Preparation (Gabriel, Hofmann, Reduction)

CHEClassification & Preparation

ISC asks for three clean routes to amines: Gabriel synthesis (pure primary aliphatic amines), Hofmann bromamide degradation (one carbon shorter), and reduction of nitro/nitrile/amide groups. Each has a signature reagent, a carbon-count change, and a scope limitation worth memorising.

Hofmann bromamide degradation

R\text{-}CONH_2 \xrightarrow{Br_2/4\,NaOH} R\text{-}NH_2 + Na_2CO_3 + 2\,NaBr + 2\,H_2O

the amine

R\text{-}NH_2

has one carbon fewer than the amide

Reduction of nitriles

R\text{-}CN \xrightarrow{H_2/Ni\ \text{or}\ LiAlH_4} R\text{-}CH_2NH_2

1^\circ

amine with one carbon more than the alkyl halide

RX

used to make

RCN

Reduction of nitrobenzene to aniline

C_6H_5NO_2 \xrightarrow{Sn/HCl} C_6H_5NH_2

Fe/HCl

H_2/\text{Pd}

are alternative reductants; standard route to aromatic

1^\circ

amines

Gabriel synthesis: potassium phthalimide $+ R\text{-}X \rightarrow$ N-alkylphthalimide, then alkaline hydrolysis (or hydrazinolysis) releases the pure $1^\circ$ amine $R\text{-}NH_2$ ; gives no $2^\circ$ / $3^\circ$ contamination.
Gabriel works only for $1^\circ$ amines and only with $1^\circ$ or $2^\circ$ alkyl halides; $3^\circ$ halides tend to eliminate rather than substitute.
Gabriel fails for aromatic amines (aniline): aryl halides do not undergo the required nucleophilic substitution with phthalimide ion, so the C-N bond cannot form.
Hofmann bromamide degradation: $R\text{-}CONH_2 \xrightarrow{Br_2/KOH} R\text{-}NH_2$ ; the amine has one carbon less than the amide because $R$ migrates from C to N and the carbonyl carbon is lost as carbonate.
Example: $CH_3CONH_2 \xrightarrow{Br_2/KOH} CH_3NH_2$ (acetamide $\rightarrow$ methylamine), a one-carbon step down.
Reduction of nitriles: $R\text{-}CN \xrightarrow{H_2/Ni \text{ or } LiAlH_4} R\text{-}CH_2NH_2$ , a $1^\circ$ amine with one more carbon than the alkyl halide used to make the nitrile.
Reduction of amides ( $LiAlH_4$ ) gives a $1^\circ$ amine with the same number of carbons (no carbon lost), unlike Hofmann degradation.
Reduction of nitro compounds ( $Sn/HCl$ , $Fe/HCl$ , or $H_2/\text{catalyst}$ ) is the standard route to aromatic $1^\circ$ amines: nitrobenzene $\rightarrow$ aniline.
Ammonolysis of alkyl halides ( $R\text{-}X + NH_3$ ) gives a mixture of $1^\circ$ , $2^\circ$ , $3^\circ$ amines and quaternary salt, so it is a poor route for a pure amine — Gabriel is preferred for clean $1^\circ$ .
Reductive amination (aldehyde/ketone $+ NH_3$ , then $H_2/Ni$ ) also gives $1^\circ$ amines and converts $C=O$ to $CH\text{-}NH_2$ .
Carbon-count summary: Hofmann loses one C, nitrile reduction gains one C, amide/nitro reduction keeps the same number of C — choose the route by the carbon change required.

Where the marks go

Claiming Gabriel synthesis can make aniline — it cannot, because aryl halides will not undergo $S_N2$ with the phthalimide anion.
Forgetting the one-carbon decrease in Hofmann degradation, or writing the lost carbon as $CO_2$ instead of carbonate ( $Na_2CO_3/K_2CO_3$ ) in alkaline medium.
Saying nitrile reduction gives the same carbon count — it gains one carbon ( $R\text{-}CN \rightarrow R\text{-}CH_2NH_2$ ); confusing this with amide reduction (same count) is a common slip.
Using $Sn/HCl$ on a nitrile expecting an amine in one neat step, or omitting the acidic workup detail; also do not confuse the reagent for nitro reduction with that for deamination.
Writing $2^\circ$ or $3^\circ$ amine as a Gabriel product — Gabriel gives exclusively $1^\circ$ amines because each alkylation step uses a fresh phthalimide unit.

How the board asks it

Conversionsignature reagent and carbon-count change of each route (hofmann, nitrile reduction, nitro reduction)
How will you convert: (i) acetamide into methylamine, (ii) ethyl chloride into propan-1-amine, and (iii) nitrobenzene into aniline? Write the reagents used in each step.
Predict the producthofmann bromamide degradation and nitrile reduction
Name the product and write the equation when (i) propanamide $CH_3CH_2CONH_2$ is treated with $Br_2$ and $KOH$ , and (ii) $CH_3CH_2CN$ is reduced with $LiAlH_4$ .
Give reasonsammonolysis gives a mixture whereas gabriel gives pure 1 degree amine
Give reasons: Gabriel phthalimide synthesis is preferred over ammonolysis of an alkyl halide for preparing a pure primary amine.
Give reasonsscope limitation of gabriel synthesis for aromatic amines
Account for the fact that aniline cannot be prepared by the Gabriel phthalimide synthesis, whereas $n$ -propylamine can.
Structure / namingchoosing the route from the required carbon change (hofmann loses one carbon)
An amine $X$ of formula $C_3H_9N$ is obtained from a four-carbon amide on treatment with $Br_2/KOH$ . Identify $X$ and the starting amide, and name the reaction involved.

Practise this topic

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Written for Sublevo. Question text quoted anywhere in these notes is the Council’s and carries its year and paper; the board’s own diagrams are not reproduced.