Nucleophile

A nucleophile is a chemical species capable of donating an electron pair to form a new covalent bond. Any molecule or ion possessing a lone pair of electrons or at least one π-bond may act as a nucleophile, and for this reason nucleophiles are Lewis bases. Their reactivity generally involves attraction to positively charged or electron-deficient centres, and they participate widely in organic and inorganic reaction mechanisms, particularly nucleophilic substitution and nucleophilic addition. Reactions in which neutral nucleophiles from the solvent act as the attacking species are known as solvolysis.

History and Etymology

The terminology of nucleophiles and electrophiles was introduced in 1933 by Christopher Kelk Ingold to replace the earlier terms anionoid and cationoid proposed by A. J. Lapworth in 1925. The word nucleophile derives from nucleus and the Greek philos meaning “loving” or “friend”, reflecting the species’ affinity for positive charge.

Fundamental Properties

Nucleophiles donate electron pairs during bond formation, and the strength with which they do so is termed nucleophilicity. Although nucleophilicity is closely related to basicity, the two concepts are not identical. Basicity is a thermodynamic property, describing equilibrium tendencies of species to accept protons. Nucleophilicity, by contrast, is a kinetic property, describing how rapidly a nucleophile reacts in a given substitution or addition process.
General principles governing nucleophilic behaviour include:

• Within a group of related species, more basic ions tend to be stronger nucleophiles.
• Within a single family of nucleophiles, such as oxygen-based nucleophiles, the order of nucleophilicity commonly follows basicity.
• Across the periodic table, sulphur is usually a better nucleophile than oxygen, owing to its greater polarizability.
• Nucleophilic attack favours centres bearing full or partial positive charge, arising from polarised bonds or electron-withdrawing substituents.

Quantifying Nucleophilicity

To compare nucleophilic strengths across different reactions, several empirical relationships have been developed.
Swain–Scott Equation (1953).This free-energy relationship expresses the logarithm of the relative rate constant k/k0k/k_{0}k/k0​ as:
log⁡10(kk0)=sn\log_{10}\left(\frac{k}{k_0}\right) = s nlog10​(k0​k​)=sn
where nnn is the nucleophilic constant and sss is the substrate constant. Values of nnn vary widely: for example, acetate (2.7), chloride (3.0), azide (4.0), hydroxide (4.2), aniline (4.5), iodide (5.0) and thiosulphate (6.4). Substrate constants include tosylate (0.66), epoxide (1.00) and benzyl chloride (0.87). The equation allows predictions of relative reaction rates, such as the azide ion reacting thousands of times faster than water in displacements on benzyl chloride.
Ritchie Equation (1972).Given by:
log⁡10(kk0)=N\log_{10}\left(\frac{k}{k_{0}}\right) = Nlog10​(k0​k​)=N
the Ritchie relationship contains a nucleophile-dependent parameter NNN but omits a substrate parameter. It implies constant selectivity, meaning relative nucleophilicities remain the same irrespective of electrophile type. Reported values include 0.5 for methanol, 5.9 for cyanide, 8.5 for azide and 10.7 for thiophenol in methanol.
Mayr–Patz Equation (1994).This widely used linear free-energy relationship is written as:
log⁡k=sN+E\log k = sN + Elogk=sN+E
where NNN and sss are nucleophile parameters and EEE is an electrophilicity parameter. Electrophilicity values range from roughly −6.2 for strongly deactivated aromatics to around +7.0 for electron-rich amines. Typical nucleophile values include piperidine (15.63; s=0.64s = 0.64s=0.64), methoxide (10.49; s=0.68s = 0.68s=0.68) and water (5.20; s=0.89s = 0.89s=0.89). Databases containing extensive NNN, sss and EEE parameters provide broad applicability for predicting reaction rates in organic processes, including many SN2 reactions.
Unified Equation.To reconcile the above models, the Mayr equation can be recast as:
log⁡k=sEsNN+sEE\log k = s_E s_N N + s_E Elogk=sE​sN​N+sE​E
where electrophile-dependent and nucleophile-dependent slope parameters clarify variations across reaction classes. Under appropriate assumptions, this equation simplifies to the Swain–Scott or Ritchie forms.

Mechanisms of Nucleophilic Attack

Nucleophiles participate in several key reaction types:

• Nucleophilic substitution (SN1 and SN2): In an SN2 mechanism, attack occurs from the side opposite the leaving group, known as backside attack, producing a transition state with simultaneous bond formation and bond cleavage. SN2 reactions result in inversion of configuration at the chiral centre, though overall chirality is typically retained.
• Nucleophilic addition: Common in reactions involving aldehydes, ketones and other electron-poor unsaturated species.
• Solvolysis: Occurring when solvent molecules, such as water or alcohols, act as neutral nucleophiles.

Ambident Nucleophiles

An ambident nucleophile possesses multiple reactive sites capable of attack. The thiocyanate ion (SCN⁻) illustrates this behaviour: reaction through sulphur yields an alkyl thiocyanate (RSCN), whereas reaction through nitrogen produces an alkyl isothiocyanate (RNCS). Similar dual reactivity is observed in reactions involving enolates and other multidentate species.

Classes of Nucleophiles

Halogen Nucleophiles.Halide anions act as potent nucleophiles, though their reactivity varies with solvent. In polar protic media, F⁻ is the weakest and I⁻ the strongest, while the pattern reverses in polar aprotic solvents owing to differences in solvation.
Carbon Nucleophiles.Carbon-based nucleophiles often arise from organometallic reagents such as Grignard reagents, organolithium compounds, acetylides and Reformatsky reagents. These species participate extensively in nucleophilic additions to carbonyl compounds. Enols and enolates also function as carbon nucleophiles, commonly in condensation reactions such as the aldol and Claisen condensations. Owing to resonance, many enols are ambident, capable of attack at the α- or β-carbon.
Oxygen Nucleophiles.Water, hydroxide ions and alkoxide ions are common oxygen nucleophiles. Alkoxides are particularly strong nucleophiles in substitution reactions, readily displacing halide ions from haloalkanes to form alcohols.