Asubstitution reaction (also known assingle displacement reaction orsingle substitution reaction) is a chemical reaction during which onefunctional group in achemical compound is replaced by another functional group.[1] Substitution reactions are of prime importance inorganic chemistry. Substitution reactions in organic chemistry are classified either aselectrophilic ornucleophilic depending upon the reagent involved, whether areactive intermediate involved in the reaction is acarbocation, acarbanion or afree radical, and whether thesubstrate isaliphatic oraromatic. 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 ofsolvent.
A good example of a substitution reaction ishalogenation. Whenchlorine gas (Cl2) is irradiated, some of the molecules are split into two chlorineradicals (Cl•), whose free electrons are stronglynucleophilic. One of them breaks aC–H covalent bond in CH4 and grabs the hydrogen atom to form the electrically neutral HCl. The other radical reforms a covalent bond with the CH3• to form CH3Cl (methyl chloride).
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| chlorination of methane by chlorine |
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In organic (and inorganic) chemistry,nucleophilic substitution is a fundamental class of reactions in which anucleophile selectively bonds with or attacks the positive or partially positive charge on an atom or a group of atoms. As it does so, it replaces a weaker nucleophile, which then becomes aleaving group; the remaining positive or partially positive atom becomes anelectrophile. The whole molecular entity of which the electrophile and the leaving group are part is usually called thesubstrate.[1]
The most general form for the reaction may be given as
whereR−LG indicates the substrate. Theelectron pair (:) from the nucleophile (Nuc:) attacks the substrate (R−LG), forming a new covalent bondNuc−R−LG. The prior state of charge is restored when the leaving group (LG) departs with an electron pair. The principal product in this case isR−Nuc. In such reactions, the nucleophile is usually electrically neutral or negatively charged, whereas the substrate is typically neutral or positively charged.
An example of nucleophilic substitution is the hydrolysis of analkyl bromide,R−Br, under basic conditions, where theattacking nucleophile is the baseOH− and the leaving group isBr−:
Nucleophilic substitution reactions are commonplace in organic chemistry, and they can be broadly categorized as taking place at a carbon of a saturatedaliphatic compound carbon or (less often) at an aromatic or other unsaturated carbon center.[1]
Nucleophilic substitutions can proceed by two different mechanisms, unimolecular nucleophilic substitution (SN1) and bimolecular nucleophilic substitution (SN2). The two reactions are named according tho theirrate law, with SN1 having a first-order rate law, and SN2 having a second-order.[2]
The SN1 mechanism has two steps. In the first step, the leaving group departs, forming acarbocation (C+). In the second step, the nucleophilic reagent (Nuc:) attaches to the carbocation and forms a covalent sigma bond. If the substrate has achiral carbon, this mechanism can result in either inversion of thestereochemistry or retention of configuration. Usually, both occur without preference. The result isracemization.
The stability of a carbocation (C+) depends on how many other carbon atoms are bonded to it. This results in SN1 reactions usually occurring on atoms with at least two carbons bonded to them.[2] A more detailed explanation of this can be found in the mainSN1 reaction page.
The SN2 mechanism has just one step. The attack of the reagent and the expulsion of the leaving group happen simultaneously. This mechanism always results in inversion of configuration. If the substrate that is under nucleophilic attack is chiral, the reaction will therefore lead to an inversion of itsstereochemistry, called aWalden inversion.
SN2 attack may occur if the backside route of attack is notsterically hindered by substituents on the substrate. Therefore, this mechanism usually occurs at an unhinderedprimary carbon center. If there is steric crowding on the substrate near the leaving group, such as at atertiary carbon center, the substitution will involve an SN1 rather than an SN2.[2]
Other types of nucleophilic substitution include,nucleophilic acyl substitution, andnucleophilic aromatic substitution. Acyl substitution occurs when a nucleophile attacks a carbon that is doubly bonded to one oxygen and singly bonded to another oxygen (can be N or S or ahalogen), called anacyl group. The nucleophile attacks the carbon causing the double bond to break into a single bond. The double can then reform, kicking off the leaving group in the process.
Aromatic substitution occurs on compounds with systems of double bonds connected in rings. Seearomatic compounds for more.
Electrophiles are involved inelectrophilic substitution reactions, particularly inelectrophilic aromatic substitutions.
In this example, the benzene ring's electron resonance structure is attacked by an electrophile E+. The resonating bond is broken and a carbocation resonating structure results. Finally a proton is kicked out and a new aromatic compound is formed.
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| 1: Free benzene + electrophile;2a: Benzene attacks electrophile; 2b: Resonance of benzene-electrophile intermediate;3: Substituted reaction product |
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Electrophilic reactions to other unsaturated compounds thanarenes generally lead toelectrophilic addition rather than substitution.
Aradical substitution reaction involvesradicals. An example is theHunsdiecker reaction.
Coupling reactions are a class of metal-catalyzed reactions involving anorganometallic compound RM and an organic halide R′X that together react to form a compound of the type R-R′ with formation of a newcarbon–carbon bond. Examples include theHeck reaction,Ullmann reaction, andWurtz–Fittig reaction. Many variations exist.[3]
Substituted compounds are compounds where one or more hydrogen atoms have been replaced with something else such as analkyl,hydroxy, orhalogen. More can be found on thesubstituted compounds page.
While it is common to discuss substitution reactions in the context of organic chemistry, the reaction is generic and applies to a wide range of compounds. Ligands in coordination complexes are susceptible to substitution. Both associative and dissociative mechanisms have been observed.[4][5]
Associative substitution, for example, is typically applied toorganometallic andcoordination complexes, but resembles theSn2 mechanism inorganic chemistry. The opposite pathway isdissociative substitution, being analogous to theSn1 pathway.
Examples of associative mechanisms are commonly found in the chemistry of 16esquare planar metal complexes, e.g.Vaska's complex andtetrachloroplatinate. Therate law is governed by theEigen–Wilkins Mechanism.
Dissociative substitution resembles theSN1 mechanism in organic chemistry. This pathway can be well described by thecis effect, or the labilization of CO ligands in thecis position. Complexes that undergo dissociative substitution are oftencoordinatively saturated and often haveoctahedral molecular geometry. Theentropy of activation is characteristically positive for these reactions, which indicates that the disorder of the reacting system increases in the rate-determining step. Dissociative pathways are characterized by arate determining step that involves release of a ligand from the coordination sphere of the metal undergoing substitution. The concentration of the substitutingnucleophile has no influence on this rate, and an intermediate of reduced coordination number can be detected. The reaction can be described with k1, k−1 and k2, which are therate constants of their corresponding intermediate reaction steps:
Normally the rate determining step is the dissociation of L from the complex, and [L'] does not affect the rate of reaction, leading to the simple rate equation:
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