V .“_W- A STUDY OF THE ALKYLATION OF SUBSTETUTED PHENYLACETONITRILES WETH BUTYL CHLORIDES Thesis {or ”10 Degree 0* M. S. MICHEGAN STATE UNIVERSITY Harold Rishel Ringler 1961 (a LIBRARY Michigan State ‘ University is,» l I fl...” iv" A‘ l ""— " r. c . .l Illklltv h'l1|llV n-1- DEFARTMLNT(G"V& .u \' _, .U EAST LANQ1:\-‘G,z~...olx;;. .144 . u [Jul‘ ABSTRACT A STUDY OF THE ALKYLATION OF SUBSTITUTED PHENYLACETONITRILES WITH BUTYL CHLORIDES by Harold Riehel Ringler The purpoee of thie etudy wee to investigate the effect of the etrnctnre of the elkyl group already located at the Mpoeition in wanbetituted phenylecetonitrilee on the reactivity of the nitrile ee reflected in yielde of producte when the phenylecetonitrilee were elkyleted with e eecond elkyl halide. Alec inveetigated wne the effect of the etrnctnre of alkyl helidee on the yielde of producte tn theee elkylntion reectione. Very cloeely interwoven with theee prohleme wee the queetion of how hindered e nitrile might poeeibly be formed. The elkyletion reaction under etudy proceede eecording to the following equation. R-fii-vCN + 3mm Ra'C-CN ' I H R' Sodamide wee the condensing agent need to place the eecond nlkyl group in the 112113 poeition end toluene we need ee the eolvent. The reaction was carried out by the elow eddition of e enepeneion of enda- mide to e eolution of nitrile end elkyl halide heated to epproxlmetely ' 90° c. The etructure of the alkyl group already located at the :13}: poeition wae found to lave n definite effect upon the yield of I—iarold Riahel Ringler Z dielkyleted product. In elkylatione with nobutyl chloride, the yields decreeeed in the order secondary hutyl 3' normal emyl > isobutyl. The etructure of the elkyl halide eleo had an effect upon the yield of product. In the elkyletione of n-i-butylphenylecetonitrile the order wee found to be eecondary butyl 3 normal hutyl > ieobutyl. In any eingle elkyletion reaction the etructuree of both the alkyl group already located at the 31311; position and that of the incoming alkyl group had a great effect upon the yield of dialkyleted product. The presence of the first named eubetituent upon elkyletion with the eecond named group reeulted in yields decreasing in the order eecondary butyl-normel hutyl 3- normal emyl- normal butyl > ieobutyl-eecondary butyl 3 ieobutylo normal butyl > di-ieobutyl > di-eocondary butyl. The yields of the resulting e. e-dielkyletod phenylecetonitrilee ere ehown in the accompany- ing Table. In the course of thie work the eix previouely unreported nitrilee shown in the teble were prepared and purified end their phyeicel propertiee determined. Attempte were made to reduce theee nitrilee to the correeponding eminee with lithium aluminum hydride. Three of the nitrilee reduced smoothly. Theee three aminee, obtained from n-n-amyl-o.~n-butylphenylecetonitrile. n-i-butyl-e-n-butylphenyl- ecetonitrile, end a. n-di-i-butylphenylecetonitrile. reacted with conephthylieocyanete to form the correeponding euhetituted ureee. lt wee not poeeible to form any derivative of the eminee obtained from nitrilee that had e eecondary butyl eubetituent in the elphe position. Harold Riehel Ringler :3” .30 32.30 and c0323? «:5 >15 :78. endurance. 33359031515; .052 an .208 gagmueu oa§>uoe3>£3ne2oc . one—m5: on egg! Privacy. ouece>oo3~>54me2é .550" an .A .m MfiU'OO‘ 38.. 37.2... 22.6 33.. 31:: «.3 “rapid“. 2.3; amid: use... «2: n: 1.3 “33-75 33.. $342 .32.... anew; $.73. no.2. :53-.. .354 $3.. 3.1:; 52.6 33.. m! «.2. 33.... .35; SS; 0375. 2:6 23.. Q: 92.. 33-: .15.... anon; t... 32.6 2.3; 3.42 Ni. 33-: area... m: ado . dd be we ado . dd . .23» 33.388355...“ 039—95. veuafiebflm ecumflfiw 3:52 3&8,‘ 32:. e5 33:: do graham 73.55 can 3:32 we .33» A 03: A STUDY OF THE ALKYLATIGN OF SUBSTITUTED PHENY LACETONITRILES WITH BUTYL CHLORIDES BY Harold Riehel Ringler A T HES-IS Submitted to Michigan State Univereity in partial fulfillment of the requiremente for the degree of MA STE-R OF SCIENCE Department of Chemietry 1961 ACKNOWLEDGMENT The author wiehee to expreee hie appreciation for the guidance and eeeietance given by Doctor Gordon 1... Goerner during the inveetigation and during the preparation of thie theeie. #*********# ii Name: Date of Birth: Place of Birth: Academic Career: Degreee Held: Employm entx VITA Herold Riehel Ringler September 20, 1929 J ohnetown, Penneylvania Attended Somereet High School Somerset, Penneylvania, 1945 to 1949 Attended Gettyeburg College. Gettyeburg, Penneylvania, 1951 to 1955 Attended Michigan State Univer city. Eaet Lansing, Michigan. 1958 to 1960 Bachelor of Arte. Gettyeburg College Chemiet. The Dow Chemical Company, 1956 to 1958 Graduate Aeeietent, Michigan State Univereity. April. 1959 through June. 1960 Chemiet, General Electric Company, Pittefield, Maeeachueette. September, 1960, to preeent iii TABLE OF CONTENTS INTRODUCTION e e e e e e e e e e 0 e e HISTORICAL e e e e e e e e e e e e e e e EXPERIMENTAL e e e e e e e e e e e e I. Rugent. O O O I O O I O O O O 0 II. Preparation of Intermediatee . 0 III. Alkylation of e-Monoalkylated Phenylacetonitrilee IV. Preparation of Derivativee . . . . . . . . . . DISCUSSION OF RESULTS . . . . . . . . . . . . SUMMARY 0 I O O O O C O O O O O O O O O O O O O SUGGESTIONS FOR FURTHER RESEARCH SELECTED REFERENCES . . . . . . . . . iv Page 25 26 27 32 37 43 50 53 56 LIST OF TABLES AND FIGURES TABLE I. II. III. IV. V. VI. VII. VIII. IX. X. Alkylation of Nitriles byAlkyl Halides . . . . . . . . . Distillation of a-n-Amylphenylacetonitrile (Prepared bythe Sodamide Procedure) . . . . . . . . . . . . . . Distillation of a-n-Amylphenylscetonitrile (Prepsred by the Sodium Hydride Procedure) . . . . . . . . . . Monoflkylphenyladctonitrilel e e o 's e s s e s o s s s s Distillation of a-i-Butyl-a-s-butylphenylecetonitrile. . - Yifllda Of a, Q'DialkYIPhODYIEC“onitrilc. s s s s s 0's 0 Physical PrOperties of o, a-Dialkylphenylacctonitriles. AminesPrepered......”.........'..'... Compsrison of Physicel Properties of Nitriles and TheirDerivedAminee'. . . . . . . . . . . . . . . . . DerivetivesPrepared.................. FIGURE I. StructuresofNewNitriles. . . . . . . . . . . . . . . Page 12 29 31 32 34 35 36 39 40 42 54 INTRODUCTION INTRODUCTION This work is a continuation of earlier studies of the alkylation of selected n-monoalkylated phenylacetonitriles with certain alkyl halides using basic condensing agents. according to reaction I. I R'X + R-é-CN w R-?-CN + NaX u H H Workman (1) investigated the use of various butyl chlorides in the alkylation of hydratroponitrile (R a methyl) and found that the structure of the butyl group entering the molecule did have a definite effect upon the yield of product. s-Butyl chloride and i-butyl chloride gave a higher yield than n-butyl chloride. and the latter a much higher yield than t-butyl chloride. The yields obtained from the s-butyl and i-butyl chlorides were 67 to 69 per cent and those obtained from n-butyl chloride were 61 per cent. The use of t-butyl chloride resulted in yields of only 4 to 12 per cent. He also found that by using n-butyl chloride, n-butyl bromide. and n-butyl iodide nearly the same yields were obtained. Variation of the halide did not affect the yield appreciably. Jacobs (2) studied the use of the amyl chlorides as alkylating agents of hydratroponitrile and found in agreement with Worlunan that . the structure of the alkyl group had a considerable effect upon the yield of product. The best yields of 90. 5 per cent and 90. 2 per cent were obtained by using chlorocyclopentane and l-chloro-Zcmethyl- butane as the alkylating agents. Somewhat lower but still high yields of between 84 and 87 per cent were obtained with i-amyl chloride, with Z- and with 3-chloropentane, and with 2-brom0pentane. A yield of 73 per cent was obtained with n-amyl chloride and only a trace of product was formed using t-amyl chloride. These results agree with those obtained earlier by Workrnan in showing that alkyl halides of the secondary and iso type give better yields than normal alkyl halides. Jacobs also found that variation of the halide had little effect upon the yield. Holzschuh (3) investigated the same reaction using the Mtyl chlorides in the alkylation of Z-phenylbutanenitrile (R :- ethyl) and compared the use of sodium hydride as the condensing agent with sodamide. With sodamide, s-butyl chloride and i-butyl chloride pro- duced better yields than the n-butyl chloride. but with sodium hydride n-butyl chloride gave a higher yield of product than did s-butyl chloride. In general, the use of sodium hydride resulted in yields 3 to 15 per cent less than with sodamide. The present work was primarily concerned with studying the effect of the length and branching of the alkyl chain. already located at the _a_1_Eh_a_position. on the introduction of a second alkyl group into the alphiposition. The effect of variation of structure in the second alkyl‘ group. i. e. in the alkyl halide. was also considered. ' lntimately related with these aspects of the problem was the desirability of finding out just how hindered a nitrile might be formed and whether or not Newman's (4) six-number concept of steric hindrance might be applic- ~ able. Alkyl chlorides were used in 0.11 alkylations and sodamide was the condensing agent used. The nitriles used in this study were o-n-amylphenylacetonitrile (R = n-amyl). ens-butylphenylacetonitrile (R = s-butyl). and e-i-butylphenylacetonitrile (R = i-butyl). The alkylating agents were n-butyl chloride. s-butyl chloride, and i-butyl chloride. Also involved in this work was the reactivity of the amines derived from the prepared nitriles, which have varying degrees of hindrance. After this work was essentially complete. Newman and co- workers (5) described the preparation of some highly hindered aliphatic nitriles. They were able to correlate the yields of carbon- alkylated products with the relative amounts of steric hindrance in the products according to the six-number concept. A similar corre~ lation of yields of products with the six-number of the resulting nitriles was not found in this work. HISTORICAL HISTORICAL Much of the chemistry of the nitriles such as phenylacetonitrile is involved with the fact that the cyano group activates the $121.13. hydrogen in these compounds much the same as carbalkoxy and carbonyl functions activate alpha hydrogens in compounds like aceto- acetic ester and malonic ester. For example. nitriles show a comparable facility to undergo base-catalyzed condensations dependent upon initial formation of an anion. A Claisen condensation occurs between a ketone as the active hydrogen component and an ester to form a Leta-diketone (equation II) and in a similar fashion between a nitrile and an ester to form a _be___t_a_-ketonitrile (equation 111). base 11 R-co-cnrn' + R"-co.c.H,————> R-CO- H-CO-R" a... g, + c.H,0H m R-CHrCNi- nucolczn, 3312-» R'-CO-CH-CN <--- a R + camon This reaction is similar to the well-known acetoacetic ester conden- sation. An example of the practical application of the reaction in synthesis is in the preparation of ethyl etc-phenylacetoacetate. Ethyl acetate reacts with phenylacetonitrile with sodium ethoxide as the ' basic catalyst to form a-acstylphenylacetonitrile (6) (equation IV). 1v cry-comm. + CHI-(3N 919.99%.) CH,-co-CH-CN + 0311,01; The product may be converted to ethyl a-phenylacetoacetate (reaction sequence V) which is not available by alkylation of acetoacetic ester (7). 0% v CHy-CO-CH-CN + c.H.0H 5-1-95 CH,-co-cH-C=NH Iii-591* H30 CH,-co-CH-co,m Although sodium ethoxide is commonly used as the basic catalyst, sodamide has also been used. Levine and Hauser (8) have effected condensations of esters with nitriles with sodamide as the basic catalyst. They found that sodamide effects such condensations in a shorter time than does sodium ethoxide and also permits certain condensations which are not possible with sodium ethoxide. The Dieckmann cyclisation is an application of the acetoacetic ester condensation to the formation of a ring system using dicarboxylic esters that have five or six carbon atoms in the acid component (equation VI). carom-comm. caveat-comm, + (argon VI NaOC H C=O I ._._.._L_I.) I / CHa'CHg'C03CIHg . CHf'CH; Dinitriles undergo a similar cyclieation (9) in the presence of sodamide. Newman and Closson (10) obtained an 85 per cent yield of 3-methyl- 3-phenyl-loitninocyclopentylcyanide from 2-phenyl-2-methyladip0c- nitrile (equation VII). NH CH3 1 VII .-c-cn,-CH.-CH,-CN I-"-3-N-§l-~>.--<':C c- cm I \ CN ' CH;— CH, The cyano group may also activate an 3.1.231 hydrogen for an aldol (11) type condensation. as in the condensation of bensaldehyde with phenylacetonitrile to produce a-phenylcinnamonitrile. in the presence of sodium ethoxide (equation VIII). vm .-cno+ ..cn..cm 312292.21... -CH:c':-CN + H10 Bodroux and Taboury used sodamide to condense benzaldehyde (l4) and p-methoxybensaldehyde (13) with phenylacetonitrile. The use of ketones (12) was also reported by Bodroux. He succeeded in condensing e-naphthylphenylketone. p-methylbensophenone, and benzophenone with phenylacetonitrile. In alkylation reactions for synthetic purposes nitriles of the type RCH3CN have an outstanding advantage over the corresponding esters lull-1.003153. This is due to the fact that the nitriles can be easily alkylated whereas an ester is difficult to alkylate directly. One of the more successful alkylations of a monosubstituted acetic ester, the alkylation of ethyl phenylacetate (15) with ethyl bromide. resulted in only a 35 per cent yield of product. 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 with alkyl halides or siniple alkyl sulfates (reaction sequence IX). RCH3CN + NaNH; ----a- [RCHCNJ’ Na.+ IX [RCHCNF Na+ + R'X —-—-> RCHR'CN + NaX The most commonly used condensing agent is sodamide, which was introduced by Bodroux and Taboury in 1910 (14). ‘ Other condensing agents which have been used include metallic sodium (16), sodium alkoxides (sodium ethoxide and isopropoxide) (16, 17. 18). potassium amide (19), sodium hydroxide and potassium hydroxide (20. 21). Sodium t-butoxide or sodium triphenylmethyl are two commonly used basic condensing agents for which no use has been reported in this reaction. The lithium, sodium. and bromomagnesium salts of secondary amines have found limited use as bases (22, 23). The use of lithium diethylamide rather than sodamide as the base for the alkylation of nitriles avoids side reactions involving addition of the amide ion to the nitrile group (equation X). x 21.0% N + Nam-I. R-C(NH;)=NNa This side reaction is reported to be particularly serious with di- substituted ac etonitriles . In addition to alkyl halides. alkylating agents for nitriles (25) that have been employed include allyl halides. dihalogenated alkanes. chloropyridines, chloroquinolines. epoxides. dialkyl sulfates. and alkyl sulfonates. The use of alkyl halides as alkylating agents for 10 nitriles was first reported by Meyer in 1889 (16) and since that time they have been widely used. The reaction of the alkyl halide with the anion is believed to be a bimolecular nucleophilic displacement reaction. In similar type reactions allyl and bensyl halides have been found to be more reactive than alkyl halides which in turn are more reactive than the generally inert vinyl and aryl halides. Workrnan (l) and Jacobs (2) found little difference in the yields of product when using normal butyl and normal amyl chlorides, bromides, or iodides in the alkylation of hydratrOponitrile in the presence of sodamide. However. Cope at :1: (25) report that in alkylations of active methylene compounds in general. for a given alkyl group, the reactivity increases from the nearly inert fluoride through the chloride and bromide to the iodide. A more unreactive halide is usually selected when dialkylation is expected to be a serious side reaction, although dialkylation in some cases can be controlled by the choice of condensing agent, solvent. and temperature. These workers further report that although the alkyl bromides are usually the most satisfactory alkylating agents. the alkyl chloride is recommended when the corresponding alkyl bromide is very reactive. If the alkyl bromide is found to be too unreactive, use of the corresponding alkyl iodide is recommended. If the desired alkyl iodide is not available, a procedure found to be satisfactory is to use the corresponding alkyl chloride or alkyl bromide with sodium iodide or potassium iodide in an alcohol medium. Alkyl halides such as tertiary-alkyl halides that i are easily dehydrohalogenated result in very low yields of product due to both the loss of alkyl halide and to the loss of base that occurs during dehydrohalogenation. 11 A large number of various alkyl halides. some of which contain other functional groups, have been used in the alkylation of nitriles. A tabular survey of alkylations of nitriles is given in Volume IX of “Organic Reactions (25); this includes work published through 1952. Other lists may be found in the M. S. theses of Wesley R. Worlonan (l) and Richard L. Jacobs (2). An additional list of more recent alkylations is given in Table I. Dihalogenated alkanes have been used for the preparation of cyclic systems when condensed with nitriles. Because vinyl and aryl halides are generally inert to nucleophilic displacement reactions, few successful alkylations of nitriles have been realized with these reagents. One notable reaction is the alkylation of acetonitrile or prepionitrile with chlorobenzene in the presence of potassium amide and liquid ammonia (19). This reaction is likened to the conversion of chlorobensene to aniline under similar conditions in which the amino group becomes attached either to the carbon atom from which the chlorine atom has become displaced from or to an adjacent carbon atom. It is not known whether the position occupied by the chlorine atom and the entering cyano-methyl or cyano-ethyl group are the same or not. A probable mechanism (3) in explanation of this is that in the presence of excessive amounts of a sufficiently strong base, the arylation proceeds 3i; the benzyne intermediate of Roberts 33: a}. (26) and others (27). The arylation may be represented by reaction XI. x1.-er KNHI [.] K+[CH,-EHCN]$ CH,-<':H-CN 12 peanmadou 05333000133630 05.3330 00 m ow ngmoua-m-a-e .c uraoaaumnanns .0 0330.3 gram .0 0:330: 00 05.333000 m hm uahaoum-mnmahos .0 .o iguana-«tans .s 3033 gnome-7m 03.8330 00350-0 03.3330 00 m 2. nahaoumoaqu-e .e udhmoumnm-«Q-e .0 0350.3 35H oEantodafioa-e $5383 m 3 cuhaouaéoane .0 uuhmoumuqu-e .0 0380.3 1502 3.330039:— am 2. issuance-a .a a ofisflotusinonm acetone. arenas—om euthanasia . 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Augean-0-332; 353.030.1030 25333380. .3 3.62 03330393 0233000 00 cm 2. 4.3203830 .06 .0 49213 «2:320 arc-Exam 03.330.233— 0533000 00 on S .1030th-u .u .a -1513 «020.030 353.3303 33330303“ 03333000 on 2. 403230.30 .u .a 43213 «33330 15.80 33:58:33-0-.. 0320303 m 0.... su533n0u0n~bm00mumue 1~hnoumumnuomb3mauua 0330.2— gram-0 0333300333-“-.. . 033303000 m cm uHhQOhm-éncngfifluo uuhfiOhnum-auugm sand 0633003 33.“ 0333000033933... 023300000 m 3 4383-0 .c .iflo-u-Esm-«é 0386.3 :33 3333300333-»...0 03.333000 m 2. 433.50% .a -1598-6-330-0-5 «3:33 15.: fi 00:0003m 303% uuflvounm 0332 0333 maul-«300 .- - 036p.- 14 Epoxides (25) can also be used to alkylate nitriles and form inter- mediate hydroxynitriles that are converted to cyclic imido esters. Use of the corresponding halohydrins results in the formation of the same products. The dialkyl carbonates (25) cannot be used to alkylate nitriles because carbethoxylation of the intermediate anion takes place instead of alkylation. Dixnethylsulfate (25) and diethylsulfate (25) have often been used and result in yields similar to those of the corresponding alkyl iodides. An advantage is that the higher boiling points of the dialkyl sulfates permit the use of higher reaction temperatures without the loss of the alkylating agent. Alkyl benzene- sulfonates (25) and alkyl p-toluenesulionates (25) give good yields of alkylated products when primary alkyl sulfonates are used but only fair yields when the sulfonate esters of secondary alcohols are used. These alkylating agents are sometimes useful when conversion of the corresponding alcohol to the alkyl halide is difficult or involves rearrangement. Like the dialkyl sulfates. these reagents have high boiling points. Several types of side reactions have been reported to occur in the alkylation of nitriles. Among these are dialkylation, reaction of the alkylating agent with the base or solvent, dehydrohalogenation oi the alkylating agent, polymerisation, and elimination of the cyano group. In order to gain insight into the causes of the relative amounts of monoalkylation and dialkylation (25, 29). it is necessary to know something of the equilibria occurring between the nitrile. alkylating agent, and base. In an alkylation of phenylacetonitrile with an alkyl halide. sodamide. the liquid ammonia and ether as the solvent, the following equilibria occur to a greater or lesser extent (equations mthrough XV). 15 9 x11 c.H,CH,CN + NH? --—--> C‘H,CHCN + NH, Q _ Q x111 c.H,CHCN + RX -——-> C‘HSCHRCN + x e o XIV c.H,CHRCN + C‘H5CHCN --—-> C‘H,CRCN + c.H.CH,CN Q Q xv C‘H.CRCN + RX --—-> c.H,CR.CN + x Among the decisive steps that determines the amount of dialkylation occurring versus monoalkylation is the equilibrium between the mono- alkylated product and its anion (equation XIV). When the rate of establishment of this equilibrium is relatively rapid compared to the formation of the monoalkylated product, a larger proportion of the phenylacetonitrile will be dialltylated. This assumes that molecular equivalents of the reactants are employed. Any reaction condition or any structural feature of the species involved that speeds the attain- ment of this equilibrium relative to that of the formation of the mono- alkylated product will then supposedly increase the ratio of dialkylated product to monoalkylated product. ' Of considerable importance is the acidity of the solvent. A large excess of any solvent with some small degree of acidity that would permit it to react with the base would decrease enormously the concen- tration of the anion of the monoalkylated product and thus cause the rate of dialkylation to be negligible. This would then suggest that replacement of this solvent by a more inert solvent would favor di- allcylation. “These statements. generalized for all active methylene compounds. have been partially demonstrated by Clemo and Tenniswood (28) in a study of the ethylation of diethyl malonate with ethyl bromide 16 with ethanol as the solvent. An increase in the acidity of the nitrile would also be expected to cause a greater amount of dialkylation. The use of very reactive halogen compounds such as bensyl halides and allyl halides also causes dialkylation to become an important side reaction in the alkylation of active methylene compounds. This may be attributed to the fact that such alkyl halides require little or no aid in a bimolecular displacement reaction from the attacking nucleophilic species in order to heterolytically break their carbon- halogen bonds. An alkyl halide of this type would then be expected to show less discrimination between an unsubstituted nucleoPhilic reactant and a somewhat more hindered substituted nucle0philic reactant than would an alkyl halide such as n-butyl chloride. The break- ing of the chlorine—carbon bond in this caseis greatly facilitated by the attacking nucleophilic reagent. 'Hauser and Brasen (29) made a study of the extent of dialkylation accompanying monoalkylation in the reaction of phenylac etonitrile with alkyl halides of various structural types with sodamide and a liquid ammonia-ether solvent (Table I). The extent of dialkylation taking place was found to be dependent upon the structure of the alkyl halide. The nitrile was first converted to its alkali derivative by means of an equivalent of sodamide in liquid ammonia and an equivalent of an alkyl halide in ether was then added. Both mono- and dialltylation occurred with methyl and benayl halides while exclusive monoalkylation resulted with o—phenylethyl chloride and with benahydryl chloride. In one of the crucial steps which supposedly determines the extent of dialltylation. V the equilibrium of the monoalkylated product and m anion (equation XIV). the anticipated regeneration of phenylacetonitrile was actually found to occur when methyl and bensyl halides were used. When dialkylation took place. the reason was believed to be that the structures of the alkyl 17 halides used permitted the rates of dialkylation to be comparable to those of monoallrylation. When monoalkylation occurred exclusively. it was suggested that the bulkiness of the alkyl group already on the monosubstituted anion and of the group entering the anion, caused the rates of dialkylation to be negligible relative to those of monoalkylation. In support of this Hauser and Brasen found that benahydrylation of the monobenzhydrylated product by treatment with potassium amide. followed by benshydryl chloride, resulted in only a 33 per cent yield of dialkylated product. The reaction period for this alkylation was twice that allowed for monoalkylation in which a 99 per cent yield was obtained. The relatively slow rate of the second benshydrylation was ascribed to a steric factor. A method sometimes used to diminish the amount of dialltylation is to use an excess of the active methylene compound. As the reaction leading to the alkylation of an active methylene compound proceeds, the ratio of the concentration of the monosubstituted anion to that of the unsubstituted anion must necessarily increase. An increase in this ratio will increase the preportion of dialkylation that occurs. This unfavorable concentration ratio may be largely overcome if an excess of the active methylene compound alone is used or an excess of both the active methylene compound and base is used in order to increase the concentration of the unsubstituted anion. Other factors that have been reported to favor monoalkylation are the use of low boiling solvents and the use of alkyl chlorides rather than alkyl bromides. Another side reaction (25) that may occur is reaction of the alkylating agent with the base or solvent. This becomes an important side reaction usually only when very reactive halides such as allyl. bensyl. 'and benehydryl halides are used, provided the anion of the reactive methylene compound is present in sufficiently high concentration. 18 A precaution to be followed in minimizing this side reaction is to treat a mixture of the alkylating agent and the nitrile with the base at a rate equal to that at which the base is consumed in the reaction. Polymerization (25) of the alkylating agent or product may result as a side reaction when allylic halides react with active methylene com. pounds. This may be minimized by slow addition of the sodium derivative of the nitrile to the alkylating agent. Tertiary alkyl halides (25) often undergo dehydrohalogenation more rapidly under the basic reaction conditions of an alkylation than they undergo the displacement reaction leading to alkylation. This side reaction usually causes alkylations with tertiary alkyl halides to be unsuccessful entirely, or to result in extremely low yields of products. Workman (1) obtained a maximum yield of only 6.4 per cent in his attempts to alkylate hydratrOponitrile with t-butyl chloride using sodamide as the basic condensing agent. Jacobs (2), using similar reaction conditions. obtained only a trace of the desired product in an attempt to alkylate the same nitrile with t-amyl chloride. Moreover. Jacobs was able to isolate relatively large amounts of alkenes among which were identified 2-methyl-l-butene and 2-methyl-2-butene. Olefin formation is far less important with secondary halides and is negligible with primary halides. Elimination of the cyano group (25, 30) has also been found to be an important side reaction in the alkylation of nitriles. Although nitriles are usually stable to ethanolic sodium ethoxide. the stronger base sodamide in boiling benzene, toluene. or xylene does attack the cyano group in some instances. For example. the decyanation shown below (equation XVI) in refluxing xylene formed the indicated product in 91 per cent yield with the elimination of the cyano group as sodium cyanamide. 19 C53: i XVI (CH3);NCH3CH3‘C‘CN + ZNaNHg 3511-5-12) I CsHs CsHs I (CH,),NCH,CH.- c-H + NH, + Na; NCN cm, Dehydrocyanations have been reported (30) for substituted nitriles that have no hydrogen atom on the carbon atom sigh; to the nitrile function but which have a hydrogen atom and a phenyl group on the carbon atom beta to the nitrile function. The elimination of hydrogen cyanide is considered a beta type elimination similar to other bimolecular elimination processes as shown below (equation XVII). E3} Hé‘ NH; "3 KNH xvn C‘Hy-CH— C(C‘H,); W c.H,CH--- C(cmg, CN 9 +Nm+cu A _b_e_ta___ hydrogen is supposedly removed as a proton by the amide ion and the cyano group is released as an anion. Hauser and Brasen (30) have reported the dehydrocyanation reaction for several polyphonyl nitriles with potassium amide in liquid ammonia to form the corres- ponding olefins. In each case the nitrile had a relatively hindered cyano group and no Mhydrogen and also had a l3e_t_a hydrogen actio vated by at least one phenyl group. These workers obtained a 94 per cent yield of triphenylethylene (equation XVII). an 80 per cent yield 20 of l, l, 2-triphenylol-propene, and a 44 per cent yield of tetraphenyl- ethylene from the respective nitriles by means of this reaction. Special attention is drawn to the alkylation procedure of Hauser and Brasen (30) that resulted in the attainment of quite high yields of alkylated nitrile. In this procedure. the nitrile was first converted to its alkali derivative by means of an equivalent of an alkali amide in liquid ammonia, and an equivalent of an alkyl halide in ether was then added. These workers obtained a 96 per cent yield of product using this procedure in the benaylation of diphenylacetonitrile. The same reaction had previously resulted in an 83 per cent yield of product with sodium ethoxide in :ethanol, in a 67 per cent yield with methyl- magnesium iodide in ether and in an unreported yield with sodamide in ether. Benshydryl chloride and e-phenylethyl chloride reacted in a similar manner with diphenylacetonitrile to form a. a. [3. fi-tetraphenyl- propionitrile (I) and u. a. B-triphenylbutyronitrile (II) in yields of 96 per cent and 88 per cent respectively. These latter two alkylations had not been reported previously. (C‘H5)3CH C‘Hg" CHCH3 I I (CsHsIsC'CN ICsHsIs C'CN I II Hauser and Brasen reported that all three of the nitriles they had so prepared were highly resistant to hydrolysis in acidic or basic media. An examme (31) of a unique application of a sodamide catalysed alkylation of phenylacetonitrile is shown in the synthesis of the important analgesic demerol (ethyl l-methyl-4ophenyl-4-piperidinecarboxylate). Phenylacetonitrile is added to methyl bis (betachloroethyl) amine hydrochloride (equation XVIII) in benzene. A suspension of sodamide 21 in benzene is added and the resulting product is converted to demerol by alcoholysis (equation XIX). The intermediate nitrile was obtained in 70 per cent yield. CH.CH,C1 C6H, CN / ZNaNH \ / xvm C.H,CH,CN+ CH,N-HC1 37—4-4 C \ 0118811. / \ CH,CH.C1 CH, ('SH; I CH3 CH1 \N/ ' a CH, C CN C CO C ‘12 , (1)C.H,0H.HC1 ‘H’\ / .' 'H' C (221.550,. HIO C xxx / \ / \ I I I CH, CH, CH. CHa \ / \ / 1*: 1? CH, CH, Similar to this reaction is the condensation of phenylacetonitrile with polymethylene halides in the presence of sodamide to synthesise three-. four-, five-, and six-membered rings (equation XXf,, where n a 0, l, 2 and 3) (32). XX X-CHg-(CH3)nOCHg-X + C‘I'If CHg‘CN W CH: CsHs / \ / CH C ( 3’n\ / \ CHz CN 22 Among the problems involved in alkylation studies of nitriles and other active methylene communds is the question of how hindered a compound it is possible to form. The acquirement of additional information concerning this question was one of the objectives of this study. After this work was essentially complete. Newman 2? a}. (5) published a paper describing the preparation of a series of aliphatic nitriles which were highly hindered. It was found that alkylation of alkylacstonitriles having a certain degree of steric hindrance to tri- alkylacetonitriles resulted in the occurrence of nitrogen alkylation as well as carbon alkylation. The more sterically hindered the nitrile, the greater was the proPortion of it transformed to nitrogen alkylated product as opposed to the usual carbon alkylated product. Newman explained this variation in position of the incoming alkyl group by consideration of an ambident anion that can undergo alkylation at two or more positions. This is illustrated by reaction sequence XXI. 3: R1 9 \ + \ ... XXI /CHCN 0H [Cw-r C “- N REX R R2 3 R1 R1 \ I a, - C-CN + Ca C== NR, / l R, R, As a method of predicting the relative amount of steric hindrance in a molecule, Newman applied his six-number concept (4). The six- number of a molecule is the number of atoms which are the sixth atom removed from a multiple bonded function (nitrogen in this case). It was found that no N-alkylation occurred in a nitrile having a 331‘ mimber of less than 12. Alkylations of di-i-propylacetonitrile 23 (six-number, 12) with i-propyl iodide yielded appreciable quantities of ketenimine. and alkylation of t-butyl-i-prepylacetonitrile (six number. 15) with i-propyl iodide yielded exclusively ketenimine. These workers did not determine the conditions necessary for obtaining the maximum yields of ketenimine. It is thought possible that alkylation of di-t- butylacetonitrile will yield mainly ketenimine with all alkyl halides. In a continuation of their efforts to synthesise highly branched aliphatic compounds. Newman at 91.03) prepared di-t-butylacetic acid and di-t-butylketene in good overall yield from hexamethylacetone. Di-t-butylacetic acid was an especially desired compound because it could be the parent of a series of highly hindered trisubstituted acetic acids. This compound was prepared by means of the following sequence of reactions (reaction sequence XXII). The hexamethylacetone under- went a Grignard addition with methylmagnesium iodide or methyl lithium to form an intermediate tertiary alcohol which was dehydrated with thionyl chloride. The resulting olefinic compound was converted to a prirnary alcohol by means of a diborane-hydrogen peroxide reaction. The latter was in turn oxidised in two steps with chromic oxide. The resulting di-t-butylacetic acid was converted to di-t-butylketene by treatment of the acid chloride with sodamide in liquid ammonia. This ketene is stable and relatively unreactive compared to other known aliphatic ketenes . CHaLi CH’ (CH ) ccoqcn ) .33....) (CH ) c—d-c ‘CH ) socnI 3 3 3 3 CHQLIEI 3 3 I 3 ’ CQE‘I‘N OH XXII CH3 1’ Ell-1‘ $HIOH I (CH,),c-c-c (CH3), gLi—‘Egb (ca,),c-cnc- (can; _.__a.>c“° Z4 (El-IO cozH (C11,), c_cnc (CI-1,), 5319-1» «CH». C- CHC (arm. (CH,),C.\ (CHahC\ S. l . /CHCO;H £1.) SHCOCI w (CH3),C (CH,)3C (CHshC \ Ca: Ca 0 EXPERIMENTAL 25 Z6 EXPERIMENTAL." 1. Reagents Phenylacetonitrile -- Matheson-Coleman-Bell. Used as received. n-Amyl bromide -- Columbia Organic Chemical Co. The fraction used distilled at 125. 5-126. 5° at 739 mm... ”D 1. 4444; reported (34) nn 1. 4444. s-Butyl bromide -- Matheson-Coleman-Bell. Used as received. i-Butyl bromide -- Matheson-Coleman-Bell. Used as received. n- Butyl chloride -- Eastman Kodak Co. . white label material was redistilled. ”The fraction used distilled at 77. 5- 77. 7° at 751 mm. . nD 1.4020; reported (35) n3 1.40159. s-Butyl chloride -. Eastman Kodak Co. . white label material was redistilled. The fraction used distilled at 68° at 761 mm. i-Butyl Chloride -- Matheson-Coleman-Bell. Redistilled. The fraction used distilled at 68° at atmospheric pressure. c-Naphthylisocyanate .- Eastman Organic Chemicals. White label. Used as received. Sodium Hydride -- Metal Hydrides, Inc. Repackaged in small bottles and stored in desiccator. Lithium Aluminum Hydride -- Metal Hydrides. Inc. Repackaged in small bottles and stored in desiccator. Sodamide -- Schaar Laboratories. Used as received. -- Farchan Research Laboratories. Repackaged in small bottles and stored in desiccator under a nitrogen atmosphere. *Au analyses were by Micro-Tech Laboratories. Skokie. Illinois. 27 11. Preparation of Intermediates The a-monoalkylated phenylacetonitriles have been prepared by two variations of the method of the base catalysed condensation of alkyl halides with phenylacetonitrile. One method used was the sodamide procedure of Cape and Hancock (36) and another was a pro- cedure using sodium hydride. Sodamide Procedure In this procedure, metallic sodium was first added to liquid ammonia in order. to form the sodamide. To this was added the phenyl- acetonitrile. the toluene solvent. and then the alkyl halide. A typical run is as follows. A 2-1. three necked flask. equipped with a reflux condenser. stirrer. and an inlet tube reaching almost to the bottom of the flask, was dried by heating with a Bunsen burner. then cooled with a soda lime drying tube attached to the top of the reflux condenser. The flask was then cooled in a dry ice-ethanol bath and approximately 540 ml. (27. 5 moles) of liquid ammonia was added and cooled. The inlet tube was then removed and replaced with a rubber stopper and the flask was taken out of the dry ice bath. Two tenths of a gram of hydrated ferric nitrate and about 0. l g. sodium metal were added and the solution stirred vigorously until the blue color disappeared. Then, with constant stirring, the remainder of the 23 g. (1. 0 mole) of the sodium metal was added about as quickly as it could be cut into thin strips. blotted. and introduced into the flask. The solution was then stirred until the blue color had disappeared. At this stage the mixture was a very dark grey with a light grey precipitate of sodamide on the bottom of the flask. The flask was then cooled once again in the dry 28 ice bath, and 117 g. (l. 0 mole) of phenylacetonitrile was added drop- wise from a dropping funnel with vigorous stirring. The solution was then removed from the dry ice bath and stirred for twenty more minutes. A solution of 572 ml. of anhydrous toluene and 71. 5 ml. of anhydrous ether was then added dropwise from the drapping funnel at a rate to cause rapid evaporation of the ammonia. The mixture was allowed to stand until it came to room temperature. during which time most of the ammonia evaporated. The remainder of the ammonia and me. at of the ether was then removed by turning off the water in the reflux condenser, warming the flask in a hot water bath and distilling most of the ether through the reflux condenser. A fresh soda lime drying tube was attached and the water turned on in the reflux condenser. To the warm solution. 163 g. (l. 08 moles) of n-amyl bromide was added dropwise with vigorous stirring during approximately 20 minutes. After the addition of the n-amyl bromide. the red colored solution was refluxed in an oil bath for 2 hours. The reaction mixture was cooled and washed with five 150 ml. portions of water. The aqueous layer was then extracted with four 50 m1. portions of benzene and these were washed with two '50 ml. portions of water. The toluene and bensene solutions were combined in a 1-1. one-necked flask and the solvent removed by distillation at atmospheric pressure. The last traces of solvent were removed at 60--70o at 20 mm. pressure using a water aspirator. The mixture was then fractionated through a 2 x 35 cm. column packed with 1/8 in. glass helices and yielded 130.7 g. of material boiling between 111451" at 3 mm. pressure. This was redistilled (Table II) and yielded the following fractions. 29 Table II. Distillation of o-n-Amylphenylacetonitrile (Prepared by the Sodamide Procedure) Fraction B. P. . 0C. n” n” Grams D D (4 mm.) 1 110-112 1.5140 1.5119 18.9 4 147-148 1.4932 1.4912 41. 1 5 153-155 1.4930 1.4910 58.2 Baldinger and Nieuland (37) reported a b.p. of 165-1680 at 22.5 mm. . n; 1.49961. This b.p. extrapolated 2° for each m. drop in pressure would be approximately 128-1310 at 4 mm. and thus in 13.1). and refractive index correspond to the material of fractions 2 and 3. These workers used essentially the same procedure as above except that liquid ammonia was used as the solvent and no toluene and other were used. Baldinger and Nieuland also reported physical constants for the series o-methyl through o-n-amylphenylacetonitrile prepared by the same method in yields of 35-50 per cent. R. L. Titus at Michigan State University using the above procedure listed the boiling point as 145-1480 at 7 mm. and ” 1.4911. These values correspond to the material of fractions 4 and 5. It is suggested that possibly the material of fractions 2 and 3 is the monosubstituted product and that the material of fractions 4 and 5 is the di- substituted product. Because of the ambiguous outcome of this preparation. another pro- cedure was followed in preparing this and other monoalkylated phenylac etonit riles . 30 Sodium Hydride Procedure In this procedure first reported by Ziegler (24), the phenylaceto- nitrile and alkyl halide were added to a suspension of sodium hydride in a toluene solvent. A typical run is as follows. Into a 1-1. three- necked flask equipped with a stirrer, reflux condenser, and powder funnel was shaken 28. 0 g. (l. 17 moles) of sodium hydride weighed by difference from a small closed bottle. The sodium hydride was immediately covered with 200 m1. of anhydrous toluene. Next were added 140.4 g. (1. 20 moles) of phenylactonitrile and 184. 2 g. (1. 22 moles) of n-amyl bromide and the powder funnel was replaced by a thermometer. The mixture was heated by a mantle. and a dry ice- keroscne bath was kept ready for immediate use in case the reaction became overlysvigor'ous.The reaction started when the temperature reached about 660 and continued without application of further heat until a temperature of 73° was attained. Some further heating was then necessary to keep the reaction going. After this the temperature rose to about 106° with a very vigorous reaction. The dry ice-kerosene bath was then applied to slow the reaction down. After the reaction had subsided, the mixture was heated at 105-1150 for two hours with continuous stirring. To the cooled mixture, 10 ml. of absolute ethanol was added drapwise cautiously, then 10 m1. of 95% ethanol with equal care, then 20 ml. of 50% ethanol. and finally 200 ml. of water. This mixture was filtered. The water layer was separated and extracted with 50 ml. of benzene. This was added to the organic layer, which was then washed with 50 m1. of water, 50 ml. of 6N hydrochloric acid, 50 ml. of 536 sodium carbonate solution. and then with 50 ml. of water. After filtering through anhydrous sodium sulfate, the toluene solvent was removed by distillation at atmospheric pressure. the last traces being removed at reduced pressure using a water aspirator. 31 The resulting mixture was then distilled through a Z x 35 cm. column packed with 1/ 8 in. glass helices and yielded the following fractions (Table 111). Table III. Distillation of don-Amylphenylacetonitrile (Prepared by the Sodium Hydride Procedure) Fraction B. P. . 0C. 11;; 113 Grams (mm.) . 1 101-104 (10), mostly at 102 13.6 2 105-108 (10), mostly at 108 6.7' 3 129-133 (9.5), mostly at 129-130 2.0 4 134-145 (9.5). mostly at 14o-14z.s 1.4998 1.4979 12.0 5 143-145 (10. 5), mostly at 145 1.4989 1.4970 53.9 6 145-146 (10. 5), mostly at 145 1.4989 1.4970 50.6 7 144-146.5 (10.5), mostly at 145-146 1.4989 1.4970 24.7 The other nitriles prepared for use in this work were also prepared by the sodium hydride procedure. The results of these preparations are summarised in Table IV. 32 Table IV. Monoallwlphenylacetonitrileea e-Alkyl B. P. . °c. n" 5” Yield D D (mm. ) % n-Amylb 145 (10. 5) 1.4989 1.4970 64. 5 s-Butylc ~ 133. 5 (10) 1. 5051 1. 5037 53. 2 i-Butyld 133-134 (10.5) 1.5000 1.4987 58.8 a'Additional monoalkylated phenylacetonitriles used in this work were obtained from Dr. Gordon L. Goerner and redistilled. These in-” cluded the a-s-butylphenylacetonitrile, b. p. 132-01330 (10 mm. ) 1.111) 1. 5036 and a-i-butylphenylacetonitrile, b. p. 1290 (10 mm. ). nD 1.4978. 1)It is to be noted that the boiling point and refractive index of the a-n-amylphenylacetonitrile corresponds more closely to those of fractions 2 and 3 (Table II) and to Baldinger and Nieuland's constants than to the constants of fractions 4 and 5 in Table 11. Also indicative that the material of fractions 4 and 5 may be the a. s-di-n-amyl com- pound is that its boiling point range of 147¢~155o at 4 mm. approximates the boiling point of 161-1620 at 9 mm. which was found for the a-n- amyl-u-n-butylphenylacetonitrile. Its refractive index of as 1.4910- 1. 4912 is also similar to the :13 1.4913 found for the last ed compound. . cThe reported values (38) are: b.p. 131-1320 (10 mm.). 113 1.5050 and n3 1 . 5035. dThe reported values are: b. p. 1320133140 (10 mm. ). (41),:1.“1 4990 andn 1.4970 (40) and b. p. 136 138 (15 mm.) (41), up 1.12978- 1. 49813 (42). III. Alkylation of a-Monoalkylated Phenylacetonitriles The procedure used for the alkylation of the e-monoalkylated phenylacetonitriles was the high temperature method developed by Ziegler and Ohlinger (22) and used successfully by Worlunan (1). 33 Jacobs (2), and Holsschuh (3). A typical reaction is as follows. In a 1-1. . three-necked flask equipped with a stirrer. reflux condenser attached with a (T) arm so that a thermometer could be inserted. and dropping funnel was placed a mixture of 43. 25 g. (0. 25 mole) of o.-i-butylphenylacetonitrile, 27.75 g. (0. 30 mole) of s-butyl chloride and an equal volume of dry toluene. Twelve to thirteen grams of sodamide was weighed out by difference from a small bottle. placed in the drapping funnel and immediately covered with about 50 ml. of dry toluene. The mixture was heated with a mantle to 90° and then the sodamide was added in small amounts. After each addition a rapid reaction with foaming and refluxing took place. The temperature stayed between 91'1"»105o without further heating. After all of the sodamide had been added. the mixture was refluxed for one hour at about 117°. To destroy any excess sodamide. the mixture was cooled and cautiously treated with 50 m1. of water. After filtering by suction the mixture was washed with two 50 m1. portions of water and the three water washings were extracted with 50 m1. of toluene. The toluene extract was added to the main toluene solution and the mixture was dried by filtering through a Buchner funnel containing anhydrous sodium sulfate, which was afterwards washed with several small portions of toluene. The mixture was then placed in a 500 ml. one-necked flask and the toluene was distilled off at atmospheric pressure. The last traces of the toluene were removed by transferring the mixture to a 100 ml. flask and distilling off the toluene at reduced pressure using a water aspirator. The remainder of the mixture was distilled at 10 mm. through a l x 25 cm. column packed with 1/16 in. glass helices and yielded the following fractions (Table V). 34 Table V. Distillation of o-i- Butyl-u-s-butylphenylacetonitrile Fraction B. P. . 0(3. n3 Grams (10 me 1 89-90 1.4858 0. 2 2 106-110 1.4867 2.5 3 117-120 1.4891 1.5 4 130-135 1.4922 0. 2 5 136-140 1.4962 0.6 6 142-145 1.4989 1. 2 7 143-146 1.4995 30.6 8 143-146 1. 5000 12. 5 Residue 0. 6 Fractions 6, 7. and 8 weighed 44. 5 g. and amount to an 80. 9 per cent yield of a-i-butyl-a-s-butylphenylacetonitrile based on the start- ing nitrile. The above procedure was followed in all alkylations for the introduction of the second alkyl group and was the procedure exactly as described before by Workinan (1) and Jacobs (2). Alkyl chlorides were used as the alkylating agents in every case. The same molar ratios of reactants were used as before and the reaction mixtures were worked up similarly and distilled through nearly identical equipment. Only in the alkylation of e-s-butylphenylacetonitrile with s-butyl chloride was any monoalkylated material recovered. In one run 39. 3 per cent of the a-s-butylphenylacetonitrile was recovered and in a second run 35. 8 per cent was recovered. In all the alkylation reactions heat was liberated. After the first addition of sodamide the color of the mixture became red and gradually turned to green as more sodamide 35 was added. Table VI summarizes the yields obtained from six different alkylation reactions and Table VII contains the physical constants of the products. Table VI. Yields of <1, o-Dialkylphenylacetonitriles ”M4..— u..-” »”"’M~~-*'~.m4 rs- -.m-‘~n._———--m—*r m—~--.~—-—~*~“n-~_ -V-‘wu _._._ -...-...__.4— .. -- 4 -. _ a b o 3"?" ' c-Substituents Run Yield C. mm. 0,. IO n-Amyl, n-butyl I 92.0 163-166 10 II 94. 0 160- 162 9 s-Butyl, n-butyl I 91. 9 153- 155 10 II 96. 4 153-155 10 Di-s-butyl 1 48. 5 144-152 10 II 48. 8 149-152 10 1- Butyl, s-butyl I 31. 4° 143- 145 10 II 78. 8 143-145 10 III 80. 9 143-146 10 Di-i-butyl 1 64. 7 141- 145 10 i-Butyl, n-butyl 1 77. 8' 144-149 10 a"I'he second listed group was the second group introduced. bBased on amount of starting nitriles. cThe low yield obtained in this reaction is attributed to the use of sodamide which was not stored under a nitrogen atmosphere in a desiccator. 36 2 .e .2 “28326 .5. 8.38100 sum .2 fiance to 833830.. 635.: 60.23300» no voaméeaefle 03... $.86 83.; $3..— 312: H53-.. .352 3 02 .e 3.3 .o 33.; on? .2 m3 ”seaside > 02 .3 52.6 2.3.2 :3; 3: 1.43.... .355... B 03.6 236 33.. 2.34 37:: 331.8 E 086 336 2.3.; «com; 37-2 ~53-.. .155... a at...“ 2.2.6 .23.; 83; 4?: ”>231. .187: a 7&8 2. 383535.... 62 a .2 3:. m: we do . .m .m 0:52 senmnficouaeosgseflggmflue .0 mo eemuhemounm 7323a“ .fl> 03.95 37 IV. Preparation of Derivatives The most common derivatives prepared from nitriles are carboxylic acids or amides obtained by hydrolysis of the nitrile. The hydrolysis (43) to carboxylic acids is often effected by heating with 75 per cent sulfuric acid at 1600-1900 or by heating with a solution of potassium hydroxide in diethylene glycol or glycerol. Hydratroponitrile can be easily converted to the amide by hydrolysis with sulfuric acid but butyl-substituted hydratroponitriles are much more difficult to hydrolyze. Using these same conditions, Workman (1) was unsuccess- ful in his attempts to hydrolyse c-methyl-o-butyl disubstituted phenyl- acetonitriles having normal butyl, secondary butyl. isobutyl, and tertiary butyl groups. Workrnan and Jacobs (2) finally were able to prepare derivatives for certain of the less hindered e-methyl-u-butyl and o-methyl-a-amyl disubstituted phenylacetonitrile-s by hydrolysis under more vigorous conditions with a solution of potassium hydroxide in ethylene glycol. conversion of the acid to the acid chloride, and then reaction of the latter with aniline to form the solid anilides. Since the nitriles prepared in this work are far more sterically hindered than those mentioned above, the hydrolysis of the nitrile to form a derivative was not attempted. Instead, attempts were made to reduce the nitriles to the corres- ponding amines with lithium aluminum hydride using the procedure of Amundsen and Nelson (44). The preparation of derivatives from these amines was then attempted. Jacobs and Holsschuh (3) had been success- ful previously in reducing many of the nitriles they prepared to the amines. The procedure used for the reduction of the nitrile to the amine follows. In a 500 m1. three-necked flask equipped with a stirrer, reflux condenser, and dropping funnel was placed a mixture of 4 g. (0. 106 mole) 38 of lithium aluminum hydride and 100 ml. of anhydrous ether. Ten grams of the nitrile was dissolved in 30 ml. of anhydrous ether and added dropwise during 15-20 minutes to the slurry in the flask. During addition gentle refluxing occurred. The mixture was then refluxed for an additional hour. The excess lithium aluminum hydride was decomposed by the slow dropwise addition, in order. of 4 ml. of water, 3 ml. of 20 per cent sodium hydroxide. and 14 ml. of water. The ether solution was decanted and the solid material in the flask rinsed with ether. The solid material was discarded. After removal of the ether. the residual oil was distilled in vacuo from a flask with a distilling head directly attached. The flask was heated in an oil bath. The amines prepared, the per cent yields, and their physical constants are listed in Table VIII. There is some question as to whether the nitriles were success- fully reduced to the corresponding amines. The boiling points. re- fractive indices. and analysis for per cent nitrogen for several of the amines as compared to these preperties for the nitriles from which they were prepared do not offer conclusive evidence that the reduction was completely successful. A comparison of the physical prOperties of the amines and of the nitriles from which they were derived is given in Table DC. The nitriles II. III. and V and their derived amines, for examme. have boiling points very close together. Nitriles II. III. and IV. have refractive indices very close to those of their respective amines. The values calculated for per cent nitrogen for a nitrile and its amine are too close together to be of practical use in distinguishing between the two compounds. The infrared spectra of all of the amines, except I. had the sharp cyanide absorption peak at 4. 5 microns identical with those of their nitriles. There were, however. some preperties to indicate differences between the two groups of compounds. 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Mid @3337“ «o newton—Ohm adamahnnm mo acumuemaoo .NH 0178 41 or four drops of a nitrile was shaken with concentrated sulfuric acid. the nitrile was found to be completely insoluble. The amines. on the other hand, were all found to be very easily soluble. Also, all of the amines showed infrared absorption at 3. 0 microns, indicative of a primary amine, whereas the nitriles did not. A great deal of difficulty was encountered in the preparation of derivatives of the amines. Attempts were made to prepare a number of derivatives, Among the derivatives which failed to form were picrates, acetamides, benzamides, phenylthioureas, hydrochlorides, chlorOplatinates. and a sulfate salt. Bensaldehyde and Z, 4, 7-trinitro- fluorenone also failed to react and produce a derivative. Failure also accompanied the attempt to prepare an acetamino or diacetamino derivative of the phenyl ring of the original nitrile as can be done with alkylbensenes (39. 40). With alkylbensenes this derivative is formed by dinitration of the phenyl group with concentrated nitric acid, reduction of the nitro groups to amino groups with tin and hydrochloric acid, and acetylation of the diamins. The end product from two attempts to prepare this derivative was an extremely viscous and sticky mass. For three of the amines. II. III. and IV. it was not possible to prepare any solid derivative. Reaction of amines I. V. and V1 with o-naphthyl- isocyanate produced substituted urea derivatives that were satisfactory. o-Naphthylisocyanate was permitted to react with the amine in an 8 inch test tube in a ratio of 1 mole to l. l mole (0.5 g. to 0.8 g.) of amine. Reaction took place immediately with the formation of a white precipitate and the evolution of considerable heat. The mixture was shaken with ten to fifteen ml. of ligroin to remove any excess reagent or impurities and then suction filtered. The solid material was recrystal- lised from absolute ethyl alcohol two or three times until a constant melting point was obtained. Fine white fluffy crystals were obtained. Table X lists the derivatives of the amines. 42 Table X. Derivatives Prepared W O No. n-Naphthyl M. P. . C. Nitro en Substituted Ureas Of Calculated Found I l-Amino-Z-phenyl- 147- 148 6. 73‘ 6. so Z-butylheptane V l-Amino-Z-phenyl- 206 6. 96b 7. 00 Z-(Z-methylpropyl)- 4-methylpentane VI l-Amino-Z-phenyl- 180 6. 96b 6. 93 Z-(Z'-methylpropyl)- hexane ‘Calculated for cnnuuzo. bCalculated for 03,11,190. Several unsuccessful attempts were made to prepare the a-naphthylisocyanate derivatives with amines 11. III, and IV. A white solid was obtained in each case. But this solid from all three amines sublimed in the temperature range of 275-2900. It is believed that the materials formed were the disubstituted urea formed by reaction of the reagent with water. Sym-di-a-naphthylurea is reported (45) to sublime at 280°C. It is insoluble in most of the common solvents but can be recrystallised as white needles from acetic acid. These properties are identical with those observed for the materials obtained in this work. DISCUSSION OF RESULTS 43 44 DISCUSSION OF RESULTS The monoalkylated phenylacetonitriles used in this work were prepared using sodium hydride as the basic condensing agent. Sodamide, which was used to prepare the dialkylated phenylacetonitriles, could have been used equally as well for this purpose. However, in a work designed to study some of the variables effecting the per cent yield of dialkylated product. it appeared desirable to use as the basic condensing agent. sodamide. which had been used by previous workers in this laboratory and had been shown to give the higher yield of product. Holzschuh (3) reported that the yields of products with sodamide were from 3 to 15 per cent higher than with sodium hydride. Sodamide is quite unstable in the presence of moisture and must be stored under a nitrogen atmosphere in a desiccator. On one occasion (see uni-Wyl- o-s-butylphenylacetonitrile, Table VI) alkylation was carried out with a batch of sodamide which was not so stored but which was still in granular form and very reactive to water. The yield of product was only 31.4 per cent as compared to yields of 78. 0 and 80. 9 per cent when sodamide was used from a newly Opened bottle. In the first reaction tried a monoalkylated phenylac etonitrile (a-n-amylphenyl- acetonitrile) was prepared using sodamide as the condensing agent and it appeared that considerable dialkylation occurred. Dialkylation did not take place when sodium hydride was used as the basic condensing agent in this and other alkylations of phenylacetonitrile. In general. there has been no evidence to indicate, however, that the use of sodamide causes dialkylation to occur in reactions where it would not.occur with the use of other basic condensing agents. Sodium hydride was used in the preparations of the monoalkylated phenylacetonitriles principally because of its ease of handling. 45 Worlcrnan (l) and Jacobs (2) have shown that variation of the halide in the alkyl halide has little effect upon the yield of product. Conclusions which can be drawn from the present work are: (1) Very good overall yields (Table VI) were obtained from the alkylation of monosubstituted phenylacetonitriles with alkyl chlorides. ‘ (Z) The yield of product in any one alkylation reaction is affected both by the structure of the alkyl group already located in the alpha position and by the structure of the incoming alkyl group. (3) In the alkylation of a series of monosubstituted phenylaceto- nitriles with the same alkyl halide. the yield of product is ‘ affected by the structure of the alkyl group already in the _a_1_Eh_a_position. (4) In the alkylation of the same monosubstituted phenylaceto- nitrile by various alkyl halides, the structure of the incoming alkyl group affects the yield of product. When the monosubstituted phenylacetonitrile was alkylated with n-butyl chloride. the highest yields were obtained when the alkyl group present on the nitrile was a secondary butyl group. Nearly the same yields resulted with a normal amyl group and a still substantially lower yield with an isobutyl group. In reactions where the alkyl group already located in the) _a_l_p_h_a_position was an isobutyl group. the best results were obtained when the incoming alkyl group was a secondary butyl group. Only a slightly lower yield resulted with a normal butyl group-and a um considerably lower yield with an isobutyl group. With a secondary butyl group already in the _a}p_h_a_position very good yields were obtained when the incoming group was a normal butyl group but much lower yields resulted with an incoming secondary butyl group. ‘16 Upon consideration of the structure of the alkyl group already located in the 3.121;: position when the nitrile is alkylated with n-butyl chloride and upon consideration of the structure of the incoming alkyl group in the alkylation of e-i-butylphenylacetonitrile. the order of reactivity of the various alkyl groups was the same. The secondary butyl group resulted in the highest yields of products followed closely by the normal amyl and normal butyl groups. with the isobutyl group contributing to the lowest yields. In any one alkylation reaction, both the structure of the alkyl group in the Mposition and the structure of the incoming group appeared to have an effect upon the yield of product. When the whydrogen atoms of phenylac etonitrils were replaced with two secondary butyl groups, the yield of product was the lowest. The substitution of two isobutyl groups resulted in a sub- stantially higher yield. Alkylation of a nitrile already having an isobutyl group on it with s-butyl chloride and with n-butyl chloride resulted in still considerably higher yields. The highest yields were obtained when a nitrile having a secondary butyl or normal amyl group was alkylated with n-butyl chloride. The primary reason for obtaining a high or low yield is believed to be the relative amount of steric hindrance found in the resulting disubstituted nitrile. By construction of models, the diosecondary butyl compound appeared to be by far the most hindered, the diisobutyl compound definitely less hindered. and the secondary butyl-isobutyl compound still less hindered. It has been reported (46) that alkyl monosubstituents of increasing chain length. and to a greater extent. branched chain groups. decrease the acidity of the remaining hydrogen atoms on monosubstituted acetic esters. Supposedly this would result in decreased yields in alkylation reactions. Also. the effect of reversal of order of alkylation on the yields of dialkylated phenylacetonitriles is not known. ’47 In the course of this work six previously unreported disubstituted phenylacetonitriles were prepared. It was desired to characterise these compounds in some way and the usual hydrolysis of the nitriles to amides or acids was not attempted. Nitriles having a certain degree of steric hindrance to addition type reactions to the cyano group are resistant to hydrolysis in an acid or basic medium. Newman (4) has prOposed an empirical method of estimating relative degrees of steric hindrance for such addition type reactions. In his six-number concept. the six-number of a compound denotes the number of atoms which are the sixth atom removed from the multiple bonded function (nitrogen in this case). In the case of substituted phenylacetonitriles. the carbon atoms included in the aromatic ring are not counted and the resulting number is called the eflectivisix-mber (3). The effect of the phenyl group is not known with certainty but it is believed to have a shielding effect and hindrance approximately equal to an isopropyl group in this series of nitriles. This effect was estimated by the construction of models. Workman (l, 47) and Jacobs (2. 48) were unsuccessful in their attempts to hydrolyse any nitrile with an alpha phenyl substituent and a minimum effective sin-number of 8 under various vigorous reaction conditions. Since all of the nitriles prepared in this work have effective six-numbers of 8 or greater. it was antici- pated that their hydrolyses would be unsuccessful and this method for the preparation of derivatives was not attempted. Newman at all. (49) were able to hydrolyze aliphatic nitriles possessing a six-number of 12 to the corresponding amides fairly readily. and one nitrile with a six-number of 15 was hydrolysed to its amide to a limited extent using vigorous acidic conditions. The hindered amides thus obtained were converted to their acids by means of nitrous acid in strong sulfuric acid solution. These workers also found that hindered aromatic amides 48 heated in a strong basic medium were dehydrated to their correspond- ing nitriles. That these results differ from the attempted hydrolyses of Workman and Jacobs is attributed to the difference in the terms six-number and effective six-number and the attendant unknown effect of the phenyl group. In an effort to prepare derivatives of the six new nitriles, they were each treated with lithium aluminum hydride in an ether solution in the hape of converting them to their corresponding amines. Attempts were made to prepare derivatives of the presumed amines. The preparation of a large number of derivatives was tried but the only preparation to meet with any success was that of the a-naphthylureas. The n-naphthylurea could be prepared only for those amines which possessed no _l_l_et__a- secondary butyl substituent. The inability to form any derivative from the amines obtained by reduction of e-s-butyl-e-n- butylphenylac etonitrils. e-i-butyl-a-s-butylphenylacetonitrile, and u. e-di-s-butylphenylacetonitrile and the lack of success in forming any other derivatives besides the substituted ureas of the amines of o-n-amyl-n-n-butylphenylacetonitrile. o-i-butyl-o.on-butylphenylaceto- nitrile, and a, a-di-i-butylphenylacetonitrile is attributed mainly to steric hindrance. However, there was considerable evidence that the reduction of the nitriles to the corresponding amines was not completely successful. even for those amines which formed derivatives with a-naphthylisocyanate. The calculated values for the per cent nitrogen in the nitriles and in their respective amines were too close to each other to be of practical value in distinguishing between the nitrile and the amine. The infrared spectra of samples of all the amines, except the amine of e-n-amyl-o.-n-butylphenylacetonitrile. showed the characteristic cyano absorption peak (50) at 4. 5 microns. This peak was identical with that of the nitriles. However, also present in the 49 spectra of the amines was a not so distinguishable peak of absorption at 3. 0 microns, characteristic of primary amines. This was not present in the spectra of the nitriles. An indication that the samples of amines were actually amines was that they were soluble in concen- trated sulfuric acid, whereas samples of their respective nitriles formed two layers with the same acid. It is believed that the samples of amines which showed the nitrile group absorption peak were impure samples and still contained a certain amount of unreduced nitrile. Although the percentage yield of dialkylated nitriles is believed to be determined by steric considerations, no correlation between the yield and the effective six-number of the nitrile was found, although such a correlation was observed in the alkylations of aliphatic nitriles by Newman at a}. (5). It should be pointed out that the six-number concept (4) of steric hindrance is based upon addition reactions to multiple bonded functions and not upon bimolecular nucleophilic dis- placement reactions. There is a correlation, however, between the effective six-number of the nitrile and the success or lack of success in forming derivatives from the amine. e-Naphthyl substituted ureas were formed from the amines which were derived from nitriles with an effective six-number of 8,. but not from those amines which were obtained from nitriles having an effective six-number larger than 8. SUMMARY SO l. 51 SUMMARY The alkylation of the series of alphlmonosubstituted phenyl- acetonitriles having as monosubstituents secondary butyl, normal amyl, and isobutyl groups with n-butyl chloride resulted in high overall yields of dialkylated products. The structure of the alkyl group already in the mposition definitely affected the yield of product, and the order of the effect in causing decreased yields was secondary butyl ; normal amyl > isobutyl. In the alkylation of a-i-butylphenylacetonitrile with s-butyl chloride, with n-butyl chloride and with i-butyl chloride, somewhat lower overall yields were obtained. The relationship of the structure of the alkylating agent in causing decreased yields was in the order secondary butyl ; normal butyl > isobutyl. These results are not in accord with those of Workrnan (1) who found that in alkylations of hydratroponitrile with the butyl chlorides. the order of reactivity was isobutyl ->' secondary butyl > normal butyl > > tertiary butyl. The alkylation of e-s-butylphenylacetonitrile with s-butyl chloride produced low yields of dialkylated product. In any one alkylation reaction, both the structure of the alkyl group already in the alp_h_a_ position and the structure of the incoming group had an effect upon the yield of dialkylated product. The presence of the first named group in the Mposition upon alkylation with the second named group resulted in decreased yields in the order secondary butyl-normal butyl ; normal amyl-normal butyl > isobutyl-secondary butyl 3 isobutyl-normal butyl > di- isobutyl > di-secondary butyl. 52 5. Six nitriles not previously reported in the literature have been prepared and their physical properties determined. All six nitriles were reduced to their corresponding amines with lithium aluminum hydride and the physical properties of the amines determined. Derivatives of three of the amines, namely the amines of a-n-amyl-a-n-butylphenylacetonitrile, o-i-butyl-o-n-butyl- phenylacetonitrile. and a. a-di-i-buty1phenylacetonitrile, were prepared by reaction with a-naphthylisocyanate to form the corres- ponding substituted ureas. It was not possible to form a derivative for any nitrile having a secondary butyl group attached to it. l. 53 SUGGESTIONS FOR FURTHER RESEARCH Investigate the effect of a tertiary alkyl group located in the 112131 position of phenylacetonitrile on the yield of dialkylated product. The tertiary alkyl substituted nitrile may possibly be obtained by condensation (51) of phenylacetonitrile with acetone. The resulting dimethylatrOponitrile may undergo a l, 4 addition with n-butyl magnesium bromide to form a compound that can be hydrolysed and rearranged to the desired tertiary alkyl substituted nitrile. Study the effect of reversing the order of alkylation in the prepara- tion of disubstituted phenylacetonitriles. For example, find if the alkylation of e-n-butylphenylacetonitrile with s-butyl chloride, with n-amyl chloride and with i-butyl chloride would increase or decrease the yields of disubstituted nitriles, as compared to the yields of the same nitriles prepared in this work. FIGURE I STRUCTURES OF NEW NITRILESa' I (8) < ’5‘ It all CH,-CH,-CH,-CH,-CH,—C-CN CH, CH, éH. CH: III (14) * ,, H‘f—I CH,-CH,.CH-C- -CN CH, CH- -CH, CH, CH, II (11) CH,-CH,-CH-C- CN C/H, CH, CH, CH, CH, Iv (11) CH,-CH-CH,-C- -CN CH—CH, CH, a. CH, 55 FIGURE I (Continued) STRUCTURES OF NEW NITRILESa v (8) VI (8) 4: *‘e a: son‘s CH, H H CH, H H I ' I I It! I! E * CH,-CH-CH,-C-CN H,-CH-CH,-C-CN CH, CH, |* ' * CH-JH, CH, IL H: CH, CH, CH, ‘The names of these nitriles are listed in Table VII. The Roman numeral refers to the compound in Table VII. The effective six-number is shown by the Arabic numeral in parentheses. The atoms counted as the sixth atom removed from the triple-bonded nitrogen are starred. SELECTED REFERENCES 56 10. ll. 12. 13. 14. 15. 16. 17. 18. 57 SELECTED REFERENCES W. R. Workman, M. S. Thesis, Michigan State College (1950). R. L. Jacobs, M. S. Thesis, Michigan State College (1955). A. A. Holsschuh, M. S. Thesis, Michigan State College (1955); G. L. Goerner and A. A. 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