You can best prepare a primary amine from its alkylazide by reduction or by the Gabriel synthesis. Preparation of Alkyl Halides by Nucleophilic Aliphatic Substitution. The LibreTexts libraries are Powered by MindTouch® and are supported by the Department of Education Open Textbook Pilot Project, the UC Davis Office of the Provost, the UC Davis Library, the California State University Affordable Learning Solutions Program, and Merlot. Therefore it is difficult to prepare pure amines by ammonolysis of alkyl halides. Although direct alkylation of ammonia by alkyl halides leads to 1º-amines, alternative procedures are preferred in many cases. The imine or enamine intermediates are normally not isolated, but are immediately reduced to the amine product. The Hofmann rearrangement of 1º-amides provides an additional synthesis of 1º-amines. The general strategy is to first form a carbon-nitrogen bond by reacting a nitrogen nucleophile with a carbon electrophile. Alkyl halides or benzyl halides on reaction with ethanolic solution of ammonia in a sealed tube at 373 K undergo of C – X bond and the halo group (- X) is replaced by amino group ( - NH2). >> The phthalimide method is only useful for preparing 1º-amines, whereas the sulfonamide procedure may be used to make either 1º or 2º-amines. The following table lists several general examples of this strategy in the rough order of decreasing nucleophilicity of the nitrogen reagent. There is again the possibility of a reversible reaction between this salt and excess ethylamine in the mixture. The final stage! This is where the reaction would start if you reacted a secondary amine with a halogenoalkane. Of the six methods described above, three are suitable for the preparation of 2º and/or 3º-amines. Limitations of ammonolysis It may be noted that: Aromatic amines such as phenylamine (aniline) are usually made differently and are discussed on a separate page. For example, consider a reaction between ethylamine (a primary amine) and bromoethane (a primary alkyl halide): In the first stage of the reaction, you get the salt of a secondary amine formed. To learn about this useful procedure Click Here. (1) from amides Another general method for preparing all classes of amines makes use of amide intermediates, easily made from ammonia or amines by reaction with carboxylic acid chlorides or anhydrides. Previous (ii) Ammonolysis is not suitable for preparing aryl amines because of the low reactivity of aryl halides towards nucleophilic substitutions. Here, the ammonia molecules in the first step and amine molecules in the subsequent steps act as nucleophiles. (c) Gabriel Phthalimide synthesis: this method is used to prepare pure 1˚ aliphatic amine or 1˚ aryl alkyl amine from alkyl halide or aryl alkyl halide respectively in this method phthalimide is first converted into potassium phthalimide by reaction with KOH.      (1) from amides Completing the CAPTCHA proves you are a human and gives you temporary access to the web property. According to the amount of reactants primary amine or secondary amine or tertiary amine or ammonium salt are produced. Write the reactivity order of alkyl halide for ammonolysis. One traditional approach uses phthalimide, and is called the Gabriel synthesis; a more common approach in modern synthesis is to use sodium azide followed by reduction. The product is an alkyl azide (RN3), which can be reduced in a separate step to RNH2 using excess H2/Pd or LiAlH4. Examples showing the application of these methods to the preparation of specific amines are shown in the following diagram. Preparation of amines from amides and alcohols If alkyl halide is in excess the major product is quaternary ammonium salt whereas if ethanolic ammonia is in excess the major product is primary amine. In a synthesis question we use (i) and (ii) to show that the reagents are added in two separate steps: As with the NH3 reaction described above, when amines are reacted it is common to obtain mixtures because of reactions with more than one molecule of alkyl halide   Under some circumstances it may be possible to drive the reaction as was seen in the preparation of primary amines. The ethylamine removes a hydrogen from the diethylammonium ion to give free diethylamine – a secondary amine. The reaction of a ketone with ammonia, followed by catalytic reduction or reduction by sodium cyanoborohydride, produces a 1° amine. (a) By reduction of Amides using Na/C2H5OH or LiAlH4: In this reaction amides get reduced to primary amines with the same number of carbon atoms as in parent amide If alkyl halide is in excess the major product is quaternary ammonium salt whereas if ethanolic ammonia is in excess the major product is primary amine. NaI and AgNO 3 Tests for Alkyl Halides. in situ). It may be noted that amine formed by this method has one carbon atom less than the parent amide. In the first stage, you get triethylammonium bromide. The last example (#6) shows how 4º-ammonium salts may be prepared by repeated (exhaustive) alkylation of amines. Finally, the activating group is removed by hydrolysis (phthalimide) or reductive cleavage (sulfonamide) to give the desired amine. Another way to prevent getting this page in the future is to use Privacy Pass. The alkylation of ammonia, Gabriel synthesis, reduction of nitriles, reduction of amides, reduction of nitrocompounds, and reductive amination of aldehydes and ketones are methods commonly used for preparing amines. © 2020 Houghton Mifflin Harcourt. The process of ammonolysis yields a mixture of primary, secondary, tertiary amines and quaternary salts. Nucleophile addition to aldehydes and ketones is often catalyzed by acids. The nucleophilic conjugate base of this acidic nitrogen species is then prepared by treatment with sodium or potassium hydroxide, and this undergoes an SN2 reaction with a 1º or 2º-alkyl halide. (c) Gabriel Phthalimide synthesis: this method is used to prepare pure 1˚ aliphatic amine or 1˚ aryl alkyl amine from alkyl halide or aryl alkyl halide respectively in this method phthalimide is first converted into potassium phthalimide by reaction with KOH. Unless otherwise noted, LibreTexts content is licensed by CC BY-NC-SA 3.0. For example if you started with ethylamine and bromoethane, you would get diethylammonium bromide. Cloudflare Ray ID: 5f15b300988edbdf For more information contact us at info@libretexts.org or check out our status page at https://status.libretexts.org. Watch the recordings here on Youtube! Missed the LibreFest? (iii) Aniline cannot be prepared by Gabriel synthesis: It is because of the fact that aryl halides do not undergo nucleophilic substitution reactions under ordinary conditions. Why benzenediazonium salt is stored at very low temperature? (i) Gabriel synthesis yield only 1˚ amines. The composition of the final mixture depends upon the molar ratio of alkyl halide and ammonia at the beginning of the reaction. This nitration reaction gives a nitro group that can be reduced to a 1º-amine by any of several reduction procedures. from your Reading List will also remove any Alkyl halides or benzyl halides on reaction with ethanolic solution of ammonia in a sealed tube at 373 K undergo of C – X bond and the halo group (- X) is replaced by amino group ( - NH2). (i) Ammonolysis of alkyl halides does not give single amine but gives a mixture of primary secondary and tertiary amines. The reaction of ammonia with an alkyl halide leads to the formation of a primary amine. N‐substituted amines are produced by reaction of ketones with primary amines, followed by reduction. This N‐alkyl phthalimide can be hydrolyzed by aqueous acids or bases into the primary amine. (b) By Hoffmann’s Bromamide reaction: primary (1˚) acid amides on reaction with Br2 in the presence of alkalies at about 343 K give primary amines. If the primary amine is desired, one way to avoid this is to use a large excess of NH3., so that the reaction rate with NH3 greatly exceeds the rate with the amine. Reduction of alkylazides You can best prepare a primary amine from its alkylazide by reduction or by the Gabriel synthesis. Here, the ammonia molecules in the first step and amine molecules in the subsequent steps act as nucleophiles.