12.3 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.

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 1.18), 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:

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:

so

Thus

𝐾_a= 𝐾_w/𝐾_b

𝐾_b= 𝐾_w/𝐾_a

and

p𝐾_a+ p𝐾_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.

Table 12.1 Basicity of Some Common Amines

Name	Structure	pKa 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

Arylamines, however, are considerably less basic than alkylamines, as are the heterocyclic amines pyridine and pyrrole. Anilinium ion has pK_a = 4.63, for instance, whereas methylammonium ion has pK_a = 10.64. Arylamines are less basic than alkylamines because the nitrogen lone-pair electrons are delocalized by interaction with the aromatic ring’s π electron system and are less available for bonding to H⁺. In resonance terms, arylamines are stabilized relative to alkylamines because of their five resonance forms.

Substituted arylamines can be either more basic or less basic than aniline, depending on the substituent. Electron-donating substituents, such as –CH₃, –NH₂, and –OCH₃, which increase the reactivity of an aromatic ring toward electrophilic substitution (Section 8.6), also increase the basicity of the corresponding arylamine. Electron-withdrawing substituents, such as –Cl, –NO₂, and –CN, which decrease ring reactivity toward electrophilic substitution, also decrease arylamine basicity. Table 12.2 considers only p– substituted anilines, but similar trends are observed for ortho and meta derivatives.

Table 12.2 Base Strength of Some p-Substituted Anilines

	Substituent, Y	pKa
	–NH2	6.15	Activating groups
	–OCH3	5.34
	–CH3	5.08
	–H	4.63
	–Cl	3.98	Deactivating groups
	–Br	3.86
	–CN	1.74
	–NO2	1.00

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.

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 12.4).

Figure 12.4 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 (pKa ≈ 36) reacts with butyllithium to yield lithium diisopropylamide (LDA). 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. They are not, however, encountered in biological chemistry.

Problem 12.4
Which compound in each of the following pairs is more basic?

(a) CH₃CH₂NH₂ or CH₃CH₂CONH₂

(b) NaOH or CH₃NH₂

(c) CH₃NHCH₃ or pyridine

Problem 12.5
The benzylammonium ion (C₆H₅CH₂NH₃⁺) has pKa = 9.33, and the propylammonium ion has pKa = 10.71. Which is the stronger base, benzylamine or propylamine? What are the pK_b’s of benzylamine and propylamine?

Problem 12.6
Without looking at Table 12.4, rank the following compounds in order of ascending basicity.

(a) p-Nitroaniline, p-aminobenzaldehyde, p-bromoaniline

(b) p-Chloroaniline, p-aminoacetophenone, p-methylaniline

(c) p-(Trifluoromethyl)aniline, p-methylaniline, p-(fluoromethyl)aniline