Chemistry of Amines

Introduction:

Amines are aliphatic and aromatic derivatives of ammonia. Amines, like ammonia, are weak bases (K_b = 10⁻⁴ to 10⁻⁶). This basicity is due to the unshared electron pair on the nitrogen atom.

Many important drugs are amines, the bases present in RNA and DNA are amines, and the fundamental building blocks of proteins are amino acids.

The functional group of an amine is the nitrogen atom connected by three sigma bonds to alkyl groups or hydrogen atoms. (Aryl groups - benzene rings - can also be connected to a nitrogen in amines, but we will not study these until later in the course.) The chemistry of amides is different enough from that of amines that they are normally not included among the amines. The nitrogen atom of an amine can also be included in a ring. Such amines are called "heterocycles." (Recall that nitrogen is a heteroatom -- not a carbon or a hydrogen.)

Amines are classified as primary, secondary, or tertiary according to the number of carbons bonded directly to the nitrogen atom. Primary amines have one carbon bonded to the nitrogen. Secondary amines have two carbons bonded to the nitrogen, and tertiary amines have three carbons bonded to the nitrogen. The system is superficially similar to the way we have classified alcohols, but the important difference is that in alcohols we were counting bonds to the carbon which carried the OH group. For amines, we are counting the carbons bonded to the nitrogen.

Since nitrogen has a normal valence of three, we can also conclude that there are two N-H bonds in primary amines and one N-H bond in secondary amines. In tertiary amines there are no N-H bonds.

Now, let's look at the bonding around the nitrogen atom of an amine. First, we need to remember that the nitrogen, in addition to forming three sigma bonds, also carries an unshared electron pair. This means that there are four groups of electrons associated with the nitrogen. Mutual repulsion of these groups leads to a tetrahedral arrangment, much like that of a typical sp³ carbon atom. This predicts a bond angle between the N-H bonds of 109.5^o which agrees pretty well with the observed value of 107^o found in ammonia (which is the "smallest" amine, like water is the smallest alcohol).

Since the bonds connected to the nitrogen are shaped like a flattened pyramid, the arrangement is often called pyramidal. This ignores the unshared electron pair, whose inclusion leads to the tetrahedral description and the corresponding understanding of the nitrogen's hybridization as sp³. The example used to illustrate this is ammonia, but the nitrogen is also well described as having sp³ hybridization primary, secondary and tertiary amines as well.

The N-H bonds in amines are somewhat polar. As we might guess from considering electronegativities (estimated from positions in the periodic table), the N-H bond is more polar than the C-H bond and less polar than the O-H bond. This polarity shows up in a comparision of physical properties of amines and alcohols.

The simplest examples are water and ammonia. Water boils at 100^oC, while ammonia boils at -33^oC. This is interpreted to mean that it takes a good deal more energy to boil water than ammonia. Correspondingly, the forces between molecules

of water (which resist separating them in the boiling process) are much stronger than those between molecules of ammonia. The most important of these forces is called the hydrogen bond.

The hydrogen bond is much weaker than a covalent bond. Breaking a hydrogen bond requires about 10% of the energy required to break a typical covalent bond. This is consistent with the fact that we can boil water without breaking any covalent bonds (the water molecules remain intact). Separation of one molecule from another only requires breaking the weaker hydrogen bonds.

One useful picture of a hydrogen bond is electrostatic -- an attraction between the positive end of a dipole on one molecule and the negative end of a dipole on another. The more polar the molecules, the greater the degree of positive and negative charge associated with the dipoles, and the stronger the hydrogen bonds. In ammonia and water, the most concentrated and available negatively charged region is where the unshared electron pair is. The positively charged regions are the hydrogen ends of the N-H bonds. We can envision the hydrogen bond as a weak (compared to covalent bonds) attraction between the unshared electron pairs on of a nitrogen in one molecule and a hydrogen (covalently bonded to nitrogen) on another.

Hydrogen bonds are extremely important in the chemistry of the genetic code. As we will study later, the double strands of DNA are held together by hydrogen bonds. The replication of DNA depends on hydrogen bonds which selectively connect specific base pairs, as do the several steps by which the genetic message determines the specific order of amino acids in a protein.

The distinguishing chemical property of amines is that they are bases. This is a direct consequence of the presence of the unshared electron pair on the nitrogen, which makes them Lewis bases. The basic unshared electron pair is less tightly held by the nitrogen of an amine than the corresponding oxygen of an alcohol, which makes it more available to act as a base. Consequently amines (and ammonia) are more basic than alcohols (and water), and less basic than alkoxide (RO^-) and hydroxide (OH^-) ions. It is convenient to think about the base strength of amines and ammonia in terms of the pK_a of their conjugate acids, the ammonium ions. These ideas can be summarized in the following scheme, where we use water and ammonia as stand-ins for alcohols and amines:

As we have come to expect, these reactions go in the direction which consumes the stronger bases and acids and generates the weaker ones. Ammonium ions (pK_a ~10) are stronger acids than water (pK_a ~16, so water is produced when an ammonium ion is treated with hydroxide ion. Ammonium ions (pK_a ~10) are weaker acids than H₃O⁺ (pK_a ~-2), so they are produced when amines are treated with aqueous solutions of strong mineral acids like sulfuric or hydrochloric acids. If the water is removed, there remains an ammonium salt which incorporates the negative counterion of the mineral acid (sulfate or chloride).

Since the basic properties of amines arise from the presence of the unshared electron pair on nitrogen, the strengths of primary, secondary and tertiary amines are quite similar. Aryl amines (those where the nitrogen is connected directly to an aromatic amine) weaker bases, but we will take that topic up later in the course.

 

 

The IUPAC names are listed first and colored blue. This system names amine functions as substituents on the largest alkyl group. The simple -NH₂ substituent found in 1º-amines is called an amino group. For 2º and 3º-amines a compound prefix (e.g. dimethylamino in the fourth example) includes the names of all but the root alkyl group.
The Chemical Abstract Service has adopted a nomenclature system in which the suffix -amine is attached to the root alkyl name. For 1º-amines such as butanamine (first example) this is analogous to IUPAC alcohol nomenclature (-ol suffix). The additional nitrogen substituents in 2º and 3º-amines are designated by the prefix N- before the group name. These CA names are colored magenta in the diagram.
Finally, a common system for simple amines names each alkyl substituent on nitrogen in alphabetical order, followed by the suffix -amine. These are the names given in the last row (colored black).
Many aromatic and heterocyclic amines are known by unique common names, the origins of which are often unknown to the chemists that use them frequently. Since these names are not based on a rational system, it is necessary to memorize them. There is a systematic nomenclature of heterocyclic compounds, but it will not be discussed here.

Natural Nitrogen Compounds

Nature abounds with nitrogen compounds, many of which occur in plants and are referred to as alkaloids. Structural formulas for some representative alkaloids and other nitrogen containing natural products are displayed below, and we can recognize many of the basic structural features listed above in their formulas. Thus, Serotonin and Thiamine are 1º-amines, Coniine is a 2º-amine, Atropine, Morphine and Quinine are 3º-amines, and Muscarine is a 4º-ammonium salt.

Back to the Top

 

Nomenclature

In the IUPAC system of nomenclature, functional groups are normally designated in one of two ways. The presence of the function may be indicated by a characteristic suffix and a location number. This is common for the carbon-carbon double and triple bonds which have the respective suffixes ene and yne. Halogens, on the other hand, do not have a suffix and are named as substituents, for example: (CH₃)₂C=CHCHClCH₃ is 4-chloro-2-methyl-2-pentene. If you are uncertain about the IUPAC rules for nomenclature you should review them now.
Amines are derivatives of ammonia in which one or more of the hydrogens has been replaced by an alkyl or aryl group. The nomenclature of amines is complicated by the fact that several different nomenclature systems exist, and there is no clear preference for one over the others. Furthermore, the terms primary (1º), secondary (2º) & tertiary (3º) are used to classify amines in a completely different manner than they were used for alcohols or alkyl halides. When applied to amines these terms refer to the number of alkyl (or aryl) substituents bonded to the nitrogen atom, whereas in other cases they refer to the nature of an alkyl group. The four compounds shown in the top row of the following diagram are all C₄H₁₁N isomers. The first two are classified as 1º-amines, since only one alkyl group is bonded to the nitrogen; however, the alkyl group is primary in the first example and tertiary in the second. The third and fourth compounds in the row are 2º and 3º-amines respectively. A nitrogen bonded to four alkyl groups will necessarily be positively charged, and is called a 4º-ammonium cation. For example, (CH₃)₄N⁽⁺⁾ Br^(–) is tetramethylammonium bromide.

In the IUPAC System, apply the following rules to name amines:

 Pick out the longest continuous chain of carbon atoms. The parent name comes from the alkane of the same number of carbons.

 Change the -e of the alkane to “amine.”

 Locate and name any substituents, keeping in mind that the chain is numbered away from the amine group. Substituents, which are attached to the nitrogen atom instead of the carbon of the chain, are designated by a capital N.

Aromatic amines belong to specific families, which act as parent molecules. For example, an amino group (—NH₂) attached to benzene produces the parent compound aniline.

The IUPAC names are listed first and colored blue. This system names amine functions as substituents on the largest alkyl group. The simple -NH₂ substituent found in 1º-amines is called an amino group. For 2º and 3º-amines a compound prefix (e.g. dimethylamino in the fourth example) includes the names of all but the root alkyl group.
The Chemical Abstract Service has adopted a nomenclature system in which the suffix -amine is attached to the root alkyl name. For 1º-amines such as butanamine (first example) this is analogous to IUPAC alcohol nomenclature (-ol suffix). The additional nitrogen substituents in 2º and 3º-amines are designated by the prefix N- before the group name. These CA names are colored magenta in the diagram.
Finally, a common system for simple amines names each alkyl substituent on nitrogen in alphabetical order, followed by the suffix -amine. These are the names given in the last row (colored black).
Many aromatic and heterocyclic amines are known by unique common names, the origins of which are often unknown to the chemists that use them frequently. Since these names are not based on a rational system, it is necessary to memorize them. There is a systematic nomenclature of heterocyclic compounds, but it will not be discussed here.

Natural Nitrogen Compounds

Nature abounds with nitrogen compounds, many of which occur in plants and are referred to as alkaloids. Structural formulas for some representative alkaloids and other nitrogen containing natural products are displayed below, and we can recognize many of the basic structural features listed above in their formulas. Thus, Serotonin and Thiamine are 1º-amines, Coniine is a 2º-amine, Atropine, Morphine and Quinine are 3º-amines, and Muscarine is a 4º-ammonium salt.

The reader should be able to recognize indole, imidazole, piperidine, pyridine, pyrimidine & pyrrolidine moieties among these structures. These will be identified by pressing the "Show Structures" button under the diagram.

Nitrogen atoms that are part of aromatic rings , such as pyridine, pyrrole & imidazole, have planar configurations (sp² hybridization), and are not stereogenic centers. Nitrogen atoms bonded to carbonyl groups, as in caffeine, also tend to be planar. In contrast, atropine, coniine, morphine, nicotine and quinine have stereogenic pyramidal nitrogen atoms in their structural formulas (think of the non-bonding electron pair as a fourth substituent on a sp³ hybridized nitrogen). In quinine this nitrogen is restricted to one configuration by the bridged ring system. The other stereogenic nitrogens are free to assume two pyramidal configurations, but these are in rapid equilibrium so that distinct stereoisomers reflecting these sites cannot be easily isolated.
It should be noted that structural factors may serve to permit the resolution of pyramidal chiral amines. Two examples of such 3º-amines, compared with similar non-resolvable analogs, are shown in the following diagram. The two nitrogen atoms in Trögers base are the only stereogenic centers in the molecule. Because of the molecule's bridged structure, the nitrogens have the same configuration and cannot undergo inversion. The chloro aziridine can invert, but requires a higher activation energy to do so, compared with larger heterocyclic amines. It has in fact been resolved, and pure enantiomers isolated. An increase in angle strain in the sp²-hybridized planar transition state is responsible for the greater stability of the pyramidal configuration. The rough estimate of angle strain is made using a C-N-C angle of 60º as an arbitrary value for the three-membered heterocycle.

Of course, quaternary ammonium salts, such as that in muscarine, have a tetrahedral configuration that is incapable of inversion. With four different substituents, such a nitrogen would be a stable stereogenic center.

 

Back to the Top

 

2. A Structure Formula Relationship

Recall that the molecular formula of a hydrocarbon (C_nH_m) provides information about the number of rings and/or double bonds that must be present in its structural formula. In the formula shown below a triple bond is counted as two double bonds.

Rings + Double Bonds in a CnHm Hydrocarbon = (2n + 2 - m) 2

Compound Molecular Formula Revised Formula Calculated Rings + C=Z Coniine C8H17N C9H18 1 Nicotine C10H14N2 C12H16 5 Morphine C17H19NO3 C18H20 9

This molecular formula analysis may be extended beyond hydrocarbons by a few simple corrections. These are illustrated by the examples in the table above, taken from the previous list of naturally occuring amines.
          • The presence of oxygen does not alter the relationship.
          • All halogens present in the molecular formula must be replaced by hydrogen.
          • Each nitrogen in the formula must be replaced by a CH moiety.

Properties of Amines

1. Boiling Point and Water Solubility

It is instructive to compare the boiling points and water solubility of amines with those of corresponding alcohols and ethers. The dominant factor here is hydrogen bonding, and the first table below documents the powerful intermolecular attraction that results from -O-H---O- hydrogen bonding in alcohols (light blue columns). Corresponding -N-H---N- hydrogen bonding is weaker, as the lower boiling boints of similarly sized amines (light green columns) demonstrate. Alkanes provide reference compounds in which hydrogen bonding is not possible, and the increase in boiling point for equivalent 1º-amines is roughly half the increase observed for equivalent alcohols.

Compound	CH3CH3	CH3OH	CH3NH2	CH3CH2CH3	CH3CH2OH	CH3CH2NH2
Mol.Wt.	30	32	31	44	46	45
Boiling Point ºC	-88.6º	65º	-6.0º	-42º	78.5º	16.6º

The second table illustrates differences associated with isomeric 1º, 2º & 3º-amines, as well as the influence of chain branching. Since 1º-amines have two hydrogens available for hydrogen bonding, we expect them to have higher boiling points than isomeric 2º-amines, which in turn should boil higher than isomeric 3º-amines (no hydrogen bonding). Indeed, 3º-amines have boiling points similar to equivalent sized ethers; and in all but the smallest compounds, corresponding ethers, 3º-amines and alkanes have similar boiling points. In the examples shown here, it is further demonstrated that chain branching reduces boiling points by 10 to 15 ºC.

Compound	CH3(CH2)2CH3	CH3(CH2)2OH	CH3(CH2)2NH2	CH3CH2NHCH3	(CH3)3CH	(CH3)2CHOH	(CH3)2CHNH2	(CH3)3N
Mol.Wt.	58	60	59	59	58	60	59	59
Boiling Point ºC	-0.5º	97º	48º	37º	-12º	82º	34º	3º

Solubility in water

The small amines of all types are very soluble in water. In fact, the ones that would normally be found as gases at room temperature are normally sold as solutions in water - in much the same way that ammonia is usually supplied as ammonia solution.

All of the amines can form hydrogen bonds with water - even the tertiary ones.

Although the tertiary amines don't have a hydrogen atom attached to the nitrogen and so can't form hydrogen bonds with themselves, they can form hydrogen bonds with water molecules just using the lone pair on the nitrogen.

Solubility falls off as the hydrocarbon chains get longer - noticeably so after about 6 carbons. The hydrocarbon chains have to force their way between water molecules, breaking hydrogen bonds between water molecules.

However, they don't replace them by anything as strong, and so the process of forming a solution becomes less and less energetically feasible as chain length grows.

The water solubility of 1º and 2º-amines is similar to that of comparable alcohols. As expected, the water solubility of 3º-amines and ethers is also similar. These comparisons, however, are valid only for pure compounds in neutral water. The basicity of amines (next section) allows them to be dissolved in dilute mineral acid solutions, and this property facilitates their separation from neutral compounds such as alcohols and hydrocarbons by partitioning between the phases of non-miscible solvents.

 Back to the Top

 

2. Basicity of Amines

Like ammonia, most amines are Brønsted and Lewis bases, but their base strength can be changed enormously by substituents. It is common to compare basicities quantitatively by using the pK_a's of their conjugate acids rather than their pK_b's. Since pK_a + pK_b = 14, the higher the pK_a the stronger the base, in contrast to the usual inverse relationship of pK_a with acidity. Most simple alkyl amines have pK_a's in the range 9.5 to 11.0, and their water solutions are basic (have a pH of 11 to 12, depending on concentration). The first four compounds in the following table, including ammonia, fall into that category.
The last five compounds (colored cells) are significantly weaker bases as a consequence of three factors. The first of these is the hybridization of the nitrogen. In pyridine the nitrogen is sp² hybridized, and in nitriles (last entry) an sp hybrid nitrogen is part of the triple bond. In each of these compounds (shaded red) the non-bonding electron pair is localized on the nitrogen atom, but increasing s-character brings it closer to the nitrogen nucleus, reducing its tendency to bond to a proton.

Compound				NH; NH; NH3						CH3C≡N
pKa	11.0	10.7	10.7	9.3	5.2	4.6	1.0	0.0	-1.0	-10.0

 

Secondly, aniline and p-nitroaniline (first two green shaded structures) are weaker bases due to delocalization of the nitrogen non-bonding electron pair into the aromatic ring (and the nitro substituent). This is the same delocalization that results in activation of a benzene ring toward electrophilic substitution. The following resonance equations, which are similar to those used to explain the enhanced acidity of ortho and para-nitrophenols illustrate electron pair delocalization in p-nitroaniline. Indeed, aniline is a weaker base than cyclohexyl amine by roughly a million fold, the same factor by which phenol is a stronger acid than cyclohexanol. This electron pair delocalization is accompanied by a degree of rehybridization of the amino nitrogen atom, but the electron pair delocalization is probably the major factor in the reduced basicity of these compounds. A similar electron pair delocalization is responsible for the very low basicity (and nucleophilic reactivity) of amide nitrogen atoms (last green shaded structure). This feature was instrumental in moderating the influence of amine substituents on aromatic ring substitution, and will be discussed further in the section devoted to carboxylic acid derivatives.

The influence of a conjugated amine group on the basicity of an existing amine will be displayed. Although 4-dimethylaminopyridine (DMAP) might appear to be a base similar in strength to pyridine or N,N-dimethylaniline, it is actually more than ten thousand times stronger, thanks to charge delocalization in its conjugate acid. The structure in the gray box shows the locations over which positive charge (colored red) is delocalized in the conjugate acid. This compound is often used as a catalyst for acyl transfer reactions.
Finally, the very low basicity of pyrrole (shaded blue) reflects the exceptional delocalization of the nitrogen electron pair associated with its incorporation in an aromatic ring. Indole (pK_a = -2) and imidazole (pK_a = 7.0), see above, also have similar heterocyclic aromatic rings. Imidazole is over a million times more basic than pyrrole because the sp² nitrogen that is part of one double bond is structurally similar to pyridine, and has a comparable basicity.

Although resonance delocalization generally reduces the basicity of amines, a dramatic example of the reverse effect is found in the compound guanidine (pK_a = 13.6). Here, as shown below, resonance stabilzation of the base is small, due to charge separation, while the conjugate acid is stabilized strongly by charge delocalization. Consequently, aqueous solutions of guanidine are nearly as basic as are solutions of sodium hydroxide.

The relationship of amine basicity to the acidity of the corresponding conjugate acids may be summarized in a fashion analagous to that noted earlier for acids.

Strong bases have weak conjugate acids, and weak bases have strong conjugate acids.

3. Acidity of Amines

We normally think of amines as bases, but it must be remembered that 1º and 2º-amines are also very weak acids (ammonia has a pK_a = 34). In this respect it should be noted that pK_a is being used as a measure of the acidity of the amine itself rather than its conjugate acid, as in the previous section. For ammonia this is expressed by the following hypothetical equation:

NH₃   +   H₂O  ——>   NH₂^(–)   +   H₂O-H⁽⁺⁾

The same factors that decreased the basicity of amines increase their acidity. This is illustrated by the following examples, which are shown in order of increasing acidity. It should be noted that the first four examples have the same order and degree of increased acidity as they exhibited decreased basicity in the previous table. The first compound is a typical 2º-amine, and the three next to it are characterized by varying degrees of nitrogen electron pair delocalization. The last two compounds (shaded blue) show the influence of adjacent sulfonyl and carbonyl groups on N-H acidity. From previous discussion it should be clear that the basicity of these nitrogens is correspondingly reduced.

Compound					C6H5SO2NH2
pKa	33	27	19	15	10	9.6

The acids shown here may be converted to their conjugate bases by reaction with bases derived from weaker acids (stronger bases). Three examples of such reactions are shown below, with the acidic hydrogen colored red in each case. For complete conversion to the conjugate base, as shown, a reagent base roughly a million times stronger is required.

C6H5SO2NH2   +   KOH   ——>  C6H5SO2NH(–) K(+)   +   H2O	a sulfonamide base
(CH3)3COH   +   NaH   ——>  (CH3)3CO(–) Na(+)   +   H2	an alkoxide base
(C2H5)2NH   +   C4H9Li   ——>  (C2H5)2N(–) Li(+)   +   C4H10	an amide base

4. Important Reagent Bases

The significance of all these acid-base relationships to practical organic chemistry lies in the need for organic bases of varying strength, as reagents tailored to the requirements of specific reactions. The common base sodium hydroxide is not soluble in many organic solvents, and is therefore not widely used as a reagent in organic reactions. Most base reagents are alkoxide salts, amines or amide salts. Since alcohols are much stronger acids than amines, their conjugate bases are weaker than amide bases, and fill the gap in base strength between amines and amide salts. In the following table, pK_a again refers to the conjugate acid of the base drawn above it.

Base Name	Pyridine	Triethyl Amine	Hünig's Base	DBU	Barton's Base	Potassium t-Butoxide	Sodium HMDS	LDA
Formula		(C2H5)3N				(CH3)3CO(–) K(+)	[(CH3)3Si]2N(–) Na(+)	[(CH3)2CH]2N(–) Li(+)
pKa	5.3	10.7	11.4	12	14	19	26	35.7

Pyridine is commonly used as an acid scavenger in reactions that produce mineral acid co-products. Its basicity and nucleophilicity may be modified by steric hindrance, as in the case of 2,6-dimethylpyridine (pK_a=6.7), or resonance stabilization, as in the case of 4-dimethylaminopyridine (pK_a=9.7). Hünig's base is relatively non-nucleophilic (due to steric hindrance), and like DBU is often used as the base in E2 elimination reactions conducted in non-polar solvents. Barton's base is a strong, poorly-nucleophilic, neutral base that serves in cases where electrophilic substitution of DBU or other amine bases is a problem. The alkoxides are stronger bases that are often used in the corresponding alcohol as solvent, or for greater reactivity in DMSO. Finally, the two amide bases see widespread use in generating enolate bases from carbonyl compounds and other weak carbon acids.

Back to the Top

Preparing amines from halogenoalkanes

The halogenoalkane is heated with a concentrated solution of ammonia in ethanol. The reaction is carried out in a sealed tube. You couldn't heat this mixture under reflux, because the ammonia would simply escape up the condenser as a gas.

We'll talk about the reaction using 1-bromoethane as a typical halogenoalkane.

You get a mixture of amines formed together with their salts. The reactions happen one after another.

 

Preparing a primary amine

The reaction happens in two stages. In the first stage, a salt is formed - in this case, ethylammonium bromide. This is just like ammonium bromide, except that one of the hydrogens in the ammonium ion is replaced by an ethyl group.

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

The ammonia removes a hydrogen ion from the ethylammonium ion to leave a primary amine - ethylamine.

The more ammonia there is in the mixture, the more the forward reaction is favoured.

Note:  You will find considerable disagreement in textbooks and other sources about the exact nature of the products in this reaction. Some of the information you'll come across is simply wrong!

Warning!  That page is in the mechanism section of the site. Return to the current page using the BACK button on your browser. If you use the links at the bottom of that page, you could get seriously lost!

Preparing a secondary amine

The reaction doesn't stop at a primary amine. The ethylamine also reacts with bromoethane - in the same two stages as before.

In the first stage, you get a salt formed - this time, diethylammonium bromide. Think of this as ammonium bromide with two hydrogens replaced by ethyl groups.

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

The ammonia removes a hydrogen ion from the diethylammonium ion to leave a secondary amine - diethylamine. A secondary amine is one which has two alkyl groups attached to the nitrogen.

Back to the Top

 

Preparing a tertiary amine

And still it doesn't stop! The diethylamine also reacts with bromoethane - in the same two stages as before.

In the first stage, you get triethylammonium bromide.

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

The ammonia removes a hydrogen ion from the triethylammonium ion to leave a tertiary amine - triethylamine. A tertiary amine is one which has three alkyl groups attached to the nitrogen.

 

Preparing 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.

Note:  This whole reaction sequence is a complete pain if you are going to have to learn it. It is much, much easier to work it out if you need to, provided you understand the mechanisms for the reactions.

You can explore the mechanisms for the various stages of the reaction by following this link. This will lead you to several pages in the mechanism section of this site. If all you want to do is make some sense of the above reactions, it would probably pay you to just read the parts of those pages concerned with primary halogenoalkanes like bromoethane.

React bromoethane with ammonia:

 A mixture of all of the products (including the various amines and their salts) shown on this page.

To get mainly the quaternary ammonium salt, you can use a large excess of bromoethane. If you look at the reactions going on, each one needs additional bromoethane. If you provide enough, then the chances are that the reaction will go to completion, given enough time.

On the other hand, if you use a very large excess of ammonia, the chances are always greatest that a bromoethane molecule will hit an ammonia molecule rather than one of the amines being formed. That will help to prevent the formation of secondary (etc) amines - although it won't stop it entirely.

Preparing primary amines from nitriles

Nitriles are compounds containing the -CN group, and can be reduced in various ways. Two possible methods are described here.

 

Reducing nitriles using LiAlH₄

One possible reducing agent is lithium tetrahydridoaluminate(III) - often just called lithium tetrahydridoaluminate or lithium aluminium hydride.

The nitrile reacts with the lithium tetrahydridoaluminate in solution in ethoxyethane (diethyl ether, or just "ether") followed by treatment of the product of that reaction with a dilute acid.Overall, the carbon-nitrogen triple bond is reduced to give a primary amine.For example, with ethanenitrile you get ethylamine:

Notice that this is a simplified equation - perfectly acceptable to UK A level examiners. [H] means "hydrogen from a reducing agent".

Note:  If you know about the reduction of aldehydes and ketones, you may know that they are also reduced by the similar compound NaBH₄.

However, NaBH₄ isn't a strong enough reducing agent to reduce nitriles the reduction of nitriles using hydrogen and a metal catalyst The carbon-nitrogen triple bond in a nitrile can also be reduced by reaction with hydrogen gas in the presence of a variety of metal catalysts.Commonly quoted catalysts are palladium, platinum or nickel.

The reaction will take place at a raised temperature and pressure. It is impossible to give exact details because it will vary from catalyst to catalyst.For example, ethanenitrile can be reduced to ethylamine by reaction with hydrogen in the presence of a palladium catalyst.

Note:  Notice that this time the hydrogen is written normally as H₂. This is a proper equation involving hydrogen gas - not a simplification

Back to the Top

 

Reactions of Amines

1. Electrophilic Substitution at Nitrogen

Ammonia and many amines are not only bases in the Brønsted sense, they are also nucleophiles that bond to and form products with a variety of electrophiles. A general equation for such electrophilic substitution of nitrogen is:

2 R2ÑH   +   E(+)   ——>  R2NHE(+)   ——>  R2ÑE  +   H(+) (bonded to a base)

A list of some electrophiles that are known to react with amines is shown here. In each case the electrophilic atom or site is colored red.

Electrophile	RCH2–X	RCH2–OSO2R	R2C=O	R(C=O)X	RSO2–Cl	HO–N=O
Name	Alkyl Halide	Alkyl Sulfonate	Aldehyde   or Ketone	Acid Halide or Anhydride	Sulfonyl Chloride	Nitrous Acid

Alkylation

It is instructive to examine these nitrogen substitution reactions, using the common alkyl halide class of electrophiles. Thus, reaction of a primary alkyl bromide with a large excess of ammonia yields the corresponding 1º-amine, presumably by a S_N2 mechanism. The hydrogen bromide produced in the reaction combines with some of the excess ammonia, giving ammonium bromide as a by-product. Water does not normally react with 1º-alkyl halides to give alcohols, so the enhanced nucleophilicity of nitrogen relative to oxygen is clearly demonstrated.

2 RCH2Br  +  NH3 (large excess)   ——>  RCH2NH2  +  NH4(+) Br(–)

It follows that simple amines should also be more nucleophilic than their alcohol or ether equivalents. If, for example, we wish to carry out a S_N2 reaction of an alcohol with an alkyl halide to produce an ether (the Williamson synthesis), it is necessary to convert the weakly nucleophilic alcohol to its more nucleophilic conjugate base for the reaction to occur. In contrast, amines react with alkyl halides directly to give N-alkylated products. Since this reaction produces HBr as a co-product, hydrobromide salts of the alkylated amine or unreacted starting amine (in equilibrium) will also be formed.

2 RNH2  +  C2H5Br  ——>  RNHC2H5  +  RNH3(+) Br(–)  ——>  RNH2C2H5(+) Br(–)  +  RNH2

Unfortunately, the direct alkylation of 1º or 2º-amines to give a more substituted product does not proceed cleanly. If a 1:1 ratio of amine to alkyl halide is used, only 50% of the amine will react because the remaining amine will be tied up as an ammonium halide salt (remember that one equivalent of the strong acid HX is produced). If a 2:1 ratio of amine to alkylating agent is used, as in the above equation, the HX issue is solved, but another problem arises. Both the starting amine and the product amine are nucleophiles. Consequently, once the reaction has started, the product amine competes with the starting material in the later stages of alkylation, and some higher alkylated products are also formed. Even 3º-amines may be alkylated to form quaternary (4º) ammonium salts. When tetraalkyl ammonium salts are desired, as shown in the following example, Hünig's base may be used to scavange the HI produced in the three S_N2 reactions. Steric hindrance prevents this 3º-amine (Hünig's base) from being methylated.

C6H5NH2  +  3 CH3I  +   Hünig's base  ——>  C6H5N(CH3)3(+) I(–)  +  HI salt of Hünig's base

Reaction with Benzenesulfonyl chloride (The Hinsberg test)

Another electrophilic reagent, benzenesulfonyl chloride, reacts with amines in a fashion that provides a useful test for distinguishing primary, secondary and tertiary amines (the Hinsberg test). As shown in the following equations, 1º and 2º-amines react to give sulfonamide derivatives with loss of HCl, whereas 3º-amines do not give any isolable products other than the starting amine. In the latter case a quaternary "onium" salt may be formed as an intermediate, but this rapidly breaks down in water to liberate the original 3º-amine (lower right equation).

The Hinsberg test is conducted in aqueous base (NaOH or KOH), and the benzenesulfonyl chloride reagent is present as an insoluble oil. Because of the heterogeneous nature of this system, the rate at which the sulfonyl chloride reagent is hydrolyzed to its sulfonate salt in the absence of amines is relatively slow. The amine dissolves in the reagent phase, and immediately reacts (if it is 1º or 2º), with the resulting HCl being neutralized by the base. The sulfonamide derivative from 2º-amines is usually an insoluble solid. However, the sulfonamide derivative from 1º-amines is acidic and dissolves in the aqueous base. Acidification of this solution then precipitates the sulfonamide of the 1º-amine.

Reaction with aldehydes and ketones

Aldehydes and ketones react with primary amines to give a reaction product (a carbinolamine) that dehydrates to yield aldimines and ketimines (Schiff bases).

If you react secondary amines with aldehydes or ketones, enamines form.

Reaction with sulfonyl chlorides

Amines react with sulfonyl chlorides to produce sulfonamides. A typical example is the reaction of benzene sulfonyl chloride with aniline.

 

Back to the Top

 

2. Preparation of 1º-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.

Example	Nitrogen Reactant	Carbon Reactant	1st Reaction Type	Initial Product	2nd Reaction Conditions	2nd Reaction Type	Final Product
1.	N3(–)	RCH2-X or R2CH-X	SN2	RCH2-N3 or R2CH-N3	LiAlH4 or 4 H2 & Pd	Hydrogenolysis	RCH2-NH2 or R2CH-NH2
2.	C6H5SO2NH(–)	RCH2-X or R2CH-X	SN2	RCH2-NHSO2C6H5 or R2CH-NHSO2C6H5	Na in NH3 (liq)	Hydrogenolysis	RCH2-NH2 or R2CH-NH2
3.	CN(–)	RCH2-X or R2CH-X	SN2	RCH2-CN or R2CH-CN	LiAlH4	Reduction	RCH2-CH2NH2 or R2CH-CH2NH2
4.	NH3	RCH=O or R2C=O	Addition / Elimination	RCH=NH or R2C=NH	H2 & Ni or NaBH3CN	Reduction	RCH2-NH2 or R2CH-NH2
5.	NH3	RCOX	Addition / Elimination	RCO-NH2	LiAlH4	Reduction	RCH2-NH2
6.	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 a 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.

Back to the Top

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.

3. Preparation of 2º & 3º-Amines

Of the six methods described above, three are suitable for the preparation of 2º and/or 3º-amines. These are:
          (i) Alkylation of the sulfonamide derivative of a 1º-amine. Gives 2º-amines.
          (ii) Reduction of alkyl imines and dialkyl iminium salts. Gives 2º & 3º-amines.
          (iii) Reduction of amide derivatives of 1º & 2º-amines. Gives 2º & 3º-amines.

Examples showing the application of these methods to the preparation of specific amines are shown in the following diagram. The sulfonamide procedure used in the first example is similar in concept to the phthalimide example #2 presented in the previous diagram. In both cases the acidity of the nitrogen reactant (ammonia or amine) is greatly enhanced by conversion to an imide or sulfonamide derivative. The nucleophilic conjugate base of this acidic nitrogen species is then prepared by treatment with sodium or potassium hydroxide, and this undergoes a S_N2 reaction with a 1º or 2º-alkyl halide. Finally, the activating group is removed by hydrolysis (phthalimide) or reductive cleavage (sulfonamide) to give the desired amine. The phthalimide method is only useful for preparing 1º-amines, whereas the sulfonamide procedure may be used to make either 1º or 2º-amines.

Examples #2 & #3 make use of the carbonyl reductive amination reaction (method #4 in the preceding table. This versatile procedure may be used to prepare all classes of amines (1º, 2º & 3º), as shown here and above. A weak acid catalyst is necessary for imine formation, which takes place by amine addition to the carbonyl group, giving a 1-aminoalcohol intermediate, followed by loss of water. The final reduction of the C=N double bond may be carried out catalytically (Pt & Pd catalysts may be used instead of Ni) or chemically (by NaBH₃CN). The imine or enamine intermediates are normally not isolated, but are immediately reduced to the amine product.

Another general method for preparing all classes of amines makes use of amide intermediates, easily made from ammonia or amines by reaction with carboxylic acid chlorides or anhydrides. These stable compounds may be isolated, identified and stored prior to the final reduction. Examples #4 & #5 illustrate applications of this method.As with the previous method, 1º-amines give 2º-amine products, and 2º-amines give 3º-amine products.
The last example (#6) shows how 4º-ammonium salts may be prepared by repeated (exhaustive) alkylation of amines.

 

4. Reaction of Amines with Nitrous Acid

Nitrous acid (HNO₂ or HONO) reacts with aliphatic amines in a fashion that provides a useful test for distinguishing primary, secondary and tertiary amines.

1°-Amines + HONO (cold acidic solution) Nitrogen Gas Evolution from a Clear Solution 2°-Amines + HONO (cold acidic solution) An Insoluble Oil (N-Nitrosoamine) 3°-Amines + HONO (cold acidic solution) A Clear Solution (Ammonium Salt Formation)

Nitrous acid is a Brønsted acid of moderate strength (pK_a = 3.3). Because it is unstable, it is prepared immediately before use in the following manner:

Under the acidic conditions of this reaction, all amines undergo reversible salt formation:

This happens with 3º-amines, and the salts are usually soluble in water. The reactions of nitrous acid with 1°- and 2°- aliphatic amines may be explained by considering their behavior with the nitrosonium cation, NO⁽⁺⁾, an electrophilic species present in acidic nitrous acid solutions.

Back to the Top

Primary Amines

Secondary Amines

The distinct behavior of 1º, 2º & 3º-aliphatic amines is an instructive challenge to our understanding of their chemistry, but is of little importance as a synthetic tool. The S_N1 product mixtures from 1º-amines are difficult to control, and rearrangement is common when branched primary alkyl groups are involved. The N-nitrosoamines formed from 2º-amines are carcinogenic, and are not generally useful as intermediates for subsequent reactions.

Aryl Amines

Nitrous acid reactions of 1º-aryl amines generate relatively stable diazonium species that serve as intermediates for a variety of aromatic substitution reactions. Diazonium cations may be described by resonance contributors, as in the bracketed formulas shown below. The left-hand contributor is dominant because it has greater bonding. Loss of nitrogen is slower than in aliphatic 1º-amines because the C-N bond is stronger, and aryl carbocations are comparatively unstable.

Aqueous solutions of these diazonium ions have sufficient stablity at 0º to 10 ºC that they may be used as intermediates in a variety of nucleophilic substitution reactions. For example, if water is the only nucleophile available for reaction, phenols are formed in good yield.

2º-Aryl Amines:

2º-Aryl amines give N-nitroso amine derivatives on reaction with nitrous acid, and thus behave identically to their aliphatic counterparts.

3º-Aryl Amines:

Depending on ring substitution, 3º-Aryl amines may undergo aromatic ring nitrosation at sites ortho or para to the amine substituent. The nitrosonium cation is not sufficiently electrophilic to react with benzene itself, or even toluene, but highly activated aromatic rings such as amines and phenols are capable of substition. Of course, the rate of reaction of NO⁽⁺⁾ directly at nitrogen is greater than that of ring substitution, as shown in the previous example. Once nitrosated, the activating character of the amine nitrogen is greatly diminished; and N-nitroso aniline derivatives, or indeed any amide derivatives, do not undergo ring nitrosation.

5. Reactions of Aryl Diazonium Salts

Substitution with Loss of Nitrogen

Aryl diazonium salts are important intermediates. They are prepared in cold (0 º to 10 ºC) aqueous solution, and generally react with nucleophiles with loss of nitrogen. Some of the more commonly used substitution reactions are shown in the following diagram. Since the leaving group (N₂) is thermodynamically very stable, these reactions are energetically favored. Those substitution reactions that are catalyzed by cuprous salts are known as Sandmeyer reactions. Fluoride substitution occurs on treatment with BF₄^(–), a reaction known as the Schiemann reaction. Stable diazonium tetrafluoroborate salts may be isolated, and on heating these lose nitrogen to give an arylfluoride product. The top reaction with hypophosphorus acid, H₃PO₂, is noteworthy because it achieves the reductive removal of an amino (or nitro) group. Unlike the nucleophilic substitution reactions, this reduction probably procedes by a radical mechanism.

These aryl diazonium substitution reactions significantly expand the tactics available for the synthesis of polysubstituted benzene derivatives. Consider the following options:

(i)   The usual precursor to an aryl amine is the corresponding nitro compound. A nitro substituent deactivates an aromatic ring and directs electrophilic substitution to meta locations.
(ii)   Reduction of a nitro group to an amine may be achieved in several ways. The resulting amine substituent strongly activates an aromatic ring and directs electrophilic substitution to ortho & para locations.
(iii)   The activating character of an amine substituent may be attenuated by formation of an amide derivative (reversible), or even changed to deacivating and meta-directing by formation of a quaternary-ammonium salt (irreversible).
(iv)   Conversion of an aryl amine to a diazonium ion intermediate allows it to be replaced by a variety of different groups (including hydrogen), which may in turn be used in subsequent reactions.

The following examples illustrate some combined applications of these options to specific cases. You should try to conceive a plausible reaction sequence for each. Once you have done so, you may check suggested answers by clicking on the question mark for each.

Back to the Top

Bonding to Nitrogen

A resonance description of diazonium ions shows that the positive charge is delocalized over the two nitrogen atoms. It is not possible for nucleophiles to bond to the inner nitrogen, but bonding (or coupling) of negative nucleophiles to the terminal nitrogen gives neutral azo compounds. As shown in the following equation, this coupling to the terminal nitrogen should be relatively fast and reversible. The azo products may exist as E / Z stereoisomers. In practice it is found that the E-isomer predominates at equilibrium.

Unless these azo products are trapped or stabilized in some manner, reversal to the diazonium ion and slow nucleophilic substitution at carbon (with irreversible nitrogen loss) will be the ultimate course of reaction, as described in the previous section. For example, if phenyldiazonium bisulfate is added rapidly to a cold solution of sodium hydroxide a relatively stable solution of sodium phenyldiazoate (the conjugate base of the initially formed diazoic acid) is obtained. Lowering the pH of this solution regenerates phenyldiazoic acid (pK_a ca. 7), which disassociates back to the diazonium ion and eventually undergoes substitution, generating phenol.

 

      C₆H₅N₂⁽⁺⁾ HSO₄^(–)  +  NaOH (cold solution)        C₆H₅N₂–OH  +  NaOH (cold)        C₆H₅N₂–O^(–) Na⁽⁺⁾ 

       phenyldiazonium bisulfate                                                              phenyldiazoic acid                                                 sodium phenyldiazoate                                      

 

Aryl diazonium salts may be reduced to the corresponding hydrazines by mild reducing agents such as sodium bisulfite, stannous chloride or zinc dust. The bisulfite reduction may proceed by an initial sulfur-nitrogen coupling, as shown in the following equation.

        

        Ar-N₂⁽⁺⁾ X^(–)            Ar-N=N-SO₃H            Ar-NH-NH-SO₃H           Ar-NH-NH₂  +  H₂SO₄        

The most important application of diazo coupling reactions is electrophilic aromatic substitution of activated benzene derivatives by diazonium electrophiles. The products of such reactions are highly colored aromatic azo compounds that find use as synthetic dyestuffs, commonly referred to as azo dyes. Azobenzene (Y=Z=H) is light orange; however, the color of other azo compounds may range from red to deep blue depending on the nature of the aromatic rings and the substituents they carry. Azo compounds may exist as cis/trans isomer pairs, but most of the well-characterized and stable compounds are trans.

Some examples of azo coupling reactions are shown below. A few simple rules are helpful in predicting the course of such reactions:
          (i)   At acid pH (< 6) an amino group is a stronger activating substituent than a hydroxyl group (i.e. a phenol). At alkaline pH (> 7.5) phenolic functions are stronger activators, due to increased phenoxide base concentration.
          (ii)   Coupling to an activated benzene ring occurs preferentially para to the activating group if that location is free. Otherwise ortho-coupling will occur.
          (iii)   Naphthalene normally undergoes electrophilic substitution at an alpha-location more rapidly than at beta-sites; however, ortho-coupling is preferred. See the diagram for examples of α / β notation in naphthalenes.

You should try to conceive a plausible product structure for each of the following couplings. Once you have done so, you may check your answers by clicking on the question mark for each.

6. Substitution and Elimination Reactions of Amines

Amine functions seldom serve as leaving groups in nucleophilic substitution or base-catalyzed elimination reactions. Indeed, they are even less effective in this role than are hydroxyl and alkoxyl groups. In the case of alcohols and ethers, a useful technique for enhancing the reactivity of the oxygen function was to modify the leaving group (OH^(–) or OR^(–)) to improve its stability as an anion (or equivalent). This stability is conveniently estimated from the strength of the corresponding conjugate acids.
As noted earlier, 1º and 2º-amines are much weaker acids than alcohols, so it is not surprising that it is difficult to force the nitrogen function to assume the role of a nucleophilic leaving group. For example, heating an amine with HBr or HI does not normally convert it to the corresponding alkyl halide, as in the case of alcohols and ethers. In this context we note that the acidity of the putative ammonium leaving group is at least ten powers of ten less than that of an analogous oxonium species. The loss of nitrogen from diazonium intermediates is a notable exception in this comparison, due to the extreme stability of this leaving group (the conjugate acid of N₂ would be an extraordinarily strong acid).

One group of amine derivatives that have proven useful in S_N2 and E2 reactions is that composed of the tetraalkyl (4º-) ammonium salts. Most applications involving this class of compounds are eliminations, but a few examples of S_N2 substitution have been reported.

C₆H₅–N(CH₃)₃⁽⁺⁾ Br^(–)  +  R-S^(–) Na⁽⁺⁾       R-S-CH₃  +  C₆H₅–N(CH₃)₂   +   NaBr

(CH₃)₄N⁽⁺⁾ OH^(–)          CH₃–OH  +  (CH₃)₃N 

Hofmann Elimination

Elimination reactions of 4º-ammonium salts are termed Hofmann eliminations. Since the counter anion in most 4º-ammonium salts is halide, this is often replaced by the more basic hydroxide ion through reaction with silver hydroxide (or silver oxide). The resulting hydroxide salt must then be heated (100 - 200 ºC) to effect the E2-like elimination of a 3º-amine. Example #1 below shows a typical Hofmann elimination. Obviously, for an elimination to occur one of the alkyl substituents on nitrogen must have one or more beta-hydrogens, as noted earlier in examining elimination reactions of alkyl halides.

Back to the Top

In example #2 above, two of the alkyl substituents on nitrogen have beta-hydrogens, all of which are on methyl groups (colored orange & magenta). The chief product from the elimination is the alkene having the more highly substituted double bond, reflecting not only the 3:1 numerical advantage of those beta-hydrogens, but also the greater stability of the double bond.
Example #3 illustrates two important features of the Hofmann elimination:
    First, simple amines are easily converted to the necessary 4º-ammonium salts by exhaustive alkylation, usually with methyl iodide (methyl has no beta-hydrogens and cannot compete in the elimination reaction). Exhaustive methylation is shown again in example #4.
    Second, when a given alkyl group has two different sets of beta-hydrogens available to the elimination process (colored orange & magenta here), the major product is often the alkene isomer having the less substituted double bond.
The tendency of Hofmann eliminations to give the less-substituted double bond isomer is commonly referred to as the Hofmann Rule, and contrasts strikingly with the Zaitsev Rule formulated for dehydrohalogenations and dehydrations. In cases where other activating groups, such as phenyl or carbonyl, are present, the Hofmann Rule may not apply. Thus, if 2-amino-1-phenylpropane is treated in the manner of example #3, the product consists largely of 1-phenylpropene (E & Z-isomers).

 To understand why the base-induced elimination of 4º-ammonium salts behaves differently from that of alkyl halides it is necessary to reexamine the nature of the E2 transition state, first described for dehydrohalogenation. The energy diagram shown earlier for a single-step bimolecular E2 mechanism is repeated below.

The E2 transition state is less well defined than is that of S_N2 reactions. More bonds are being broken and formed, with the possibility of a continuum of states in which the extent of C–H and C–X bond-breaking and C=C bond-making varies. For example, if the bond to the leaving group (X) is substantially broken relative to the other bond changes, the transition state approaches that for an E1 reaction (initial ionization followed by a fast second step). At the other extreme, if the acidity of the beta-hydrogens is enhanced, then substantial breaking of C–H may occur before the other bonds begin to be affected. For most simple alkyl halides it was proper to envision a balanced transition state, in which there was a synchronous change in all the bonds. Such a model was consistent with the Zaitsev Rule.
When the leaving group X carries a positive charge, as do the 4º-ammonium compounds discussed here, the inductive influence of this charge will increase the acidity of both the alpha and the beta-hydrogens. Furthermore, the 4º-ammonium substituent is much larger than a halide or hydroxyl group and may perturb the conformations available to substituted beta-carbons. It seems that a combination of these factors acts to favor base attack at the least substituted (least hindered and most acidic) set of beta-hydrogens. The favored anti orientation of the leaving group and beta-hydrogen, noted for dehydrohalogenation, is found for many Hofmann eliminations; but syn-elimination is also common, possibly because the attraction of opposite charges orients the hydroxide base near the 4º-ammonium leaving group.

Three additional examples of the Hofmann elimination are shown in the following diagram. Example #1 is interesting in two respects. First, it generates a 4º-ammonium halide salt in a manner different from exhaustive methylation. Second, this salt is not converted to its hydroxide analog prior to elimination. A concentrated aqueous solution of the halide salt is simply dropped into a refluxing sodium hydroxide solution, and the volatile hydrocarbon product is isolated by distillation.

Example #2 illustrates an important aspect of the Hofmann elimination. If the nitrogen atom is part of a ring, then a single application of this elimination procedure does not remove the nitrogen as a separate 3º-amine product. In order to sever the nitrogen function from the molecule, a second Hofmann elimination must be carried out. Indeed, if the nitrogen atom was a member of two rings (fused or spiro), then three repetitions of the Hofmann elimination would be required to sever the nitrogen from the remaining molecular framework.
Example #3 is noteworthy because the less stable trans-cyclooctene is the chief product, accompanied by the cis-isomer. An anti-E2-transition state would necessarily give the cis-cycloalkene, so the trans-isomer must be generated by a syn-elimination. The cis-cyclooctene produced in this reaction could also be formed by a syn-elimination. Cyclooctane is a conformationally complex structure.  Some eclipsed bonds occur in all these conformers, and transannular hydrogen crowding is unavoidable. Since the trimethylammonium substituent is large (about the size of tert-butyl) it will probably assume an equatorial-like orientation to avoid steric crowding. An anti-E2 transition state is likely to require an axial-like orientation of this bulky group, making this an unfavorable path.

7. Oxidation States of Nitrogen

In comparing the chemistry of the amines with alcohols and ethers, we discover many classes of related compounds in which nitrogen assumes higher oxidation states, in contrast to limited oxidation states of oxygen. In this context, keep in mind that the oxidation state of elemental oxygen (O₂) and nitrogen (N₂) is defined as zero.
The most prevalent state of covalently bonded oxygen is -2. This is the case for water, alcohols, ethers and carbonyl compounds. The only common higher oxidation state (-1) is found in the peroxides, R–O–O–R, where R=hydrogen, alkyl, aryl or acyl. Because of the low covalent bond energy of the peroxide bond (ca.35 kcal/mole), these compounds are widely used as free radical initiators, and are sometimes dangerously explosive in their reactivity (e.g. triacetone triperoxide used by terrorist bombers).
Nitrogen compounds, on the other hand, encompass oxidation states of nitrogen ranging from -3, as in ammonia and amines, to +5, as in nitric acid. The following table lists some of the known organic compounds of nitrogen, having different oxidation states of that element. Some of these classes of compounds have been described; others will be discussed later.

 

Oxidation State	_3	_2	_1	0	+1	+3
Formulas (names)	R3N (amines) R4N(+) (ammonium) C=N–R (imines) C≡N (nitriles)	R2N–NR2 (hydrazines) C=N–NR2 (hydrazones)	RN=NR (azo cpd.) R2NOH (hydroxyl amine) R3NO (amine oxide)	N2 (nitrogen) R–N2(+) (diazonium)	R–N=O (nitroso)	R-NO2 (nitro) RO–N=O (nitrite ester)

Back to the Top

Amine Oxides

Amine oxides are prepared by oxidizing 3º-amines or pyridines with hydrogen peroxide or peracids (e.g. ZOOH, where Z=H or acyl).

R3N:   +   ZOOH

R3N(+)–O(–)   +   ZOH

Amine oxides are reatively weak bases, pK_a ca. 4.5, compared with the parent amine. The coordinate covalent N–O function is polar, with the oxygen being a powerful hydrogen bond acceptor. If one of the alkyl substituents consists of a long chain, such as C₁₂H₂₅, the resulting amine oxide is an amphoteric surfactant and finds use in shampoos and other mild cleaning agents.

 

An elimination reaction, complementary to the Hofmann elimination, occurs when 3º-amine oxides are heated at temperatures of 150 to 200 ºC. This reaction is known as the Cope Elimination. It is commonly carried out by dropwise addition of an amine oxide solution to a heated tube packed with small glass beads. A stream of nitrogen gas flowing through the column carries the volatile alkene products to a chilled receiver. The nitrogen-containing product is a hydroxyl amine. Unlike the Hofmann elimination, this reaction takes place by a concerted cyclic reorganization, as shown in the following diagram. For such a mechanism, the beta-hydrogen and amine oxide moieties necessarily have a syn-relationship.

Cope elimination of diastereomeric amine oxides, such as those shown in examples #2 & 3 above, provide proof of the syn-relationship of the beta-hydrogen and amine oxide groups. These examples also demonstrate a strong regioselectivity favoring the more stable double bond.

Pyrolytic syn-Eliminations Amine oxides are not the only functions that undergo a unimolecular syn-elimination on heating.

Nitroxide Radicals

2º-Amines lacking α-hydrogens are oxidized by peroxides (ZOOH) to nitroxide radicals of surprising stability. In the example shown at the top of the following diagram it should be noted that resonance delocalization of the unpaired electron contributes to a polar N–O bond. The R=H compound, known by the acronym TEMPO, is a relatively stable red solid. Many other nitroxides have been prepared, three of which are drawn at the lower right. If one or more hydrogens are present on an adjacent carbon, the nitroxide decomposes to mixtures including amine oxides and nitrones, as shown at the lower left. Nitroxides are oxidized to unstable oxammonium cations by halogens.

The spin of the nitroxyl unpaired electron may be studied by a technique called electron paramagnetic resonance (epr or esr). Experiments of this kind have demonstrated that the epr spectra are sensitive to substituents on the radical as well as its immediate environment. This has led to a spin labeling strategy for investigating the conformational structures of macromolecules like proteins. Thus, site-directed spin labeling (SDSL) has emerged as a valuable technique for mapping elements of secondary structure, at the level of the backbone fold, in a wide range of proteins, including those not amenable to structural characterization using classical structural techniques, such as nuclear magnetic resonance and X-ray crystallography.

 

Back to the Top