23.2. Preparation of Amines

Nucleophilic substitution of haloalkanes

This was discussed earlier in section 9.4.

Primary amines can be synthesized by alkylation of ammonia. A large excess of ammonia is used if the primary amine is the desired product. Haloalkanes react with amines to give a corresponding alkyl-substituted amine, with the release of a halogen acid. Such reactions, which are most useful for alkyl iodides and bromides, are rarely employed because the degree of alkylation is difficult to control. If the reacting amine is tertiary, a quaternary ammonium cation results. Many quaternary ammonium salts can be prepared by this route with diverse R groups and many halide and pseudohalide anions.

When primary amines are heated with halogenoalkanes, a complicated series of reactions occurs, giving 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with bromoethane to give tetraethylammonium bromide – a quaternary ammonium salt (one in which all four hydrogens have been replaced by alkyl groups).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 (large excess) 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	S_N2	RCH₂-N₃ or R₂CH-N₃	LiAlH₄ or 4 H₂ & Pd	Hydrogenolysis	RCH₂-NH₂ or R₂CH-NH₂
C₆H₅SO₂NH^(–)	RCH₂-X or R₂CH-X	S_N2	RCH₂-NHSO₂C₆H₅ or R₂CH-NHSO₂C₆H₅	Na in NH₃ (liq)	Hydrogenolysis	RCH₂-NH₂ or R₂CH-NH₂
CN^(–)	RCH₂-X or R₂CH-X	S_N2	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⁽⁺⁾	S_N1	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 S_N2 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.

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.

Reduction of Other Functional Groups that Contain Nitrogen

Reduction of Nitro Groups

Several methods for reducing nitro groups to amines are known, and some of these were discussed at the end of section 14.2. These include catalytic hydrogenation (H₂ + Pd/C), zinc or tin in dilute HCl, and sodium sulfide in ammonium hydroxide solution.

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.

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

Reductive amination

Aldehydes and ketones can be converted into 1^o, 2^o and 3^o 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).

Hofmann rearrangement

Hofmann rearrangement, also known as Hofmann degradation and not to be confused with Hofmann elimination, is the reaction of a primary amide with a halogen (chlorine or bromine) in strongly basic (sodium or potassium hydroxide) aqueous medium, which converts the amide to a primary amine. For example: