Nitrogen Nucleophiles

The nitrogen atom of primary and secondary amines acts as a nucleophile similarly to the oxygen atom in primary and secondary alcohols. Addition of amines to a carbonyl leads to the formation of either an imine or an enamine. An imine is an organic compound containing the ${\rm{C{=}NH}}$ group or its substituted form NR that is derived from ammonia by replacement of two hydrogen atoms by a hydrocarbon group or other nonacid organic group. An enamine is an amino group containing the double-bond linkage ${\rm{C{=}C{-}N}}$. An acid catalyst is necessary to generate the formation of either an imine or an enamine; however, the pH of the reaction should be maintained around 5 and must be monitored carefully. The reaction will proceed more slowly at low pH because most of the amine starting material will also be protonated, effectively decreasing its nucleophilicity, or ability to act as a nucleophile.

In the mechanism, the oxygen atom of a carbonyl (${\rm{C{=}O}}$) is protonated, and the nucleophilic nitrogen of the amine will attack the electrophilic carbon of the carbonyl, breaking the $\pi$ bond between the carbon and the oxygen. A proton is transferred from the protonated nitrogen to the oxygen atom, converting the oxygen into a good leaving group ($-{{\rm{OH}}_2}^+$). The nitrogen then donates this electron pair to the electrophilic carbon to form a $\pi$ bond, causing the leaving group to leave. The resulting iminium ion is then deprotonated, yielding the final imine product.

The mechanism for the formation of imines, oximes, and hydrazones follows the same pathway. A hydrazone is a compound containing the group ${-}{\rm{C{=}NNHR}}$ formed by the action of hydrazine or a substituted hydrazine (such as phenylhydrazine) on a carbonyl-containing compound. A hydrazine is a derivative of NH₂NH₂, such as NH₂NHPh.

The mechanism of enamines deviates at the deprotonation step. Since enamines are generated from secondary amines (RNHR), there is not a second proton available for the deprotonation step. The only proton on the secondary amine was lost in the alcohol protonation step. The proton is provided by the alpha carbon (the carbon next to the electrophilic carbon) instead. When the alpha proton is removed, a double bond forms between the alpha carbon and the carbon of the iminium ion, and the iminium ion is converted into a tertiary amine. In addition to using nucleophilic amines to form imines, enamines, hydrazones, or oximes, nitrogen nucleophiles can also act as the intermediates in the removal of carbonyl groups using the Wolff-Kishner reduction. The Wolff-Kishner reduction is a reduction of a ketone or aldehyde to an alkane by conversion to a hydrazone followed by the addition of a strong base. The conversion of the hydrazone into nitrogen gas via the strong base is the driving force of this reaction. This reaction is typically done at high temperatures in solvents like ethylene glycol; therefore, compounds that are sensitive to heat or a strong base will not tolerate these reaction conditions.

The formation of the hydrazone is identical to the imine formation mechanism. Once the hydrazone has been formed, hydroxide (${}^{-}{\rm{OH}}$) is added. The NH₂ group of the hydrazone is deprotonated by the hydroxide. The resulting nitrogen anion is in resonance with a carbanion, which is more nucleophilic and will become protonated. A second deprotonation of the nitrogen group forms a nitrogen anion that is converted into nitrogen gas and leaves, producing a carbanion, which is protonated, yielding the final alkane product. The Wolff-Kishner reduction involves the removal of the ketone or aldehyde under basic conditions as opposed to desulfurization, which uses neutral conditions, or the Clemmensen reduction, which uses acidic conditions. The Clemmensen reduction is a reaction for converting aromatic ketones to alkanes; it does not work well with nonaromatic groups. It employs a mercury zinc amalgam and requires acidic conditions.