View source for Chemistry:Nucleophile

{{short description|Chemical species that donates an electron pair}}
[[File:Hydrox subst.png|thumb|A hydroxide ion acting as a nucleophile in an S<sub>N</sub>2 reaction, converting a haloalkane into an alcohol]]
In [[Chemistry:Chemistry|chemistry]], a '''nucleophile''' is a [[Chemistry:Chemical species|chemical species]] that forms bonds by donating an [[Physics:Electron pair|electron pair]]. All [[Physics:Molecule|molecule]]s and [[Physics:Ion|ion]]s with a free pair of electrons or at least one [[Chemistry:Pi bond|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 [[Chemistry:Alcohol|alcohol]]s and water are named [[Chemistry:Solvolysis|solvolysis]]. Nucleophiles may take part in [[Chemistry:Nucleophilic substitution|nucleophilic substitution]], whereby a nucleophile becomes attracted to a full or partial positive charge, and [[Chemistry:Nucleophilic addition|nucleophilic addition]]. Nucleophilicity is closely related to basicity. The difference between the two is, that basicity is a [[Physics:Thermodynamic|thermodynamic]] property (i.e. relates to an equilibrium state), but nucleophilicity is a [[Chemistry:Chemical kinetics|kinetic]] property, which relates to rates of certain chemical reactions.<ref>Nucleophilicity—Periodic Trends and Connection to Basicity. Einar Uggerud. https://doi.org/10.1002/chem.200500639</ref>

== History ==
The terms ''nucleophile'' and ''[[Chemistry:Electrophile|electrophile]]'' were introduced by [[Biography:Christopher Kelk Ingold|Christopher Kelk Ingold]] in 1933,<ref>{{cite journal | doi = 10.1039/jr9330001120| title = 266. Significance of tautomerism and of the reactions of aromatic compounds in the electronic theory of organic reactions| journal = Journal of the Chemical Society (Resumed)| pages = 1120| year = 1933| last1 = Ingold| first1 = C. K.}}</ref> replacing the terms ''anionoid'' and ''cationoid'' proposed earlier by A. J. Lapworth in 1925.<ref>{{cite journal|last = Lapworth|first= A.|journal= Nature |date=1925|volume= 115|page= 625|title = Replaceability of Halogen Atoms by Hydrogen Atoms}}</ref> The word nucleophile is derived from [[Physics:Atomic nucleus|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 pK<sub>a</sub> 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 [[Physics:Reaction rate|reaction rate]]s for many reactions involving many nucleophiles and electrophiles. Nucleophiles displaying the so-called [[Chemistry:Alpha effect|alpha effect]] are usually omitted in this type of treatment.

==== Swain–Scott equation ====
The first such attempt is found in the Swain–Scott equation<ref>''Quantitative Correlation of Relative Rates. Comparison of Hydroxide Ion with Other Nucleophilic Reagents toward Alkyl Halides, Esters, Epoxides and Acyl Halides'' C. Gardner Swain, Carleton B. Scott J. Am. Chem. Soc.; '''1953'''; 75(1); 141-147. [https://pubs.acs.org/doi/abs/10.1021/ja01097a041 Abstract]</ref><ref>{{cite book |doi=10.1351/goldbook.S06201 |doi-access=free |chapter=Swain–Scott equation |title=The IUPAC Compendium of Chemical Terminology |year=2014 }}</ref> derived in 1953:
:<math>\log_{10}\left(\frac{k}{k_0}\right) = sn</math>

This [[Chemistry:Free-energy relationship|free-energy relationship]] relates the pseudo first order [[Chemistry:Reaction rate constant|reaction rate constant]] (in water at 25&nbsp;°C), ''k'', of a reaction, normalized to the reaction rate, ''k''<sub>0</sub>, 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: [[Chemistry:Acetate|acetate]] 2.7, [[Chemistry:Chloride|chloride]] 3.0, [[Chemistry:Azide|azide]] 4.0, [[Chemistry:Hydroxide|hydroxide]] 4.2, [[Chemistry:Aniline|aniline]] 4.5, [[Chemistry:Iodide|iodide]] 5.0, and [[Chemistry:Thiosulfate|thiosulfate]] 6.4. Typical substrate constants are 0.66 for ethyl tosylate, 0.77 for [[Chemistry:Lactone|β-propiolactone]], 1.00 for [[Chemistry:Epoxide|2,3-epoxypropanol]], 0.87 for [[Chemistry:Benzyl chloride|benzyl chloride]], and 1.43 for [[Chemistry:Benzoyl chloride|benzoyl chloride]].

The equation predicts that, in a nucleophilic displacement on [[Chemistry:Benzyl chloride|benzyl chloride]], the [[Chemistry:Azide|azide]] anion reacts 3000 times faster than water.

==== Ritchie equation ====
The Ritchie equation, derived in 1972, is another free-energy relationship:<ref>{{cite book |doi=10.1351/goldbook.R05402 |doi-access=free |chapter=Ritchie equation |title=The IUPAC Compendium of Chemical Terminology |year=2014 }}</ref><ref>''Nucleophilic reactivities toward cations'' Calvin D. Ritchie Acc. Chem. Res.; '''1972'''; 5(10); 348-354. [http://pubs.acs.org/cgi-bin/abstract.cgi/achre4/1972/5/i10/f-pdf/f_ar50058a005.html Abstract]</ref><ref>''Cation–anion combination reactions. XIII. Correlation of the reactions of nucleophiles with esters'' Calvin D. Ritchie J. Am. Chem. Soc.; '''1975'''; 97(5); 1170–1179.
[http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/1975/97/i05/f-pdf/f_ja00838a035.html Abstract]</ref>
:<math>\log_{10}\left(\frac{k}{k_0}\right) = N^+</math>

where ''N''<sup>+</sup> is the nucleophile dependent parameter and ''k''<sub>0</sub> the [[Chemistry:Reaction rate constant|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 [[Physics:Reactivity–selectivity principle|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 [[Chemistry:Carbocation|carbocation]]s such as tropylium or diazonium cations:
:[[File:RichieEquationDiazonium.png|400px|Ritchie equation diazonium ion reactions]]

or (not displayed) ions based on [[Chemistry:Malachite green|malachite green]]. Many other reaction types have since been described.

Typical Ritchie '''N<sup>+</sup>''' values (in [[Chemistry:Methanol|methanol]]) are: 0.5 for [[Chemistry:Methanol|methanol]], 5.9 for the [[Chemistry:Cyanide|cyanide]] anion, 7.5 for the [[Chemistry:Methoxide|methoxide]] anion, 8.5 for the [[Chemistry:Azide|azide]] anion, and 10.7 for the [[Chemistry:Thiophenol|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 [[Chemistry:Tropylium cation|tropylium cation]].

==== Mayr–Patz equation ====
In the Mayr–Patz equation (1994):<ref>{{cite journal | doi = 10.1002/anie.199409381| title = Scales of Nucleophilicity and Electrophilicity: A System for Ordering Polar Organic and Organometallic Reactions| journal = Angewandte Chemie International Edition in English| volume = 33| issue = 9| pages = 938| year = 1994| last1 = Mayr| first1 = Herbert| last2 = Patz| first2 = Matthias}}</ref>
:<math>\log(k) = s(N + E)</math>

The second order [[Chemistry:Reaction rate constant|reaction rate constant]] ''k'' at 20&nbsp;°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 [[Chemistry:Electrophile|electrophile]]s:<ref>{{cite journal | doi = 10.1021/ja010890y| pmid = 11572670| title = Reference Scales for the Characterization of Cationic Electrophiles and Neutral Nucleophiles | journal = Journal of the American Chemical Society| volume = 123| issue = 39| pages = 9500–12| year = 2001| last1 = Mayr| first1 = Herbert| last2 = Bug| first2 = Thorsten| last3 = Gotta| first3 = Matthias F| last4 = Hering| first4 = Nicole| last5 = Irrgang| first5 = Bernhard| last6 = Janker| first6 = Brigitte| last7 = Kempf| first7 = Bernhard| last8 = Loos| first8 = Robert| last9 = Ofial| first9 = Armin R| last10 = Remennikov| first10 = Grigoriy| last11 = Schimmel| first11 = Holger| s2cid = 8392147}}</ref>
:[[File:Benzhydryliumion.png|150px|benzhydrylium ions used in the determination of Mayr–Patz equation]]

and a diverse collection of π-nucleophiles:
:[[File:MayrNucleophiles.png|300px|Nucleophiles used in the determination of Mayr–Patz equation, X = tetrafluoroborate anion]].

Typical E values are +6.2 for R = [[Chemistry:Chlorine|chlorine]], +5.90 for R = [[Chemistry:Hydrogen|hydrogen]], 0 for R = methoxy and −7.02 for R = [[Chemistry:Dimethylamine|dimethylamine]].

Typical N values with s in parentheses are −4.47 (1.32) for [[Chemistry:Electrophilic aromatic substitution|electrophilic aromatic substitution]] to [[Chemistry:Toluene|toluene]] (1), −0.41 (1.12) for [[Chemistry:Electrophilic addition|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 [[Chemistry:Enamine|enamine]] 7.<ref>An internet database for reactivity parameters maintained by the Mayr group is available at http://www.cup.uni-muenchen.de/oc/mayr/</ref>

The range of organic reactions also include [[Chemistry:SN2 reaction|SN2 reaction]]s:<ref name=Mayr2006>{{cite journal | doi = 10.1002/anie.200600542| pmid = 16646102| title = Towards a General Scale of Nucleophilicity?| journal = Angewandte Chemie International Edition| volume = 45| issue = 23| pages = 3869–74| year = 2006| last1 = Phan| first1 = Thanh Binh| last2 = Breugst| first2 = Martin| last3 = Mayr| first3 = Herbert| citeseerx = 10.1.1.617.3287}}</ref>
:[[File:Mayr2006.png|400px|Mayr equation also includes SN2 reactions]]

With E = −9.15 for the ''S-methyldibenzothiophenium ion'', typical nucleophile values N (s) are 15.63 (0.64) for [[Chemistry:Piperidine|piperidine]], 10.49 (0.68) for [[Chemistry:Methoxide|methoxide]], and 5.20 (0.89) for water. In short, nucleophilicities towards sp<sub>2</sub> or sp<sub>3</sub> centers follow the same pattern.

==== Unified equation ====
In an effort to unify the above described equations the Mayr equation is rewritten as:<ref name=Mayr2006 />
:''<math>\log(k) = s_Es_N(N + E)</math>''

with s<sub>E</sub> the electrophile-dependent slope parameter and s<sub>N</sub> the nucleophile-dependent slope parameter. This equation can be rewritten in several ways:
* with s<sub>E</sub> = 1 for carbocations this equation is equal to the original Mayr–Patz equation of 1994,
* with s<sub>N</sub> = 0.6 for most n nucleophiles the equation becomes
::<math>\log(k) = 0.6s_EN + 0.6s_EE</math>
:''or the original Scott–Swain equation written as:''
::<math>\log(k) = \log(k_0) + s_EN</math>
* with s<sub>E</sub> = 1 for carbocations and s<sub>N</sub> = 0.6 the equation becomes:
::<math>\log(k) = 0.6N + 0.6E</math>
:or the original Ritchie equation written as:
::<math>\log(k) - \log(k_0) = N^+</math>

== Types ==
Examples of nucleophiles are anions such as Cl<sup>−</sup>, or a compound with a [[Chemistry:Lone pair|lone pair]] of electrons such as NH<sub>3</sub> ([[Chemistry:Ammonia|ammonia]]) and PR<sub>3</sub>.

In the example below, the [[Chemistry:Oxygen|oxygen]] of the hydroxide ion donates an electron pair to form a new chemical bond with the [[Chemistry:Carbon|carbon]] at the end of the bromopropane molecule. The bond between the carbon and the [[Chemistry:Bromine|bromine]] then undergoes heterolytic fission, with the bromine atom taking the donated electron and becoming the [[Chemistry:Bromide|bromide]] ion (Br<sup>−</sup>), because a S<sub>N</sub>2 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<sub>N</sub>2 reactions result in a inversion of the [[Physics:Molecular configuration|configuration]] of the electrophile. If the electrophile is chiral, it typically maintains its chirality, though the S<sub>N</sub>2 product's [[Chemistry:Absolute configuration|absolute configuration]] is flipped as compared to that of the original electrophile.
:[[File:hydrox subst.png|Displacement of bromine by a hydroxide]]

===Ambident Nucleophile===
An '''ambident nucleophile''' is one that can attack from two or more places, resulting in two or more products. For example, the [[Chemistry:Thiocyanate|thiocyanate]] ion (SCN<sup>−</sup>) may attack from either the sulfur or the nitrogen. For this reason, the [[Chemistry:SN2 reaction|S<sub>N</sub>2 reaction]] of an alkyl halide with SCN<sup>−</sup> often leads to a mixture of an alkyl thiocyanate (R-SCN) and an alkyl [[Chemistry:Isothiocyanate|isothiocyanate]] (R-NCS). Similar considerations apply in the [[Chemistry:Kolbe nitrile synthesis|Kolbe nitrile synthesis]].

=== Halogens ===
While the halogens are not nucleophilic in their diatomic form (e.g. I<sub>2</sub> is not a nucleophile), their anions are good nucleophiles. In polar, protic solvents, F<sup>−</sup> is the weakest nucleophile, and I<sup>−</sup> the strongest; this order is reversed in polar, aprotic solvents.<ref>''Chem 2401 Supplementary Notes''. Thompson, Alison and Pincock, James, Dalhousie University Chemistry Department</ref>

=== Carbon ===
Carbon nucleophiles are often [[Chemistry:Organometallic chemistry|organometallic reagent]]s such as those found in the [[Chemistry:Grignard reaction|Grignard reaction]], [[Chemistry:Blaise reaction|Blaise reaction]], [[Chemistry:Reformatsky reaction|Reformatsky reaction]], and [[Chemistry:Barbier reaction|Barbier reaction]] or reactions involving [[Chemistry:Organolithium reagent|organolithium reagent]]s and [[Chemistry:Acetylide|acetylide]]s. These reagents are often used to perform [[Chemistry:Nucleophilic addition|nucleophilic addition]]s.

[[Biology:Enol|Enol]]s are also carbon nucleophiles. The formation of an enol is catalyzed by [[Chemistry:Acid catalysis|acid]] or [[Chemistry:Base|base]]. Enols are ambident nucleophiles, but, in general, nucleophilic at the [[Chemistry:Alpha and beta carbon|alpha carbon]] atom. Enols are commonly used in [[Chemistry:Condensation reaction|condensation reaction]]s, including the [[Chemistry:Claisen condensation|Claisen condensation]] and the [[Chemistry:Aldol condensation|aldol condensation]] reactions.

=== Oxygen ===
Examples of oxygen nucleophiles are [[Chemistry:Water|water]] (H<sub>2</sub>O), [[Chemistry:Hydroxide|hydroxide]] anion, [[Chemistry:Alcohol|alcohol]]s, [[Chemistry:Alkoxide|alkoxide]] anions, [[Chemistry:Hydrogen peroxide|hydrogen peroxide]], and [[Chemistry:Carboxylate|carboxylate anions]].
Nucleophilic attack does not take place during intermolecular hydrogen bonding.

=== Sulfur ===
Of sulfur nucleophiles, [[Chemistry:Hydrogen sulfide|hydrogen sulfide]] and its salts, [[Chemistry:Thiol|thiol]]s (RSH), thiolate anions (RS<sup>−</sup>), anions of thiolcarboxylic acids (RC(O)-S<sup>−</sup>), and anions of dithiocarbonates (RO-C(S)-S<sup>−</sup>) and dithiocarbamates (R<sub>2</sub>N-C(S)-S<sup>−</sup>) 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 [[Chemistry:Ammonia|ammonia]], [[Chemistry:Azide|azide]], [[Chemistry:Amine|amine]]s, [[Chemistry:Nitrite|nitrite]]s, [[Chemistry:Hydroxylamine|hydroxylamine]], [[Chemistry:Hydrazine|hydrazine]], [[Chemistry:Carbazide|carbazide]], [[Chemistry:Phenylhydrazine|phenylhydrazine]], [[Chemistry:Semicarbazide|semicarbazide]], and [[Chemistry:Amide|amide]].

=== Metal centers ===
Although metal centers (e.g., Li<sup>+</sup>, Zn<sup>2+</sup>, Sc<sup>3+</sup>, 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<sub>3</sub>Sn<sup>–</sup> is about 10000 times more nucleophilic than I<sup>–</sup>, while the Co(I) form of [[Biology:Vitamin B12|vitamin B<sub>12</sub>]] (vitamin B<sub>12s</sub>) is about 10<sup>7</sup> times more nucleophilic.<ref>{{Cite journal|last1=Schrauzer|first1=G. N.|last2=Deutsch|first2=E.|last3=Windgassen|first3=R. J.|date=April 1968|title=The nucleophilicity of vitamin B(sub 12s)|url=https://pubs.acs.org/doi/abs/10.1021/ja01011a054|journal=Journal of the American Chemical Society|language=en|volume=90|issue=9|pages=2441–2442|doi=10.1021/ja01011a054|pmid=5642073|issn=0002-7863}}</ref> Other supernucleophilic metal centers include low oxidation state carbonyl metalate anions (e.g., CpFe(CO)<sub>2</sub><sup>–</sup>).<ref>{{Cite journal|last1=Dessy|first1=Raymond E.|last2=Pohl|first2=Rudolph L.|last3=King|first3=R. Bruce|date=November 1966|title=Organometallic Electrochemistry. VII. 1 The Nucleophilicities of Metallic and Metalloidal Anions Derived from Metals of Groups IV, V, VI, VII, and VIII|url=https://pubs.acs.org/doi/abs/10.1021/ja00974a015|journal=Journal of the American Chemical Society|language=en|volume=88|issue=22|pages=5121–5124|doi=10.1021/ja00974a015|issn=0002-7863}}</ref>

== See also ==
* {{annotated link|Chemistry:Electrophile}}
* {{annotated link|Chemistry:Lewis acids and bases}}
* {{annotated link|Chemistry:Nucleophilic abstraction}}

== References ==
{{reflist}}

[[Category:Physical organic chemistry]]

{{Sourceattribution|Nucleophile}}