Amines are the nitrogen analogs of alcohols and ethers. The reference compound for a discussion of amines is ammonia, NH3, just as water is the reference point for talking about alcohols and ethers.
There are several ways of looking at and classifying amines. Figure 1 views amines as derivatives of ammonia in which one or more hydrogen atoms are replaced by alkyl or aryl groups.
The Amine Family
Figure 2 shows specific examples of compounds represented in Figure 1.
Representative Examples of the Amine Family
Methylamine, benzylamine, pyrrolidine, and triethylamine are all classified as aliphatic amines. This means that the carbon atoms attached to the nitrogen atom are saturated, i.e. sp3 hybridized. Figure 3 shows the structures of compounds in which at least one of the carbon atoms attached to the nitrogen is sp2 hybridized. In these compounds a lone pair of electrons on a nitrogen atom interacts with, i.e. is conjugated to, the pi system of the adjacent double bond(s).
Exercise 1 Draw the resonance contributor that results from the interaction of the lone pair of electrons on the nitrogen atom of aniline with the ortho position of the aromatic ring.
Exercise 2 How does the resonance interaction between the lone pair of electrons on the nitrogen and the adjacent double bond of the aromatic ring in aniline affect the electron density at the nitrogen? It increases the electron density around the nitrogen. It decreases the electron density around the nitrogen.
Exercise 3 What does the resonance interaction between the lone pair of electrons on the nitrogen and the adjacent double bond mean in terms of the basicity of the nitrogen? It increases the basicity of the nitrogen. It decreases the basicity ofthe nitrogen.
Exercise 4 Draw the resonance contributor that results from the interaction of the lone pair of electrons on the nitrogen atom of pyrrole with one of the double bonds of the aromatic ring.
The representation of aniline in Figure 3 is misleading since it suggests that the nitrogen is pyramidal. Various lines of evidence indicate clearly that this is not the case. In fact, the nitrogen adopts a planar geometry in order to maximize the interaction of the orbital containing the lone pair of electrons with the pi system of the phenyl ring. Figure 4 shows a ball and stick model of aniline that has been energy minimized by maximizing orbital overlap.
A Model of Aniline
One piece of chemical evidence which is suggestive of this interaction is that aniline is approximately 1,000,000 times less basic than cyclohexylamine. Since the lone pair on the nitrogen in aniline experiences greater nuclear attractions, it is less likely to be attracted to another nucleus, e.g. a proton. Figure 5 compares the acid-base equilibria for aniline and cyclohexylamine.
Acid-Base Comparison of Aromatic and Aliphatic Amines
The cyclic amines in Figure 3 are examples of heteroaromatic compounds. In these structures a lone pair of electrons on one of the nitrogen atoms conjugates to the adjacent pi system to generate a cyclic array of pi electrons that conforms to Huckel's 4n+2 rule. In pyrrole, imidazole, and pyrimidine, 4n+2=6, while in purine it equals 10. In imidazole, pyrimidine, and purine, the lone pairs on the other nitrogen atoms occupy orbitals that are co-planar with the ring.
Preparation of amines
Amines may be prepared by a variety of methods. Equation 1 indicates a 2-step approach that begins with an Sn2 reaction of an alkyl halide with cyanide ion to produce a nitrile. After isolation and appropriate characterization this compound is reduced to an amine with lithium aluminum hydride.
Exercise 5 Draw the structure of compounds 5A and 5B in the following reaction sequence:
Exercise 6 Draw the structure of compounds 6A and 6B in the following reaction sequence:
Exercise 7 Draw the structure of compounds 7A and 7B in the following reaction sequence:
The most common method for preparing aromatic amines begins with nitration of an aromatic ring. Equation 2 presents a familiar example.
Exercise 8 Draw the structure of the numbered compounds in each of the following reaction sequences.
A third method of preparing amines involves the reaction of alkyl halides with ammonia or another amine. The reaction of methyl bromide with ammonia, Equation 3, is a simple example.
While reaction 3 looks simple, it is, in fact, tricky to obtain methylamine in good yield. The reason for this is that methyl amine is more reactive than ammonia; as soon as it is formed, it reacts with methyl bromide to produce dimethylamine. This, in turn, reacts with more methyl bromide to generate trimethylamine. Ultimately, tetramethyl ammonium bromide is formed as shown in Equation 4.
The trick required to obtain monoalkylation is to use a large excess of ammonia. By using an NH3/CH3Br ratio of, say, 100/1 or 1000/1, it becomes statistically more likely that a methyl bromide molecule will encounter an ammonia molecule than a methyl amine molecule. Once all the methyl bromide has reacted, the excess ammonia, which has a lower boiling point than the methyl bromide, is boiled off, leaving the methyl amine behind. (Ammonium bromide is also left behind from the reaction of the HBr that is produced in reaction 3 with some of the excess ammonia. This is separated from the methyl bromide during the work-up of the reaction mixture.)
There are instances where multiple alkylation like that shown in reaction 4 are desireable. Equation 5 demonstrates a reaction where this "poly-alkylation" is used to advantage.
The quaternary ammonium salt, benzyltrimethylammonium bromide, is used as a phase-transfer catalyst; in reactions that are run under heterogenous conditions, it acts as a carrier, transporting reagents that are soluble in water across the aqueous/non-aqueous interface into the organic layer where they can react with a substrate that is not soluble in water. These molecules are similar to soaps and lipids in that they have a polar "head" and a non-polar "tail". Figure 6 presents a cartoon of how a quaternary ammonium salt acts to transfer cyanide ion across the boundary between an aqueous phase and a less dense organic phase containing an alkyl bromide. The non-polar "tail" of the salt projects into the non-polar organic phase, thus bringing the cationic "head" to the interface between the two layers. This, in turn, brings an anion to the interface where it is likely to encounter the alkyl bromide that is dissolved in the non-polar phase.
Breaking the Barrier
Finally, amines may be prepared by reduction of imines, which, as we have seen, are readily prepared by the reaction of aldehydes and ketones with primary amines. Equation 6 offers a simple example.
Imines may also be reduced to amines with NaBH4 or by catalytic hydrogenation. Figure 7 presents an example of the reduction of an imine with NaBH4 that played a key role in the first total synthesis of reserpine, an alkaloid obtained from Indian snakeroot Rauwolfia serpentina Benth:
Recipe for Reserpine
In the first step of the sequence shown in Figure 7, the amino group of 6-methoxytryptamine adds to the aldehydic carbon (arrow 1) of a pentasubstituted substituted cyclohexane to produce, after loss of a molecule of water, the corresponding imine. This compound was reduced directly with a methanolic solution of NaBH4. Under the reaction conditions, the resulting secondary amine attacked the adjacent carbomethoxy group (arrow 2) to form a cyclic amide.