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25.7 Preparation of Amines

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    28455
  • This page summarises the reactions of amines as nucleophiles. This includes their reactions with halogenoalkanes (haloalkanes or alkyl halides), with acyl chlorides (acid chlorides) and with acid anhydrides.

    Amines by direct nucleophilic substitution

    A nucleophile is something which is attracted to, and then attacks, a positive or slightly positive part of another molecule or ion. All amines contain an active lone pair of electrons on the very electronegative nitrogen atom. It is these electrons which are attracted to positive parts of other molecules or ions.

    The reactions of primary amines with halogenoalkanes

    You get a complicated series of reactions on heating to give a mixture of products - probably one of the most confusing sets of reactions you will meet at this level. The products of the reactions include secondary and tertiary amines and their salts, and quaternary ammonium salts.

    Making secondary amines and their salts

    In the first stage of the reaction, you get the salt of a secondary amine formed. For example if you started with ethylamine and bromoethane, you would get diethylammonium bromide

    In the presence of excess ethylamine in the mixture, there is the possibility of a reversible reaction. The ethylamine removes a hydrogen from the diethylammonium ion to give free diethylamine - a secondary amine.

    Making tertiary amines and their salts

    But it doesn't stop here! The diethylamine also reacts with bromoethane - in the same two stages as before. This is where the reaction would start if you reacted a secondary amine with a halogenoalkane.

    In the first stage, you get triethylammonium bromide.

    There is again the possibility of a reversible reaction between this salt and excess ethylamine in the mixture.

    The ethylamine removes a hydrogen ion from the triethylammonium ion to leave a tertiary amine - triethylamine.

    Making a quaternary ammonium salt

    The final stage! The triethylamine reacts with bromoethane to give tetraethylammonium bromide - a quaternary ammonium salt (one in which all four hydrogens have been replaced by alkyl groups).

    This time there isn't any hydrogen left on the nitrogen to be removed. The reaction stops here.

    Preparation of Primary Amines

    Although direct alkylation of ammonia by alkyl halides leads to 1º-amines, alternative procedures are preferred in many cases. These methods require two steps, but they provide pure product, usually in good yield. The general strategy is to first form a carbon-nitrogen bond by reacting a nitrogen nucleophile with a carbon electrophile. The following table lists several general examples of this strategy in the rough order of decreasing nucleophilicity of the nitrogen reagent. In the second step, extraneous nitrogen substituents that may have facilitated this bonding are removed to give the amine product.

    Nitrogen
    Reactant

    Carbon
    Reactant

    1st Reaction
    Type

    Initial Product

    2nd Reaction
    Conditions

    2nd Reaction
    Type

    Final Product

    N3(–) RCH2-X or
    R2CH-X
    SN2 RCH2-N3 or
    R2CH-N3
    LiAlH4 or
    4 H2 & Pd
    Hydrogenolysis RCH2-NH2 or
    R2CH-NH2
    C6H5SO2NH(–) RCH2-X or
    R2CH-X
    SN2 RCH2-NHSO2C6H5 or
    R2CH-NHSO2C6H5
    Na in NH3 (liq) Hydrogenolysis RCH2-NH2 or
    R2CH-NH2
    CN(–) RCH2-X or
    R2CH-X
    SN2 RCH2-CN or
    R2CH-CN
    LiAlH4 Reduction RCH2-CH2NH2 or
    R2CH-CH2NH2
    NH3 RCH=O or
    R2C=O
    Addition /
    Elimination
    RCH=NH or
    R2C=NH
    H2 & Ni
    or NaBH3CN
    Reduction RCH2-NH2 or
    R2CH-NH2
    NH3 RCOX Addition /
    Elimination
    RCO-NH2 LiAlH4 Reduction RCH2-NH2
    NH2CONH2
    (urea)
    R3C(+) SN1 R3C-NHCONH2 NaOH soln. Hydrolysis R3C-NH2

    A specific example of each general class is provided in the diagram below. In the first two, an anionic nitrogen species undergoes an SN2 reaction with a modestly electrophilic alkyl halide reactant. For example #2 an acidic phthalimide derivative of ammonia has been substituted for the sulfonamide analog listed in the table. The principle is the same for the two cases, as will be noted later. Example #3 is similar in nature, but extends the carbon system by a methylene group (CH2). In all three of these methods 3º-alkyl halides cannot be used because the major reaction path is an E2 elimination.

    aminerx1.gif

    The methods illustrated by examples #4 and #5 proceed by attack of ammonia, or equivalent nitrogen nucleophiles, at the electrophilic carbon of a carbonyl group. A full discussion of carbonyl chemistry is presented later, but for present purposes it is sufficient to recognize that the C=O double bond is polarized so that the carbon atom is electrophilic. Nucleophile addition to aldehydes and ketones is often catalyzed by acids. Acid halides and anhydrides are even more electrophilic, and do not normally require catalysts to react with nucleophiles. The reaction of ammonia with aldehydes or ketones occurs by a reversible addition-elimination pathway to give imines (compounds having a C=N function). These intermediates are not usually isolated, but are reduced as they are formed (i.e. in situ). Acid chlorides react with ammonia to give amides, also by an addition-elimination path, and these are reduced to amines by LiAlH4.
    The 6th example is a specialized procedure for bonding an amino group to a 3º-alkyl group (none of the previous methods accomplishes this). Since a carbocation is the electrophilic species, rather poorly nucleophilic nitrogen reactants can be used. Urea, the diamide of carbonic acid, fits this requirement nicely. The resulting 3º-alkyl-substituted urea is then hydrolyzed to give the amine.
    One important method of preparing 1º-amines, especially aryl amines, uses a reverse strategy. Here a strongly electrophilic nitrogen species (NO2(+)) bonds to a nucleophilic carbon compound. This nitration reaction gives a nitro group that can be reduced to a 1º-amine by any of several reduction procedures.

    The Hofmann rearrangement of 1º-amides provides an additional synthesis of 1º-amines. To learn about this useful procedure Click Here.

    Reduction of Other Functional Groups that Contain Nitrogen

    Reduction of Nitro Groups

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    Several methods for reducing nitro groups to amines are known. These include catalytic hydrogenation (H2 + catalyst), zinc or tin in dilute mineral acid, and sodium sulfide in ammonium hydroxide solution. The procedures described above are sufficient for most case

    Nitriles can be converted to 1° amines by reaction with LiAlH4

    During this reaction the hydride nucleophile attacks the electrophilic carbon in the nitrile to form an imine anion. Once stabilized by a Lewis acid-base complexation the imine salt can accept a second hydride to form a dianion. The dianion can then be converted to an amine by addition of water.

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    Amides can be converted to 1°, 2° or 3° amines using LiAlH4

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    Reductive amination

    Aldehydes and ketones can be converted into 1o, 2o and 3o amines using reductive amination. The reaction takes place in two parts. The first step is the nucleophiic addition of the carbonyl group to form an imine. The second step is the reduction of the imine to an amine using an reducing agent. A reducing agent commonly used for this reaction is sodium cyanoborohydride (NaBH3CN).

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