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In chemistry, a nucleophile is a
chemical species A chemical species is a chemical substance or ensemble composed of chemically identical molecular entities that can explore the same set of molecular energy levels on a characteristic or delineated time scale. These energy levels determine the wa ...
that forms bonds by donating an electron pair. All molecules and
ion An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
s with a free pair of electrons or at least one
pi bond In chemistry, pi bonds (π bonds) are covalent chemical bonds, in each of which two lobes of an orbital on one atom overlap with two lobes of an orbital on another atom, and in which this overlap occurs laterally. Each of these atomic orbital ...
can act as nucleophiles. Because nucleophiles donate electrons, they are
Lewis base A Lewis acid (named for the American physical chemist Gilbert N. Lewis) is a chemical species that contains an empty orbital which is capable of accepting an electron pair from a Lewis base to form a Lewis adduct. A Lewis base, then, is any sp ...
s. ''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
alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
s 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 In organic chemistry, a nucleophilic addition reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic additions ...
. Nucleophilicity is closely related to
basicity In chemistry, there are three definitions in common use of the word base, known as Arrhenius bases, Brønsted bases, and Lewis bases. All definitions agree that bases are substances that react with acids, as originally proposed by G.-F. Ro ...
.

# History

The terms ''nucleophile'' and ''
electrophile In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carrie ...
'' were introduced by
Christopher Kelk Ingold Sir Christopher Kelk Ingold (28 October 1893 – 8 December 1970) was a British chemist based in Leeds and London. His groundbreaking work in the 1920s and 1930s on reaction mechanisms and the electronic structure of organic compounds was resp ...
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 Empirical evidence for a proposition is evidence, i.e. what supports or counters this proposition, that is constituted by or accessible to sense experience or experimental procedure. Empirical evidence is of central importance to the sciences and ...
data have been obtained by measuring reaction rates for many reactions involving many nucleophiles and electrophiles. Nucleophiles displaying the so-called
alpha effect The alpha effect refers to the increased nucleophilicity of an atom due to the presence of an adjacent (alpha) atom with lone pair electrons. This first atom does not necessarily exhibit increased basicity compared with a similar atom without an ...
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: :$\log_\left\left(\frac\right\right) = sn$ 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, ''k''0, 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 An acetate is a salt formed by the combination of acetic acid with a base (e.g. alkaline, earthy, metallic, nonmetallic or radical base). "Acetate" also describes the conjugate base or ion (specifically, the negatively charged ion called an ...
2.7, chloride 3.0,
azide In chemistry, azide is a linear, polyatomic anion with the formula and structure . It is the conjugate base of hydrazoic acid . Organic azides are organic compounds with the formula , containing the azide functional group. The dominant applicat ...
4.0, hydroxide 4.2,
aniline Aniline is an organic compound with the formula C6 H5 NH2. Consisting of a phenyl group attached to an amino group, aniline is the simplest aromatic amine. It is an industrially significant commodity chemical, as well as a versatile starting m ...
4.5,
iodide An iodide ion is the ion I−. Compounds with iodine in formal oxidation state −1 are called iodides. In everyday life, iodide is most commonly encountered as a component of iodized salt, which many governments mandate. Worldwide, iodine defic ...
5.0, and
thiosulfate Thiosulfate ( IUPAC-recommended spelling; sometimes thiosulphate in British English) is an oxyanion of sulfur with the chemical formula . Thiosulfate also refers to the compounds containing this anion, which are the salts of thiosulfuric acid, ...
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 Benzyl chloride, or α-chlorotoluene, is an organic compound with the formula C6H5CH2Cl. This colorless liquid is a reactive organochlorine compound that is a widely used chemical building block. Preparation Benzyl chloride is prepared indu ...
, and 1.43 for benzoyl chloride. The equation predicts that, in a
nucleophilic displacement In chemistry, a nucleophilic substitution is a class of chemical reactions in which an electron-rich chemical species (known as a nucleophile) replaces a functional group within another electron-deficient molecule (known as the electrophile). The ...
on
benzyl chloride Benzyl chloride, or α-chlorotoluene, is an organic compound with the formula C6H5CH2Cl. This colorless liquid is a reactive organochlorine compound that is a widely used chemical building block. Preparation Benzyl chloride is prepared indu ...
, the
azide In chemistry, azide is a linear, polyatomic anion with the formula and structure . It is the conjugate base of hydrazoic acid . Organic azides are organic compounds with the formula , containing the azide functional group. The dominant applicat ...
anion reacts 3000 times faster than water.

### Ritchie equation

The Ritchie equation, derived in 1972, is another free-energy relationship: :$\log_\left\left(\frac\right\right) = N^+$ where ''N''+ is the nucleophile dependent parameter and ''k''0 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 Cyanide is a naturally occurring, rapidly acting, toxic chemical that can exist in many different forms. In chemistry, a cyanide () is a chemical compound that contains a functional group. This group, known as the cyano group, consists of a ...
anion, 7.5 for the methoxide anion, 8.5 for the
azide In chemistry, azide is a linear, polyatomic anion with the formula and structure . It is the conjugate base of hydrazoic acid . Organic azides are organic compounds with the formula , containing the azide functional group. The dominant applicat ...
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): :$\log\left(k\right) = s\left(N + E\right)$ 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
electrophile In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carrie ...
s: : and a diverse collection of π-nucleophiles: :. Typical E values are +6.2 for R =
chlorine Chlorine is a chemical element with the Symbol (chemistry), symbol Cl and atomic number 17. The second-lightest of the halogens, it appears between fluorine and bromine in the periodic table and its properties are mostly intermediate betwee ...
, +5.90 for R = hydrogen, 0 for R =
methoxy In organic chemistry, a methoxy group is the functional group consisting of a methyl group bound to oxygen. This alkoxy group has the formula . On a benzene ring, the Hammett equation classifies a methoxy substituent at the ''para'' position a ...
and −7.02 for R =
dimethylamine Dimethylamine is an organic compound with the formula (CH3)2NH. This secondary amine is a colorless, flammable gas with an ammonia-like odor. Dimethylamine is commonly encountered commercially as a solution in water at concentrations up to aroun ...
. Typical N values with s in parenthesis are −4.47 (1.32) for
electrophilic aromatic substitution Electrophilic aromatic substitution is an organic reaction in which an atom that is attached to an aromatic system (usually hydrogen) is replaced by an electrophile. Some of the most important electrophilic aromatic substitutions are aromatic n ...
to toluene (1), −0.41 (1.12) for
electrophilic addition In organic chemistry, an electrophilic addition reaction is an addition reaction where a chemical compound containing a double or triple bond has a π bond broken, with the formation of two new σ bonds.March, Jerry; (1985). Advanced Organic C ...
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 An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates. : The word "enamine" is derived from the affix ''en''-, used as the suffix of alkene, and the ...
7. The range of organic reactions also include
SN2 reaction The SN2 reaction is a type of reaction mechanism that is common in organic chemistry. In this mechanism, one bond is broken and one bond is formed in a concerted way, i.e., in one step. The name SN2 refers to the Hughes-Ingold symbol of the m ...
s: : With E = −9.15 for the ''S-methyldibenzothiophenium ion'', typical nucleophile values N (s) are 15.63 (0.64) for
piperidine Piperidine is an organic compound with the molecular formula (CH2)5NH. This heterocyclic amine consists of a six-membered ring containing five methylene bridges (–CH2–) and one amine bridge (–NH–). It is a colorless liquid with an odor de ...
, 10.49 (0.68) for methoxide, and 5.20 (0.89) for water. In short, nucleophilicities towards sp2 or sp3 centers follow the same pattern.

### Unified equation

In an effort to unify the above described equations the Mayr equation is rewritten as: :''$\log\left(k\right) = s_Es_N\left(N + E\right)$'' with sE the electrophile-dependent slope parameter and sN the nucleophile-dependent slope parameter. This equation can be rewritten in several ways: * with sE = 1 for carbocations this equation is equal to the original Mayr–Patz equation of 1994, * with sN = 0.6 for most n nucleophiles the equation becomes ::$\log\left(k\right) = 0.6s_EN + 0.6s_EE$ :''or the original Scott–Swain equation written as:'' ::$\log\left(k\right) = \log\left(k_0\right) + s_EN$ * with sE = 1 for carbocations and sN = 0.6 the equation becomes: ::$\log\left(k\right) = 0.6N + 0.6E$ :or the original Ritchie equation written as: ::$\log\left(k\right) - \log\left(k_0\right) = N^+$

# Types

Examples of nucleophiles are anions such as Cl, or a compound with a
lone pair In chemistry, a lone pair refers to a pair of valence electrons that are not shared with another atom in a covalent bondIUPAC ''Gold Book'' definition''lone (electron) pair''/ref> and is sometimes called an unshared pair or non-bonding pair. Lone ...
of electrons such as NH3 ( ammonia) and PR3. In the example below, the oxygen of the hydroxide ion donates an electron pair to form a new chemical bond with the carbon at the end of the bromopropane molecule. The bond between the carbon and the bromine then undergoes heterolytic fission, with the bromine atom taking the donated electron and becoming the bromide ion (Br), because a SN2 reaction occurs by backside attack. This means that the hydroxide ion attacks the carbon atom from the other side, exactly opposite the bromine ion. Because of this backside attack, SN2 reactions result in a inversion of the configuration of the electrophile. If the electrophile is chiral, it typically maintains its chirality, though the SN2 product's
absolute configuration Absolute configuration refers to the spatial arrangement of atoms within a chiral molecular entity (or group) and its resultant stereochemical description. Absolute configuration is typically relevant in organic molecules, where carbon is bonded ...
is flipped as compared to that of the original electrophile. : An ambident nucleophile is one that can attack from two or more places, resulting in two or more products. For example, the thiocyanate ion (SCN) may attack from either the sulfur or the nitrogen. For this reason, the SN2 reaction of an alkyl halide with SCN often leads to a mixture of an alkyl thiocyanate (R-SCN) and an alkyl
isothiocyanate In organic chemistry, isothiocyanate is the functional group , formed by substituting the oxygen in the isocyanate group with a sulfur. Many natural isothiocyanates from plants are produced by enzymatic conversion of metabolites called glucosin ...
(R-NCS). Similar considerations apply in the Kolbe nitrile synthesis.

## Halogens

While the
halogens The halogens () are a group in the periodic table consisting of five or six chemically related elements: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), astatine (At), and tennessine (Ts). In the modern IUPAC nomenclature, this group is ...
are not nucleophilic in their diatomic form (e.g. I2 is not a nucleophile), their anions are good nucleophiles. In polar, protic solvents, F is the weakest nucleophile, and I the strongest; this order is reversed in polar, aprotic solvents.

## Carbon

Carbon nucleophiles are often organometallic reagents such as those found in the
Grignard reaction The Grignard reaction () is an organometallic chemical reaction in which alkyl, allyl, vinyl, or aryl-magnesium halides (Grignard reagent) is added to a carbonyl group in an aldehyde or ketone. This reaction is important for the formation of ...
, Blaise reaction, Reformatsky reaction, and Barbier reaction or reactions involving
organolithium reagent In organometallic chemistry, organolithium reagents are chemical compounds that contain carbon–lithium (C–Li) bonds. These reagents are important in organic synthesis, and are frequently used to transfer the organic group or the lithium atom ...
s and
acetylide In organometallic chemistry, acetylide refers to chemical compounds with the chemical formulas and , where M is a metal. The term is used loosely and can refer to substituted acetylides having the general structure (where R is an organic side ch ...
s. These reagents are often used to perform
nucleophilic addition In organic chemistry, a nucleophilic addition reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic additions ...
s. Enols are also carbon nucleophiles. The formation of an enol is catalyzed by acid or base. Enols are ambident nucleophiles, but, in general, nucleophilic at the alpha carbon atom. Enols are commonly used in condensation reactions, including the
Claisen condensation The Claisen condensation is a carbon–carbon bond forming reaction that occurs between two esters or one ester and another carbonyl compound in the presence of a strong base, resulting in a β-keto ester or a β-diketone. It is named after Rain ...
and the aldol condensation reactions.

## Oxygen

Examples of oxygen nucleophiles are
water Water (chemical formula ) is an inorganic, transparent, tasteless, odorless, and nearly colorless chemical substance, which is the main constituent of Earth's hydrosphere and the fluids of all known living organisms (in which it acts as a s ...
(H2O), hydroxide anion,
alcohol Alcohol most commonly refers to: * Alcohol (chemistry), an organic compound in which a hydroxyl group is bound to a carbon atom * Alcohol (drug), an intoxicant found in alcoholic drinks Alcohol may also refer to: Chemicals * Ethanol, one of sev ...
s,
alkoxide In chemistry, an alkoxide is the conjugate base of an alcohol and therefore consists of an organic group bonded to a negatively charged oxygen atom. They are written as , where R is the organic substituent. Alkoxides are strong bases and, when ...
anions, hydrogen peroxide, and
carboxylate anions In organic chemistry, a carboxylate is the conjugate base of a carboxylic acid, (or ). It is an ion with negative charge. Carboxylate salts are salts that have the general formula , where M is a metal and ''n'' is 1, 2,...; ''carboxylat ...
. Nucleophilic attack does not take place during intermolecular hydrogen bonding.

## Sulfur

Of sulfur nucleophiles,
hydrogen sulfide Hydrogen sulfide is a chemical compound with the formula . It is a colorless chalcogen-hydride gas, and is poisonous, corrosive, and flammable, with trace amounts in ambient atmosphere having a characteristic foul odor of rotten eggs. The under ...
and its salts, thiols (RSH), thiolate anions (RS), anions of thiolcarboxylic acids (RC(O)-S), and anions of dithiocarbonates (RO-C(S)-S) and dithiocarbamates (R2N-C(S)-S) are used most often. In general, ''sulfur is very nucleophilic because of its large size'', which makes it readily polarizable, and its lone pairs of electrons are readily accessible.

## Nitrogen

Nitrogen nucleophiles include ammonia,
azide In chemistry, azide is a linear, polyatomic anion with the formula and structure . It is the conjugate base of hydrazoic acid . Organic azides are organic compounds with the formula , containing the azide functional group. The dominant applicat ...
, amines,
nitrite The nitrite ion has the chemical formula . Nitrite (mostly sodium nitrite) is widely used throughout chemical and pharmaceutical industries. The nitrite anion is a pervasive intermediate in the nitrogen cycle in nature. The name nitrite also re ...
s, hydroxylamine, hydrazine, carbazide, phenylhydrazine, semicarbazide, and amide.

## Metal centers

Although metal centers (e.g., Li+, Zn2+, Sc3+, etc.) are most commonly cationic and electrophilic (Lewis acidic) in nature, certain metal centers (particularly ones in a low oxidation state and/or carrying a negative charge) are among the strongest recorded nucleophiles and are sometimes referred to as "supernucleophiles." For instance, using methyl iodide as the reference electrophile, Ph3Sn is about 10000 times more nucleophilic than I, while the Co(I) form of vitamin B12 (vitamin B12s) is about 107 times more nucleophilic. Other supernucleophilic metal centers include low oxidation state carbonyl metalate anions (e.g., CpFe(CO)2).