W. G. Nlgh University of Puget Sound Tacoma, Washington 98416
The Gabriel Synthesis of Benzylamine An undergraduate organic experiment
The adoption of "Organic Chemistry," by Hendrickson, Cram, and Hammond ( I ) in our first year organic chemistry course presented some problems in relation to the laboratory portion of the course. Due to the text's unique approach and organization there are essentially no laboratory manuals available which are designed to parallel its presentation. Therefore, several experiments were developed in an effort to provide a greater correlation between the laboratory and lecture portions of the course. One of these experiments is described in this paper. The Gabriel synthesis involves the reaction of the conjugate base of phthalimide and an alkyl halide to give an alkyl phthalimide which is subsequently hydrolyzed to the primary alkyl amine
The reaction is important historically for the synthesis of pure primary amines uncontaminated by secondary or tertiary amine by-products. Due to its relatively mild reaction conditions and high yields, it has a wide range of synthetic applications (2). Although the reaction is discussed in nearly all beginning organic texts, there are no applicatioris of the Gabriel synthesis described in the corresponding lahoratory manuals. The reaction, however, possesses a number of advantaees which sueeest its general use in .. the student laboratory. The reaction illustrates the acidity of the N-H bond of imides (pK, 9) in contrast to the~neutrality@K, 16, .DK," 15) of amides and the basicity (pK, 33, pKb 4) of amines. Further, it represents~an example of a bimolecular nucleophilic substitution a t saturated carbon (i.e., S N ~as) weli as a nucleophilic substitution at unsaturated carbon (i.e., the B ~ c 2type). In addition to these mechanistic implications, the reaction also demonstrates the laboratory techniques involved in simple and steam distillation, filtration, extraction, and recrystallization. The Gabriel synthesis of benzylamine is based on the "Organic Syntheses" preparation of N-benzylphthalimide from phthalimide and benzyl chloride (3). The phthalimide is sufficiently acidic to he partially converted to its conjugate base by potassium carbonate. The resulting anion functions as a nucleophile in a substitution on the reactive alkyl chloride.
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670 / Journalof Chemical Education
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The efficiency of the reaction may be increased substantially by using the preformed phthalimide salt (4) and a polar aprotic solvent such as N,N-dimethylformamide (5). Under these homogeneous conditions, the reaction proceeds rapidly at temperatures below 50°C so that the suhstitution product is obtained in a higher state of purity and in a shorter period of time. However, the cost of the reagents is significantly increased and the instructional advantage of the steam distillation is lost. Hydrazinolysis (i.e., transamination) is used as an alternative to either acid- or hase-catalyzed hydrolyis of the N-benzylphthalimide. Treatment of the imide with hydrazine in methanol solution results in an initial nucleophilic substitution at one of the carbonyl groups to form acvl hvdrazide and amide erouus. Subseauent intramolec" ular nucleophilic substitutibn at the amide group leads to the formation of ohthalhvdrazide and henzvlamine. Although hydrazine is a godd nucleophile there is an additional driving force for the formation of the products. Due to the gain in resonance stability, phthalhydrazide tautomerizes to a species which exhibits phenolic type acidity and is thus readily converted tg the corresponding conjugate base by benzylamine
.
4
7 + H,NNH,
N-R 0
+
Figure 1. Infrared spectrum of benzylamine (reference peak-1949
cm-'). Addition of a strong acid converts t h e anion t o free phthalhydrazide which is water insoluble and easily removed by vacuum filtration. T h e free benzylamine is liherated fmm the filtrate by t h e addition of strong base and is readily separated by extraction with diethyl ether. T h e purified product can he easily characterized by analysis of the ir and n m r spectra a n d conversion t o t h e picrate derivative.
T h e usual procedure for t h e preparation of the picrate salts of amines involves t h e addition of t h e amine t o aqueous or ethanolic solutions of picric acid (6, 7). However, our experience has shown t h a t i t is generally difficult t o induce crystallization of t h e derivative with this procedure. This difficulty appears t o he avoided by the use of toluene solutions of picric acid. Picric acid also forms charge-transfer complexes with polynuclear aromatic hydrocarbons and aryl ethers (6). Alternately, t h e henzenesulfonamide derivative m a y he used t o characterize t h e amine. N-Benzyl henzenesulfonamide is soluble in dilute sodium hydroxide due t o its acidbond. T h i s hase-solubility of sulfonamides deic N-H rived from primary amines is t h e basis of t h e Hinsherg test which distinguishes between primary, secondary, a n d tertiary amines (6, 7).
Experimental Preparation of N-Benzyl Phthalimide Thoroughly mix 13.8 g of anhydrous potassium carbonate and 24 g of phthalimide by grinding to a very fine powder with a mortar and pestle. Transfer the mixture to a 250-ml round-bottomed flask and add 42 g of benzyl chloride. Caution, benzyl chloride is a potent lachrymator as well as being a strong skin irritant. Heat the resulting mixture at a gentle reflux for 2 hr. Set up the reaction flask for steam distillation (use two eondensers in series). Vigorously steam distill the mixture until the distillate is free of benzyl chloride. Cool the reaction mixture and break up the solid which forms into as small pieces as possible. Filter the solid, wash thoroughly with water, wash again with 40 ml of 60% aqueous ethanol, and dry as completely as possible by
Figure 2. N M R spectrum of benzylamine (TMS reference)
suction. The yield of crude product (mp 100-llO'C) is 28-31 g (72-79% yield). Preparation of Benzylamine Combine 23.7 g of N-henzyl phthalimide, 7 ml of bydrazine hydrate (85%), and 80 ml of methanol in a 250-ml round-hottorned flask and reflux the mixture for 1 hr. Caution, hydrazine is highly toxic (inhalation, ingestion, and skin absorption) in addition ta being explosive near its boiling point. A large amount of a white creamy precipitate generally separates fmm solution during the reflua. Add 18 ml of water and 27 ml of concentrated hydrochloric acid and continue to heat the mixture for another 1-2 min. Cool the reaction mixture and filter off the precipitated phthalhydrazide (mp 340-344'C). Wash the solid with a small amount of cold water. Combine the wash water and the filtrates and reduce the volume to approximately 50 ml of distillation, Use concentrated (-40%) sodium hydroxide to make the solution strongly alkaline (a second liquid phase separates) and extract the resulting mixture with two 40-ml portions of diethyl ether. Combine the ether extracts and dry them over 2-3 g of anhydrous sodium sulfate. Decant the ether from the solid and wash the desiccant once with a 10-ml portion of fresh ether. Evaporate the ether solvent and distill the residual yellow ail. Collect the fraction boiling at 183-186'C. The yield of pure benzylamine is 60-70%. Characterization
of Benzyiamine
Measure the refractive indelt (nozo 1.5401) and obtain the ir (Fig. 1) and nmr (Fig. 2) spectra of benzylamine. Assign the major peaks in each spectrum. Prepare the picrate derivative by adding five drops of benzylamine to 3 ml of a 7% solution of picric acid in toluene. Caution, pieric acid is both a strong acid and a high explosive; handle with care. If the salt does not precipitate immediately, scratch the inner wall of the test tube with a Pyrex stirring rod. Filter the yellow solid and wash it with a small amount of toluene. The product may be recrystallized from ethanol if desired. Determine the melting point of the picrate and compare it with the literature value (194°C).
Literature Cited Hammond. G. S., "Organic Chemiriry." 3rd cram. D. J.. Ed., McGraw-HillBookCo., New York, 1970. (2) Gihwn. M S . . and Bmdrhaw.R. W . , A ~ p e u Chpm . 1°C. Ed.. 7.919(19681. (3) Manake. R. H. F., in "Oraanie Syntheses," (Editoi Blatl, A. H.I. Coll. Vol 11. John Wileyand Sons. NPWYO.~, 1943.083. In Sahherg. P. L., and Supniewrki, in "Orsanic Synthere%" (Editors: Gilrnan. H.. andB1art.A. H.).Coll.Yol.1. John Wiley andSon%.NewYork. 1941. p 119. (61 Sheehan,J.C.,andBolhofer, W.A.,JAmer. Chem Soc., 72,2786(19501. 16) R I.- ... ~ u r o n .R. c.. and curtin. D. Y.. he Svirematic Identification of , ~ Shnnpr ~~~~~~~~~. , Orpganic ~ ~ ~ ~ ~ ~ Ed.. ~ ~John d ~ i l: &"s n5dsons, L hI"*:. NewYork, 1964. 17) Pasts 0. J.. and Johnson. C. R.. "Oqanic Structure Determination." PrenfieeH s l l . h e . . EngiewodCliffs. N.J., 1969. (1) Hendriekwn. J . B..
Volume 52, Number 10. October 1975 / 671
