nucleophile

nucleophile

[noo-klee-uh-fil-ik, nyoo-]

Atom or molecule that contains an electron pair available for bonding and in chemical reactions therefore seeks a positive centre, such as the nucleus of an atom or the positive end of a polar molecule (see covalent bond; electric dipole). In the Lewis electron theory (see acid-base theory), advanced by the U.S. chemist Gilbert Lewis (1875–1946) in 1923, nucleophiles are by definition Lewis bases. Examples include the hydroxide ion (OH), the ions of the halogens chlorine, bromine, and iodine (Cl, Br, and I, respectively), ammonia (NH3), and water (H2O). Seealso base; electrophile.

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In chemistry, a nucleophile (literally nucleus lover as in nucleus and phile) is a reagent that forms a chemical bond to its reaction partner (the electrophile) by donating both bonding electrons. Because nucleophiles donate electrons, they are by definition Lewis bases (see acid-base reaction theories). All molecules or ions with a free pair of electrons can act as nucleophiles, although negative ions (anions) are more potent than neutral reagents. 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 on an element and displaces the group it is bonded to.

Nucleophilic is an adjective that describes the affinity of a nucleophile to the nuclei, while nucleophilicity or nucleophile strength refers to the nucleophilic character. Nucleophilicity is often used to compare an atom's relative affinity to another's.

In general, in a row 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. 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) is more nucleophilic than the fluoride ion (F).

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 or the . For this reason, the SN2 reaction of an alkyl halide with SCN often leads to a mixture of RSCN (an alkyl thiocyanate) and RNCS (an alkyl isothiocyanate). Similar considerations apply in the Kolbe nitrile synthesis.

The terms nucleophile and electrophile were introduced by Christopher Kelk Ingold in 1929, replacing the terms cationoid and anionoid proposed earlier by A. J. Lapworth in 1925.

Common examples

In the example below, the oxygen of the hydroxide ion donates an electron to bond with the carbon at the end of the 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): The picture is incorrect, 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 reversal of the stereochemistry of the electrophile. If the electrophile is chiral, it typically maintains it's chirality, though the SN2 product's configuration is flipped as compared to that of the original electrophile.

Carbon nucleophiles

Carbon nucleophiles are alkyl metal halides found in the Grignard reaction, Blaise reaction, Reformatsky reaction, and Barbier reaction, organolithium reagents and anions of a terminal alkyne.

Enols are also carbon nucleophiles. The formation of an enol is catalyzed by acid or base. Enols are ambident nucleophiles, but generally nucleophilic at the alpha carbon atom. Enols are commonly used in condensation reactions, including the Claisen condensation and the aldol condensation reactions.

Oxygen nucleophiles

Examples of oxygen nucleophiles are Water (H2O) and Alcohols.

Sulfur nucleophiles

Sulfur nucleophiles are Thiols (HS).

Sulfur is generally very nucleophilic because of its large size, which makes it easily polarizable, and its lone pairs of electrons (in some cases).

Nitrogen nucleophiles

Nitrogen nucleophiles are Ammonia, Azide and Amines.

Nucleophilicity scales

Many schemes have been devised attempting to quantify relative nucleophilic strength. The following empirical data have been obtained by measuring reaction rates for a large number of reactions involving a large number of nucleophiles and electrophiles and linear regression. 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 so-called Swain-Scott equation derived in 1953:

log(k/k_0) = s*n

This free-energy relationship relates the pseudo first order reaction 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 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 ethyl tosylate, 0.77 for β-propiolactone, 1.00 for 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.

Richie equation

The Richie equation named after its creator and derived in 1972 is another free-energy relationship:

log(k/k_0) = N^+

or

log(k) = N^+ + log(k_0)

where N+ is the nucleophile dependent parameter and k0 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 carbocations such as tropylium cations:

or diazonium cations:

or (not displayed) ions based on Malachite green. Subsequently many other reaction types were described.

Typical Richie 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):

log(k) = s(N + E)

The 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 ions as the electrophiles:

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 parenthesis are -4.47 (1.32) for electrophilic aromatic substitution to toluene (1), -1.41 (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 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:

log(k) = s_Es_N(N + E)

with sE the electrophile-dependent slope parameter and sN the nucleophile-dependent slop 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

log(k) = 0.6s_EN + 0.6s_EE
or the original Scott-Swain equation written as:
log(k) = log(k_0) + s_EN

  • with sE = 1 for carbocations and sN = 0.6 the equation becomes:

log(k) = 0.6N + 0.6E
or the original Ritchie equation written as:
log(k) - log(k_0) = N^+

See also

References

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