John McMurry, Professor Emeritus

24.3 • Basicity of Amines

The chemistry of amines is dominated by the lone pair of electrons on nitrogen, which makes amines both basic and nucleophilic. They react with acids to form acid–base salts, and they react with electrophiles in many of the polar reactions seen in past chapters. Note in the following electrostatic potential map of trimethylamine how the negative (red) region corresponds to the lone pair of electrons on nitrogen.

The ball-and-stick model in the electrostatic potential map of amine. A reaction shows an amine (a Lewis base) reacts with a Lewis acid to form a salt and anion A.

Amines are much stronger bases than alcohols and ethers, their oxygen-containing analogs. When an amine is dissolved in water, an equilibrium is established in which water acts as an acid and transfers a proton to the amine. Just as the acid strength of a carboxylic acid can be measured by defining an acidity constant K_a (Section 2.8), the base strength of an amine can be measured by defining an analogous basicity constant K_b. The larger the value of K_b and the smaller the value of pK_b, the more favorable the proton-transfer equilibrium and the stronger the base.

For the reaction

\begin{array}{l} {RNH}_{2} {+ H}_{2} O ⇄ {RNH}_{3}^{+} {+ OH}^{–} \\ K_{b} = \frac{{[RNH}_{3}^{+} {] [OH}^{–}]}{{[RNH}_{2}]} \\ p K_{b} = –log K_{b} \end{array}

In practice, K_b values are not often used. Instead, the most convenient way to measure the basicity of an amine (RNH₂) is to look at the acidity of the corresponding ammonium ion (RNH₃⁺).

For the reaction

\begin{array}{l} {RNH}_{3}^{+} {+ H}_{2} O ⇄ {RNH}_{2} {+ H}_{3} O^{+} \\ K_{a} = \frac{{[RNH}_{2} {] [H}_{3} O^{+}]}{{[RNH}_{3}^{+}]} \end{array}

so

\begin{matrix} K_{a} \cdot K_{b} = [\frac{{[RNH}_{2} {] [H}_{3} O^{+}]}{{[RNH}_{3}^{+}]}] [\frac{{[RNH}_{3}^{+} {] [OH}^{–}]}{{[RNH}_{2}]}] \\ {= [H}_{3} O^{+} {] [OH}^{–}] = K_{w} = 1 .00 \times 10^{–14} \end{matrix}

Thus

K_{a} = \frac{K_{w}}{K_{b}} and K_{b} = \frac{K_{w}}{K_{a}}

and

p K_{a} + p K_{b} = 14

These equations say that the K_b of an amine multiplied by the K_a of the corresponding ammonium ion is equal to K_w, the ion-product constant for water (1.00 × 10^–1⁴). Thus, if we know K_a for an ammonium ion, we also know K_b for the corresponding amine base because K_b = K_w/K_a. The more acidic the ammonium ion, the less tightly the proton is held and the weaker the corresponding base. That is, a weaker base has an ammonium ion with a smaller pK_a and a stronger base has an ammonium ion with a larger pK_a.

Weaker base	Smaller pK_a for ammonium ion
Stronger base	Larger pK_a for ammonium ion

Table 24.1 lists pK_a values of the ammonium ions from a variety of amines and indicates that there is a substantial range of amine basicities. Most simple alkylamines are similar in their base strength, with pK_a’s for their ammonium ions in the narrow range 10 to 11. Arylamines, however, are considerably less basic than alkylamines, as are the heterocyclic amines pyridine and pyrrole.

Table 24.1 Basicity of Some Common Amines

Name	Structure	pK_a of ammonium ion
Ammonia	NH₃	9.26
Primary alkylamine
Methylamine	CH₃NH₂	10.64
Ethylamine	CH₃CH₂NH₂	10.75
Secondary alkylamine
Diethylamine	(CH₃CH₂)₂NH	10.98
Pyrrolidine		11.27
Tertiary alkylamine
Triethylamine	(CH₃CH₂)₃N	10.76
Arylamine
Aniline		4.63
Heterocyclic amine
Pyridine		5.25
Pyrimidine		1.3
Pyrrole		0.4
Imidazole		6.95

In contrast with amines, amides (RCONH₂) are nonbasic. Amides aren’t protonated by aqueous acids, and they are poor nucleophiles. The main reason for this difference in basicity between amines and amides is that an amide is stabilized by delocalization of the nitrogen lone-pair electrons through orbital overlap with the carbonyl group. In resonance terms, amides are more stable and less reactive than amines because they are hybrids of two resonance forms. This amide resonance stabilization is lost when the nitrogen atom is protonated, so protonation is disfavored. The following electrostatic potential maps clearly show a reduced electron density on the amide nitrogen.

The structure and electrostatic potential map of methylamine and acetamide. The electron-rich nitrogen in methylamine and electron-poor nitrogen in acetamide are labeled. The figure shows the resonance structures of acetamide.

To purify amines, it’s often possible to take advantage of their basicity. For example, if a mixture of a basic amine and a neutral compound such as a ketone or alcohol is dissolved in an organic solvent and aqueous acid is added, the basic amine dissolves in the water layer as its protonated salt, while the neutral compound remains in the organic solvent layer. Separation of the water layer and neutralization of the ammonium ion by addition of NaOH then provides the pure amine (Figure 24.4).

The separation process of amines. Amine and neutral compound is dissolved in ether. Acid dissolves the amine as the protonated salt. Sodium hydroxide and ether are added to obtain amine.

Figure 24.4 Separation and purification of an amine component from a mixture by extraction of its ammonium salt into water.

In addition to their behavior as bases, primary and secondary amines can also act as very weak acids because an N–H proton can be removed by a sufficiently strong base. We’ve seen, for example, how diisopropylamine (pK_a ≈ 36) reacts with butyllithium to yield lithium diisopropylamide (LDA; Section 22.5). Dialkylamine anions like LDA are very strong bases that are often used in laboratory organic chemistry for the generation of enolate ions from carbonyl compounds (Section 22.7). They are not, however, encountered in biological chemistry.

Butyllithium reacts with diisopropylamine in the presence of tetrahydrofuran solvent to form lithium diisopropylamide (L D A) and butane.

Problem 24-4

Which compound in each of the following pairs is more basic?

(a)

CH₃CH₂NH₂ or CH₃CH₂CONH₂

(b)

NaOH or CH₃NH₂

(c)

CH₃NHCH₃ or pyridine

Problem 24-5

The benzylammonium ion (C₆H₅CH₂NH₃⁺) has pK_a = 9.33, and the propylammonium ion has pK_a = 10.71. Which is the stronger base, benzylamine or propylamine? What are the pK_b’s of benzylamine and propylamine?

24.3 Basicity of Amines