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, pKa 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 pKas 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.
