herbicide that penetrates stem and l e a f , and the rate of penetration of the herbicide.  into the Blackman  and h i s workers have shown that c e r t a i n plants r e t a i n more spray when the spray i s an o i l emulsion type.  The rate of penetration of a h e r b i -  cide into a plant i s also affected by the o i l .  These factors are very  important and must be considered when using herbicides that are p r a c t i c a l l y insoluble i n water.  These herbicides are u s u a l l y dissolved  i n oil-water emulsions. Understanding the above factors has aided workers t o develop f a i r l y good weed control of cereal, vegetable and f r u i t crops.  However, a serious  problem has arisen from the continuous and heavy a p p l i c a t i o n of herbicides to crops.  Various groups of workers have shown that by heavy and  continuous a p p l i c a t i o n of herbicides i t i s possible to breed v a r i e t i e s of plants that are r e s i s t a n t to these herbicides.  Thus, while i t may  be possible to produce food crops that are p r a c t i c a l l y one hundred percent r e s i s t a n t to s p e c i f i c herbicides i t may also be possible to produce weeds that are just as r e s i s t a n t . In the United States very heavy and continuous spraying of areas alongside highways with mineral o i l has destroyed  the o r i g i n a l undesired vegetation.. However, the o r i g i n a l type  of undesired vegetation has been replaced by a new type that i s o i l resistant.  S i m i l a r l y the extensive use of 2:4  dichloro-phenoxy-ac'etic  acid has kept down the rate of spread of the dicotyledonous  weed but i t  has increased the spread of the more r e s i s t a n t monocotyledonous weed. Thus i t appears that nature tends to look a f t e r her own.  This  perhaps i s fortunate f o r the chemist as new effective'herbicides w i l l have to be developed as the old herbicides become I n e f f e c t i v e .  -7-  The History of the Preparation of Nitro-Alkyl-Phenols. Interest i n the preparation of a l k y l phenols was by the works of Johnson and Lane^  instigated  i n 1921 and also by Dohme, Cox and  0  12 Miller  i n 1926.  These workers introduced the a n t i s e p t i c hexyl-  r e s o r c i n o l into medicine.  They showed that the germicidal value of  4-n-alkyl resorcinol rose to a maximum at 4-n-hexyl r e s o r c i n o l . 28 In  1928 Rosenmund and Lohfert  showed that the a l k y l phenols  could be prepared by the Clemmensen reduction of the appropriate hydroxy-ketone.  In 1930 Coulthard, Marshal and Pyman^using s i m i l a r  procedures as those used by Rosenmund and Lohfert, prepared the a l k y l derivatives of phenol, cresol, and guaiacol, and then went on to make a systematic study of the v a r i a t i o n of the phenol c o e f f i c i e n t s of the compounds they had prepared.  Coulthard prepared the  hydroxy-ketones  by the following four methods: ( i ) the Menchi condensation of acid and phenol using zinc chloride as a catalyst; ( i i ) the F r i e s isomerization of phenyl esters with aluminum chloride; ( i i i ) the isomerization of phenyl esters using zinc chloride  which gave lower y i e l d s than the  F r i e s method; (iv) the condensation of acids with phenols by means of phosphorus oxychloride. They reduced the hydroxy-ketones by r e f l u x i n g the ketones with alcohol, d i l u t e hydrochloric acid and amalgamated zinc f o r twelve to twenty hours.  I t was. found that  took longer to reduce than the para homologues.  ortho-hydroxy-ketones Coulthard and h i s  fellow workers prepared the ortho and para n-butyl to n-heptyl phenols. Sandulesco and G i r a r d ^ carried out a project similar to that carried 2  out by Coulthard.  Sandulesco and Girard prepared the straight chain  alkyl-phenols from methyl to nonyl. ester and the F r i e s rearrangement  They did the preparation of the  i n one step by heating phenol, aluminum  chloride and the acid chloride up to 130° C. f o r one hour.  I t was found  that the hydroxy-ketones were more r e a d i l y reduced by d i l u t i n g concentrated hydrochloric acid with g l a c i a l acetic acid instead of d i l u t i n g i t with water and alcohol.  The g l a c i a l a c e t i c acid was a b e t t e r solvent  f o r the ketones than the alcohol.  Sandulesco and Girard prepared the  phenols with the object of studying the hypnotic properties of these compounds. 13 Farenholt, Harden and Twiss, phenols  i n 1933 prepared a series of a l k y l -  using the F r i e s rearrangement method.  In 1935 Bartz, Adams and Miller ^ showed that butyl-phenols could -  be prepared from the methyl-allyl ethers of phenol.  They rearranged the  ether compounds by heating the ethers at 245° C. and then reducing the rearranged methyl-allyl-phenols to the saturated butyl-phenols. In 1937 J . B. Niederl and co-workers ^ 2  treated molecular amounts  of phenol, a c e t i c acid and various aldehydes at -5° C. with dry hydroc h l o r i c acid f o r two hours.  The resultant material was slowly dried to  give mixtures of alkyl-phenols. Pure alkyl-phenols were d i f f i c u l t to obtain by t h i s method. •3/ Tsukervanik and Tambovtseva,  i n 1937, obtained mixtures of phenols  by means of a l k y l a t i n g phenol or anisole with an a l k y l chloride.  This  method gave mostly tertiary-alkyl-phenols. In 1938 Najarova -^ prepared isoamyl-phenol by a very tedious 2  procedure.  He nitrated isoamyl benzene with n i t r i c acid, reduced the  n i t r o compound to the amine, diazotized the amine, and decomposed the diazo compound. 3 Baddely, i n 1938, prepared ortho and para ethyl-phenols by heating phenol, d i e t h y l ether and aluminum chloride at 100° C.  -9Numerous workers have prepared the para-alkyl-phenols by condensing phenol and an a l k y l chloride using aluminum chloride as a c a t a l y s t .  The  tertiary-alkyl-phenols are very e a s i l y prepared by t h i s method. 2 In 1938 Archer, Simons and Passino  showed that i t was possible to  prepare tertiary-butyl-phenol by condensing t e r t i a r y - b u t y l chloride and phenol using anhydrous hydrofluoric acid instead of aluminum chloride. Further investigation into the use of hydrofluoric acid as a condensing agent showed that the tertiary-alkyl-phenols could be prepared by condensing secondary or t e r t i a r y - a l k y l alcohols with phenol using anhydrous hydrofluoric acid as catalyst and as solvent. 15 In 1949 Hart  developed a unique method f o r the preparation of  ortho-tertiary-butyl-phenol.  He condensed  isobutylene with para-bromo-  phenol i n toluene using s u l f u r i c acid as the condensing agent.  He then  removed the bromine from the nucleus by reduction using Raney n i c k e l a l l o y and d i l u t e sodium hydroxide. In general the F r i e d e l and C r a f t type reactions already mentioned are best suited f o r the preparation of para t e r t i a r y and para secondary alkyl-phenols.  The ortho secondary, i s o , and normal alkyl-phenols  may be prepared by the Grignard method. Preparation of Nitro-Alkyl-Phenols. Phenols have been nitrated by various procedures.  In 1936  Baroni eCnd KLeinau^ nitrated phenols by d i s s o l v i n g the phenol i n chloroform and adding n i t r i c acid at 15° C. monondtro derivatives were formed.  At low temperatures  The d i n i t r o and t r i n i t r o derivatives  were prepared by adding the n i t r i c acid to the phenol i n b o i l i n g chloroform.  In t h i s way Baroni and Kleinau prepared d i n i t r o derivatives  of ortho-methyl-phenol and ortho-cyclohexyl-phenol.  In 1938 I p a t i e f f , Pines and Friedman  prepared 2:4 d i n i t r o - 6 -  tert.-butyl-phenol by condensing p-nitro-phenol with isobutene using ninety percent phosphoric acid as a catalyst.  The r e s u l t i n g 2-nitro-  6-tert.-butyl-phenol was then nitrated by d i s s o l v i n g the mononitro compound i n acetic acid and adding n i t r i c a c i d . 00  Monti and C i a n e t t i , " i n 1938, nitrated alkyl-phenols at 15-20  o  C.  by passing through t h e i r solutions nitrous vapours evolved from a mixture of arsenious oxide and n i t r i c a c i d .  They showed that the  choice of solvent f o r t h i s reaction was important.  The d i n i t r o com-  pounds were prepared when a c e t i c acid was used as the solvent.  Mono-  n i t r o compounds were prepared when petroleum ether (40-70) was used as a solvent. Workers i n England nitrated alkyl-phenols by d i s s o l v i n g the phenol i n concentrated s u l f u r i c acid and heating the solution at 100° C. f o r one hour, cooling the solution, and adding i t to n i t r i c acid which had been cooled to -15° C. Preparation of the Amine S a l t s of the Dinitro-Alkyl-Phenols. In 1943 Coleman and G r i e s s ^ prepared the amine s a l t d e r i vatives of the dinitro-alkyl-phenols by mixing together an aqueous solution of the a l k a l i s a l t of the dinitro-alkyl-phenol and an aqueous solution of the inorganic s a l t of the amine. Workers i n England have shown that the amine s a l t derivative can be prepared by simply mixing the d i n i t r o compound and the amine together and r e c r y s t a l l i z i n g the product from benzene.  -11EXPERIMENTAL A l l b o i l i n g points and melting points are uncorrected and measured i n °C.  Melting points were taken using sealed glass tubes inserted i n t o  an e l e c t r i c a l l y heated melting point block. THE PREPARATION OF THE DINITRO-ALKYL -PHENOLS, I.  The Preparation of the Alkyl-Phenols by the F r i e s Rearrangement. A. The Preparation of the Acid Chlorides. The acid chlorides were prepared by the reaction df  t h i o n y l chloride on carboxylic acids. The preparation of isobutyryl chloride: Thionyl chloride (1.1) moles was  cooled to 0° In a  2-necked 1 - l i t r e f l a s k which was f i t t e d with a graduated dropping funnel. Isobutyric acid (1.0 moles) was minutes.  slowly added over a period of twenty  The f l a s k was frequently shaken during the addition.  addition of the isobutyric acid was  A f t e r the  complete the mixture was refluxed  for one hour and then the product was d i s t i l l e d through a f r a c t i o n a t i n g column. With the exception of propionyl chloride a l l the acid chlorides were prepared  i n a similar manner and are recorded i n table I .  In the  preparation of propionyl chloride the molecular r a t i o of the acid to the t h i o n y l chloride was reversed, i . e . an excess of propionic acid was used. B.  The Preparation of the Phenyl-Esters. The phenyl-esters were prepared by reacting an  excess of phenol with the acid c h l o r i d e . The Preparation of phenyl-isobutyrate: Isobutyryl chloride (180 grams, 2.05  moles) was  placed  -12-  TABLE I PHYSICAL CONSTANTS OF ACID CHLORIDES CHLORIDE  BOILING POINT °C/mm. Obs. Lit.  YIELD  80  Propionyl  50$  Butyryl  85%  102  Isobutyryl  90%  93  92  n-Valeryl  50%  127  128  Isovaleryl  80%  115  115  n-Caproyl  75%  151  153  n-Heptyl  87%  173  176  n-Capryl  80%  194  196  Stearoyl  65%  79-84  102 '  208-215/15 215/15  TABLE I I PHYSICAL CONSTANTS OF PHENYL-ESTERS PHENYL-ESTER  YIELD  BOILING POINT °C/mm. Obs. Lit.  REFRACTIVE INDEX 0bs./25° Lit./20°  85%  192  196  1.5017  1.5038  Phenyl-propionate  80%  206  211  1.5002  1.5011  Phenyl-butyrate  82%  224  227  1.4934  Phenyl-isobutyrate  82%  209  111/25  1.4919  Phenyl-valerate  75%  160/14  -  1.4869  -  Phenyl-isovalerate  80%  228  224  1.4831  -  Phenyl-caproate  75%  260  1.4840  1.4876  Phenyl-heptylate  90%  120/2  282  1.4829  1.4840  Phenyl-caprylate  85%  136/2  300  1.4810  Phenyl-acetate  145/2.5  -  -  in a 1-litre flask.  Phenol (200 grams, 2.1 moles) was added i n small  portions over a period of twenty minutes. hydrogen chloride gas was observed.  A vigorous evolution of  The ester was then p u r i f i e d by  d i s t i l l i n g through a f r a c t i o n a t i n g column. A l l the esters were prepared i n a similar manner and are recorded i n table I I . C.  The F r i e s Rearrangement of the Phenyl Esters. The ortho and para hydroxy-ketones were prepared by  the F r i e s rearrangement.  The reaction was carried out i n the absence  of a solvent as t h i s procedure not only gave good y i e l d s but i t was also more convenient t o carry out than the usual solvent processes. The temperature of the reaction was adjusted i n order to obtain equimolecular amounts of the ortho and para forms. The preparation of ortho and para Aluminum chloride (540  hydroxy-acetophenones:  grams, 4 moles) was placed i n a  2-necked 2 - l i t r e f l a s k and heated to 70°.  Phenyl-acetate (360 grams,  2.6 moles) was added to the heated aluminum chloride i n small portions. The temperature of the mixture rose t o 100-110° during t h i s a d d i t i o n . The reaction was carried out i n the fume hood because of the vigorous evolution of hydrogen chloride gas.  A f t e r the addition the temperature  of the reaction mixture was brought to 140° and the mixture was maintained at t h i s temperature f o r three-quarters of an hour.  The  mixture was i n the form of a soft orange glass. The mixture was cooled to room temperature, and i t was then hydrolysed by pouring very slowly over i t 1500 mis. of 6N hydrochloric acid.  In order to complete the hydrolysis the mixture had to be heated  to approximately 70° f o r f i f t e e n minutes.  A f t e r hydrolysis was  complete,  -14-  a viscous red o i l came to the top of the aqueous l a y e r .  The o i l y layer  was separated and washed with 200 mis. of 6N hydrochloric acid by two 200 ml;, portions of warm water. the water o f f under water suction.  followed  The o i l was dried by d i s t i l l i n g  The dry o i l was  and the f r a c t i o n was collected i n a Bruel receiver.  then vacuum d i s t i l l e d The ortho-hydroxy-  acetophenone was a viscous clear o i l and d i s t i l l e d approximately 70° below the para-hydroxy-acetophenone. acetophenone was a pink colored s o l i d . separately  On cooling the para-hydroxyBoth compounds were then  redistilled.  The remaining hydroxy-ketones i n t h i s series were prepared i n a s i m i l a r manner.  The p a r t i c u l a r experimental conditions f o r each of the  hydroxy-ketones prepared are recorded i n table I I I .  The physical  constants of the hydroxy-ketones prepared are recorded i n table IV. The 2t4 dinitro-phenyl-hydrazone derivatives of the ketones were 25 prepared. The melting points of the derivatives and the nitrogen 25 analysis are recorded i n table V.  A few of the semi-carbazon®-  derivatives were prepared and these are also l i s t e d i n table V.  J  -15-  TABLE I I I EXPERIMENTAL CONDITIONS f o r the PREPARATION of HYDROXY KETONES ESTER  PhenylAcetate  TEMP, of ESTER ADDED °C.  TEMP, of AICI3 °C.  TEMP. C. COLOR of MAINTAINED COMPLEX at f o r 3/4 hr.  COLOR OF HYDROLYSED OIL  135-140  Light Orange  Red  70  135-140  Orange  Red  40  70  135-140  Dark Orange  Green  PhenylIsobuyrate  40  70  135-140  Dark Orange  Green  PhenylValerate  40  70  145-150  Red  Dark Red  PhenylIsovalerate  40  70  145-150  Red  Dark Red  PhenylCapyroate  60  70  150-160  Dark Red  Purple  PhenylHeptylate  60  80  160  Dark Red  Dark Purple  PhenylCapyrlate  60  80  160-165  Dark Red  Dark Purple  24  70  PhenylPropionate  24  PhenylButyrate  -16-  TABLE IV PHYSICAL CONSTANTS of the HYDROXY-KETONES PHENONES  BOILING POINT oc./mm. Hg. Obs. Lit.  MELTING POINT REFRACTIVE INDEX °C. />C. Obs. L i t . 0bs./25° L i t .  YIELD  o-OH-aceto-  44-5/0.1  110/15  1.5570  1.558/21  362  o-OH-propio-  52-6/0.1  115/15  1.5485  1.548/22  48#  o-OH-n-butyro-  63-5/0.1  124/15  1.5375/21  36^  o-OH-isobutyro-  66-8/0.1  -  1.5379 1.5360  -  442  o-OH-n-valero-  74-5/0.1  130/10  1.5310  1.5290/21  372  o-OH-isovalero-  72-5/0.1  1.5297  -  342  o-OH-capro-  83-5/0.1 145-7/15  1.5262  1.5254/21  452  o-OH-hepto-  93-5/0.1  155/10  1.5211  1.5209/22  512  o-OH-caprjfc-  102-5/0.1  169/11  1.5170  1.5169/22  412  p-OH-aceto-  160/1  190/15  p-OH-propio-  164/1  191/10  146  148  402  p-OH-n-butyro-  161/1  200/15  89-91  91  342  p-OH-isobutyro-  143/0.6  -  59-60  56  382  210/15  61-62  62  412  88-89  90  412  -  106-7 106-7  502  p-OH-n-valero-  160-2/0.7  p-OH-isovalero-  162-5/1.5  p-OH-capro-  172-5/1  207/10  60  63  302  p-OH-hepto-  169-71/0.7  220/15  90  93  342  58-59  62  342  p-OH-caprjJo-  -  181-4/0.7' 224/10  -17-  TABLE V DERIVATIVES OF THE HYDROXY-ALKYL-PHENONES  PHENONES  MELTING POINT 2:4 D i n i t r o Phenyl Hydrazone Obs. °C. L i t .  PERCENT NITROGEN Found  Calc.  MELTING POINT Semi-carbazone °c Obs. Lit.  o-OH-aceto-  210  211  17.53  17.72  218  209-10  o-OH-propio-  189  189  16.80  16.97  214  213  o-OH-n-butyro-  203  202  16.14  16.29  189  192  -  -  -  -  -  15.38  15.65  202  o-OH-isobutyro-  -•  -  o-OH-n-valero-  178*  o-OH-isovalero-  178*-  -  15.74  15.65  -  o-OH-capro-  153 ^  154  15.28  15.08  177  179  o-OH-hepto-  153  14.48  14.50  161  162  o-OH-capryfo-  140  -  13.96  14.00  155  157  p-OH-aceto-  255  261  17.22  17.72  198  198  p-OH-propio-  23 2  229  16.50  16.97  168  -  p-OH-n-butyro-  215  212  16.11  16.29  -  -  p-OH-isobutyro-  167  -  16.63  16.29  -  p-OH-n-valero-  182  -  15.65  -  -  p-OH-isovalero-  201  -  15.49 15.71  15.65  -  -  p-OH-capro-  184  182  14.93  15.08  150  151  p-OH-hepto-  174  -  14.41  14.50  148  -  p-OH-capryb-  171  -  13.99  14.00  148  -  U  -  ....  a. Mixed melting point taken of o-OH-n-valero- and o-OH-isovalero gave melting point depression of 8°. Ir Mixed melting point taken of o-OH-capro- and o-OH-hepto- gave melting point depression of 9 ° .  -18D. The Reduction of the Hydroxy-Ketones. The hydroxy-ketones  were reduced to the corresponding  phenols by r e f l u x i n g the compounds with zinc amalgam and f a i r l y concentrated hydrochloric a c i d .  This method of reduction i s commonly known  as the Clemmensen reduction. The r a t i o of zinc amalgam and hydrochloric acid to the ketonic compound i s not too important provided both the zinc and hydrochloric acid are i n excess of the t h e o r e t i c a l amount.^" The zinc amalgam was prepared by shaking a mixture of 100 grams of mossy zinc, 10 grams of mercuric chloride and 150 mis. of 1 N. hydroc h l o r i c acid f o r approximately f i v e minutes.  The aqueous solution was 21  decanted and the zinc amalgam was washed with hot water. The Clemmensen reduction of o-OH-acetophenone: Zinc amalgam (100 grams) was placed i n a 500-ml. groundglass f l a s k f i t t e d with a r e f l u x condenser.  A mixture of 175 mis. of  concentrated hydrochloric acid and 75 mis. of water was added. keto compound (40 grams) was added. hours.  The  The mixture was refluxed f o r  2-1/4  I t was then cooled and the o i l y layer which floated on the  aqueous acid layer was tested with f e r r i c chloride and also with 2:4  dinitro-phenyl-hydrazine.  Both tests gave negative r e s u l t s  indicating that the keto compound was  reduced.  The o i l y layer was separated and the aqueous layer was extracted twice with 60 ml. portions of benzene. added to the o i l y l a y e r .  The benzene extractions were  The benzene-oil layer was then washed twice  with cold water and dried over magnesium s u l f a t e .  The benzene was  d i s t i l l e d o f f and the product was vacuum d i s t i l l e d .  -19A s i m i l a r procedure was followed f o r the reduction of the para and ortho hydroxy-propiophenones  and ortho and para hydroxy-butyro-  phenones.^ The r e f l u x time f o r the reduction of ortho-hydroxy-butyrophenone was fourteen hours.  I t was also noticed that the ortho homo-  logues required a longer reflux time than the para homologues. The time of reflux also increased with the length of the a l k y l chain. Two -ether procedures were t r i e d i n an attempt to reduce r e f l u x time. Method A:  Ortho-hydroxy-heptyl-phenone  (40 grams) was refluxed  with a mixture of 100 grams of zinc amalgam, 175 mis. of concentrated hydrochloric acid and 75 mis. of water. reduction was t h i r t y hours. Method  The time of r e f l u x f o r complete  The y i e l d was seventy-five percent.  Ortho-hydroxy-heptyl-phenone  (40 grams) was refluxed  with a mixture of 100 grams of zinc amalgam, 175 mis. of concentrated hydrochloric acid, 75 mis. of water and 200 mis. o f ethanol. The time of r e f l u x was twenty-five hours f o r complete reduction of the keto compound.  The y i e l d was seventy-five percent.  Method C:  Ortho-hydroxy-heptyl-phenone  (40 grams) was refluxed  with a mixture of 100 grams of zinc amalgam, 160 grams of concentrated 21 hydrochloric acid and 160 grams of g l a c i a l a c e t i c a c i d . of r e f l u x f o r complete reduction was seven hours.  The time  The y i e l d was eighty-  s i x percent. Method " C proved t o be more e f f i c i e n t than method "A" or "B" and also required the shortest r e f l u x time. reduced by method C" M  Thus the hydroxy-ketones were  and the physical constants f o r the r e s u l t i n g  phenols are recorded i n table V I . Some of the phenoxy-acetic acid derivatives -" of the phenols were 2  prepared with d i f f i c u l t y .  The melting points of the phenoxy-acetic acid  derivatives are recorded i n table V I I .  The 3*5 dinitro-benzoate d e r i -  vatives of most of the phenols were prepared and the melting points are  •20  recorded i n table V I I . II.  The Preparation of the Dinitro-Alkyl-Phenols. Two methods of n i t r a t i o n of phenols were t r i e d on  O-isopropyl-phenol S. ' : Method 1:  . •' "\. 'i r  W  „• ."  \x.  :  Concentrated s u l f u r i c acid (26 grams) was added to  25 grams of b-isopropyl-phenol with constant s t i r r i n g .  The solution  was heated on a steam bath f o r one hour during which time the color of the solution turned to a cherry red. and diluted with 25 mis. of water.  The solution was then cooled  The temperature rose so the  mixture was recooled. N i t r i c acid (34 grams, density 1.42) was cooled to -15° i n a stainless s t e e l beaker. . Chloroform and dry i c e were used f o r the low temperature bath.  The sulfonated material was then added with constant  s t i r r i n g to the n i t r i c a c i d .  The addition took three hours during which  time the temperature was maintained at -15°.  The mixture was then  allowed to warm slowly to room temperature over a period of sixteen hours. A yellow p r e c i p i t a t e had formed during t h i s time.  The acid mixture  was d i l u t e d with three times i t s volume of water.  The p r e c i p i t a t e was  r e c r y s t a l l i z e d from ethyl a l c o h o l . phenol was d i s t i l l e d .  The 2t4 dinitro-ortho-isopropyl-  The y i e l d was f i f t y - f i v e percent and the b o i l i n g  point was 132° at 0.15 mm. Method 2:  Ortho-isopropyl-phenol (25 grams) was dissolved In 60  mis. of g l a c i a l a c e t i c acid and t h i s solution was added dropwise, with constant s t i r r i n g , to a solution of 40 mis. of fuming n i t r i c acid and 75 mis. of a c e t i c acid which had been cooled to -15° i n a s t a i n l e s s s t e e l beaker.  The addition took about three-quarters of an hour.  After  t h i s addition the mixture was allowed to come slowly to room temperature over a period of one and one-half hours.  The solution was kept at  •21-  TABLE 71 PHYSICAL CONSTANTS FOR ALKYL-PHENOLS FROM CI-EMMENS6N REDUCTION  ALKYLPHENOL  BOILING POINT °C/mra. Obs. Lit.  REFRACTIVE INDEX Obs. 25°  L i t . 20° 1.5348  YIELD  72%  c—ethyl-  64-6/2  101/20  1.5352  o-propyl-  65-6/1.2  122/20  1.5280  o-butyl-  69/0.6  109/10  1.5182  o-isobutyl-  62/0.7  81/6  1.5170  o-amyl-  82/0.7  122/10  1.5141  o-isoamyl-  88/1.8  m*  1.5121  o-caproyl-  121/3.5  135/10  1.5090  1.5089  842  o-heptyl-  105/0.6  147/10  1.5058  1.5058  862  o-capryl-  129/1.5  160/11  1.5052  1.5029  782  p-ethyl-  79/1.6  210-12  1.5239  752  p-propyl-  72/0.7  228-30  1.5220  1.5379  722  p-butyl-  83/0.6  238-42  1.5160  1.5165  672  235-9  MP=52°  1.5319  832  110/3  248-53  1.5107  1.5119  802  p-isoamyl-  102-5/1.5  126/15  1.5100  1.5050  582  p-caproyl-  128/2.5  146/10  1.50 55  p-heptyl-  142/2.4  271-8  1.5040  p-capryl-  137-42/1.8  169/10  1.5052  p-isobutylp-amyl-  81-2/0.7  MP=45°  1.5180  1.5132  -  1.5090  -  60% 65% 55% 88% 68%  812 752 632  -22-  TABLE VII DERIVATIVES OF ALKYL-PHENOLS  ALKYLPHENOL o-ethylo-propylo-butyl-  PHENOXY-ACETIC ACID Melting point °C Obs. Lit. 135  140  99  99  3:5 DINITRO-BENZOATE Melting Point °C 107 96 . .97  103  o-isobutyl-  93  o-amyl-  76  o-isoamyl-  58  o-caproyl-  86  o-heptyl-  54  o-capryl-  84  -  p-ethyl-  91  90  139  p-propyl-  87  86  123  p-butyl-  80  81  92  106  124  131  p-amyl-  89  90  94  p-isoamyl-  80  p-isobutyl-  p-caproylp-heptylp-capryl-  -  93 98 95 95 92  93  128  -  87 97 91  -23room temperature f o r one-half hour and then i t was of water and  cracked i c e .  c i p i t a t e was  f i l t e r e d , washed, dried and d i s t i l l e d .  poured over a mixture  A yellow p r e c i p i t a t e settled out.  f i v e percent, and the b o i l i n g point was  132°  The  pre-  The y i e l d was  at 0.13  sixty-  mm.  Method 1 took twenty-four hours with a y i e l d of f i f t y - f i v e percent while method 2 took three hours with a y i e l d of s i x t y - f i v e percent. Thus method 2 proved to be the better method, i . e . i t gave s l i g h t l y better y i e l d s and was much quicker to carry  out.  A l l the phenols were nitrated by the a c e t i c acid method. of the ortho-nitro-alkyl-phenols  The  majority  separated out as o i l s when poured over  cracked i c e , whereas, the majority of the para compounds precipitated out as yellow s o l i d s . the phenol was  The amount of a c e t i c acid used f o r d i s s o l v i n g  varied s l i g h t l y depending on the s o l u b i l i t y of the phenols  i n the acetic a c i d .  The red o i l or yellow p r e c i p i t a t e was  i n chloroform and the aqueous acid layer was  dissolved  extracted twice with  further portions of chloroform which were added to the f i r s t The  extraction.  chloroform layer was washed with water containing a trace of sodium  bicarbonate.  The  chloroform layer was  and the solvent was d i s t i l l e d o f f . distilled.  The  then dried over magnesium s u l f a t e  The product was  then vacuum  complete series of dinitro-alkyl-phenols were prepared  i n t h i s manner and are recorded i n table V I I I . III.  The S a l t Formation of the  Dinitro-Alkyl-Phenols.  Each of the dinitro-alkyl-phenols was  characterized  by three d e r i v a t i v e s , the piperidine s a l t , the cyclohexyl-amine s a l t , and the morpholine s a l t . The preparation of the piperidine s a l t of DNOC: Dinitro-ortho-cresol (1/2 erlenmeyer and approximately 3/4  gram  gram) was  placed i n a 25  of piperidine was  added.  ml.  About  -2410 mis. of benzene was then added and the mixture was gently warmed f o r f i v e minutes.  The mixture was cooled and approximately 25 mis.  of petroleum ether (30-60) was added. immediately. ether.  Small colored flakes appeared  The p r e c i p i t a t e was f i l t e r e d and washed with petroleum  The p r e c i p i t a t e was r e c r y s t a l l i z e d from a three-solvent  solution made up of f i v e parts benzene, one part ethanol and two parts petroleum ether. A l l the s a l t derivatives of the dinitro-alkyl-phenols, including the cyclohexyl-amine s a l t s and the morpholine s a l t s were prepared by the above procedure. The s a l t s of the 2:4 dinitro-6-alkyl-phenols were r e c r y s t a l l i z e d from a three-solvent solution made up of f i v e parts benzene, one part ethanol and two parts petroleum ether (30-60). The s a l t s of the 2:6 dinitro-4-alkyl-phenols were r e c r y s t a l l i z e d from a two-solvent solution made up of f i v e parts benzene and one part petroleum ether (30-60). The melting points and d e s c r i p t i o n of the p i p e r i d i n e , morpholine, and cyclohexyl-amine s a l t s are recorded i n tables IX, X, XI r e s p e c t i v e l y .  r25r TABLE VTII PHYSICAL CONSTANTS OF DINITRO-ALKYL-PHENOLS DINITRO-ALKYL-PHENOL  BOILING POINT °C/mm.  o-methyl-  Given  o-ethyl-  130/0.5  o-propyl-  120/0.05  o-isopropyl-  130/0.1  o-butyl-  136/0.05  o-isobutyl-  130/0.1  o-sec-butyl-  Given  MELTING POINT °C Obs. L i t .  36  mm  642  -  m*  712  54  120  o-tert-butyl-  YIELD  o-amyl-  145/0.1  o-isoamyl-  135/0.06  o-hexyl-  155/0.05  o-heptyl-  191/0.4  o-octyl-  190/0.4  -  p-methyl-  135/0.1  82  p-ethyl-  140/0.25  36  p-propyl-  121/0.03  41  p-isopropyl-  130/0.2  68  p-butyl-  152/0.1  47  p-isobutyl-  121/0.03  p-sec-butyl-  122/0.03  -  p-tert-butyl-  123/0.05  95  p-amyl-  156/0.1  p-isoamyl-  163/0.3  p-tert-amyl-  133/0.05  p-hexyl-  160/0.07  p-heptyl-  148/0.02  p-octyl-  156/0.02  66  -  -  662  122  802  -  602  83  -  662 672  572 602 602 512 602 602 502 652 582  mm  552  mm  602  96  802  67  -  612 552 502 492 522 452  TABLE IX PIPERIDINE SALTS OF DINITRO-ALKYI.**PHENOLS DINITRO-ALKYL-PHENOL  MELTING POINT of SALT °G.  DESCRIPTION OF CRYSTALLINE SALT  o-methyl  157  Small yellow needles  o-ethyl  214  Yellow, finely divided  o-propyl  186  Yellow flakes  o-isopropyl  204  Small yellow needles  o-butyl  148  Yellow, finely divided  o-isobutyl  .187  Yellow needles  o-sec-butyl  154  Yellow, finely divided  o-tert-butyl  219  Orange, finely divided  o-aroyl  138  Yellow needles  o-isoamyl  167  Yellow flakes  o-hexyl  123  Yellow, finely divided  o-heptyl  121  Yellow, finely divided  o-octyl  125  Yellow, finely divided  p-methyl  195  Small orange needles  p-ethyl  234  Orange, finely divided  p-prop^rl  193  Small orange flakes  p-isopropyl  218  Small orange flakes  p-butyl  140  Orange needles  p-isobutyl  189  Orange flakes  p-sec-butyl  211  Yellow, finely divided  p-tert-btityl  232  Orange, finely divided  p-arayl  137  Small orange needles  p-isoamyl  176  Small orange flakes  p-tert-amyl  198  Small orange flakes  p-hexyl  154  Large orange flakes  p-heptyl p-octyl  157  Large orange flakes  141  Large orange flakes  -27TABLE X MORPHOLINE SALTS OF DINITRO-ALKYL-PHENOLS r  DINITRO-ALKYL-PHENOL  MELTING POINT o f SALT ° C .  DESCRIPTION OF CRYSTALLINE SALT  o-methyl  189  Small red flakes  o-ethyl  192  S m a l l orange n e e d l e s  o-propyl  167  Red, f i n e l y  o-isopropyl  204  Long orange n e e d l e s  o-butyl  169  L a r g e orange f l a k e s  o-isobutyl  168  Yellow needles  o-sec-butyl  147  Red n e e d l e s  o-tert-butyl  203  Red n e e d l e s  o-amyl  159  Orange f l a k e s  o-isoamyl  190  Orange f l a k e s  o-hexyl  155  Orange r e d f l a k e s  o-heptyl  146  Orange f l a k e s  o-Qctyl  147  Orange, f i n e l y  p-methyl  201  Yellow needles  p-ethyl  217  Orange f l a k e s  p-propyl  165  Yellow, f i n e l y  p-isopropyl  216  Yellow f l a k e s  p-butyl  135  Orange n e e d l e s  p-isobutyl  164  Yellow needles  p-sec-butyl  191  Yellow, f i n e l y  p-tert-butyl  232  Yellow needles  p-amyl  13?  Orange f l a k e s  p-isoamyl  169  S m a l l orange needles  p-tert-amyl  174  Yellow  p-hexyl  150  Orange f l a k e s  p-heptyl  148  Yellow, f i n e l y  p-octyl  135  Yellow f l a k e s  divided  divided  divided  divided  flakes  divided  -28-  T ABLE XI CYCLOHEXYL-AMI NE SALTS OF DINITRO-ALKYL-PHENOLS DINITRO-ALKYL-PHENOL  MELTING POINT of SALT°C.  DESCRIPTION OF CRYSTALLINE SALT  o-methyl  171  Yellow, finely divided  o-ethyl  176  Yellow, finely divided  o-propyl  185  Yellow, finely divided  o-lsopropyl  207  Yellow, finely divided  o-btityl  175  Large yellow flakes  o-isobutyl  193  Yellow, finely divided  o-sec-butyl  210  Yellow, finely divided  o-tert-butyl  203  Small orange needles  o-amyl  164  Yellow flakes  o-isoamyl  188  Yellow flakes  o-hexyl  176  Yellow, finely divided  o-heptyl  175  large orange flakes  o-octyl  158  Small yellow flakes  p-methyl  193  Small orange needles  p-ethyl  190  Small orange needles  p-propyl  178  Small orange needles  p-isopropyl  213  Small orange needles  p-butyl  148  Orange, finely divided  p-isobutyl  192  Small orange needles  p-seo-butyl  204  Yellow, finely divided  p-tert-butyl  230  Small orange needles  p-amyl  154  Yellow, finely divided  p-isoamyl  185  Long orange needles  p-tert-amyl  219  Small yellow needles  p-hexyl  135  Yellow, finely divided  p-heptyl  125  Yellow, finely divided  p-octyl  120  Orange, finely divided  -29-  INVESTIGATION OF U.S. PATENT 2.385-719. This patent describes a method of preparing amine s a l t s of n i t r a t e d phenolic compounds.  These s a l t s were prepared by mixing together an  aqueous solution of the a l k a l i s a l t of the nitrated phenolic compound and an aqueous solution of the inorganic s a l t of the amine. A comparison of some of the s a l t s mentioned i n t h i s patent with the corresponding s a l t s mentioned i n t h i s thesis i s given i n table X I I .  TABLE XII A COMPARISON OF PATENT AND THESIS MINE SALTS PIPERIDINE SALT of DINITRO-ALKYL-PHENOL  PATENT M.P. °C. COLOR,  THESIS M.P. °C, COLOR  o-raethyl  140  brown  157  yellow  p-tert-butyl  112  yellow  232  orange  p-tert-amyl  128  brown  198  orange  o-methyl  155  red  189  red  p-tert-butyl  137  yeilow  232  yellow  p-tert-amyl  136  yellow  174  yellow  MORPHOLINE SALT of DINITRO-ALKYL-PHENOL  An attempt was made to prepare the above s a l t s by the procedure mentioned i n the patent. The sodium s a l t of dinitro-ortho-cresol (2.2 grams) was dissolved i n 80 mis. of cold water.  To t h i s solution was added, with constant  s t i r r i n g , a solution of 1.6 grams of morpholine-hydrochloride of cold water. tion.  i n 80 mis.  An orange p r e c i p i t a t e settled out of the orange solu-  The melting point range of t h i s s o l i d was 168-178°.  On close  inspection the s o l i d appeared t o be made up of a yellow compound and a red  compound.  -30The orange p r e c i p i t a t e was then r e c r y s t a l l i z e d from a large volume of water.  On cooling a yellow p r e c i p i t a t e formed.  The p r e c i p i t a t e was  f i l t e r e d and the orange solution was boiled down to a smaller volume and  cooled.  Long red needle c r y s t a l s settled out.  The melting point  of the yellow precipitate was the same as the melting point of d i n i t r o ortho-cresol.  When a mixed melting point was carried out with the  yellow p r e c i p i t a t e and dinitro-ortho-cresol no depression of the melting point of dinitro-ortho-cresol was observed. The melting point of the red crystals was the same as the melting point of the morpholine s a l t of d i n i t r o - o r t h o - c r e s o l l i s t e d i n table X. When a mixed melting point was carried out with the red c r y s t a l s and the morpholine s a l t of the dinitro-ortho-cresol no depression of the melting point of the morpholine s a l t was observed. I t was assumed that the morpholine s a l t mentioned i n the patent was i n r e a l i t y a mixture of dinitro-ortho-cresol and the morpholine s a l t of d i n i t r o - o r t h o - c r e s o l .  Various mixtures of the d i n i t r o - o r t h o -  cresol and the morpholine s a l t of dinitro-ortho-cresol were prepared and the melting points ranged from 150° to 178°.  -31IY.  The Preparation of Alkyl-Phenols by Miscellaneous Methods. 1.  The Preparation of Para-Tert.-Butyl and Para-Tert.-Amyl Phenols. 35 A.  Preparation of t e r t . - b u t y l and tert.-amyl chlorides: Tertiary-butyl alcohol (200 grams) was shaken f o r  twenty minutes i n a 2 - l i t r e separatory funnel with 650 mis. of concentrated hydrochloric a c i d .  Two layers were formed.  The top l a y e r  was separated from the lower layer and washed with a weak solution of sodium bicarbonate, and then with cold water. t e r t . - b u t y l chloride 0.851/25°.)  (Specific g r a v i t y of  The crude chloride was dried over  magnesium sulfate and i t was then p u r i f i e d by d i s t i l l i n g through an eighteen inch Vigreaux column. The b o i l i n g point of t e r t i a r y - b u t y l o 35 chloride was 51 and the y i e l d was ninety-five percent. The reported b o i l i n g point was  51°.  Tertiary-amyl chloride was prepared i n a s i m i l a r manner.  The b o i l i n g  point of tertiary-amyl chloride was 86° and the y i e l d was eighty percent. The reported-^ 5 b o i l i n g point was 86 . B. Preparation of para-tert.-butyl and para-tert.-amyl  phenols:  Phenol (103 grams) was added to 100 grams of t e r t i a r y b u t y l chloride i n a 1 - l i t r e f l a s k . chloride were added.  Approximately  5 grams of aluminum  The mixture was gently heated.  Hydrogen chloride  gas was given o f f . The mixture was allowed to stand f o r sixteen hours. The s o l i d product that formed during t h i s time was f i l t e r e d and washed with cold water.  The product was p u r i f i e d by d i s t i l l a t i o n .  Para-tertiary-amyl-phenol was prepared i n a similar manner.  The  physical constants f o r para-tertiary-butyl-phenol and p a r a - t e r t i a r y amyl-phenol are recorded i n table X I I I .  -32-  TABLE XIII PHYSICAL CONSTANTS of P-TERT-BUTYL and P-TERT-AMYL PHENOLS PHENOL  BOILING POINT °C. Obs. L i t .  MELTING POINT °C. Obs. L i t .  YIELD  3:5 DINITRO BENZOATE MELTING POINT &C.  p-tert-butyl-  227-30  237  97  97  10%  158  p-tert-amyl-  240-50  266  92  92  60%  139  2.  The Preparation of Para-Secondary-Butyl-Phenol. A. Preparation of secondary-butyl chloride: ^ -  A mixture of 184 mis. of secondary-butyl alcohol, 544 grams of zinc chloride (anhydrous) and 320 grams of concentrated hydroc h l o r i c acid was refluxed f o r two hours. d i s t i l l e d from the reaction mixture.  The crude chloride was  The chloride was washed with a  f i v e percent sodium bicarbonate solution followed by cold water and then i t was r e d i s t i l l e d .  The b o i l i n g point was 67-69° and the y i e l d o 35  was seventy percent.  The reported b o i l i n g point was 67-69 •  B. Preparation of Para-secondary-butyl-phenol: Phenol (62 grams) was added to 60 grams of secondary butyl chloride.  Approximately 10 grams of aluminum chloride were  added and the mixture was refluxed f o r three hours. cooled and the product was washed with cold water. distilled.  The mixture was The product was  No para-secondary-butyl-phenol had formed.  Twenty percent  of the chloride and f i f t y percent of the phenol were recovered. Using the above specified conditions para-secondary-butyl-phenol could not be prepared. A second attempt to prepare the above phenol was made using hydrogen f l u o r i d e .  A mixture of 74 grams of secondary-butyl alcohol  and 120 grams of phenol was slowly added with constant stirring to 160 grams of anhydrous hydrogen fluoride cooled to 0°. After the addition, which took one-half hour, the mixture was brought to room temperature so that the hydrogen fluoride could evaporate. After the hydrogen fluoride was removed the product was washed with water and distilled.  Only phenol was recovered.  It was thought that conditions were not drastic enough so another run with hydrogen fluoride was made. This time the temperature of the hydrogen fluoride during the addition was 10°. After the addition the mixture was heated on a steam bath until the hydrogen fluoride had evaporated.  The product was washed with cold water and d i s t i l l e d .  The para-secondary-butyl-phenol boiled at 235-250°, and the refractive index was 1.5134 at 25°. The yield was thirty-five percent. The 30 o reported constants were boiling point 236 and refractive index 1.5182. It was thought that the hydrogen fluoride method would be more successful i f the reaction could be carried out i n a pressure vessel in order to reach a higher temperature. 27  A third method  was then tried i n order to prepare the para-  secondary-butyl-phenol. A mixture of 57 grams of. phenol and 100 grams of zinc chloride was placed i n a 3-necked flask fitted with a stirrer, reflux condenser, graduated dropping funnel and thermometer. After the temperature of the mixture was brought to 120° a mixture of 9.4 grams of concentrated hydrochloric acid and 23.5 grams of n-butyl alcohol was added over a period of one hour. vigorously stirred.  During the addition the mixture was  The temperature of the reaction was raised to approxi-  mately 130° and a mixture of 9.4 grams of hydrochloric acid and 71 grams of n-butyl alcohol was added with vigorous stirring over a period of six hours. After this addition the mixture was refluxed for three hours.  -34The mixture was  cooled and the o i l y product was washed with cold water  and i t was then d i s t i l l e d . pheric pressure.  The b o i l i n g point was 238-246° at atmos-  The r e f r a c t i v e index was 1.5114 and the y i e l d  was  f i f t y percent. 3.  The Preparation of Ortho-Tertiary-Butyl-Phenol. The f i r s t step i n the preparation of o r t h o - t e r t i a r y -  butyl-phenol was the preparation of para-bromo-phenol.  With the para  p o s i t i o n to the hydroxyl group now blocked a F r i e d e l and Craft type reaction and condensation type reactions were t r i e d i n order to obtain a t e r t i a r y - b u t y l group i n the ortho position to the hydroxyl group. After this was accomplished,  the next step was the removal of the  bromine from the benzene nucleous to give ortho-tertiary-butyl-phenol. A.  Preparation of para-bromo-phenol: Phenol (200 grams) and 200 mis. of carbon disulphide  were placed i n a 3-necked 1 - l i t r e f l a s k f i t t e d with a reflux condenser, s t i r r e r and thermometer. approximately 4°»  The contents of the f l a s k were cooled to  A mixture of 109 mis. of bromine and 100 mis. of  carbon disulphide was added with constant s t i r r i n g to the mixture i n the f l a s k .  A f t e r the addition, which took two hours, the mixture  refluxed f o r one-half hour.  The carbon disulphide was then d i s t i l l e d  o f f and the product was vacuum d i s t i l l e d . at 3 mm.  The b o i l i n g point was  The y i e l d was seventy-five percent.  derivative melted at 163°.  was  The phenoxy-acetic  95° acid  The reported b o i l i n g point was 145-150° at  20-30 mm.  and the melting point of the phenoxy-acetic acid derivative  was 159°.  3  5  B.  Preparation of ortho-tertiary-butyl-para-bromo-phenol: (i).  The aluminum chloride method: T e r t i a r y - b u t y l chloride (48 grams) was  added to 88 grams of para-bromo-phenol.  The mixture was  heated  -35s l i g h t l y and approximately 5 grams of aluminum chloride were added to i t .  The mixture was maintained at a temperature of 50° f o r four  hours.  The mixture was then cooled.  water, dried and d i s t i l l e d .  The product was washed with  Some of the t e r t i a r y - b u t y l chloride and  most of the para-bromo-phenol were recovered.  I t was assumed that  ortho-tertiary-butyl-para-bromo-phenol could not be prepared by the above method. (ii) .  The hydrogen f l u o r i d e method: Anhydrous hydrofluoric acid (90 grams)  was placed i n a copper beaker.  A mixture of 38 grams of t e r t i a r y -  butyl alcohol and 90 grams of para-bromo-phenol was slowly added t o the hydrogen f l u o r i d e . tained at 5°.  During the addition the temperature was main-  The mixture was brought to room temperature and allowed  to stand over-night. The product was a t a r . No attempt was made t o d i s t i l l the t a r . The reaction was considered a f a i l u r e . (iii) .  15 The Hart Reaction:  35 (a). Preparation of isobutylene: A mixture of 200 mis. of concentrated s u l f u r i c acid and 400 mis. of water was placed i n a 1 - l i t r e flask.  T e r t i a r y - b u t y l alcohol, (177 mis) was added dropwise.  The  isobutylene was d i s t i l l e d o f f as i t formed and i t was collected i n an open tube which was immersed i n a bath of acetone and dry i c e .  The  crude product was r e d i s t i l l e d by placing i t i n a f l a s k which was held at room temperature and which was connected to a receiver f l a s k immersed i n a cold bath consisting of dry i c e and acetone. (b).  Preparation of ortho-tertiary-butyl-p-bromo-phenol: A mixture of 170 grams of para-bromo-phenol,  290 mis. of benzene and 5.8 mis. of concentrated s u l f u r i c acid was placed  -36-  i n a 1 - l i t r e 3-necked f l a s k f i t t e d with a s t i r r e r , C l a i s e n adapter, which held the thermometer, and r e f l u x condenser, and a ; sintered glass gas j e t f o r the introduction of the isobutylene. was  heated to 65° and was vigorously s t i r r e d .  The mixture  The isobutylene  then introduced through the scintered glass gas j e t which was below the surface of the l i q u i d .  cooled and the acid l a y e r was removed.  over magnesium s u l f a t e . The solvent was  15  then dried  removed and the product  o The b o i l i n g point was 109-116 at 2.6 mm.  phenoxy-acetic acid derivative melting point was constants  The  The benzene  layer was washed with cold water four times and i t was  vacuum d i s t i l l e d .  well  The addition took f i v e hours and  during t h i s time the solution turned a dark redish c o l o r . solution was  was  185°.  The  was  The reported  o were b o i l i n g point 123-31 and the phenoxy-acetic acid  derivative melting point 183-184°. C.  Preparation of ortho-tertiary-butyl-phenol: A mixture of 80 grams of  butyl-phenol,  240  para-bromo-ortho-tertiary-  grams of Raney n i c k e l a l l o y , and400 mis. of ninety-  f i v e percent ethyl alcohol was placed i n a 5 - l i t r e f l a s k f i t t e d with a r e f l u x condenser an..a graduated dropping funnel.  To t h i s mixture  2400 mis. of ten percent sodium hydroxide were added over a period of two hours. hour.  A f t e r the addition the mixture was  The mixture was then f i l t e r e d while hot.  refluxed f o r one The f i l t r a t e was  and neutralized with concentrated  hydrochloric a c i d .  appeared on top of the f i l t r a t e .  The f i l t r a t e was  benzene.  A yellow o i l  then extracted with  The benzene layer was washed with cold water and dried over  magnesium s u l f a t e . The solvent was d i s t i l l e d o f f and the product distilled.  cooled  The b o i l i n g point of the ortho-tertiary-butyl-phenol  209-213° at atmospheric pressure.  was was  The r e f r a c t i v e index was 1.5168 at  -3725°.  The phenoxy-acetic acid d e r i v a t i v e melting point was 1 4 7 ° .  The reported c o n s t a n t s ^ were b o i l i n g point 217-220° a t atmospheric pressure, r e f r a c t i v e index 1.5160 at 20°, and the phenoxy-acetic a c i d derivative melting point 145-146°. 4.  Attempted Preparation of Ortho-Tertiary-Amyl-Phenol. An attempt was made t o prepare ortho-tertiary-amyl-phenol  using the Hart procedure. A.  Preparation of isoamylene: A mixture of 300 mis. of concentrated s u l f u r i c acid  and 600 mis. of water was placed i n a 2 - l i t r e f l a s k f i t t e d with a d i s t i l l a t i o n condenser and a dropping funnel. of tertiary-amyl alcohol was added dropwise. d i s t i l l e d o f f as i t formed. tion.  The isoamylene was  The isoamylene was p u r i f i e d by r e d i s t i l l a -  The b o i l i n g point was 38°. B.  To t h i s mixture 200 mis.  Reported b o i l i n g point"^ was 38.5°.  Preparation of ortho-tertiary-amyl-para-bromo-phenol: A mixture of 370 mis. of benzene, 180 grams of para-  bromo-phenol and 6 mis. of concentrated s u l f u r i c acid was placed i n a 2 - l i t r e 3-necked f l a s k f i t t e d with a s t i r r e r , a r e f l u x condenser and a dropping funnel.  This mixture was s t i r r e d and heated to 65°.  amylene (90 grams) was then added over a period of three hours.  IsoAfter  the addition the mixture was cooled and washed with cold water t o remove the s u l f u r i c a c i d .  The solvent was removed and the product was d i s t i l l e d .  The product proved t o be recovered para-bromo-phenol.  The reaction  apparently was not successful. A second attempt was made using 85 grams of para-bromo-phenol, 200 mis. of benzene, 3 mis. of concentrated s u l f u r i c acid and 45 grams of isoamylene. liquid.  The isoamylene was added as a gas below the surface of the  The temperature of the reaction mixture was raised to approxi-  -38mately 80°.  The addition of the isoamylene took four hours.  mixture was then cooled and washed with cold water. removed and the product was d i s t i l l e d .  The  The solvent was  Only para-bromo-phenol was  recovered. I t was assumed that ortho-tertiary-amyl-para-bromo-phenol could not be prepared by the Hart procedure as described above.  COMPARISON OF ALKYL-PHENOLS PREPARED BY THE GRIGNARD AND FRIES METHODS. As previously shown the ortho and para isobutyl and isoamyl phenols have been prepared by the F r i e s method.  These phenols were also  prepared by the Grignard method as part of an undergraduate research project.  (A description of the Grignard reaction as used f o r the  preparation of alkyl-phenols may be found i n the following section.) A comparison of the r e s u l t s using both methods i s recorded i n table XIV. The phenols from both methods were nitrated and the three amine s a l t derivatives were prepared f o r each d i n i t r o - a l k y l - p h e n o l .  A  comparison  of the r e s u l t s obtained i s recorded i n table XV. There i s p r a c t i c a l l y no chance of rearrangement  occurring during  the preparation of the isobutyl and isoamyl phenols by the Grignard method.  The p o s s i b i l i t y of rearrangements  occurring during the pre-  paration of these phenols by the F r i e s method always e x i s t s .  The  comparison of the melting points of the amine s a l t s shown i n table XV shows that f o r the above phenols prepared by the F r i e s method no rearrangement  occurred.  Thus, i t may be assumed that no rearrangement  occurred during the preparation of the other phenols made by the F r i e s method using the same experimental conditions.  -39-  TABLE XIV COMPARISON OF ALKYL-PHENOLS made by FRIES REARRANGEMENT AND GRIGNARD METHODS REFRACTIVE INDEX  BOILING POINT  ALKYLPHENOL  Fries  Grig.  F r i e s 25"  Grig. 18  o-isobutyl-  62/0.7  101/10  1.5170  1.5199  p-isobutyl-  81.2/0.7  110/10  MP* 52°  1.5104  110-12/10  1.5121  1.5110  125-7/8  1.5100  1.5011  o-isoamyl-  88/1.8  p-isoamyl-  102.5/1.5  U  TABLE XV COMPARISON OF DERIVATIVES OF THE DINITRO-ALKYL-PHENOLS made by FRIES REARRANGEMENT and GRIGNARD METHODS DINITROALKYL-PHENOL  MELTING POINT °C MORPHOLINE SALT Fries Grig.  MELTING POINT °C CYCLOHEXYLi4MINE SALT Fries Grig.  MELTING POINT °C PIPERID:[NE SALT Fries Grig.  o-isobutyl-  168  168  193  193  187  188  p-isobutyl-  164  164  192  192  189  189  0-isoamyl-  190  190  188  188  167  168  p-isoamyl-  169  169  185  184  176  176  -40-  A CHECK ON THE PHYSICAL CONSTANTS OF THE INTEPJ»E)IATE COMPOUNDS PREPARED DURING THE SYNTHESIS OF ORTHO AND PARA ISOBUTYL AND ISOAMYL PHENOLS USING THE GRIGNARD METHOD. Some of the intermediate compounds prepared during the synthesis of ortho and para isobutyl and isoamyl phenols were tested with quantitat i v e 2:4 dinitro-phenylhydrazine reagent.  The compounds were found to  be contaminated with the aldehydic s t a r t i n g material.  I t was  thought  that there was enough contamination to a f f e c t the b o i l i n g point and r e f r a c t i v e index and that a recheck should be made.  The above compounds  were prepared as part of an undergraduate research project. A Grignard reaction was carried out i n the normal fashion using equimolecular amounts of benzaldehyde, isopropyl bromide and magnesium. The f i n a l product contained benzaldehyde.  I t was found that washing  with sodium b i s u l f i t e did not take out a l l the benzaldehyde.  Further  experiments were t r i e d i n which the r a t i o of a l k y l bromide and magnesium to the aldehyde was v a r i e d .  I t was found that to every mole  of aromatic aldehyde used two moles of magnesium and a l k y l bromide had to be used i n order to give a product free from aldehyde.  A  t y p i c a l example i s given i n the following section. I.  The Preparation of Para-Methoxy-Phenyl-Isopropyl-Carbinol: Magnesium turnings (12 grams) were placed i n a 3-necked  f l a s k f i t t e d with a s t i r r e r , a r e f l u x condenser and a dropping funnel. A mixture of 200 mis. of dry ether and 44 mis. of isopropyl bromide was slowly added over a period of twenty minutes.  A f t e r the addition of  the bromide, 200 mis. of dry ether were added to the f l a s k and the contents were refluxed with s t i r r i n g f o r twenty minutes.  The mixture  was cooled to 0° and a mixture of 25 grams of para-anisaldehyde and 250 mis. of dry ether was added with vigorous s t i r r i n g over a period of t h i r t y minutes.  Dry ether (100 mis.) was then added and the mixture  was s t i r r e d and refluxed f o r f i v e hours.  The mixture was then cooled  -Al-  and slowly poured into a large beaker containing i c e , water and s o l i d ammonium chloride.  The ether layer was separated and washed several  times with cold water and then i t was dried over magnesium s u l f a t e . The ether was d i s t i l l e d o f f and the product was tested with quantitative 2:4 dinitro-phenylhydrazine reagent. product was then vacuum d i s t i l l e d .  No anisaldehyde was present.  The  The carbinol product appeared t o  be p a r t i a l l y unstable during the d i s t i l l a t i o n as p a r t i a l dehydration occurred.  The f i r s t f r a c t i o n contained the dehydrated  compound, the  middle f r a c t i o n contained both carbinol and unsaturated compound, and the l a s t f r a c t i o n contained r e l a t i v e l y pure carbinol.  The b o i l i n g  point of para-methoxy-phenyl-isopropyl-carbinol was 105° at 0.6 The r e f r a c t i v e index was  1.5220 at  mm.  22°.  A methoxyl determination was made and i t was found that the percentage methoxyl was 17.4 percent. II.  The t h e o r e t i c a l value was 17.2 percent.  The Preparation of Para-Methoxy-Phenyl-Isobutene-1: The para-raethoxy-phenyl-isopropyl-carbinol which had  p a r t i a l l y dehydrated was r e d i s t i l l e d .  The constants f o r the para-  methoxy-phenyl-isobutene-1 were b o i l i n g point 80° at 1 mm. and r e f r a c t i v e index 1.5462 at 23°. The reported constant *" f o r the b o i l i n g point 2  5  was 118° at 15 mm. A methoxyl determination was carried out on the compound and i t was found that the percentage methoxyl was 19.0 percent.  The t h e o r e t i c a l  value was 19.1 percent. III.  The Preparation of Para-Methoxyl-Isobutylr»Benzene: The para-methoxy'-phenyl-isobutene-1 was  hydrogenated  using ethanol as a solvent and Raney n i c k e l as a c a t a l y s t . point f o r the para-methoxy-isobutyl-bezene o r e f r a c t i v e index was 1.5077 at 21 .  The b o i l i n g  was 70° a t 0.8 mm. and the  The reported constants  9  were b o i l i n g  -42point  123°  at 15 mm. and r e f r a c t i v e index  1.4980  at  25°.  A methoxyl determination was carried out on the para-methoxy isobutyl-benzene and i t was found that the percentage methoxyl was 18.9 percent. IV.  The t h e o r e t i c a l value was 19.0  percent.  The Preparation of Ortho-Methoxy-Phenyl-Isopropyl-Carbinol: The preparation was the same as that mentioned i n the  preparation of para-methoxy-isopropyl-carbinol except that orthoanisaldehyde was used i n place of para-anisaldehyde.  The ortho-methoxy-  phenyl-isopropyl-carbinol was stable to d i s t i l l a t i o n .  The b o i l i n g point  of the ortho-methoxy-phenyl-isopropyl-carbinol was 105° a t 1.7 mm. and the r e f r a c t i v e index was  1.5201  at  20o .  20  The reported constants  were  o b o i l i n g point 109  at 14 mm. and the r e f r a c t i v e index 1.545  at 17 .  I t was f e l t that the reported r e f r a c t i v e index was i n c o r r e c t . A methoxyl determination on the carbinol was carried out and i t was found that the percentage methoxyl was 17.2 percent. value was 17.2 percent. the carbinol.  The t h e o r e t i c a l  The phenyl-urethane derivative was made of  The melting point was 148°.  A methoxyl determination  of the urethane derivative was carried out and the percentage methoxyl was found to be 10.4 V.  percent.  The t h e o r e t i c a l value was 10.4  percent.  The Preparation of Para-Methoxy-Phenyl-Isobutyl-Carbinolt Para-methoxy-isobutyl-carbinol was prepared i n a s i m i l a r  manner as previously described.  The compounds used were para-anis-  aldehyde, magnesium turnings, and isobutyl bromide.  Some of the para-  methoxy-isobutyl-carbinol dehydrated during the d i s t i l l a t i o n .  The  b o i l i n g point of para-methoxy-isobutyl-carbinol was 95° at 0.1 mm. and the r e f r a c t i v e index was  1.5203  at  21°.  A methoxyl determination was carried out and the percentage methoxyl  -43was found to be 16.2 percent. VI.  The t h e o r e t i c a l value was 16.0 percent.  The Preparation of Para-Methoxy-Phenyl-Isoamylene-1: The f i r s t f r a c t i o n obtained during the d i s t i l l a t i o n of  the para-methoxy-phenyl-isobutyl-carbinol was placed i n a Dean and Stark apparatus t o ensure complete dehydration. vacuum d i s t i l l e d .  The b o i l i n g point of  The unsaturated compound was para-methoxy-phenyl-isoaraylene-1  was 75° at 0.1 mm. and the r e f r a c t i v e index was 1.5472 at 20°. A methoxyl determination was carried out and the percentage methoxyl was found to be 17.5 percent.  The t h e o r e t i c a l value was 17.6  percent. VII.  The Preparation of Para-Methoxy-Isoamyl-Benzene: The para-methoxy-phenyl-lsoamylene-l  i n a s i m i l a r method as previously described. para-methoxy-isoarayl-benzene  was hydrogenated  The b o i l i n g point of  was 87° at 1.2 mm. and the r e f r a c t i v e 20  index was 1.5040 at 2 3 ° .  The reported constants  were b o i l i n g point  120° at 11 mm. and r e f r a c t i v e index 1.4995 a t 22°. A methoxyl determination was carried out and the percentage methoxyl was found to be 17.5 percent.  The t h e o r e t i c a l value was 17.5  percent. VIII.  The Preparation of  Ortho-Methoxy-Phenyl-Isoamyl-Carbinol:  A Grignard reaction was carried out i n a manner s i m i l a r to that previously described.  The compounds used were ortho anis-  aldehyde, magnesium turnings and isobutyl bromide. carbinol was a white s o l i d .  The r e s u l t i n g  I t was r e c r y s t a l l i z e d from a mixture of  petroleum ether (30-60) and benzene.  The melting point was 73°.  A methoxyl determination was carried out and the percentage methoxyl was found to be 16.0 percent. percent.  The phenyl-urethane  point was 107°.  The t h e o r e t i c a l value was 16.0  derivative was prepared and the melting  -44THE PREPARATION OF ORTHO-METHOXY-ACETOPHENONE. Ortho-methoxy-acetophenone Is the s t a r t i n g material used i n the synthesis of ortho-secondary-amyl and hexyl phenols by the Grignard method.  This compound was prepared by methylating ortho-hydroxy-  acetophenone which was made from the F r i e s isomerization of phenylacetate. Ortho-hydroxy-acetophenone  (50 grams) was dissolved i n 200 mis.  of ethanol i n a 2 - l i t r e round bottom f l a s k f i t t e d with a mechanical s t i r r e r and a graduated dropping funnel.  To t h i s solution was added  a mixture of 32 grams of sodium hydroxide and 400 grams of ethanol. The temperature of the contents In the f l a s k was raised to 50° and 104 grams of dimethyl sulfate was slowly added with vigorous s t i r r i n g . The temperature was kept at 50° during the addition.  A f t e r the addition  of the dimethyl sulfate the mixture was s t i r r e d and refluxed f o r twenty hours.  During t h i s time the mixture turned a dark brown color.  After twenty hours, the mixture was p a r t i a l l y  cooled and then the  ethanol was d i s t i l l e d o f f . The mixture was a l k a l i n e .  No o i l y layer  separated upon cooling which indicated that methylation had not taken place.  The mixture was a c i d i f i e d  with benzene.  Ortho-hydroxy-acetophenone  and extracted several times (42 grams) was recovered.  The methylation was unsuccessful and another attempt was made. Ortho-hydroxy-acetophenone  (100 grams) was dissolved i n a solution  of 35 grams of sodium hydroxide and 300 grams of water i n a 500 -ml. erlenmeyer.  Dimethyl sulfate (126 grams) was added a t such a rate o  that the temperature of the mixture never went above 50 . A f t e r the addition was completed the mixture was allowed to stand f o r one-half hour.  A yellow o i l y layer formed on top of the a l k a l i n e solution.  -45The o i l y layer was separated, washed repeatedly with water and vacuum distilled.  The b o i l i n g point of the ortho-methoxy-acetophenone was  95° at 2 mm.  The semi-carbazone derivative was prepared and the 35  melting point was 184°.  The reported constants  were b o i l i n g point  245° at atmospheric pressure and melting point of semi-carbazone derivative 183°. The remaining a l k a l i n e solution was a c i d i f i e d and approximately 40 grams of unreacted ortho-hydroxy-acetophenone was recovered. Although the reaction yielded only f i f t y percent of the methylated compound i t was s t i l l of use as most of the unreacted compound could be recovered.  -46DISCUSSION The F r i e s rearrangement of the esters was found to give s a t i s factory r e s u l t s .  The r e s u l t i n g ortho and para hydroxy-ketones were  e a s i l y separated because the ortho homologues boiled at • much lower temperatures'than the para homologues.  This was probably due to  hydrogen bondage between the hydroxy and ketone groups.  For the  ortho homologues the bondage would be intramolecular and f o r the para homologues the bondage would be intermolecular. A derivative of ortho-hydroxy-isobutyrophenone could not be made although a derivative was prepared f o r ortho-hydroxy-valerophenone.  The only explanation offered i s that the methyl groups  on the end of the a l k y l chain of ortho-hydroxy-isobutyrophenone have offered s t e r i c hindrance to the ketone group. the  may  In the case of  ortho-hydroxy-valerophenone the methyl groups  are more removed  from the ketone group. The ortho-hydroxy-ketones were a l l d i s t i l l e d under the same amount of vacuum.  For a plot of b o i l i n g point versus the length  of the a l k y l side chain see Graph No. I l l following page 47.  A  similar plot f o r the r e f r a c t i v e index may be found i n Graph No. TV following page 47.  A f a i r l y good c o r r e l a t i o n was noted between the  length of the a l k y l side chain and the b o i l i n g point and also between the  length of the a l k y l side chain and the r e f r a c t i v e index. The best r e s u l t s f o r the Clemmensen reduction of the hydroxy-  ketones were obtained using g l a c i a l a c e t i c a c i d .  The g l a c i a l a c e t i c  acid was probably a better solvent f o r the ketones than the water. The preparation of ortho-tertiary-amyl-phenol by the Hart r e a c t i o n using benzene and s u l f u r i c acid was not successful.  I t i s thought  that t h i s alkyl-phenol may be made by the Hart reaction i f toluene or  -47xylene were used as the solvent and phosphoric a c i d used as the catalyst.  Time did not permit t h i s i n v e s t i g a t i o n .  The preparation of the ortho-tertiary-alkyl-phenols has been found to be d i f f i c u l t .  I t may be possible to prepare the d i n i t r o -  ortho-tertiary-alkyl-phenol without having to make the  ortho-  tertiary-alkyl-phenol * i f the following procedure were to be carried through. (i)  A l k y l a t i o n of para-nitro-anisole with t e r t i a r y alcohol using hydrofluoric acid as catalyst to give orthotertiary-alkyl-para-nitro-anisole.  ( i i ) Demethylation of the above compound using constant b o i l i n g hydrobromic acid and g l a c i a l a c e t i c acid to give ortho-tertiary-alkyl-para-nitro-phenol. ( i i i ) N i t r a t i o n of mononitro-phenol to give the desired dinitro-tertiary-alkyl-phenol. The ortho-methoxy-phenyl-isopropyl-carbinol and the ortho-methoxyphenyl-Isobutyl-carbinol  were stable to d i s t i l l a t i o n but the para-  methoxy homologues were not.  I t i s thought that the  bondage i n the ortho-methoxy homologues was  intramolecular  responsible f o r t h e i r  greater s t a b i l i t y to heat. The dinitro-alkyl-phenols and t h e i r amine s a l t s should be handled with care as these compounds have been shown to be injurious to one's health.  F i g . u.  Refractive Index of o-Hydroxyketones  Number of carbon atoms i n alkyl group R.  -48-  BIBLIOGRAPHY 1.  Adams R., "Organic Reactions",  Volume I , John Wiley & Sons Inc.,  New York (1942). 2.  Archer S., Simons J . , Passino H.,  60,  2956  " J . Amer. Chem. S o c " ,  (1938).  3.  Baddeley G., " J . Chem. S o c " ,  330 (1944).  4.  Baroni £., KLeinau W., "Monatsh%  68, 251 (1936)j  C.A., 30, 7554 (1936). 5.  Bartz Q., Adams R., M i l l e r R., " J . Amer. Chem. S o c " , 57, 371 (1935).  6.  Blackman G., " J . Royal Soc. A r t s " , XCVIII,  500 (1950).  7.  Bousquet A., "Ind. Eng. Chem.", 27,  8.  Bovingdon H., Grove J . , "Ann. App. Biology", 34, 113  9.  Brazidec Le, " B u l l . Soc. Chim.",  1342 (1935). (1947).  31, 263 (1922).  10.  Coleman G. H., Griess G., U.S. Patent  2,365,056 (1943).  11.  Coulthard C , Marshall J . , Pyman F., " J . Chem. S o c " , 280  12.  Dohme A. R., Cox E. H., M i l l e r E., " J . Amer. Chem. S o c " ,  (1930).  48, 1689 (1926). 13.  Farenholt L., Harden W., Twiss D., " J . Amer. Chem. S o c " ,  55, 3383 (1933). 24, 7 (1936).  14.  Harden W., Rice R., " J . Amer. Pharm. Assoc.",  15.  Hart H., " J . Amer. Chem. S o c " , 71,  16.  I p a t i e f f I . , Pines H., Friedman S., " J . Amer. Chem. S o c " ,  60, 2495  1966 (1949).  (1938).  35, 1014 (1913).  17.  Johnson B., Hodge W., " J . Amer. Chem. S o c " ,  18.  Johnson B., Lane F. W., " J . Amer. Chem. S o c " ,  43, 348 (1921).  -49-  19.  Kagy J . P., " J . Ec. E n i t . " , 34, 660 (1941).  20.  Levy J . , Tiffeneau M., " B u l l . Soc. Chim.", 39, 776  21.  Martin E., " J . Amer. Chem. S o c " ,  22.  Monti I . , B i a n e t t i E., "Gazz. Chim. i t a l . " , 67, 628 (1937);  (1926).  58, 1438 (1936).  C.A., 32, 4551 (1938). 23.  Najarova Z., " J . Gen. Chem. (U.S.S.R.)", 8, 1336 (1938). C.A., 33, 4214 (1934).  24.  Niederl J . B., Niederl V., Shapiro S., McGreal E., " J . Amer. Chem. S o c " , 59, 1113 (1937).  25.  Openshaw H. I . , "A Laboratory Manual of Q u a l i t a t i v e Organic Analysis", Cambridge U n i v e r s i t y Press (1946).  26.  P l a n t e f o l L., "Compt. rend.", CLXXIV, 123 (1922).  27.  Read R., U.S. Patent 2,391,798;  28.  Rosenmund K., Lohfert H., "Liebig's Annalen de chemie", 56, 460 (1928);  C.A., 40, 1972 (1946).  C.A., 23, 2161 (1939). 29.  Sandulesco G., Girard A., " B u l l . Soc. Chim.", 47, 1300 (1930); .C.A., 25, 1228 (1931).  30.  Smith R. A., " J . Amer. Chem. S o c " , 55, 3718 (1933).  31.  T a t t e r s f i e l d F., "Ann. Appl. Biology", 12, 218 (1941).  32.  Templeman W., "Nature",  33.  Truffant G., Pastac I . , French Patent 425,295.  34.  Tsukervanik I . , Tambovtseva V., " B u l l . univ. Asie Central"  CLV, 497 (1945).  22, 221 (1938); 35.  C.A., 34, 4729 (1940).  Vogel A. I . , " P r a c t i c a l Organic Chemistry", Logman, Green & Co., New Yor, Toronto (1948).  36.  Whaley A. M., Copenhaver J . E., " J . Amer. Chem. S o c " , 60, 2495 (1938).  

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