In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are Lewis bases. Nucleophilic describes the affinity of a nucleophile to bond with positively charged atomic nuclei. Nucleophilicity, sometimes referred to as nucleophile strength, refers to a substance's nucleophilic character and is often used to compare the affinity of atoms. Neutral nucleophilic reactions with solvents such as alcohols and water are named solvolysis. Nucleophiles may take part in nucleophilic substitution, whereby a nucleophile becomes attracted to a full or partial positive charge, and nucleophilic addition. Nucleophilicity is closely related to basicity. The difference between the two is, that basicity is a thermodynamic property (i.e. relates to an equilibrium state), but nucleophilicity is a kinetic property, which relates to rates of certain chemical reactions.
History and etymology The terms nucleophile and electrophile were introduced by Christopher Kelk Ingold in 1933, replacing the terms anionoid and cationoid proposed earlier by A. J. Lapworth in 1925. The word nucleophile is derived from nucleus and the Greek word φιλος, philos, meaning friend.
Properties In general, in a group across the periodic table, the more basic the ion (the higher the pKa of the conjugate acid) the more reactive it is as a nucleophile. Within a series of nucleophiles with the same attacking element (e.g. oxygen), the order of nucleophilicity will follow basicity. Sulfur is in general a better nucleophile than oxygen.
Nucleophilicity Many schemes attempting to quantify relative nucleophilic strength have been devised. The following empirical data have been obtained by measuring reaction rates for many reactions involving many nucleophiles and electrophiles. Nucleophiles displaying the so-called alpha effect are usually omitted in this type of treatment.
Swain–Scott equation The first such attempt is found in the Swain–Scott equation derived in 1953:
log 10 ( k k 0 ) = s n {\displaystyle \log _{10}\left({\frac {k}{k_{0}}}\right)=sn}
This free-energy relationship relates the pseudo first order reaction rate constant (in water at 25 °C), k, of a reaction, normalized to the reaction rate, k0, of a standard reaction with water as the nucleophile, to a nucleophilic constant n for a given nucleophile and a substrate constant s that depends on the sensitivity of a substrate to nucleophilic attack (defined as 1 for methyl bromide). This treatment results in the following values for typical nucleophilic anions: acetate 2.7, chloride 3.0, azide 4.0, hydroxide 4.2, aniline 4.5, iodide 5.0, and thiosulfate 6.4. Typical substrate constants are 0.66 for ethyl tosylate, 0.77 for β-propiolactone, 1.00 for 2,3-epoxypropanol, 0.87 for benzyl chloride, and 1.43 for benzoyl chloride. The equation predicts that, in a nucleophilic displacement on benzyl chloride, the azide anion reacts 3000 times faster than water.
Ritchie equation The Ritchie equation, derived in 1972, is another free-energy relationship:
log 10 ( k k 0 ) = N + {\displaystyle \log _{10}\left({\frac {k}{k_{0}}}\right)=N^{+}}
where N+ is the nucleophile dependent parameter and k0 the reaction rate constant for water. In this equation, a substrate-dependent parameter like s in the Swain–Scott equation is absent. The equation states that two nucleophiles react with the same relative reactivity regardless of the nature of the electrophile, which is in violation of the reactivity–selectivity principle. For this reason, this equation is also called the constant selectivity relationship. In the original publication the data were obtained by reactions of selected nucleophiles with selected electrophilic carbocations such as tropylium or diazonium cations:
or (not displayed) ions based on malachite green. Many other reaction types have since been described. Typical Ritchie N+ values (in methanol) are: 0.5 for methanol, 5.9 for the cyanide anion, 7.5 for the methoxide anion, 8.5 for the azide anion, and 10.7 for the thiophenol anion. The values for the relative cation reactivities are −0.4 for the malachite green cation, +2.6 for the benzenediazonium cation, and +4.5 for the tropylium cation.
Mayr–Patz equation In the Mayr–Patz equation (1994):
log ( k ) = s ( N + E ) {\displaystyle \log(k)=s(N+E)}
The second order reaction rate constant k at 20 °C for a reaction is related to a nucleophilicity parameter N, an electrophilicity parameter E, and a nucleophile-dependent slope parameter s. The constant s is defined as 1 with 2-methyl-1-pentene as the nucleophile. Many of the constants have been derived from reaction of so-called benzhydrylium ions as the electrophiles:
and a diverse collection of π-nucleophiles:
. Typical E values are +6.2 for R = chlorine, +5.90 for R = hydrogen, 0 for R = methoxy and −7.02 for R = dimethylamine. Typical N values with s in parentheses are −4.47 (1.32) for electrophilic aromatic substitution to toluene (1), −0.41 (1.12) for electrophilic addition to 1-phenyl-2-propene (2), and 0.96 (1) for addition to 2-methyl-1-pentene (3), −0.13 (1.21) for reaction with triphenylallylsilane (4), 3.61 (1.11) for reaction with 2-methylfuran (5), +7.48 (0.89) for reaction with isobutenyltributylstannane (6) and +13.36 (0.81) for reaction with the enamine 7. The range of organic reactions also include SN2 reactions:
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