3.3. Refresher and Expansion: Nucleophilicity and Basicity of Amines
Recall that an electrophile is a group (or atom) that wants to accept electrons. Often this is the result of having a deficiency of electron density on the group/atom from a permanent dipole and/or partial positive (cationic) charge due to resonance delocalization. Conversely, a nucleophile is a group (or atom) that wants to donate electrons. Often this is the result of having an excess of electron density on the group/atom from a permanent dipole and/or partial negative (anionic) charge due to resonance delocalization
The definitions of electrophile and nucleophile are functionally identical to the definitions of Lewis acids and Lewis bases, respectively. The distinction of terms is semi-arbitrary. Technically, under the definitions of nucleophile and electrophile all Brønsted acid-base reactions are also nucleophile-electrophile reactions (Figure 3.11). The proton of the acid is electron-deficient and can be classed as an electrophile, while the base is electron-rich and can be classed as a nucleophile.
Figure 3.11 – Acid-Base Reactions as Nucleophile-Electrophile Reactions.
Acid-base reactions are simply a common type of nucleophile-electrophile reaction. However, there are often (extreme) differences in the rates of reactions between Brønsted acid-base reactions and other nucleophile-electrophile reactions, with acid-base reactions generally being MUCH faster. As a result, a distinction is still made between the two reactivities.
All amines (primary, secondary, tertiary) meet the conditions to be classed as nucleophiles/bases (Figure 3.12). The nitrogen of the amine is nucleophilic/basic: there is a permanent excess of electron density on the nitrogen from its polar bonds; the nitrogen has a lone pair that it can donate to an electrophile/acidic hydrogen.
Figure 3.12 – Example of an Amine as a Nucleophile/Base with Methylamine, Hydrochloric Acid, and Methanal (Formaldehyde).
At an introductory level nucleophilicity and basicity may usually be considered equivalent: whichever compound is a stronger base is also a stronger nucleophile. Basicity is evaluated using the standard procedure and parameters (see Qualitative Estimates of Acidity and/or Section 11.2.4.1 for a summary).
This is not always true. The most common exceptions to nucleophilicity and basicity being equivalent result from steric interactions. Recall that steric strain involves the electron clouds of two non-bonded groups overlapping (interpenetrating) slightly. Steric strain may vary from small to (VERY) large energy costs for bringing non-bonded groups close together. As the electron clouds on the two groups increase in size more overlap occurs, and the energy cost associated with the interaction increases. In other words, bigger groups cause larger steric interactions.
Atoms that are nucleophilic/basic typically have one or more groups around them. The relative size of these groups is sometimes referred to as their “steric bulk”. In general, having more steric bulk (having physically larger groups around the atom) has a moderate-to-large reduction on nucleophilicity but a negligible affect on basicity. Consider three amines: trimethylamine, triethylamine, and triisopropylamine (Figure 3.13). The ethyl group is physically larger (sterically bulkier) than the methyl group. The isopropyl group is physically larger (sterically bulkier) than the ethyl group. In chemical reactions these three amines have functionally identical strength as bases. However, trimethylamine is a moderate nucleophile, triethylamine is a weak nucleophile, and triisopropylamine is not nucleophilic. Steric bulk reduces nucleophilicity but not basicity.
Figure 3.13 – Effect of Steric Bulk on Basicity vs. Nucleophilicity by Contrasting Trimethylamine, Triethylamine, and Triisopropylamine.
Some trends in the basicity of amines are important.
In general, basicity increases as alkyl groups are added to the nitrogen (Figure 3.14). Recall that alkyl groups are weakly electron-donating through a phenomenon called hyperconjugation (see Sections 6.3.6, 8.5.2, and 10.10.1). This stabilizes the cationic charge in the corresponding cationic conjugate acid. A primary amine is more basic than ammonia, a secondary amine is more basic than a primary amine. This trend does not extend to tertiary amines. The reasons for this are complex and involve solvation of the cation (it is NOT simply due to steric bulk).
Figure 3.14 – Comparison of Basicity/Nucleophilicity of Amines by Number of Attached Alkyl Groups.
In general, basicity (slightly) increases when the nitrogen is part of a non-aromatic ring (Figure 3.15). The geometric constraint of the ring pulls the hydrogens of the adjacent CH2’s slightly further away from the lone pair, slightly reducing steric bulk around the nitrogen. This only applies to small rings, generally 6-membered or smaller.
Figure 3.15 – Comparison of Basicity/Nucleophilicity of Amines by Ring Size of Attached Alkyl Groups.
Basicity sharply decreases when the nitrogen is conjugated to another group(s) (Figure 3.16). Resonance/Delocalization is highly stabilizing. If the lone pair on the nitrogen is participating in resonance then it loses that resonance stabilization when the lone pair is used as a base/nucleophile; the product (conjugate acid) has less resonance stabilization than the starting material, which costs (a lot) of energy to do.
Figure 3.16 – Comparison of Basicity/Nucleophilicity of Amines with and without Conjugation to Attached Groups.
