6.3: Nucleophiles

The word “nucleophile” has a Greek root and translates to nucleus-loving. Nucleophiles are either negatively charged or neutral species with a pair of electrons in a high-energy occupied molecular orbital (HOMO). As these species tend to donate electron pairs, nucleophiles are considered Lewis bases as well. Negatively charged species, like OH⁻, Cl⁻, or HS⁻, with one or several pairs of electrons, are typically nucleophiles. Similarly, neutral species such as ammonia, amines, water, and alcohol have non-bonding lone pairs of electrons and can act as nucleophiles. Furthermore, molecules without a lone pair of electrons can still act as nucleophiles, such as alkenes and aromatic rings with bonding π orbitals.

The relative strength of a nucleophile to displace a leaving group in a substitution reaction is called nucleophilicity. The negatively charged species are more nucleophilic than their neutral counterpart species. As an empirical rule, the higher the pK_a of a conjugate acid, the better the nucleophile. For example, the hydroxide ion — a conjugate base of water (pK_a 15.7) is a better nucleophile than the acetate ion — a conjugate base of acetic acid (pK_a~5).

Since nucleophilicity is not the inherent property given to a specific species, it is affected by many factors, including the type of solvent in which the reaction is conducted. In polar protic solvents, high solvation of anions reduces the nucleophile’s availability to participate in substitution reactions.

When comparing halides, fluoride, being the smallest and most electronegative anion, is solvated the strongest, while iodide, the largest and least electronegative ion, is solvated the least. Thus, in polar protic solvents, iodide is the best nucleophile. In polar aprotic solvents, however, anions are “naked” due to poor solvation and can participate freely in a nucleophilic attack. In polar aprotic solvents, the nucleophile’s basicity dictates its nucleophilicity making fluoride the best nucleophile.

Furthermore, the polarizability of atoms affects nucleophilicity. Polarizability describes how easily electrons in the cloud can be distorted. A nucleophile with a large atom has greater polarizability, meaning it can donate a higher electron density to the electrophile compared to a small atom, whose electrons are held more tightly.

In a nucleophilic substitution reaction, the reactant molecule that displaces the leaving group in the substrate is called a nucleophile.

Nucleophiles are electron-rich species and, by definition, Lewis bases.  The nucleophilic atom has a high electron density and donates its electrons to a partially positive, electron-deficient center, thereby making a new bond.

Nucleophilic reagents are either anionic or neutral. Anionic nucleophiles are negative ions containing one or more lone pairs of equal energy, usually on heteroatoms. The non-bonding lone pairs occupy high-energy molecular orbitals, which makes them less stable and more reactive.

For example, the anionic carbon nucleophile, like the cyanide ion, has a lone pair on both the carbon and nitrogen. However, since the carbon’s sp orbital is higher in energy than the nitrogen’s, carbon is the nucleophilic center.

Neutral nucleophiles have one or more unshared electron pairs on the highest occupied molecular orbitals of, mostly, heteroatoms.

Furthermore, in species like alkenes that have no lone pairs, a high electron density region — the pi bond — functions as the nucleophilic site.

A neutral nucleophile is less nucleophilic than its anionic form, owing to the absence of a negative charge.

In general, pK_a values of acids can be used to evaluate the strength of their conjugate bases or nucleophiles. In the case of molecules containing the same nucleophilic atom, the higher the pK_as of their conjugate acids, the stronger the nucleophile will be.     

The product of a nucleophilic substitution reaction depends on the type of nucleophile used.

When an anionic nucleophile reacts with the substrate, the covalent bond formed neutralizes the formal charge of the nucleophile, resulting in a neutral product.

In comparison, when a neutral nucleophile reacts with the substrate, the nucleophile gains a positive formal charge. A deprotonation step that follows completes the reaction, resulting in a neutral product.