Nitrogen nucleophiles: a problem and a solution
المؤلف:
Jonathan Clayden , Nick Greeves , Stuart Warren
المصدر:
ORGANIC CHEMISTRY
الجزء والصفحة:
ص353-354
2025-05-26
513
Amines are good nucleophiles, but reactions between ammonia and alkyl halides rarely lead cleanly to single products. The problem is that the product of the substitution is at least as nucleophilic as the starting material, so it competes for reaction with the alkyl halide.
Even this is not all! The alkylation steps keep going, forming the secondary and tertiary amines, and stopping only when the non-nucleophilic tetra-alkylammonium ion R4N+ is formed. The problem is that the extra alkyl groups push more and more electron density onto N, making each product more reactive than the previous. The quaternary ammonium salt could probably be made cleanly if a large excess of alkyl halide RX is used, but other more controlled methods are needed for the synthesis of primary, secondary, and tertiary amines. One solution for primary amines is to replace ammonia with azide ion N3−.
This linear tri atomic species, nucleophilic at both ends, is a slender rod of electrons able to insert itself into almost any electrophilic site. It is available as the water-soluble sodium salt NaN3.
Azide reacts only once with alkyl halides because the product, an alkyl azide, is no longer nucleophilic. However, rarely is the azide product required: it is usually reduced to a primary amine by catalytic hydrogenation (H2 over a Pd catalyst—see Chapter 23), LiAlH4, or triphenylphosphine.
Azides react with epoxides too. This epoxide is one diastereoisomer (trans) but racemic and the symbol (±) under each structure reminds you of this (Chapter 14). Azide attacks at either end of the three-membered ring (the two ends are the same) to give the hydroxy-azide. The reaction is carried out in a mixture of water and an organic solvent with ammonium chloride as buffer to provide a proton for the intermediate. Triphenylphosphine in water is used for reduction to the primary amine.
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