~2025-35033-57: /* Histor and etymology */

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Histor and etymology

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{{short description|Chemical species that donates an electron pair}}
[[File:Hydrox subst.png|thumb|A [[hydroxide]] ion acting as a nucleophile in an [[SN2 reaction|SN2 reaction]], converting a [[haloalkane]] into an [[Alcohol (chemistry)|alcohol]]]]
In [[chemistry]], a '''nucleophile''' is a [[chemical species]] that forms bonds by donating an [[electron pair]]. All [[molecule]]s and [[ion]]s with a free pair of electrons or at least one [[pi bond]] can act as nucleophiles. Because nucleophiles donate electrons, they are [[Lewis base]]s.

''Nucleophilic'' describes the affinity of a nucleophile to bond with positively charged [[Atomic nucleus|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 [[atom]]s. Neutral nucleophilic reactions with [[solvent]]s such as [[Alcohol (chemistry)|alcohol]]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]]. 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 [[chemical kinetics|kinetic]] property, which relates to rates of certain chemical reactions.<ref>{{Cite journal |last=Uggerud |first=Einar |date=2006-01-23 |title=Nucleophilicity—Periodic Trends and Connection to Basicity |url=https://chemistry-europe.onlinelibrary.wiley.com/doi/10.1002/chem.200500639 |journal=Chemistry – A European Journal |language=en |volume=12 |issue=4 |pages=1127–1136 |doi=10.1002/chem.200500639 |pmid=16247828 |issn=0947-6539|url-access=subscription }}</ref>

== History and etymology ==
The terms ''nucleophile'' and ''[[electrophile]]'' were introduced by [[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 (journal)|Nature]] |date=1925|volume= 115|page= 625|title = Replaceability of Halogen Atoms by Hydrogen Atoms}}</ref> The word nucleophile is derived from [[atomic nucleus|nucleus]] and the Greek word φιλος, philos, meaning friend.{{cn|date=April 2025}}

== 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.{{cn|date=March 2024}}

=== Nucleophilicity ===
Many schemes attempting to quantify relative nucleophilic strength have been devised. The following [[empirical]] data have been obtained by measuring [[reaction rate]]s for many reactions involving many nucleophiles and electrophiles. Nucleophiles displaying the so-called [[alpha effect]] are usually omitted in this type of treatment.{{cn|date=March 2024}}

==== Swain–Scott equation ====
The first such attempt is found in the Swain–Scott equation<ref>{{Cite journal |last1=Swain |first1=C. Gardner |last2=Scott |first2=Carleton B. |date=January 1953 |title=Quantitative Correlation of Relative Rates. Comparison of Hydroxide Ion with Other Nucleophilic Reagents toward Alkyl Halides, Esters, Epoxides and Acyl Halides 1 |url=https://pubs.acs.org/doi/abs/10.1021/ja01097a041 |journal=Journal of the American Chemical Society |language=en |volume=75 |issue=1 |pages=141–147 |doi=10.1021/ja01097a041 |bibcode=1953JAChS..75..141S |issn=0002-7863|url-access=subscription }}</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 [[free-energy relationship]] relates the [[pseudo first order reaction|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]] 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 [[tosylate|ethyl tosylate]], 0.77 for [[lactone|β-propiolactone]], 1.00 for [[epoxide|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:<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>{{Cite journal |last=Ritchie |first=Calvin D. |date=1972-10-01 |title=Nucleophilic reactivities toward cations |url=https://pubs.acs.org/doi/abs/10.1021/ar50058a005 |journal=Accounts of Chemical Research |language=en |volume=5 |issue=10 |pages=348–354 |doi=10.1021/ar50058a005 |issn=0001-4842|url-access=subscription }}</ref><ref>{{Cite journal |last=Ritchie |first=Calvin D. |date=March 1975 |title=Cation-anion combination reactions. XIII. Correlation of the reactions of nucleophiles with esters |url=https://pubs.acs.org/doi/abs/10.1021/ja00838a035 |journal=Journal of the American Chemical Society |language=en |volume=97 |issue=5 |pages=1170–1179 |doi=10.1021/ja00838a035 |bibcode=1975JAChS..97.1170R |issn=0002-7863|url-access=subscription }}</ref>
:<math>\log_{10}\left(\frac{k}{k_0}\right) = N^+</math>

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 [[carbocation]]s such as [[tropylium]] or [[diazonium]] cations:
:[[File:RichieEquationDiazonium.png|400px|Ritchie equation diazonium ion reactions]]

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):<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 [[rate law|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 ion]]s as the [[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| bibcode = 2001JAChS.123.9500M| 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 = [[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.<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 [[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 [[piperidine]], 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:<ref name=Mayr2006 />
:''<math>\log(k) = s_Es_N(N + E)</math>''

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
::<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 sE = 1 for carbocations and sN = 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−, or a compound with a [[lone pair]] of electrons such as NH3 ([[ammonia]]) and PR3.{{cn|date=March 2024}}

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 [[alkyl halide|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 an inversion of the [[Molecular configuration|configuration]] of the electrophile. If the electrophile is [[chiral]], it typically maintains its chirality, though the SN2 product's [[absolute configuration]] is flipped as compared to that of the original electrophile.{{cn|date=March 2024}}
:[[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 [[thiocyanate]] ion (SCN−) may attack from either the sulfur or the nitrogen. For this reason, the [[SN2 reaction|SN2 reaction]] of an alkyl halide with SCN− often leads to a mixture of an alkyl thiocyanate (R-SCN) and an alkyl [[isothiocyanate]] (R-NCS). Similar considerations apply in the [[Kolbe nitrile synthesis]].{{cn|date=March 2024}}

=== Halogens ===
While the [[halogens]] 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.<ref>''Chem 2401 Supplementary Notes''. Thompson, Alison and Pincock, James, Dalhousie University Chemistry Department</ref>

=== Carbon ===
{{See also|Carbanion}}
Carbon nucleophiles are often [[Organometallic chemistry|organometallic reagent]]s such as those found in the [[Grignard reaction]], [[Blaise reaction]], [[Reformatsky reaction]], and [[Barbier reaction]] or reactions involving [[organolithium reagent]]s and [[acetylide]]s. These reagents are often used to perform [[nucleophilic addition]]s.{{cn|date=March 2024}}

[[Enol]]s are also carbon nucleophiles. The formation of an enol is catalyzed by [[Acid catalysis|acid]] or [[Base (chemistry)|base]]. Enols are [[wikt:ambident|ambident]] nucleophiles, but, in general, nucleophilic at the [[Alpha and beta carbon|alpha carbon]] atom. Enols are commonly used in [[condensation reaction]]s, including the [[Claisen condensation]] and the [[aldol condensation]] reactions.{{cn|date=March 2024}}

=== Oxygen ===
Examples of oxygen nucleophiles are [[water]] (H2O), [[hydroxide]] anion, [[Alcohol (chemistry)|alcohol]]s, [[alkoxide]] anions, [[hydrogen peroxide]], and [[Carboxylate|carboxylate anions]].
Nucleophilic attack does not take place during intermolecular hydrogen bonding.

=== Sulfur ===
Of sulfur nucleophiles, [[hydrogen sulfide]] and its salts, [[thiol]]s (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]], [[amine]]s, [[nitrite]]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 B12]] (vitamin B12s) is about 107 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)|journal=Journal of the American Chemical Society|language=en|volume=90|issue=9|pages=2441–2442|doi=10.1021/ja01011a054|pmid=5642073|bibcode=1968JAChS..90.2441S |issn=0002-7863}}</ref> Other supernucleophilic metal centers include low oxidation state carbonyl metalate anions (e.g., CpFe(CO)2–).<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|journal=Journal of the American Chemical Society|language=en|volume=88|issue=22|pages=5121–5124|doi=10.1021/ja00974a015|bibcode=1966JAChS..88.5121D |issn=0002-7863}}</ref>

== Examples ==
The following table shows the nucleophilicity of some molecules with methanol as the solvent:<ref>{{cite web |author1=Ian Hunt |title=Chapter 8: Nucleophiles |url=http://www.chem.ucalgary.ca/courses/350/Carey5th/Ch08/ch8-5.html |website=chem.ucalgary.ca |publisher=University of Calgary |access-date=15 April 2024 |language=en}}</ref>
{| class="wikitable"
!Relative nucleophilicity
!Molecules
|-
|Very Good
|I⁻, HS⁻, RS⁻
|-
|Good
|Br⁻, OH⁻, RO⁻, CN⁻, N3⁻
|-
|Fair
|NH3, Cl⁻, F⁻, RCO2⁻
|-
|Weak
|H2O, ROH
|-
|Very Weak
|RCO2H
|}

== See also ==
* {{annotated link|Electrophile}}
* {{annotated link|Lewis acids and bases}}
* {{annotated link|Nucleophilic abstraction}}
* {{annotated link|Addition to pi ligands}}

== References ==
{{reflist}}

[[Category:Physical organic chemistry]]

Nucleophile - Revision history

~2025-35033-57: /* Histor and etymology */