Inchemistry, anucleophile is achemical species that forms bonds by donating anelectron pair. Allmolecules andions with a free pair of electrons or at least onepi bond can act as nucleophiles. Because nucleophiles donate electrons, they areLewis bases.
Nucleophilic describes the affinity of a nucleophile to bond with positively chargedatomic nuclei. Nucleophilicity, sometimes referred to as nucleophile strength, refers to a substance's nucleophilic character and is often used to compare the affinity ofatoms. Neutral nucleophilic reactions withsolvents such asalcohols and water are namedsolvolysis. Nucleophiles may take part innucleophilic substitution, whereby a nucleophile becomes attracted to a full or partial positive charge, andnucleophilic addition. Nucleophilicity is closely related tobasicity. The difference between the two is, thatbasicity is athermodynamic property (i.e. relates to an equilibrium state), but nucleophilicity is akinetic property, which relates to rates of certain chemical reactions.[1]
The termsnucleophile andelectrophile were introduced byChristopher Kelk Ingold in 1933,[2] replacing the termsanionoid andcationoid proposed earlier byA. J. Lapworth in 1925.[3] The word nucleophile is derived fromnucleus and the Greek wordφιλος, philos, meaning friend.
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.[citation needed]
Many schemes attempting to quantify relative nucleophilic strength have been devised. The followingempirical data have been obtained by measuringreaction rates for many reactions involving many nucleophiles and electrophiles. Nucleophiles displaying the so-calledalpha effect are usually omitted in this type of treatment.[citation needed]
The first such attempt is found in the Swain–Scott equation[4][5] derived in 1953:
Thisfree-energy relationship relates thepseudo first orderreaction rate constant (in water at 25 °C),k, of a reaction, normalized to the reaction rate,k0, of a standard reaction with water as the nucleophile, to a nucleophilic constantn for a given nucleophile and a substrate constants that depends on the sensitivity of a substrate to nucleophilic attack (defined as 1 formethyl 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, andthiosulfate 6.4. Typical substrate constants are 0.66 forethyl tosylate, 0.77 forβ-propiolactone, 1.00 for2,3-epoxypropanol, 0.87 forbenzyl chloride, and 1.43 forbenzoyl chloride.
The equation predicts that, in anucleophilic displacement onbenzyl chloride, theazide anion reacts 3000 times faster than water.
The Ritchie equation, derived in 1972, is another free-energy relationship:[6][7][8]
whereN+ is the nucleophile dependent parameter andk0 thereaction rate constant for water. In this equation, a substrate-dependent parameter likes 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 thereactivity–selectivity principle. For this reason, this equation is also called theconstant selectivity relationship.
In the original publication the data were obtained by reactions of selected nucleophiles with selected electrophiliccarbocations such astropylium ordiazonium cations:
or (not displayed) ions based onmalachite green. Many other reaction types have since been described.
Typical RitchieN+ values (inmethanol) are: 0.5 formethanol, 5.9 for thecyanide anion, 7.5 for themethoxide anion, 8.5 for theazide anion, and 10.7 for thethiophenol anion. The values for the relative cation reactivities are −0.4 for the malachite green cation, +2.6 for thebenzenediazonium cation, and +4.5 for thetropylium cation.
In the Mayr–Patz equation (1994):[9]
Thesecond orderreaction rate constantk at 20 °C for a reaction is related to a nucleophilicity parameterN, an electrophilicity parameterE, and a nucleophile-dependent slope parameters. The constants is defined as 1 with2-methyl-1-pentene as the nucleophile.
Many of the constants have been derived from reaction of so-calledbenzhydrylium ions as theelectrophiles:[10]
and a diverse collection of π-nucleophiles:
.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) forelectrophilic aromatic substitution totoluene (1), −0.41 (1.12) forelectrophilic 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 with2-methylfuran (5), +7.48 (0.89) for reaction with isobutenyltributylstannane (6) and +13.36 (0.81) for reaction with theenamine 7.[11]
The range of organic reactions also includeSN2 reactions:[12]
With E = −9.15 for theS-methyldibenzothiophenium ion, typical nucleophile values N (s) are 15.63 (0.64) forpiperidine, 10.49 (0.68) formethoxide, and 5.20 (0.89) for water. In short, nucleophilicities towards sp2 or sp3 centers follow the same pattern.
In an effort to unify the above described equations the Mayr equation is rewritten as:[12]
with sE the electrophile-dependent slope parameter and sN the nucleophile-dependent slope parameter. This equation can be rewritten in several ways:
Examples of nucleophiles are anions such as Cl−, or a compound with alone pair of electrons such as NH3 (ammonia) and PR3.[citation needed]
In the example below, theoxygen of the hydroxide ion donates an electron pair to form a new chemical bond with thecarbon at the end of thebromopropane molecule. The bond between the carbon and thebromine then undergoesheterolytic fission, with the bromine atom taking the donated electron and becoming thebromide 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 theconfiguration of the electrophile. If the electrophile ischiral, it typically maintains its chirality, though the SN2 product'sabsolute configuration is flipped as compared to that of the original electrophile.[citation needed]
Anambident nucleophile is one that can attack from two or more places, resulting in two or more products. For example, thethiocyanate ion (SCN−) may attack from either the sulfur or the nitrogen. For this reason, theSN2 reaction of an alkyl halide with SCN− often leads to a mixture of an alkyl thiocyanate (R-SCN) and an alkylisothiocyanate (R-NCS). Similar considerations apply in theKolbe nitrile synthesis.[citation needed]
While thehalogens 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.[13]
Carbon nucleophiles are oftenorganometallic reagents such as those found in theGrignard reaction,Blaise reaction,Reformatsky reaction, andBarbier reaction or reactions involvingorganolithium reagents andacetylides. These reagents are often used to performnucleophilic additions.[citation needed]
Enols are also carbon nucleophiles. The formation of an enol is catalyzed byacid orbase. Enols areambident nucleophiles, but, in general, nucleophilic at thealpha carbon atom. Enols are commonly used incondensation reactions, including theClaisen condensation and thealdol condensation reactions.[citation needed]
Examples of oxygen nucleophiles arewater (H2O),hydroxide anion,alcohols,alkoxide anions,hydrogen peroxide, andcarboxylate anions.Nucleophilic attack does not take place during intermolecular hydrogen bonding.
Of sulfur nucleophiles,hydrogen sulfide 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 nucleophiles includeammonia,azide,amines,nitrites,hydroxylamine,hydrazine,carbazide,phenylhydrazine,semicarbazide, andamide.
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 ofvitamin B12 (vitamin B12s) is about 107 times more nucleophilic.[14] Other supernucleophilic metal centers include low oxidation state carbonyl metalate anions (e.g., CpFe(CO)2–).[15]
The following table shows the nucleophilicity of some molecules with methanol as the solvent:[16]
| 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 |
