Alkylation, Acylation and the Carbylamine Reaction of Amines

Alkylation. An amine's nucleophilic nitrogen attacks an alkyl halide in a

straightforward $S_N2$ substitution, exactly as ammonia does in ammonolysis (Section

25.5.2), and suffers from the identical problem: the alkylated product is itself

nucleophilic and reacts further with more alkyl halide, so exhaustive alkylation with

excess reagent (e.g. aniline with excess $\text{CH}_3\text{I}$) drives the reaction all

the way to the quaternary ammonium salt,

$\text{C}_6\text{H}_5\text{N}(\text{CH}_3)_3^+\ \text{I}^-$, rather than stopping

cleanly at any intermediate stage. Because of this, alkylation is rarely used

synthetically to make a specific mono-alkylated amine in good yield.

Acylation. Reaction with an acid chloride or acid anhydride (Schotten-Baumann

conditions: the acid chloride, a mild base such as aqueous $\text{NaOH}$ or pyridine to

mop up the $\text{HCl}$ by-product) gives a clean, single-substitution amide product,

because the amide nitrogen formed is FAR less nucleophilic than the starting amine (its

lone pair is delocalised into the adjacent carbonyl, exactly the resonance that also

makes amides weak bases and poor nucleophiles) -- so, unlike alkylation, the reaction

does not run past the first substitution. Acetylation of aniline

($\text{C}_6\text{H}_5\text{NH}_2 + \text{CH}_3\text{COCl} \to \text{C}_6\text{H}_5\text{NHCOCH}_3 + \text{HCl}$) is a standard step in synthesis: it

tames the ring-activating power of the free amino group (moderating it from a very

strong to a milder activator) so that subsequent electrophilic substitution, such as

nitration, can be controlled and does not over-oxidise or over-react the free amine.

The carbylamine (isocyanide) reaction. Warming a PRIMARY amine with chloroform and

alcoholic $\text{KOH}$ generates an intensely foul-smelling isocyanide:

The base first converts chloroform to dichlorocarbene ($:\text{CCl}_2$), which the …