In
chemistry
Chemistry is the scientific study of the properties and behavior of matter. It is a natural science that covers the elements that make up matter to the compounds made of atoms, molecules and ions: their composition, structure, proper ...
, 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
In chemistry, an electron pair or Lewis pair consists of two electrons that occupy the same molecular orbital but have opposite spins. Gilbert N. Lewis introduced the concepts of both the electron pair and the covalent bond in a landmark paper he ...
. All
molecule
A molecule is a group of two or more atoms held together by attractive forces known as chemical bonds; depending on context, the term may or may not include ions which satisfy this criterion. In quantum physics, organic chemistry, and b ...
s 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 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
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
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. R ...
.
History
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
Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to:
* Atomic nucleus, the very dense central region of an atom
*Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA
Nucl ...
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 pK
a 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:
:
This
free-energy relationship relates the
pseudo first order reaction rate constant In chemical kinetics a reaction rate constant or reaction rate coefficient, ''k'', quantifies the rate and direction of a chemical reaction.
For a reaction between reactants A and B to form product C
the reaction rate is often found to have the ...
(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 2.7,
chloride
The chloride ion is the anion (negatively charged ion) Cl−. It is formed when the element chlorine (a halogen) gains an electron or when a compound such as hydrogen chloride is dissolved in water or other polar solvents. Chloride s ...
3.0,
azide 4.0,
hydroxide
Hydroxide is a diatomic anion with chemical formula OH−. It consists of an oxygen and hydrogen atom held together by a single covalent bond, and carries a negative electric charge. It is an important but usually minor constituent of water. ...
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 starti ...
4.5,
iodide 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, e ...
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 in ...
, and 1.43 for
benzoyl chloride.
The equation predicts that, in a
nucleophilic displacement 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 in ...
, the
azide anion reacts 3000 times faster than water.
Ritchie equation
The Ritchie equation, derived in 1972, is another free-energy relationship:
:
where ''N''
+ is the nucleophile dependent parameter and ''k''
0 the
reaction rate constant In chemical kinetics a reaction rate constant or reaction rate coefficient, ''k'', quantifies the rate and direction of a chemical reaction.
For a reaction between reactants A and B to form product C
the reaction rate is often found to have the ...
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 In chemistry the reactivity–selectivity principle or RSP states that a more reactive chemical compound or reactive intermediate is less selective in chemical reactions. In this context selectivity represents the ratio of reaction rates.
This prin ...
. 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
In organic chemistry, the tropylium ion or cycloheptatrienyl cation is an aromatic species with a formula of 7H7sup>+. Its name derives from the molecule tropine from which cycloheptatriene (tropylidene) was first synthesized in 1881. Salts of ...
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
Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...
) are: 0.5 for
methanol
Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical and the simplest aliphatic alcohol, with the formula C H3 O H (a methyl group linked to a hydroxyl group, often abbreviated as MeOH). It is ...
, 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 ...
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):
:
The
second order reaction rate constant In chemical kinetics a reaction rate constant or reaction rate coefficient, ''k'', quantifies the rate and direction of a chemical reaction.
For a reaction between reactants A and B to form product C
the reaction rate is often found to have the ...
''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
Chlorine is a chemical element with the 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 between them. Chlorine i ...
, +5.90 for R =
hydrogen
Hydrogen is the chemical element with the symbol H and atomic number 1. Hydrogen is the lightest element. At standard conditions hydrogen is a gas of diatomic molecules having the formula . It is colorless, odorless, tasteless, non-to ...
, 0 for R =
methoxy 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 arou ...
.
Typical N values with s in parenthesis are −4.47 (1.32) for
electrophilic aromatic substitution to
toluene
Toluene (), also known as toluol (), is a substituted aromatic hydrocarbon. It is a colorless, water-insoluble liquid with the smell associated with paint thinners. It is a mono-substituted benzene derivative, consisting of a methyl group (CH3) ...
(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:
:
With E = −9.15 for the ''S-methyldibenzothiophenium ion'', typical nucleophile values N (s) are 15.63 (0.64) for
piperidine, 10.49 (0.68) for
methoxide, and 5.20 (0.89) for water. In short, nucleophilicities towards sp
2 or sp
3 centers follow the same pattern.
Unified equation
In an effort to unify the above described equations the Mayr equation is rewritten as:
:''
''
with s
E the electrophile-dependent slope parameter and s
N the nucleophile-dependent slope parameter. This equation can be rewritten in several ways:
* with s
E = 1 for carbocations this equation is equal to the original Mayr–Patz equation of 1994,
* with s
N = 0.6 for most n nucleophiles the equation becomes
::
:''or the original Scott–Swain equation written as:''
::
* with s
E = 1 for carbocations and s
N = 0.6 the equation becomes:
::
:or the original Ritchie equation written as:
::
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. L ...
of electrons such as NH
3 (
ammonia
Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous ...
) and PR
3.
In the example below, the
oxygen
Oxygen is the chemical element with the symbol O and atomic number 8. It is a member of the chalcogen group in the periodic table, a highly reactive nonmetal, and an oxidizing agent that readily forms oxides with most elements ...
of the hydroxide ion donates an electron pair to form a new chemical bond with the
carbon
Carbon () is a chemical element with the symbol C and atomic number 6. It is nonmetallic and tetravalent—its atom making four electrons available to form covalent chemical bonds. It belongs to group 14 of the periodic table. Carbon ma ...
at the end of the
bromopropane molecule. The bond between the carbon and the
bromine
Bromine is a chemical element with the symbol Br and atomic number 35. It is the third-lightest element in group 17 of the periodic table ( halogens) and is a volatile red-brown liquid at room temperature that evaporates readily to form a simi ...
then undergoes
heterolytic fission
In chemistry, heterolysis or heterolytic fission () is the process of cleaving/breaking a covalent bond where one previously bonded species takes both original bonding electrons from the other species. During heterolytic bond cleavage of a neutr ...
, with the bromine atom taking the donated electron and becoming the
bromide ion (Br
−), because a S
N2 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, S
N2 reactions result in a inversion of the
configuration of the electrophile. If the electrophile is
chiral, it typically maintains its chirality, though the S
N2 product's
absolute configuration 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 glu ...
(R-NCS). Similar considerations apply in the
Kolbe nitrile synthesis.
Halogens
While the
halogens are not nucleophilic in their diatomic form (e.g. I
2 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,
Blaise reaction,
Reformatsky reaction, and
Barbier reaction or reactions involving
organolithium reagents and
acetylides. These reagents are often used to perform
nucleophilic additions.
Enol
In organic chemistry, alkenols (shortened to enols) are a type of reactive structure or intermediate in organic chemistry that is represented as an alkene ( olefin) with a hydroxyl group attached to one end of the alkene double bond (). T ...
s 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 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 ...
(H
2O),
hydroxide
Hydroxide is a diatomic anion with chemical formula OH−. It consists of an oxygen and hydrogen atom held together by a single covalent bond, and carries a negative electric charge. It is an important but usually minor constituent of water. ...
anion,
alcohols,
alkoxide anions,
hydrogen peroxide
Hydrogen peroxide is a chemical compound with the formula . In its pure form, it is a very pale blue liquid that is slightly more viscous than water. It is used as an oxidizer, bleaching agent, and antiseptic, usually as a dilute solution (3 ...
, 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 (R
2N-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
Ammonia is an inorganic compound of nitrogen and hydrogen with the formula . A stable binary hydride, and the simplest pnictogen hydride, ammonia is a colourless gas with a distinct pungent smell. Biologically, it is a common nitrogenous ...
,
azide,
amine
In chemistry, amines (, ) are compounds and functional groups that contain a basic nitrogen atom with a lone pair. Amines are formally derivatives of ammonia (), wherein one or more hydrogen atoms have been replaced by a substituent ...
s,
nitrites,
hydroxylamine,
hydrazine,
carbazide,
phenylhydrazine,
semicarbazide, and
amide
In organic chemistry, an amide, also known as an organic amide or a carboxamide, is a compound with the general formula , where R, R', and R″ represent organic groups or hydrogen atoms. The amide group is called a peptide bond when it i ...
.
Metal centers
Although metal centers (e.g., Li
+, Zn
2+, Sc
3+, 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, Ph
3Sn
– is about 10000 times more nucleophilic than I
–, while the Co(I) form of
vitamin B12 (vitamin B
12s) is about 10
7 times more nucleophilic. Other supernucleophilic metal centers include low oxidation state carbonyl metalate anions (e.g., CpFe(CO)
2–).
See also
*
*
*
*
References
{{reflist
Physical organic chemistry