Nucleophile

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A hydroxide ion acting as a nucleophile in an SN2 reaction, converting a haloalkane into an alcohol Hydrox subst.png
A hydroxide ion acting as a nucleophile in an SN2 reaction, converting a haloalkane into an alcohol

In chemistry, a nucleophile is a chemical species that forms bonds by donating an electron pair. All molecules and ions with a free pair of electrons or at least one pi bond can act as nucleophiles. Because nucleophiles donate electrons, they are Lewis bases.

Contents

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 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, 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 kinetic property, which relates to rates of certain chemical reactions. [1]

History and Etymology

The terms nucleophile and electrophile were introduced by Christopher Kelk Ingold in 1933, [2] replacing the terms anionoid and cationoid proposed earlier by A. J. Lapworth in 1925. [3] The word nucleophile is derived from 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 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 ]

Nucleophilicity

Many schemes attempting to quantify relative nucleophilic strength have been devised. The following empirical data have been obtained by measuring reaction rates for many reactions involving many nucleophiles and electrophiles. Nucleophiles displaying the so-called alpha effect are usually omitted in this type of treatment.[ citation needed ]

Swain–Scott equation

The first such attempt is found in the Swain–Scott equation [4] [5] derived in 1953:

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.

Ritchie equation

The Ritchie equation, derived in 1972, is another free-energy relationship: [6] [7] [8]

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 or diazonium cations:

RichieEquationDiazonium.png

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): [9]

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: [10]

Benzhydryliumion.png

and a diverse collection of π-nucleophiles:

MayrNucleophiles.png .

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. [11]

The range of organic reactions also include SN2 reactions: [12]

Mayr2006.png

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: [12]

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
or the original Scott–Swain equation written as:
  • with sE = 1 for carbocations and sN = 0.6 the equation becomes:
or the original Ritchie equation written as:

Types

Examples of nucleophiles are anions such as Cl−, or a compound with a lone pair of electrons such as NH3 (ammonia) and PR3.[ citation needed ]

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 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 a inversion of the 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.[ citation needed ]

Hydrox subst.png

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 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.[ citation needed ]

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. [13]

Carbon

Carbon nucleophiles are often organometallic reagents such as those found in the Grignard reaction, Blaise reaction, Reformatsky reaction, and Barbier reaction or reactions involving organolithium reagents and acetylides. These reagents are often used to perform nucleophilic additions.[ citation needed ]

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.[ citation needed ]

Oxygen

Examples of oxygen nucleophiles are water (H2O), hydroxide anion, alcohols, alkoxide anions, hydrogen peroxide, and carboxylate anions. Nucleophilic attack does not take place during intermolecular hydrogen bonding.

Sulfur

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

Nitrogen nucleophiles include ammonia, azide, amines, nitrites, 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 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]

Examples

The following table shows the nucleophilicity of some molecules with methanol as the solvent: [16]

Relative nucleophilicityMolecules
Very GoodI⁻, HS⁻, RS⁻
GoodBr⁻, OH⁻, RO⁻, CN⁻, N3⁻
FairNH3, Cl⁻, F⁻, RCO2⁻
WeakH2O, ROH
Very WeakRCO2H

See also

Related Research Articles

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A chemical reaction is a process that leads to the chemical transformation of one set of chemical substances to another. When chemical reactions occur, the atoms are rearranged and the reaction is accompanied by an energy change as new products are generated. Classically, chemical reactions encompass changes that only involve the positions of electrons in the forming and breaking of chemical bonds between atoms, with no change to the nuclei, and can often be described by a chemical equation. Nuclear chemistry is a sub-discipline of chemistry that involves the chemical reactions of unstable and radioactive elements where both electronic and nuclear changes can occur.

In chemistry, a nucleophilic substitution (SN) is a class of chemical reactions in which an electron-rich chemical species replaces a functional group within another electron-deficient molecule. The molecule that contains the electrophile and the leaving functional group is called the substrate.

The unimolecular nucleophilic substitution (SN1) reaction is a substitution reaction in organic chemistry. The Hughes-Ingold symbol of the mechanism expresses two properties—"SN" stands for "nucleophilic substitution", and the "1" says that the rate-determining step is unimolecular. Thus, the rate equation is often shown as having first-order dependence on the substrate and zero-order dependence on the nucleophile. This relationship holds for situations where the amount of nucleophile is much greater than that of the intermediate. Instead, the rate equation may be more accurately described using steady-state kinetics. The reaction involves a carbocation intermediate and is commonly seen in reactions of secondary or tertiary alkyl halides under strongly basic conditions or, under strongly acidic conditions, with secondary or tertiary alcohols. With primary and secondary alkyl halides, the alternative SN2 reaction occurs. In inorganic chemistry, the SN1 reaction is often known as the dissociative substitution. This dissociation pathway is well-described by the cis effect. A reaction mechanism was first introduced by Christopher Ingold et al. in 1940. This reaction does not depend much on the strength of the nucleophile, unlike the SN2 mechanism. This type of mechanism involves two steps. The first step is the ionization of alkyl halide in the presence of aqueous acetone or ethyl alcohol. This step provides a carbocation as an intermediate.

<span class="mw-page-title-main">Leaving group</span> Atom(s) which detach from the substrate during a chemical reaction

In chemistry, a leaving group is defined by the IUPAC as an atom or group of atoms that detaches from the main or residual part of a substrate during a reaction or elementary step of a reaction. However, in common usage, the term is often limited to a fragment that departs with a pair of electrons in heterolytic bond cleavage. In this usage, a leaving group is a less formal but more commonly used synonym of the term nucleofuge. In this context, leaving groups are generally anions or neutral species, departing from neutral or cationic substrates, respectively, though in rare cases, cations leaving from a dicationic substrate are also known.

S<sub>N</sub>2 reaction Organic chemistry reaction

The bimolecular nucleophilic substitution (SN2) is a type of reaction mechanism that is common in organic chemistry. In the SN2 reaction, a strong nucleophile forms a new bond to an sp3-hybridised carbon atom via a backside attack, all while the leaving group detaches from the reaction center in a concerted fashion.

In chemistry, an electrophile is a chemical species that forms bonds with nucleophiles by accepting an electron pair. Because electrophiles accept electrons, they are Lewis acids. Most electrophiles are positively charged, have an atom that carries a partial positive charge, or have an atom that does not have an octet of electrons.

In organic chemistry, a nucleophilic addition (AN) reaction is an addition reaction where a chemical compound with an electrophilic double or triple bond reacts with a nucleophile, such that the double or triple bond is broken. Nucleophilic additions differ from electrophilic additions in that the former reactions involve the group to which atoms are added accepting electron pairs, whereas the latter reactions involve the group donating electron pairs.

A substitution reaction is a chemical reaction during which one functional group in a chemical compound is replaced by another functional group. Substitution reactions are of prime importance in organic chemistry. Substitution reactions in organic chemistry are classified either as electrophilic or nucleophilic depending upon the reagent involved, whether a reactive intermediate involved in the reaction is a carbocation, a carbanion or a free radical, and whether the substrate is aliphatic or aromatic. Detailed understanding of a reaction type helps to predict the product outcome in a reaction. It also is helpful for optimizing a reaction with regard to variables such as temperature and choice of solvent.

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<span class="mw-page-title-main">Nucleophilic aromatic substitution</span> Chemical reaction mechanism

A nucleophilic aromatic substitution (SNAr) is a substitution reaction in organic chemistry in which the nucleophile displaces a good leaving group, such as a halide, on an aromatic ring. Aromatic rings are usually nucleophilic, but some aromatic compounds do undergo nucleophilic substitution. Just as normally nucleophilic alkenes can be made to undergo conjugate substitution if they carry electron-withdrawing substituents, so normally nucleophilic aromatic rings also become electrophilic if they have the right substituents.

<span class="mw-page-title-main">Nucleophilic conjugate addition</span> Organic reaction

Nucleophilic conjugate addition is a type of organic reaction. Ordinary nucleophilic additions or 1,2-nucleophilic additions deal mostly with additions to carbonyl compounds. Simple alkene compounds do not show 1,2 reactivity due to lack of polarity, unless the alkene is activated with special substituents. With α,β-unsaturated carbonyl compounds such as cyclohexenone it can be deduced from resonance structures that the β position is an electrophilic site which can react with a nucleophile. The negative charge in these structures is stored as an alkoxide anion. Such a nucleophilic addition is called a nucleophilic conjugate addition or 1,4-nucleophilic addition. The most important active alkenes are the aforementioned conjugated carbonyls and acrylonitriles.

In organic chemistry, umpolung or polarity inversion is the chemical modification of a functional group with the aim of the reversal of polarity of that group. This modification allows secondary reactions of this functional group that would otherwise not be possible. The concept was introduced by D. Seebach and E.J. Corey. Polarity analysis during retrosynthetic analysis tells a chemist when umpolung tactics are required to synthesize a target molecule.

An electron-withdrawing group (EWG) is a group or atom that has the ability to draw electron density toward itself and away from other adjacent atoms. This electron density transfer is often achieved by resonance or inductive effects. Electron-withdrawing groups have significant impacts on fundamental chemical processes such as acid-base reactions, redox potentials, and substitution reactions.

In organic chemistry, the Hammett equation describes a linear free-energy relationship relating reaction rates and equilibrium constants for many reactions involving benzoic acid derivatives with meta- and para-substituents to each other with just two parameters: a substituent constant and a reaction constant. This equation was developed and published by Louis Plack Hammett in 1937 as a follow-up to qualitative observations in his 1935 publication.

The alpha effect refers to the increased nucleophilicity of an atom due to the presence of an adjacent (alpha) atom with lone pair electrons. This first atom does not necessarily exhibit increased basicity compared with a similar atom without an adjacent electron-donating atom, resulting in a deviation from the classical Brønsted-type reactivity-basicity relationship. In other words, the alpha effect refers to nucleophiles presenting higher nucleophilicity than the predicted value obtained from the Brønsted basicity. The representative examples would be high nucleophilicities of hydroperoxide (HO2−) and hydrazine (N2H4). The effect is now well established with numerous examples and became an important concept in mechanistic chemistry and biochemistry. However, the origin of the effect is still controversial without a clear winner.

<span class="mw-page-title-main">Flippin–Lodge angle</span>

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Electrophilic amination is a chemical process involving the formation of a carbon–nitrogen bond through the reaction of a nucleophilic carbanion with an electrophilic source of nitrogen.

<span class="mw-page-title-main">Carbonyl α-substitution reaction</span> Chemical reaction

Carbonyl α-substitution reactions occur at the position next to the carbonyl group, the α-position, and involves the substitution of an α-hydrogen by an electrophile through either an enol or enolate ion intermediate.

The Edwards equation in organic chemistry is a two-parameter equation for correlating nucleophilic reactivity, as defined by relative rate constants, with the basicity of the nucleophile and its polarizability. This equation was first developed by John O. Edwards in 1954 and later revised based on additional work in 1956.

<span class="mw-page-title-main">Superelectrophilic anion</span> Superelectrophilic anions

Superelectrophilic anions are a class of molecular ions that exhibit highly electrophilic reaction behavior despite their overall negative charge. Thus, they are even able to bind the unreactive noble gases or molecular nitrogen at room temperature. The only representatives known so far are the fragment ions of the type [B12X11]– derived from the closo-dodecaborate dianions [B12X12]2–. X represents a substituent connected to a boron atom (cf. Fig. 1). For this reason, the following article deals exclusively with superelectrophilic anions of this type.

References

  1. ↑ Uggerud, Einar (2006-01-23). "Nucleophilicity—Periodic Trends and Connection to Basicity". Chemistry – A European Journal. 12 (4): 1127–1136. doi:10.1002/chem.200500639. ISSN   0947-6539.
  2. ↑ Ingold, C. K. (1933). "266. Significance of tautomerism and of the reactions of aromatic compounds in the electronic theory of organic reactions". Journal of the Chemical Society (Resumed): 1120. doi:10.1039/jr9330001120.
  3. ↑ Lapworth, A. (1925). "Replaceability of Halogen Atoms by Hydrogen Atoms". Nature . 115: 625.
  4. ↑ Swain, C. Gardner; Scott, Carleton B. (January 1953). "Quantitative Correlation of Relative Rates. Comparison of Hydroxide Ion with Other Nucleophilic Reagents toward Alkyl Halides, Esters, Epoxides and Acyl Halides 1". Journal of the American Chemical Society. 75 (1): 141–147. doi:10.1021/ja01097a041. ISSN   0002-7863.
  5. ↑ "Swain–Scott equation". The IUPAC Compendium of Chemical Terminology. 2014. doi: 10.1351/goldbook.S06201 .
  6. ↑ "Ritchie equation". The IUPAC Compendium of Chemical Terminology. 2014. doi: 10.1351/goldbook.R05402 .
  7. ↑ Ritchie, Calvin D. (1972-10-01). "Nucleophilic reactivities toward cations". Accounts of Chemical Research. 5 (10): 348–354. doi:10.1021/ar50058a005. ISSN   0001-4842.
  8. ↑ Ritchie, Calvin D. (March 1975). "Cation-anion combination reactions. XIII. Correlation of the reactions of nucleophiles with esters". Journal of the American Chemical Society. 97 (5): 1170–1179. doi:10.1021/ja00838a035. ISSN   0002-7863.
  9. ↑ Mayr, Herbert; Patz, Matthias (1994). "Scales of Nucleophilicity and Electrophilicity: A System for Ordering Polar Organic and Organometallic Reactions". Angewandte Chemie International Edition in English. 33 (9): 938. doi:10.1002/anie.199409381.
  10. ↑ Mayr, Herbert; Bug, Thorsten; Gotta, Matthias F; Hering, Nicole; Irrgang, Bernhard; Janker, Brigitte; Kempf, Bernhard; Loos, Robert; Ofial, Armin R; Remennikov, Grigoriy; Schimmel, Holger (2001). "Reference Scales for the Characterization of Cationic Electrophiles and Neutral Nucleophiles". Journal of the American Chemical Society. 123 (39): 9500–12. doi:10.1021/ja010890y. PMID   11572670. S2CID   8392147.
  11. ↑ An internet database for reactivity parameters maintained by the Mayr group is available at http://www.cup.uni-muenchen.de/oc/mayr/
  12. 1 2 Phan, Thanh Binh; Breugst, Martin; Mayr, Herbert (2006). "Towards a General Scale of Nucleophilicity?". Angewandte Chemie International Edition. 45 (23): 3869–74. CiteSeerX   10.1.1.617.3287 . doi:10.1002/anie.200600542. PMID   16646102.
  13. ↑ Chem 2401 Supplementary Notes. Thompson, Alison and Pincock, James, Dalhousie University Chemistry Department
  14. ↑ Schrauzer, G. N.; Deutsch, E.; Windgassen, R. J. (April 1968). "The nucleophilicity of vitamin B(sub 12s)". Journal of the American Chemical Society. 90 (9): 2441–2442. doi:10.1021/ja01011a054. ISSN   0002-7863. PMID   5642073.
  15. ↑ Dessy, Raymond E.; Pohl, Rudolph L.; King, R. Bruce (November 1966). "Organometallic Electrochemistry. VII. 1 The Nucleophilicities of Metallic and Metalloidal Anions Derived from Metals of Groups IV, V, VI, VII, and VIII". Journal of the American Chemical Society. 88 (22): 5121–5124. doi:10.1021/ja00974a015. ISSN   0002-7863.
  16. ↑ Ian Hunt. "Chapter 8: Nucleophiles". chem.ucalgary.ca. University of Calgary. Retrieved 15 April 2024.
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