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 pKa of a conjugate acid, the better the nucleophile. For example, the hydroxide ion — a conjugate base of water (pKa 15.7) is a better nucleophile than the acetate ion — a conjugate base of acetic acid (pKa~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.
