Nucleophilic Aromatic Substitution
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A nucleophilic aromatic substitution (SNAr) is a
substitution reaction A substitution reaction (also known as single displacement reaction or single substitution reaction) is a chemical reaction during which one functional group in a chemical compound is replaced by another functional group. Substitution reactions ar ...
in
organic chemistry Organic chemistry is a subdiscipline within chemistry involving the science, scientific study of the structure, properties, and reactions of organic compounds and organic matter, organic materials, i.e., matter in its various forms that contain ...
in which the
nucleophile 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 ...
displaces a good
leaving group In organic chemistry, a leaving group typically means a Chemical species, molecular fragment that departs with an electron, electron pair during a reaction step with heterolysis (chemistry), heterolytic bond cleavage. In this usage, a ''leaving gr ...
, such as a
halide In chemistry, a halide (rarely halogenide) is a binary chemical compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative (or more electropositive) than the halogen, to make a fl ...
, on an
aromatic ring In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugation alone. The e ...
. Aromatic rings are usually nucleophilic, but some aromatic compounds do undergo nucleophilic substitution. Just as normally nucleophilic
alkenes In organic chemistry, an alkene, or olefin, is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or at the terminal position. Terminal alkenes are also known as Alpha-olefin, α-olefins. The Internationa ...
can be made to undergo conjugate substitution if they carry electron-withdrawing substituents, so normally nucleophilic aromatic rings also become
electrophilic 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 carr ...
if they have the right
substituents In organic chemistry, a substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety (chemistry), moiety in the resultant (new) molecule. The suffix ''-yl'' is used when naming organic compounds that conta ...
.This reaction differs from a common SN2 reaction, because it happens at a trigonal carbon atom (sp2 hybridization). The mechanism of SN2 reaction does not occur due to steric hindrance of the benzene ring. In order to attack the C atom, the nucleophile must approach in line with the C-LG (leaving group) bond from the back, where the benzene ring lies. It follows the general rule for which SN2 reactions occur only at a tetrahedral carbon atom. The SN1 mechanism is possible but very unfavourable unless the leaving group is an exceptionally good one. It would involve the unaided loss of the leaving group and the formation of an aryl
cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...
. In the SN1 reactions all the cations employed as intermediates were planar with an empty p orbital. This cation is planar but the p orbital is full (it is part of the aromatic ring) and the empty orbital is an sp2 orbital outside the ring.


Nucleophilic aromatic substitution mechanisms

Aromatic rings undergo
nucleophilic substitution In chemistry, a nucleophilic substitution (SN) is a class of chemical reactions in which an electron-rich chemical species (known as a nucleophile) replaces a functional group within another electron-deficient molecule (known as the electrophile) ...
by several pathways. #SNAr (addition-elimination) mechanism #aromatic SN1 mechanism encountered with
diazonium salt Diazonium compounds or diazonium salts are a group of organic compounds sharing a common functional group where R can be any organic group, such as an alkyl or an aryl, and X is an inorganic or organic anion, such as a halide. The parent, comp ...
s # benzyne mechanism (E1cB-AdN) #
free radical A daughter category of ''Ageing'', this category deals only with the biological aspects of ageing. Ageing Biogerontology Biological processes Causes of death Cellular processes Gerontology Life extension Metabolic disorders Metabolism ...
SRN1 mechanism #
ANRORC mechanism The ANRORC mechanism in organic chemistry describes a special type of substitution reaction. ANRORC stands for Addition of the Nucleophile, Ring Opening, and Ring Closure in nucleophilic attack on ring systems and it helps to explain product format ...
#
Vicarious nucleophilic substitution In organic chemistry, the vicarious nucleophilic substitution is a special type of nucleophilic aromatic substitution in which a nucleophile replaces a hydrogen atom on the aromatic ring and not leaving groups such as halogen substituents which are ...
The SNAr mechanism is the most important of these. Electron withdrawing groups activate the ring towards nucleophilic attack. For example if there are nitro functional groups positioned ortho or para to the
halide In chemistry, a halide (rarely halogenide) is a binary chemical compound, of which one part is a halogen atom and the other part is an element or radical that is less electronegative (or more electropositive) than the halogen, to make a fl ...
leaving group, the SNAr mechanism is favored.


SNAr reaction mechanism

The following is the
reaction mechanism In chemistry, a reaction mechanism is the step by step sequence of elementary reactions by which overall chemical reaction occurs. A chemical mechanism is a theoretical conjecture that tries to describe in detail what takes place at each stage ...
of a nucleophilic aromatic substitution of 2,4-dinitrochlorobenzene (1) in a
basic Basic or BASIC may refer to: Science and technology * BASIC, a computer programming language * Basic (chemistry), having the properties of a base * Basic access authentication, in HTTP Entertainment * Basic (film), ''Basic'' (film), a 2003 film ...
solution in water. Since the
nitro Nitro may refer to: Chemistry *Nitrogen, a chemical element and a gas except at very low temperatures, with which many compounds are formed: **Nitro compound, an organic compound containing one or more nitro functional groups, -NO2 **Nitro ligand ...
group is an activator toward nucleophilic substitution, and a meta director, it is able to stabilize the additional electron density (via resonance) when the aromatic compound is attacked by the
hydroxide Hydroxide is a diatomic anion with chemical formula OH−. It consists of an oxygen and hydrogen atom held together by a single covalent bond, and carries a negative electric charge. It is an important but usually minor constituent of water. It ...
nucleophile. The resulting intermediate, named the Meisenheimer complex (2a), the '' ipso'' carbon is temporarily bonded to the
hydroxyl group In chemistry, a hydroxy or hydroxyl group is a functional group with the chemical formula and composed of one oxygen atom covalently bonded to one hydrogen atom. In organic chemistry, alcohols and carboxylic acids contain one or more hydroxy ...
. This Meisenheimer complex is extra stabilized by the additional electron-withdrawing nitro group (2b). In order to return to a lower energy state, either the hydroxyl group leaves, or the chloride leaves. In solution, both processes happen. A small percentage of the intermediate loses the chloride to become the product (2,4-dinitrophenol, 3), while the rest return to the reactant (1). Since 2,4-dinitrophenol is in a lower energy state, it will not return to form the reactant, so after some time has passed, the reaction reaches
chemical equilibrium In a chemical reaction, chemical equilibrium is the state in which both the Reagent, reactants and Product (chemistry), products are present in concentrations which have no further tendency to change with time, so that there is no observable chan ...
that favors the 2,4-dinitrophenol, which is then deprotonated by the basic solution (4). The formation of the resonance-stabilized Meisenheimer complex is slow because the loss of
aromaticity In organic chemistry, aromaticity is a chemical property describing the way in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibits a stabilization stronger than would be expected from conjugation alone. The e ...
due to nucleophilic attack results in a higher-energy state. By the same coin, the loss of the chloride or hydroxide is fast, because the ring regains aromaticity. Recent work indicates that, sometimes, the Meisenheimer complex is not always a true intermediate but may be the
transition state In chemistry, the transition state of a chemical reaction is a particular configuration along the reaction coordinate. It is defined as the state corresponding to the highest potential energy along this reaction coordinate. It is often marked w ...
of a 'frontside SN2' process, particularly if stabilization by electron-withdrawing groups is not very strong. A 2019 review argues that such 'concerted SNAr' reactions are more prevalent than previously assumed. Aryl halides cannot undergo the classic 'backside' SN2 reaction. The carbon-halogen bond is in the plane of the ring because the carbon atom has a trigonal planar geometry. Backside attack is blocked and this reaction is therefore not possible. An SN1 reaction is possible but very unfavourable. It would involve the unaided loss of the
leaving group In organic chemistry, a leaving group typically means a Chemical species, molecular fragment that departs with an electron, electron pair during a reaction step with heterolysis (chemistry), heterolytic bond cleavage. In this usage, a ''leaving gr ...
and the formation of an aryl cation. The nitro group is the most commonly encountered activating group, other groups are the
cyano In chemistry, cyanide () is an inorganic chemical compound that contains a functional group. This group, known as the cyano group, consists of a carbon atom triple-bonded to a nitrogen atom. Ionic cyanides contain the cyanide anion . This a ...
and the
acyl In chemistry, an acyl group is a moiety derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids. It contains a double-bonded oxygen atom and an organyl group () or hydrogen in the case of formyl grou ...
group. The leaving group can be a halogen or a sulfide. With increasing
electronegativity Electronegativity, symbolized as , is the tendency for an atom of a given chemical element to attract shared electrons (or electron density) when forming a chemical bond. An atom's electronegativity is affected by both its atomic number and the ...
the reaction rate for nucleophilic attack increases. This is because the rate-determining step for an SNAr reaction is attack of the nucleophile and the subsequent breaking of the aromatic system; the faster process is the favourable reforming of the aromatic system after loss of the leaving group. As such, the following pattern is seen with regard to halogen leaving group ability for SNAr: F > Cl ≈ Br > I (i.e. an inverted order to that expected for an SN2 reaction). If looked at from the point of view of an SN2 reaction this would seem counterintuitive, since the C-F bond is amongst the strongest in organic chemistry, when indeed the fluoride is the ideal leaving group for an SNAr due to the extreme polarity of the C-F bond. Nucleophiles can be amines, alkoxides,
sulfides Sulfide (also sulphide in British English) is an inorganic anion of sulfur with the chemical formula S2− or a compound containing one or more S2− ions. Solutions of sulfide salts are corrosive. ''Sulfide'' also refers to large families of ...
and stabilized carbanions.


Nucleophilic aromatic substitution reactions

Some typical substitution reactions on arenes are listed below. * In the Bamberger rearrangement N-phenylhydroxylamines rearrange to 4-aminophenols. The nucleophile is water. * The Smiles rearrangement is the intramolecular version of this reaction type. Nucleophilic aromatic substitution is not limited to arenes, however; the reaction takes place even more readily with heteroarenes.
Pyridine Pyridine is a basic (chemistry), basic heterocyclic compound, heterocyclic organic compound with the chemical formula . It is structurally related to benzene, with one methine group replaced by a nitrogen atom . It is a highly flammable, weak ...
s are especially reactive when substituted in the aromatic ortho position or aromatic para position because then the negative charge is effectively delocalized at the nitrogen position. One classic reaction is the Chichibabin reaction ( Aleksei Chichibabin, 1914) in which pyridine is reacted with an alkali-metal amide such as
sodium amide Sodium amide, commonly called sodamide (systematic name sodium azanide), is the inorganic compound with the formula . It is a salt composed of the sodium cation and the azanide anion. This solid, which is dangerously reactive toward water, is whit ...
to form 2-aminopyridine. In the compound methyl 3-nitropyridine-4-carboxylate, the ''meta'' nitro group is actually displaced by
fluorine Fluorine is a chemical element; it has Chemical symbol, symbol F and atomic number 9. It is the lightest halogen and exists at Standard temperature and pressure, standard conditions as pale yellow Diatomic molecule, diatomic gas. Fluorine is extre ...
with cesium fluoride in
DMSO Dimethyl sulfoxide (DMSO) is an organosulfur compound with the formula . This colorless liquid is the sulfoxide most widely used commercially. It is an important polar aprotic solvent that dissolves both polar and nonpolar compounds and is ...
at 120 °C. Although the Sandmeyer reaction of diazonium salts and halides is formally a nucleophilic substitution, the reaction mechanism is in fact radical.


Asymmetric nucleophilic aromatic substitution

With carbon nucleophiles such as 1,3-dicarbonyl compounds the reaction has been demonstrated as a method for the asymmetric synthesis of chiral molecules. First reported in 2005, the
organocatalyst In organic chemistry, organocatalysis is a form of catalysis in which the rate of a chemical reaction is increased by an Organic compound, organic catalyst. This "organocatalyst" consists of carbon, hydrogen, sulfur and other nonmetal elements fo ...
(in a dual role with that of a phase transfer catalyst) is derived from cinchonidine (
benzyl In organic chemistry, benzyl is the substituent or molecular fragment possessing the structure . Benzyl features a benzene ring () attached to a methylene group (). Nomenclature In IUPAC nomenclature, the prefix benzyl refers to a substituent ...
ated at N and O). :


See also

*
Electrophilic aromatic substitution Electrophilic aromatic substitution (SEAr) is an organic reaction in which an atom that is attached to an aromatic ring, aromatic system (usually hydrogen) is replaced by an electrophile. Some of the most important electrophilic aromatic substitut ...
*
Nucleophile 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 ...
*
Substitution reaction A substitution reaction (also known as single displacement reaction or single substitution reaction) is a chemical reaction during which one functional group in a chemical compound is replaced by another functional group. Substitution reactions ar ...
*
SN1 reaction 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 th ...
*
SN2 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 t ...
* SNi reaction * Nucleophilic aliphatic substitution


References

{{Reaction mechanisms Nucleophilic substitution reactions Reaction mechanisms