Organic Chemistry Part 4 : Amines

Animated Amines

Chemistry of Amines

1. Nomenclature and Structure of Amines

Different Types of Amines

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Amines are derivatives of ammonia in which one or more of the hydrogens has been replaced by an alkyl or aryl group.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.

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

Different Types of Amines

Classes of amines:

Amines are organized into four subcategories:

Different Classes Of Amines

Primary amines - Primary amines arise when one of three hydrogen atoms in ammonia is replaced by an alkyl or aromatic. Important primary alkyl amines include methylamine, ethanolamine (2-aminoethanol), and the buffering agent tris, while primary aromatic amines include aniline.

Secondary amines - Secondary amines have two organic substituents (alkyl, aryl or both) bound to N together with one hydrogen (or no hydrogen if one of the substituent bonds is double). Important representatives include dimethylamine and methylethanolamine, while an example of an aromatic amine would be diphenylamine.

Tertiary amines - In tertiary amines, all three hydrogen atoms are replaced by organic substituents. Examples include trimethylamine, which has a distinctively fishy smell or triphenylamine.

Cyclic amines - Cyclic amines are either secondary or tertiary amines. Examples of cyclic amines include the 3-member ring aziridine and the six-membered ring piperidine. N-methylpiperidine and N-phenylpiperidine are examples of cyclic tertiary amines.

It is also possible to have four organic substituents on the nitrogen. These species are not amines but are quaternary ammonium cations and have a charged nitrogen center. Quaternary ammonium salts exist with many kinds of anions.

Different Types of Amines

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.

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

Amine Producing Processes

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.

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.

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

2. Basicity of Amines

A review of basic acid-base concept should be helpful to the following discussion. 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`sof 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.

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 bezene ring toward electrophilic substitutionThe following resonance equations, which are similar to those used to explain the enhanced acidity of orthro and para-nitrophoenols 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 th e influence of amine substituents on aromatic ring substitution, and will be discussed further in the section devoted to carboxylic acid derivatives.

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 pKa =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.

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

Amine Reactions

1. Electrophilic Substitution at Nitrogen

Reactions of Amines

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.

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 Wiliamson sysnthesis 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

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.

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.

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.