I’Wl’fl'hlhlllll'fl l I WWW _'O_§ Iuw CD—\\l A STUQY OF THE ALKYLATEON OF HYDRATRGPQNETMLF WETH SUT‘.’ L HALEDES fixed: far H19 99g?” cf M. S. MECHEGAN STATE COLLEG£ W’miay Ray" W’mkman 195:0 This is to certify that the thesis entitled "A Study of the Alkylation of Hydratroponitrilo with Butyl Halides'. presented by Wesley Bay Workman has been accepted towards fulfillment of the requirements for _l_‘_-_§_-__ degree in mchemi It 17 W Major professor Date Ma 2“ 1 0 A STUDY OF THE ALKYLA’I‘ION OF HYDRATROPONITRILE WITH BTTTYL HALI DES By Wesley Ray workman A THESIS Submitted to the School of Graduate Studies of Michigan State College of Agriculture and Applied Science in partial fulfillment of the requirements for the degree of NAS TER OF SCI ENCE Department of Chemistry 1950 Wm. ~7547 .i-J ”i ~' ‘4‘ , i‘.‘ l.) ACKNO‘v EDGI'TEN T The author wishes to express his appreciation for the aid and guidance given by Doctor Gordon L. Goerner dur- ing the investigation and preparation of this thesis. **t#*#*t** tttttttt *ttttt **** *t 1: rw?flflf“3 ,-’--‘ ‘~‘.J TABLE OF CONTENTS I}JTRODUCTIONOOOOOOOOOOOO0.00.0.000...OOOOOOOOOOOOOOOOOOOOOO0...... HISTORICM‘.COOOOCOOOOOO0.000000...OOOOOOOOOOOOOOOOOOO0.00.00.00.00 mpERI?mqu’OOOOOCOOOOOOOOO.00.....0OOOOOOOOOOOOOOOCOOOOO...0.0... Reagentseeeeeeeeeoeeeeoeoeeoeeoeeeeoeeeeeeeeoeeeeee Preparation of Hydratroponitrile................... Alkylation Of Hydmtroponitrile..uuwoman..." Preparation Of Derivatives......................... DISCUSSION OF RmLTI-ITSOOOOOOOO0.0.0.0...0.00.0.0...OOOOOOOOOOOOO... SUZGJARYOOCOOOOOOOOOOOOOOCOOCOOO0.0.0....OOOOOOOOOOOCOOOOOOOO.00... SYJGGmTIOIIS FOR FURTIIER RESEARCHOOOOOOO000OOOOOOOOOOOOOOOOOOOOO... REFEIZEIICEBOOOOOOOOOOOOO000......0......0.00.00.00.0000.000.00.000. Page 1 2 12 12 13 15 18 22 25 26 27 TABLE II III IV VI VII LIST OF TABLES ACYLATION OF NITRILES BY ESTERS......................... ALKYLATION OF NITRILES BY ALKYL SULFATES................ ALKYLATION OF NITRILES BY ALKYL HALIDES................. ALKYLATION OF NITRILES BY HALIDES CONTAINING OTHER FUNCTIONAL GROUPSOOCOOOOOOOOOOOOCOOO0.00.00.00.00... YIELDS OF HYDRATROPONITMIIEOOOOOOOOO.I...OOOOOOOIOOOOOOO YIELDS OF mm HYDMTROPONITMLEOOOOOO000......O0.. PHYSICAL PROPERTIES OF ALKYLATED HYDRATROPINITRILES..... PAGE 8 15 17 18 INTRODUCTION This problem is an outgrowth of several attempts to prepare oL-phenyl- at, (3, Q-trimethylvaleronitrile from hydratroponitrile and tert.-amy1 chloride, according to equation I. Because of the very low yields of this product. it appeared desireable to study the alkylation O 9133 . 9H3 (.33 I cs -.—CN + Cl-C-CHz-CH3 moss-032-0 .. g 3.. 3 H CH CH CN 3 3 of hydratroponitrile in greater detail. The condensing agent used throughout this investigation was sodamide. By using normal butyl chloride, bromide and iodide, the effect of the halogen upon theyield was determined. The influence of the structure of the alkyl group was investigated by using normal, iso, secondary and tertiary butyl chlorides. -1... HISTORICAL The activating influence of the cyano group on an adjacent methylene group is similar in many respects to that shown by carbalkoxy and car- bonyl groups. A Claisen type condensation occurs between carbonyl comp pounds and esters (equation II). Nitriles react with carbonyl compounds 31 H 11 NaOC H ' - ' 11 2 5 , R-C - c-cooa II RPCHO + RICHZ - COOR in an analogous fashion (equation III). In 1889 Heyer (39) reported 1 1 “awn III I3 111 R-CHO + R CH ~03 :_;:2_+. REC = C-CN 2 effecting the condensation of phenylacetonitrile and benzaldehyde in the presence of sodium ethoxide to produce‘Kpphenyl-cinnamonitrile. Bodroux and Taboury used sodamide to condense phenylacetonitrile with benzalde- hyde (B) and with p-methoxy-benzaldehyde (7). The use of ketones was also reported by Bodroux (6). He succeeded in condensingtipnaphthyl- phenylketone, p-methylbenzophenone, and benzophenone with phenylacetoni- trile. Nitriles undergo a reaction with esters to give F3-keto-nitriles (41) as shown in equation IV. This reaction is similar to the well- 11 9 R IV RCOO CZHS + RHCHZCN 213712., R-c-(m-CN known acetoacetic ester condensation (equation V). Levine and Hauser (37) -2- 0 V CH -coo c H + CH coo c H5 NaO C2H OHS-C-CHz-COO c 3 25 3 2 5+ H5 2 have studied the condensation of esters with nitriles, using sodamide as the condensing agent. Their results are summarized in Table I. TAB LE I ACYLATION OF NITRILES BY ETERS Product Yield, % ot-Acetylphenylacetonitrile 68 Propionylacetonitrile 40 o(- Prepionylph any lacet onit ri 1e 60 n-Butyrylacetonitrile 33 a(-Benzoylphenylacetonitrile 61 Ethyl cyanoacetate 4O Ethyl ac-cyanophenylacetate 69 The Diecknann cyclization is an acetoacetic ester type condensation which occurs with esters of dibasic acids containing five or six carbon 3 o CH—CH -\ ,40 H (3—0 ' C\oc H 2 2 c\ 2 5 VI 002115 __________ H 0 0:0 040 2 \C/ atoms (equation VI). Dinitriles undergo a similar cyclization (41) in the presence of sodamide. Newman and Closson (46) obtained an 85% yield of 3-methyl-3-phenyl-2-iminocyclopentylcyanide from d-phenylp- {-methyl- adiponitrile as shown in equation VII. =NH CH3 C CN N T / H-C-CN VII 0 - CHz-CHz-CHZCN 13312.. I CH3 CH 2 :11 0—0 2 There is, however, one outstanding difference between esters of the type RCH coo Et ’ and the corresponding nitriles, RCHZCN. This is the 2 fact that these esters cannot be alkylated directly whereas a nitrile can be easily alkylated. In this respect the reactive methylene group of the nitriles resembles that in.malonic or'acetoacetic ester. The sodium.salt of the nitrile is formed first and this is then alkylated by alkyl halides or by simple alkyl sulfates (equation VIII). RCHZCN + NaNHZ ....__.. [RCHCNJ' Na" [RCHCN]- Na" + Rlx —_——+ RCIIRICN + NaX VIII The condensing agents which have been used include sodamide, metallic sodium, (37,39) sodium alkoxides (sodium.ethoxide and isopropoxide) (20, 39,40), potassium.amide (4), and potassium hydroxide (26,47). The most commonly used condensing agent is sodamide, which was introduced by Bodroux and Taboury in 1910 (9). Among the commonly employed basic con- densing agents, no references were found for the use of sodium.tert.- butoxide or sodium.triphenylmethyl. The sodium salts formed by the action of sodamide an a nitrile were investigatei by Rising and Zoe, (51,52). They came to the conclusion that the salts existed in two forms: the ”nitride" ion R2=c=N'Ne* and a tautomeric "carbide" ion R2=C' - CN Na’. The existence of the nitride ion was shown by the reaction of the sodium salt with acid. For example sodium.phenylacetonitrile reacted with sulfuric acid to give hydrogen cyanide and benzyl alcohol. Under the same conditions sodium.e(-phenyl- butyronitrile yielded 3,4-diphenyl-3-hexene. These reactions were assumed to proceed in the following steps. 0611ch :1 c = N'Nal' + 32804—>06H5HC : c : NH + NaHSO4 IX CSH5HC I C a NH—vHN : C :T +CGH5HC : CSH5HC The existence of the carbide ion was demonstrated by the reaction.with +HOH —'—> €5H5H2 con alkyl halides. In this reaction the «ti-carbon atom was alkylated rather than the nitrogen. x ch‘ - more" + R'x-e. RZR'C - CN + NaX It has been stated above that alkyl sulfates my be used as alkylat- ing agents. In'Table II are listed some allcylations using alkyl sulfates. It should be noted that only methyl and ethyl sulfates inve been so employed. The yields are comparable to those obtained by the use of the corresponding halide (Table III). Cope and Hancock (20) report that the former are more conveniently used in the laboratory than are the alkyl halides. The use of an alkyl halide as the alkylating agent was reported in 1889 by Meyer (39) and has been widely used since then. In Table III are sunmari zed many of the simple alkyl halides used as alkylating agents in this type of reaction. It is noticeable from this table that a great variety of branched and unbranched alkyl halides has been used. These groups vary in size TABLE II ALKYLATION OF NITRILES BY ALKYI. SWEATES Sulfate Nitrile Product Yield Ref. % Methyl sulfate Phenylacetonitrile Hydratroponitrile 55 57 " " aC-Cyanoacetomesi- B-Methoxy— P-mesitylacrylo- tylene nitrile a 26 Ethyl sulfate Valeronitrile Ethylpropylacetonitrile 13 " " Phenylacet onit ri le cc -Ph enylbuty ronit ril e 8 9 13 " " Ethyl(1-methylbutyl- Ethyl ethyl-( l-methyl-l- idene)-cyanoace- but enyl )-cyanoacetat e tate 80b 20 " " Methyl(l-methylhexy- Methyl ethyl-( l-met'nyl-l- lidene)-cyanoace- hexenyl)-cyanoacetate tate 13 20 a Condensing agent was potassium hydroxide. b Condensing agent was sodium isopropoxide. -6... “omen was: peonwpnoov no n.~s zoumfiemvoimmonzmfinmmov e e e no em zonfiemvmuummuuzNAnmmov cease onoaoflaeec.flaneoeo e e an me e e e e an em cantpanoeooeflasoecaapenea e e e mm om«peacoeooeflaeoncfiauemuc cantenooeoooflaeoea e e 3. no ofitfioopooelrt “Sheets e e e me me onnnpaeonoeefiapeeflarpoan oadnpaoopooeflaeennn e e mm 00 z z z z mmnocoe e swamp cauupuo0900oamvnmim oflwupHnOpood oeasoan ahpsmin mw eHanPanaceooahaovimiHamoamonH eHauvanoweooahfloalm s a an om 0H“upwoopooeaanonmazmoamomH eaaapwqopeoeazconm compo“ HamoaaomH mm s a s z m oHanpanopooeazm0Lm0muahnonm oaahpanopeoeazflezm z 2 mm m.mv onufimoabspffioamougml undo oawupamouhvnnahmonmogtu. .. a we on oHatenoopooefiacoecoeaflaeeoan oaneneoeooeHaeeoam e e mm m.os camp»anoazpanhEOLQOanvt oaappanopeoeaznpm seasons HamoaaouH on He ca“neeeoeoeefianoreaeflamona cannrnoonooeaaeoecna oeneoafiamocmuc m z e = mm oflaheaoopooeaamoneaaeoem ofleneaeoeooeflaeoem ” e we no omenpeooeeoeflaeeesfiamonmue omeneneoncocc e e an or oHaLanOpooeHzmoumaae oHahvanopoo< ouwaoan Hamoumin can on em oflaepmeoeooeflaeeoHanoreflaxonoeoao inenooeooeflanoedaagoeoaoaO e e on we canceaeoeoeefiaepoHaeoeeaa cancpaeoeoefiaeoeeeo e e m z s z s an we canneneonapenflagormis. centraeopeeeaaeoec condom Harem mm m.ee r oHahpeooceeem e e me me canneanoeooeflaepena cancennoeco< oneness Harem on me oH“neeooeooeaaencsflaeoncaa cantemeoeeoeflaeoecna e e an om : s 2 = on e cancpaooeoceeceam ofiaepmoopooeflaooem compo“ Hanson e“ .eom each» respond oaaneez confirm mmmHA m Ahmq< Mm mqumst ho ZoHadqhmnd HHH mnmda -7- Aswan axon oesqapnoov mm mm onexonoaohoocehonaindonmlfl efiaapmnouoooaznosm omopnemoanpamim.H we pm». oflaapdnoahhoeammoamouulu Iaagosmiu. : endpsDOuHoaoHnewmim.H ma m.m¢ enipnomoHonchkopneonfiinzuonmia : onevsnoeoanamiv.a no nos oHacpageensconeconeofloaoaaeeoa«-Hauoemafi e oneneeocoanoeeum.fl ea m.eH conveneHoaoaxonneoufluaaeoemua e oeecohcosepnae-n.fi on m.>n onsmoamoHomomwopaeoiaiamaonmia cadavacopooeflhnozm oedeoan encamfipm ea ewe condoneofioaooeeaeueAHaneeeezna-Vim oHacpneoeeoeHaeereozuoe oeapoHeo ooofiaepm. no we oeaneacoeooefiaooecaaeeofiHaeeeeeziflY.a oHacraooeeeeHanoec consecn ”Ere; H2232; T a me so canneneonfiefianoncnx A ~22?qu Ye odnraeorooofiéerdozd ocoetosone- «Angora; mm oHan»“nonooeaznonmamuoonwo : z a an o s s z c mm o oflenrnooeoceenooneflaenem ofianpeeopeoomaooem e e on oHanpnoorooeHaeooeHaneoan canceacopocefiareoao e e on ofintufleoeoceaaeeonfiaxom canneenoeooeflanom e e on canneneococeflaenonaanem canceneopoeefiaeem : e on .peeeo oHanpaeopooefiaeposfiancoeem cameranoneonm c e w ma onoE m¢ .mv : s z t we m.me ones oe no oaanrnooeooeflaenom cannpnooeooe concoaeo Haeeom em resume oHaneneoeooeaaxoeofloacaaeorc oflanpneoeoceflaeonm ceasohe HaxoeoHoao ee we oHateneoeooeaaueeaaeeofiaroo-.con e censonp Hmpoon.oon 3 8 oatficoeooofifioolpefiafim oHEfiqotceHFeflEfi e r . en n.0s oH“cameorooeaapeeaapoonenna omenenoopooeflapnm e e «e an ofiatrncoeooefiapoo canneneopooe censoen aspects no we oHecpneoeocefiaeooemeaaueeue oflenpnoopoooaauemuc : e no we oHenenooeooofiaeeosflaeeoenm emacenooneopm ceased; Haeeomwe no es oH“teneoeoeefianoeaarenflaeem oHaneanoeooeHapeeHanpm e e ed em eaaapanopoooazxenammoaaomuazzpm cadavanOpooeHzmopmonflnzhpm = : so an cannuneoeooefiawom ofianpeeoeocs ceasotn assent: an an canceaeoeooeaaseaae cancenooeooeaas< e e no on canneaoonoeeflaeeeHaeeaa cancennoeeoeaauem oenaone HaaH mumdy -8- £285 33: 5 9:- pa “:5 coves a 33x93» 85.35» mg psowu ma“ 9.8930 d mm 8 03338 fisflzfifi? mdgfinfibfi A fiboflswswuogozoé Ty. uofiefléfi Si -Hmnonmnu. -oflafiépo EA .. mm mm .22 £8.“ 33H?o&€ cafficoufifi IA HmaofiswnTeoEol. 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A amguozou I >H mag from methyl to octyl and normal, secondary, iso and cycloalkyl groups have been employed. It is noteworthy that no report has been found regarding the introduction of a tertiary alkyl group. Benzyl chloride and other halides containing an aromatic ring are listed and chloro- benzene was used to "arylate" acetonitrile and propionitrile. This is interesting inasmuch as malonic ester and acetoacetic ester are not "arylated" by aromatic halides. The use of ethylene dichloride and other dihalides such as 1,6- dibromohexane is also shown in Table III and may result in the forma- tion of cyclic compounds. This is similar to "dialkylation" which has been obtained along with "monoalkylation" by several investigators (4, 33,53,58). For reactions of this type it 1. necessary that the nitrile be of the general formula R-CHz-CN and that two moles of the condensing agent be used for each mole of the nitrile. The reported yields vary widely, perhaps due to different investi- gators and conditions of temperature, solvent, and time of reaction. The iodides appear to give better yields than the corresponding brom- ides, although the evidence for this statement is meager. The chlorides have been little used, except for benzyl chloride, perhaps because as Sperber, et al. (53) stated, the chlorides react sluggishly at first and then with uncontrollable vigor. A comparison of yields as effected by the structure of the alkyl halide is difficult. The work of Newbery and Webster (44) and of Ziegler and Ohlinger (58) shows only that the yields are dependent upon the nitrile as well as the alkyl group. For example, when acetonitrile is used, norml hecxyl bromide gives greater yields than norml octyl bromide, but the reverse is true when ethylbutylacetonitrile is used. Condensations in which other functional groups are presert in the alkyl halide are summarized in Table IV. This table shows that a di- halide may be condensed with a nitrile, only one halogen reacting, to give a cyanohalide as the product, Haloesters react to give low yields of cyanoesters (21,54). The use of halo-substituted amines was intro- duced in 1939 by Eisleb (23,24) and has been frequently used since then. The yields appear to be very good, especially with the quinoline deriva- tives (22). Cutler, et a1. (22) 'arylated" phenylacetonitrile and eC-substituted phenylacetonitriles with 4-chloro, 4,5-dichloro, and 4,7-dichloroquinolines in yields of 76 to 100 percent. The alkylation of nitriles having no hydrogen on the oc-carbon atom was reported in 1938 by Cope and Hancock (20). The dL-carbon atoms of such nitriles are connected by a double bond to other carbon atoms. An example of the reaction reported by Cops and Hancock is shown in equation XI . ' c H x1 CHS-CHZCHZ-C : C-CN + (02%)st4 Woes-CHZCH-ag - cz-scn 3 6500:32115 Ha 6000235 Recently Jaclmnn and coworkers (31) reported a similar reaction. H2 H.2 Hz H2 /c - c N NH 9N ,c - c\ CH'-C-CN+HC \N-CHCHCli—ACSH-C-CH-CH-N CH 5 5 u 2 \ / 2 2 5 2 2 . / 2 XII I \ c-- c / \\ c— c Hztl: c'H2 H2 Hz Hzclz (if! Hz 112 HZQ\ /CH2 Hzc\ [CH2 c c Hz Hz -10- EXPERI TEN TAL Reagents Hydratropic aldehyde - van Ameringeanaebler, Inc. Used as received. n-Butyl chloride - Columbia Organic Chemical Co. Used fraction dis- tilled at 76.B° - 77.0° C. at 734 mm. n-Butyl bromide - Columbia Organic Chemical Co. Used fraction distilled at 98° — 99.2° c. at 750 mm. n-Butyl iodide - Columbia Organic Chemical Co. Used fraction distilled at 127° - 128.50 c. at 735 mm. Isobutyl chloride - Eastman Kodak 00., white label. Used as received. sec.-Butyl chloride - Columbia Organic Chemical Co. Used fraction dis- tilled at 67.50 - 68° c. at 748 nmu tert.-Butyl chloride - Columbia Organic Chemical Co. Used fraction dis- tilled at 50° - 51° c. at 749 mm. Sodamide - The sodamide used throughout this investigation was prepared by a modification of the method described by Hancock and Cope (27). A 1-1. three-necked flask was equipped with a stirrer, inlet tube, and a soda lime tube. The flask was cooled in a Dry Ice-acetone bath and 500 ml. of liquid ammonia was introduced through the yinlet tube from an inverted ammonia cylinder. The Dry Ice bath was removed, the inlet tube was replaced by a rubber stopper, and a few crystals of hydrated ferric nitrate were added. A small piece of sodium was cut, blotted with filter paper, and added to the liquid ammonia. The solution was stirred until the blue color -12- disappeared, after which 90 g. of sodium.was added in small pieces as rapidly as it could be cut, while the solution was stirred vigorously. After the solution had turned from blue to grey, the flask was swirled by hand until the sodium.which had been splattered onto the upper part of the flask was washed into the solution. The excess ammonia was then permitted to evaporate through the soda lime tube. After all of the ammonia had evapor- ated, the flask was evacuated to 12-13 mm. by water pump for a period of approximately an hour. The vacuum was broken by nitro- gen and after pulverizing the sodamide under a nitrogen atmos- phere, the sodamide was transferred to nitrogen-filled clear glass bottles. About 36 g. of sodamide was placed in each bottle, the bottle corked, and sealed with paraffin. The yield amounted to 95% based on the sodium.used. ggeparation of Hydratroponitrile Hydratroponitrile has been prepared by various means. The most direct method is the monoalkylation of phenylacetonitrile by means of either methyl iodide (21,39) or methyl sulfate (57). However, the product obtained is contaminated with the disubstituted nitrile. This was shown.by Bruzau (14), who converted the product obtained from treat- ment of phenylacetonitrile with sodamide and methyl iodide into the amide. He separated the solid amides and showed them.to be derived from the Iono- and disubstituted acids. Another direct method is the conden- sation of propionitrile and chlorobenzene with potassium.amide as -13- reported by Bergstrom (4). The success of the latter method depends upon the wide difference between the boiling points of the Iono- and disubstituted nitriles. Another method which leaves no doubt as to the composition of the nitrile was used by Newman and Closson (46). They converted hydratrcp— aldehyde to hydratropaldoxime by means of hydroxylamine and pyridine. F H 1‘? XIII -g-CHO + HZNOH w O Eli-C = nos + H20 3 He The oxime was then dehydrated to the nitrile by acetic anlwdride. This 0 \ H ‘c - CH H o XIV .c-c ;: NOH +o’ 3 _____,,_ / \ C-CN + 2CH3-C: CH ‘c - CH --— CH OH 3 o” 3 3 procedure was used in preparing hydratroponitrile throughout this work. _. A typical preparation is as follows. To a mixture of 100 g. of hydratropaldehyde, ZOO ml. of water, and 125 g. of hydroxylamine hydro- chloride was added 400 ml. of pyridine. This was refluxed five hours and then poured into a liter of ‘ 6 N. acetic acid. The organic layer was separated and the aqueous layer extracted with benzene. The two organic layers were combined and.distilled without drying. The fraction distilling between 900-1450 C. (mostly at l4l°-l42° C.) at 20 mm. was assumed to be the crude hydratropaldoxime. This amounted to 72.4 g. or a yield of 65% based on the original aldehyde. This hydratropaldoxime was converted to the nitrile by refluxing with 240 ml. of acetic anhydride over'a period of about five hours. -14- Acetic acid was removed as it was formed through a 3 x 40 cm. column packed with 3/16 in. glass helices. The resulting mixture was then fractionated under reduced pressure. Forty-five grams of nitrile boil- ing at llO°-ll4o C. at 21 mm. was collected. This corresponded to a yield of 71% based on the aldoxime. The yields on all runs are shown in Table Ve TABLE V YIELDS OF HYDRATROPONITRILE Run 'Wt. of aldehyde Oxime, %' Nitrile} % Nitrilee % I 100 g. 65 . 71 46 II 100 69.3 72 50 III 100 72), 54 27 IV 500 37 ' V 500 47 56.5 27 VI 500 62 77.4 48.5 VII 430 52 #30 15 VIII 430 74 73 54 1 Based on oxime. 2 Based on aldehyde. ‘ Lost about half of product because of an accident. Alkylation of Hydratroponitrile The procedure used for the alkylation of the hydratroponitrile was similar to that of Ziegler and Ohlinger (58). A typical run is as follows. In a 1-1. three-necked flask equipped with a stirrer, reflux condenser, and dropping funnel was placed a mixture of 34 g. (.26 moles) of hydratroponitrile, 28 g. (.3 moles) of n-butyl chloride, and an equal volumn of dry toluene. This was warmed to 80° C. A sus- pension of powdered sodamide (12-13 g.) in toluene was added in small portions from.the dropping funnel. Little reaction was observed until the temperature rose to 900_950 C. At this temperature the reaction became vigorous and each addition of sodamide was followed by rapid refluxing and foaming. After all of the sodamide had been added, the nflxture was refluxed for an hour, cooled, and treated with water. The organic layer was washed twice with water, and the combined aqueous layers were then extracted with toluene. ‘The combined toluene layers were dried over anhydrous sodium.sulfate and the toluene distilled at atmospheric pressure. The concentrated mixture was then.vacuum dis- tilled through a z x 20 cm. column packed with 3/16 in. glass helices. The fractions collected were: I B.P., 50397°at 2 mm. Weight = 4.6 g. II B.P., 971107°at 2 mm. Weight - 29.7 g. The fraction which distilled between 973107° C. at 2 mm. was the mono- alkylated hydratroponitrile and amounted to a theoretical yield of 61% based on the weight of starting nitrile. This procedure was followed in every run. 'When n-butyl iodide was used the initiation temperature was about 97° C. and with tert.-butyl chloride it was impossible to obtain a temperature of 800 C. before the addition of sodamide. The following table summarizes the yields obtained from the various halides. -16- TABLE VI YIELDS OF ALKYIATED HYDRATROPONITRILE L A - L #k‘ k A __L A AA Halide Run Yielda Conversionb B.p.,°C./?., % % mm- n-Butyl chloride I 61 71 97-107/2 n-Butyl bromide I 61 74 92-116/3-4 n-Butyl iodide I 62 77 90-107/2 Isobutyl chloride I 69 79 95-112/4-5 II 60° 76 93-106/3 sec.-Butyl chloride I 67 7e 95-115/4 II 68 76 91-114/4 tert.-Butyl chloride I 12 34 90-107/3 II trace III trace Iv 4.3 14 107-112/4 v 6.4 26 107-112/4 V1 6.0 20 107-113/3 a Based on weight of starting nitrile. b Based on weight of starting nitrile converted. ° Redistilled before calculation of percent yield. The physical constants of these nitriles were determined after combining the products of the individual runs and redistilling through a 3 x 40 cm. column packed with 3/16 in. glass helices. -17- TABLE VII PHYSICAL PROPERTIES OF ALKYLATED HYDRATROPCNITRILES Compound 0 B.p. ngo D20 a dynes Nitrogen? % C. m. cm. Hydratroponitrile 62 5 1.5120 .9853 41.2 b10.76 10.89 aL-Phenyl- «ac-methyl- Capronitrile 102 2 1.4997 .9405 36.7 c 7.58 7.58 OG-Phenyl- 0‘, r-di- . hethylvaleronitrile 102 2 1.4992 .9407 35.6 ° 7.63 7.66 aC-Phenyl- at, (5’ -di- Methylvaleronitrile 105 2 1.5062 .9556 57.4 c 7.50 7.66 aL-Phenyl- °‘, ? , Q-tri- V Methylbutyronitrile 107 4 1.5156 .9724 38.6 0 7.67 7.66 a Surface tension measurements were made at 21° C. by the ring method. b Calculated for 09H N: 10.62% c Calculated for C13 171T: 7.47% By method of Dumas. Preparation of Derivatives The derivatives commonly prepared from nitriles are amides and acids. Amides are generally prepared by treating the nitrile with sul- furic acid having a concentration of 20 to 100% and at various tempera- tures. Aqueous alkali or alkaline hydrogen peroxide may also be employed in the preparation of amides from nitriles. A nitrile may be converted to the corresponding acid by heating with sulfuric acid of various concentrations longer than is necessary for the conversion to the amide. Solutions of 20% hydrochloric acid or alcoholic alkali have -18- also been used to prepare acids from.nitriles. If thoracid obtained is a liquid, the usual solid derivatives of it may be prepared (41). Hydratrcponitrile was easily converted to the amide by hydrolysis with sulfuric acid. One part of hydratroponitrile by weight was warmed on a steam.bath with five parts concentrated sulfuric acid and one and one half parts water by volume for fifteen minutes. This mixture was poured into an ammonium.hydroxide and ice mixture. The white crystals were filtered off and recrystallized from hot water. The hydratropamide melted at 93.5°-94° 0. (reported by Brazen as 94°-98° c. (14)), and it was obtained in 56% yield from.the original nitrile. Anal. Calc'd. for CQHllN’ N, 9.38. Found: N, 9.24, 9.27. (By Dumas' method) Attempts to prepare solid amides from the other nitriles were not successful. The same method that was used to prepare hydratropamide was tried as well as several modifications of it. Some of the modifi- cations attempted (for the most part on oC-phenyl-oC-methylcapronitrile) are the following: 1. Four parts of concentrated sulfuric acid and one part of nitrile were allowed to stand at room temperature for four weeks. 2. Four parts of concentrated sulfuric acid and one part of nitrile were warmed on a steam bath for three hours. 3. Same as No. 2, but heated for ten hours. 4. Same as No. 2, but heated for thirteen hours. m 0 A.ndxture of nine parts concentrated sulfuric acid, three parts water and two parts nitrile was stirred while heated at 700 C. for eight hours. 6. A mixture of eleven parts concentrated sulfuric acid, one part water, and two parts nitrile was heated for one half hour on a steam bath. 7. A mixture of eight parts sulfuric acid, three parts water and two parts nitrile was heated with frequent shaking on a steam.bath for an hour. I 8. A.mixture of three parts concentrated sulfuric acid, two parts water and one part nitrile was heated over an open flame for ten minutes. Other attempts at hydrolysis involved either phosphoric acid, alkaline hydrogen peroxide or alcoholic alkali and are as follows: 1. A mixture of eight grams of 100% phosphoric acid and two grams of nitrile was heated at 1750-180o C. for three hours. 2. A mixture of 27 g. of 100% phosphoric acid and five grams of nitrile was heated at 180° C. for five hours. 3. A.ndxture of 30 m1. of 3% hydrogen peroxide, three m1. of 25% sodium hydroxide and two grams of nitrile was heated at 60° c. with stirring for three hours. 4. Same as No. 3 except that 30% hydrogen peroxide was used. 5. A mixture of two grams of potassium hydroxide, 40 m1. of ethyl alcohol and two grams of nitrile was refluxed for 48 hours. A method.was devised whereby the nitrile was converted to the anilide of the corresponding acid. A mixture of 20 ml. of amyl alcohol, -20- one gram of potassium hydroxide and five grams of nitrile (either ef-phenyl- aC-metbylcaprcnitrile or eC-phenyl- 06, F-dimethylvaleroni- trile, but not oC--phel'l.yl-°‘, F ,5 -trimethylbutyronitrile or of ~phenyl- 4, P-dimethylvaleronitrile) was refluxed for ten hours. The anwl alcohol was distilled, the residue acidified with 10% hydrochloric acid, and extracted with benzene. After evaporation of the benzene, the re- sulting liquid was refluxed with thionyl chloride for one-half hour. The excess thionyl chloride was distilled and the residue cooled before pouring into a cold mixture of benzene and aniline. This mixture was extracted with 10% hydrochloric acid, 10% sodium hydroxide and water. Evaporation of the benzene left a brown solid. The solid was dissolved in aqueous ethyl alcohol, treated with Norite and the hot solution filtered. The resulting colorless solution deposited fine white needles upon cooling. More product was obtained by diluting the alcoholic solu- tion with water and cooling. M. . 7Na aC«Phenyl-eC-metmrlcaproanilide III.5°C. 5.14 5.10 eC-Phenyl- ac, r-dimethylvaleroanilide 120° C. 5.17 4.99 ‘ Calc'd. for 019H23NO: N, 4.98 (By Dumas' Method). A mixture of these anilides melted at 105°-107° 0. This. procedure did not yield a derivative for either of the other two nitriles. Further attempts using benzyl alcohol and diethylene glycol as the solvents did not result in hydrolysis of the nitrile. Thus no solid derivatives were obtained for either .C-phenyl- ca, {32'- dimethylvaleronitrile or oC-phenyl- 0C, (9 , é-trimethylbutyronitrile. -21- DISCUSSION OF RESULTS The preparation of pure hydratroponitrile from hydratropaldehyde is a satisfactory method of preparation. However, as is shown in Table V, the yield of nitrile varies. One possible reason for this is the fact that hydratropaldehyde is easily oxidized in the air. In runs I through V, the aldehydewas obtained from the same bottle and runs IV and V were made from aldehyde which probably contained more acid than was present for earlier preparations. Runs VI, VII and VIII were made simultaneously from a second bottle of hydratropaldehyde. Some information has been obtained concerning the relative reactiv- ity of the halogen in the allql halide for the reaction under considera- tion. Table VI shows that n-butyl iodide gives only a one percent better yield than n-butyl chloride and n-butyl bromide, namely 62% against 61% for each of the latter halides. It appears that the yield of alkylated product is not affected by the halogen in the alkyl halide. The structure of the alkyl group does affect the yield considerably. Table VI shows that secondary and isobutyl chlorides give a better yield than n-butyl chloride, and the latter a much better yield than tert.-butyl chloride. These results seem to be in agreement with those shown in Table III, where it my be observed that norml, secondary and isoalkyl halides give generally good yields. This work shows, how»- ever, alkyl halides of the secondary and iso type give better yields than the normal alkyl halides. The very small yield of oC-phenyl- cc, .3 , F—trimethylbutyronitrile may be due to one of, or a combination of, the following three factors: (1) When tert.-butyl chloride was the alkylating agent, a temperature of 80° C. was not reached before the addition of sodamide. The initia- tion temperature for the reaction, using the other alkyl halides, was above 900 C. Hence the reaction may not have started under the best conditions. (2) Steric hindrance may prevent the tert.-buty1 group from becoming attached to the oC-carbon atom. When molecules of the nitriles were constructed from Hirschfelder models, free rotation between the tert.-butyl group and the rest of the molecule was found to be im- possible. (3) Alkaline condensing agents such as sodium ethoxide are known to cause dehydrohalogenation of tert.-alkyl groups with the formation of an unsaturated hydrocarbon. Sodamide is, of course, an alkaline condensing agent and might be expected to give this type of reaction. Attempts were made to isolate some isobutylene from.the ammonia given off during the reaction, but the results were inconclusive. An.increase in.the number of alkyl groups on the dz-carbon of the nitrile increases the difficulty of hydration or hydrolysis. For example, hydratroponitrile, with an oC-hydrogen and an ec-methyl group, was easily hydrated to the amide. When the oL-hydrogen was replaced by one of the butyl groups, the neanitrile could no longer be hydrated to the amide by the methods tried. The nassing of methyl groups near the cyano group tends to lessen the ease of hydrolysis of the cyano group. For example, oC-phenyl- a: methylcapronitrile and oC-phenyl- of, r-dimethylvaleronitrile were both hydrolyzed with about the same difficulty. Hence a methyl group in the ' ‘L: 93‘. I- y'position has little effect on the cyano group. However, when the methyl group was in the 9 instead of the Y position, as in .l. -phenyl- 4, @-dimethy1valeronitrile, it was impossible to affect hydrolysis by any of the drastic conditions used. aC-Phenyl-.~; P, P-trimethylbutyro- nitrile should be still more difficult to hydrolyze. Table VII shows the similarity in the physical properties of vC-phenyl- J-methylcapronitrile and £-phenyl- 0‘, V—dimethylvaleronitrile. E Since these properties are so similar, there was the possibility that they were identical compounds. However, the mixed melting point of the two anilides was 1050-1070 0. as compared to 111.5° and 120° for the pure anilides. -24- 1. 2. 3. SUMMARY The reaction between hydratroponitrile and n-butyl chloride, bromide, and iodide in the presence of sodamide indicates that the halogen has little effect on the yield of x-phenyl- aC-methylcapronitrile. The reaction between hydratroponitrile and n-butyl, isobutyl, sec.- butyl and tert.—buty1 chlorides indicates that the structure of the butyl group does effect the yield. Yields decrease in the order iso 2 secondary > normal >>tertiary. Four nitriles not previously reported in the literature have been prepared and their physical properties determined. No of these, i-phenyl- «st-methylcapronit rile and ol-phenyl- 4, r -dimethvlvalero- nitrile, have been hydrolyzed to the acids and converted to the anilides. -25- SUGGESTIONS FOR FURTHER RESEARCH 1. Determine the effect of the structure of the nitrile on the yield of alkylated nitrile under the same conditions used in this in- vestigation. 2. Investigate the arylation of nitriles with phenyl halides, sub- stituted phenyl halides and naphthyl halides. 3. Determine the effect of the positions of methyl groups on the rate E of hydration of nitriles to amides. 1. 2. 3. 4. 5. 6. 7. B. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. REFERENCES Abramovitch and Hauser, J. Am. Chem. 800., pg, 2720 (1942). Bergel, Hindley, Morrison and Rinderknecht, J. Chem. 300., 269 (1944). Bergel, Morrison, and Rinderknecht, J. Chem. Soc., 265 (1944). Bergstrom, J. Am. Chem. 800., 61, 2152 (1945). Bergstrom and Fernelius, Chem. Rev., 29, 451-454 (1927). Bodroux, Bull. Soc. Chim., 2, 758 (1911). Bodroux, Compt. rend., 153, 350 (1911). Bodroux.and Taboury, Bull. Soc. Chim., Z, 735 (1910). Bodroux and Taboury, Bull. Soc. Chim., _7_, 666 (1910). Bodroux and Taboury, Bull. Soc. Chim., Z, 670 (1910). Bodroux and Taboury, Bull. Soc. Chim., Z, 732 (1910). Bodroux and Taboury, Compt. rend. L52, 1241 (1910). Bowden, J. Am. Chem. Soc., g9, 151 (1938). Bruzau, Ann. Chim., (11) 1, 266 (1954). Carre and Libermann, Compt. rend., Egg, 117 (1955). Case, J. Am. Chem. 800., 56, 715 (1934). Chamberlain, Chap, Doyle, and Spaulding, J. Am. Chem. Soc., 57, 352 (1935). Cloke, Anderson, Lachmann and Smith, J. Am. Chem. 800., 53, 2791 (1951). "‘ Cloke and Leary, J. Am. Chem. Soc., 51, 1249 (1945). Cope and HanCOCk, Jo Ame Chem. 8°C., 2, 2903 (1938). CI‘EWfOrd. Jo Alfie Chen. 8000’ g, 139 (1934). Cutler, Surrey and Cloke, J. Am. Chem. 300., 11, 3375 (1949). 23. 24. 25. 26. 27. 28. 29. 34. 35. 36. 37. 38. 39. 40. 41. 42. 43. 44. 45. 46. 47. Eisleb, U. 8. Pat. 2,167,551, C. 1., 55:, 9925 (1959). Eisleb, Ben, :49, 1455 (1941); C. 11., 55, 5495 (1942). I. 0. Farbeninduetrie, Brit. Pat. 501,155; C. A., 55, 5972 (1959). Fuson, Ullyot and Gehrt, J. Am. Chem. Soc., 62, 1199 (1938). Hancock and Cope, Org. Syn.. 22, 25 (1945). Hastings and Cloke, J. Am. Chem. Soc., 56, 2136 (1934). Hintikka, Ann. Acad. Sci. Fennecae, EA, No. 1, 4 pp. (1923); C. 4., 13, 51 (1925). Hudson and Hauser, J. Am. Chem. 300., 95; 3156 (1941). Jacknmn, Nachod and Archer, J. Am. Chem. Soc., z_2_, 716 (1950). ' Janssen, 11111., 250, 125 (1999). Jullien, Bull. Soc. Chim., g, 1252 (1959). Knowles and Cloke, J. Am. Chem. Soc., 54, 2028 (1932). Kwartler and Lucas, J. Am. Chem. Soc., _6_8_, 2395 (1946). Larsen, Ruddy, Elpern and Machhfllin, J. Am. Chem. Soc., 71, 532 (1949). "" Levine and Hauser, J. Am. Chem. 800., _6_8_, 760 (1946). Lipp, Buchkremer and Scales, Ann., 499, 13 (1932). Meyer, Ann., §_5_9_, 119 (1999). Michel, Ber., 53, 2403 (1900). Migridichian, "The Chemistry of Organic Cyanogen Compounds”, Reinhold Publishing Corp., New York, 1947, pp. 263-318. Murray and Cloke, J. Am. Chem. 800., 59, 2014 (1956). Nelson and Creteher, J. Am. Chem. 800., 52, 2758 (1928). Newbery and Webster, J. Chem. 800., 738 (1947). Newman, J. Org. Chem., 9, 519 (1944). Newman and Closson, J. Am. Chem. Soc., 62, 1553 (1944). Nicolet and Sattler, J. Am. Chem. Soc., 49, 2067 (1927). -25- 48. 49. 50. 51. 52. 53. 54. 55. 56. 57. 58. 59. Nieuwland, J. Am. Chem. 300., 54, 828 (1932). Ramart, Bull. Soc. Chim., 35! 196 (1924). Ramart, Compt. rend., 182, 1226 (1926). Rising and Zoe, J..Am. Chem. 800., 42, 541 (1927). Rising and Zoe, J. Am. Chem. 800., 59, 1699 (1928). Sperber, Papa and Schwenk, J. Am. Chem. 300., 10, 5091 (1949). Upsom and Thompson, .J. Am. Chem. 300., 44, 181 (1922). 'Weiss, Cordasco and Rainer, J..Am. Chem. 300., 21, 2650 (1949). ‘Weston, J. Am. Chem. 300., 68, 2345 (1946). Widegvist, Svensk. Kem. Tid., 55, 125 (1943); C. A.. 38, 5211 (1944). "' '- Ziegler and Ohlinger, Ann., 425, 84 (1932). Ziegler, 661'; Pat. 570,594 and Fr. Pat. 728,241} C. A... 51’ 4251 (1955) and C. A., _2__§_, 5575 (1952). Lm cm NIIUZO'SI MIA-u 0074- ”(2715 9:920“. Julis Is. a! "1 “I“ '01 / 1 [T547 W925 9113;911:1111! W Workman 234502 3 1293 02446 678