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| A '''nucleophile''' is a [[chemical species]] that donates an [[electron pair]] to an [[electrophile]] to form a [[chemical bond]] in relation to a [[Chemical reaction|reaction]]. All [[molecule]]s or [[ion]]s with a free pair of electrons or at least one [[pi bond]] can act as nucleophiles. Because nucleophiles donate electrons, they are by definition [[Lewis base]]s.
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| '''Nucleophilic''' describes the affinity of a nucleophile to the 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.
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| Neutral nucleophilic reactions with solvents such as [[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.
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| ==History==
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| The terms ''nucleophile'' and ''electrophile'' were introduced by [[Christopher Kelk Ingold]] in 1929,<ref>Ingold, C. K. Recl. TraV. Chim. Pays-Bas '''1929'''</ref> replacing the terms ''anionoid'' and ''cationoid'' proposed earlier by [[A. J. Lapworth]] in 1925.<ref>Lapworth, A. [[Nature (journal)|Nature]] '''1925''', 115, 625</ref>
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| The word nucleophile is derived from [[atomic nucleus|nucleus]] and the Greek word [[-phil-|φιλος, philos]] for love.
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| ==Properties== | |
| In general, in a row 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. In a given group, [[polarizability]] is more important in the determination of the nucleophilicity: The easier it is to distort the electron cloud around an atom or molecule the more readily it will react; e.g., the [[iodide]] ion (I<sup>−</sup>) is more nucleophilic than the [[fluoride]] ion (F<sup>−</sup>).
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| ===Nucleophilicity===
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| Many schemes attempting to quantify relative nucleophilic strength have been devised. The following [[empirical]] data have been obtained by measuring [[reaction rate]]s for a large number of reactions involving a large number of nucleophiles and electrophiles. Nucleophiles displaying the so-called [[alpha effect]] are usually omitted in this type of treatment.
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| ====Swain-Scott equation====
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| 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. [http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/1953/75/i01/f-pdf/f_ja01097a041.pdf Abstract]</ref><ref>[[Gold Book]] definition (Swain-Scott) [http://www.iupac.org/goldbook/S06201.pdf Link]</ref> derived in 1953:
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| :<math>\log_{10}\left(\frac{k}{k_0}\right) = sn</math>
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| 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''<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]]).
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| 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]].
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| The equation predicts that, in a [[nucleophilic displacement]] on [[benzyl chloride]], the [[azide]] anion reacts 3000 times faster than water.
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| ====Ritchie equation====
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| The Ritchie equation, derived in 1972, is another free-energy relationship:<ref>[[Gold Book]] definition (Ritchie) [http://www.iupac.org/goldbook/R05402.pdf Link]</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.pdf Abstract]
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| </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.
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| [http://pubs.acs.org/cgi-bin/abstract.cgi/jacsat/1975/97/i05/f-pdf/f_ja00838a035.pdf Abstract]</ref> | |
| :<math>\log_{10}\left(\frac{k}{k_0}\right) = N^+</math>
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| where ''N''<sup>+</sup> is the nucleophile dependent parameter and ''k''<sub>0</sub> 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''.
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| In the original publication the data were obtained by reactions of selected nucleophiles with selected electrophilic [[carbocation]]s such as [[tropylium]] cations:
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| or [[diazonium]] cations:
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| :[[Image:RichieEquationDiazonium.png|400px|Ritchie equation diazonium ion reactions]]
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| or (not displayed) ions based on [[Malachite green]]. Many other reaction types have since been described.
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| Typical Ritchie '''N<sup>+</sup>''' 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]].
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| ====Mayr-Patz equation====
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| In the Mayr-Patz equation (1994):<ref>''Scales of Nucleophilicity and Electrophilicity: A System for Ordering Polar Organic and Organometallic Reactions'' [[Angewandte Chemie]] International Edition in English, Vol. 33, No. 9, P. 938-957 {{DOI|10.1002/anie.199409381}}</ref>
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| <math>\ log(k) = s(N + E)</math>
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| 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.
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| Many of the constants have been derived from reaction of so-called benzhydrylium ions as the [[electrophile]]s:<ref>''Reference Scales for the Characterization of Cationic Electrophiles and Neutral Nucleophiles''Herbert Mayr, Thorsten Bug, Matthias F. Gotta, Nicole Hering, Bernhard Irrgang, Brigitte Janker, Bernhard Kempf, Robert Loos, Armin R. Ofial, Grigoriy Remennikov, and Holger Schimmel [[J. Am. Chem. Soc.]]; '''2001'''; 123(39) pp 9500 - 9512; (Article) {{DOI|10.1021/ja010890y}}</ref>
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| [[Image:Benzhydryliumion.png|150px|benzhydrylium ions used in the determination of Mayr-Patz equation]]
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| and a diverse collection of π-nucleophiles: | |
| :[[Image:MayrNucleophiles.png|300px|Nucleophiles used in the determination of Mayr-Patz equation, X = tetrafluoroborate anion]].
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| Typical E values are +6.2 for R = [[chlorine]], +5.90 for R = [[hydrogen]], 0 for R = [[methoxy]] and -7.02 for R = [[dimethylamine]].
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| Typical N values with s in parenthesis 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>
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| The range of organic reactions also include [[SN2 reaction]]s:<ref name=Mayr2006>''Towards a General Scale of Nucleophilicity?'' Thanh Binh Phan, Martin Breugst, Herbert Mayr, [[Angewandte Chemie International Edition]]
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| Volume 45, Issue 23 , Pages 3869 - 3874 '''2006''' {{DOI|10.1002/anie.200600542}}</ref>
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| [[Image:Mayr2006.png|400px|Mayr equation also includes SN2 reactions]]
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| 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<sub>2</sub> or sp<sub>3</sub> centers follow the same pattern.
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| ====Unified equation====
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| In an effort to unify the above described equations the Mayr equation is rewritten as:<ref name=Mayr2006/>
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| <math>\log(k) = s_Es_N(N + E)</math>
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| 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,
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| * with s<sub>N</sub> = 0.6 for most n nucleophiles the equation becomes
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| :<math>\log(k) = 0.6s_EN + 0.6s_EE</math>
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| :or the original Scott-Swain equation written as:
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| :<math>\log(k) = \log(k_0) + s_EN</math>
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| * with s<sub>E</sub> = 1 for carbocations and s<sub>N</sub> = 0.6 the equation becomes:
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| :<math>\log(k) = 0.6N + 0.6E</math>
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| :or the original Ritchie equation written as:
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| :<math>\log(k) - \log(k_0) = N^+</math>
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| ==Types==
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| Examples of nucleophiles are anions such as Cl<sup>−</sup>, or a compound with a [[lone pair]] of electrons such as NH<sub>3</sub> (ammonia).
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| In the example below, the [[oxygen]] of the hydroxide ion donates an electron pair to 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<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 reversal of the [[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 configuration is flipped as compared to that of the original electrophile.
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| [[image:hydrox subst.png|Displacement of bromine by a hydroxide]]
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| 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<sup>−</sup>) may attack from either the {{sulfur}} or the {{nitrogen}}. For this reason, the [[SN2 reaction|S<sub>N</sub>2 reaction]] of an alkyl halide with SCN<sup>−</sup> often leads to a mixture of RSCN (an alkyl thiocyanate) and RNCS (an alkyl [[isothiocyanate]]). Similar considerations apply in the [[Kolbe nitrile synthesis]].
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| ===Carbon===
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| Carbon nucleophiles are alkyl metal halides found in the [[Grignard reaction]], [[Blaise reaction]], [[Reformatsky reaction]], and [[Barbier reaction]], [[organolithium reagent]]s, and [[anion]]s of a [[Polymer|terminal]] [[alkyne]].
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| 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 and the aldol condensation reactions.
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| ===Oxygen===
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| Examples of oxygen nucleophiles are [[water]] (H<sub>2</sub>O), [[hydroxide]] anion, [[alcohol]]s, [[alkoxide]] anions, [[hydrogen peroxide]], and [[Carboxylate|carboxylate anions]]
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| Nuclophilic attack does not take place during intermolecular hydrogen bonding.
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| ===Sulfur===
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| Of sulfur nucleophiles, [[hydrogen sulfide]] and its salts, [[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.
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| 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.
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| ===Nitrogen===
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| Nitrogen nucleophiles include [[ammonia]], [[azide]], [[amine]]s, and [[nitrite]]s.
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| == See also ==
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| *[[Electrophile]]
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| *[[Lewis acids and bases]]
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| *[[Nucleophilic abstraction]]
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| *[[Addition to pi ligands]]
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| ==References==
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| {{reflist}}
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| [[Category:Physical organic chemistry]]
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