Amine alkylation

Amine alkylation (amino-de-halogenation) is a type of organic reaction between an alkyl halide and ammonia or an amine.^[1] The reaction is called nucleophilic aliphatic substitution (of the halide), and the reaction product is a higher substituted amine. The method is widely used in the laboratory, but is less important industrially, where alkyl halides are not preferred alkylating agents.

${\displaystyle {\ce {\underbrace {H-\!\!{\overset {\displaystyle R1 \atop |}{\underset {| \atop \displaystyle R2}{N}}}\!\!\!\!:} _{{primary\ or \atop secondary} \atop amine}}}+\underbrace {\ce {R3X}} _{{\text{halogeno-}} \atop {\text{alkane}}}{\ce {->}}\underbrace {\ce {:\!\!\!\!{\overset {\displaystyle R1 \atop |}{\underset {| \atop \displaystyle R2}{N}}}\!\!-R3}} _{\begin{matrix}{{{\text{alkyl-}} \atop {\text{substituted}}} \atop {\text{amine}}}\\{\ce {(secondary \atop or\ tertiary)}}\end{matrix}}+{\ce {\underbrace {HX} _{halogen \atop acid}}}}$

When the amine is a tertiary amine the reaction product is a quaternary ammonium salt in the Menshutkin reaction:

${\displaystyle {\ce {\underbrace {R3-\!\!{\overset {\displaystyle R1 \atop |}{\underset {| \atop \displaystyle R2}{N}}}\!\!\!\!:} _{tertiary \atop amine}}}+\underbrace {\ce {R4X}} _{{\text{halogeno-}} \atop {\text{alkane}}}{\ce {->\underbrace {\underbrace {R3-{\overset {\displaystyle R1 \atop |}{\underset {| \atop \displaystyle R2}{N+}}}\!\!-R4} _{{quaternay \atop ammonium} \atop cation}+\underbrace {X^{-}} _{halide \atop anion}} _{quaternay\ ammonium\ salt}}}}$

Amines and ammonia are generally sufficiently basic to undergo direct alkylation, often under mild conditions. The reactions are difficult to control because the reaction product (a primary amine or a secondary amine) are often more nucleophilic than the precursor and will thus preferentially react with the alkylating agent. For example, reaction of 1-bromooctane with ammonia yields almost equal amounts of the primary amine and the secondary amine.^[2] Therefore, for laboratory purposes, N-alkylation is often limited to the synthesis of tertiary amines. A notable exception is the reactivity of alpha-halo carboxylic acids that do permit synthesis of primary amines with ammonia.^[3] Intramolecular reactions of haloamines X-(CH₂)_n-NH₂ give cyclic aziridines, azetidines and pyrrolidines.

N-alkylation is a general and useful route to quaternary ammonium salts from tertiary amines, because overalkylation is not possible.

Examples of N-alkylation with alkyl halides are the syntheses of benzylaniline,^[4] 1-benzylindole,^[5][6] and azetidine.^[7] Another example is found in the derivatization of cyclen.^[8] Industrially, ethylenediamine is produced by alkylation of ammonia with 1,2-dichloroethane.

Aniline and related aryl derivatives

Traditionally, aryl halides (ArX) alkylate amines only reluctantly. The reaction usually requires "activated" aryl halides, such as those with strong electron-withdrawing groups such as nitro groups ortho or para to the halogen atom.^[9] For the arylation of amines with unactivated aryl halides, the Buchwald-Hartwig reaction is useful. In this process, palladium complexes serve as catalysts.^[10]

Alkylation using alcohols

Industrially, most alkylations are typically conducted using alcohols, not alkyl halides. Alcohols are less expensive than alkyl halides and their alkylation does not produce salts, the disposal of which can be problematic. Key to the alkylation of alcohols is the use of catalysts that render the hydroxyl group a good leaving group. The largest scale N-alkylation is the production of the methylamines from ammonia and methanol, resulting in approximately 500,000 tons/y of methylamine, dimethylamine, and trimethylamine. The reaction is poorly selective, requiring separation of the three products. Many other industrially significant alkyl amines are produced, again on a large scale, from the alcohols. Epoxides are another class of halide-free N-alkylating agents, useful in the production of ethanolamines.^[11]

Alternative alkylation methods

For laboratory use, the N-alkylation reaction is often unselective. A variety of alternative methods have been developed, such as the Delépine reaction, which uses hexamine. The Gabriel synthesis, involving the use of an equivalent to NH₂⁻, only applies to primary alkyl halides.^[12]

References

1. March, Jerry (1985), Advanced Organic Chemistry: Reactions, Mechanisms, and Structure (3rd ed.), New York: Wiley, ISBN 0-471-85472-7
2. Organic Chemistry John McMurry 2nd Ed.
3. Organic Syntheses, Coll. Vol. 1, p.48 (1941); Vol. 4, p.3 (1925). Link
4. Organic Syntheses, Coll. Vol. 1, p.102 (1941); Vol. 8, p.38 (1928). Link
5. Organic Syntheses, Coll. Vol. 6, p.104 (1988); Vol. 54, p.58 (1974). Link
6. Organic Syntheses, Coll. Vol. 6, p.106 (1988); Vol. 54, p.60 (1974). Link
7. Organic Syntheses, Coll. Vol. 6, p.75 (1988); Vol. 53, p.13 (1973). Link
8. Org. Synth. 2008, 85, 10-14 Link
9. Organic Chemistry 4th Ed. Morrison & Boyd.
10. J. F. Hartwig, "Organotransition Metal Chemistry: From Bonding to Catalysis" University Science Books, 2010. ISBN 978-1-891389-53-5.
11. Karsten Eller, Erhard Henkes, Roland Rossbacher, Hartmut Höke "Amines, Aliphatic" in Ullmann's Encyclopedia of Industrial Chemistry, Wiley-VCH, Weinheim, 2005. doi:10.1002/14356007.a02_001
12. Ervithayasuporn, V. (2012). "Synthesis and Reactivity of Nitrogen Nucleophiles-Induced Cage-Rearrangement Silsesquioxanes". Inorg. Chem. 51 (22): 12266–12272. doi:10.1021/ic3015145.