Thebimolecular nucleophilic substitution (SN2) is a type ofreaction mechanism that is common inorganic chemistry. In the SN2 reaction, a strongnucleophile forms a new bond to ansp3-hybridised carbon atom via a backside attack, all while theleaving group detaches from the reaction center in aconcerted (i.e. simultaneous) fashion.
The name SN2 refers to theHughes-Ingold symbol of the mechanism: "SN" indicates that the reaction is anucleophilic substitution, and "2" that it proceeds via abimolecular mechanism, which means both the reacting species are involved in therate-determining step. What distinguishes SN2 from the other major type of nucleophilic substitution, theSN1 reaction, is that the displacement of the leaving group, which is the rate-determining step, is separate from the nucleophilic attack in SN1.
The SN2 reaction can be considered as an organic-chemistry analogue of theassociative substitution from the field ofinorganic chemistry.
The reaction most often occurs at analiphaticsp3 carbon center with anelectronegative, stable leaving group attached to it, which is frequently ahalogen (often denoted X). The formation of the C–Nu bond, due to attack by the nucleophile (denoted Nu), occurs together with the breakage of the C–X bond. The reaction occurs through atransition state in which the reaction center ispentacoordinate and approximately sp2-hybridised.
The SN2 reaction can be viewed as aHOMO–LUMO interaction between the nucleophile and substrate. The reaction occurs only when the occupied lone pair orbital of the nucleophile donates electrons to the unfilledσ* antibonding orbital between the central carbon and theleaving group. Throughout the course of the reaction, a p orbital forms at the reaction center as the result of the transition from themolecular orbitals of the reactants to those of the products.[1]
To achieve optimal orbital overlap, the nucleophile attacks 180° relative to the leaving group, resulting in the leaving group being pushed off the opposite side and the product formed withinversion of tetrahedral geometry at the central atom.
For example, the synthesis of macrocidin A, a fungalmetabolite, involves an intramolecular ring closing step via an SN2 reaction with aphenoxide group as the nucleophile and a halide as the leaving group, forming anether.[2] Reactions such as this, with an alkoxide as the nucleophile, are known as theWilliamson ether synthesis.
If the substrate that is undergoing SN2 reaction has achiral centre, then inversion ofconfiguration (stereochemistry andoptical activity) may occur; this is called theWalden inversion. For example, 1-bromo-1-fluoroethane can undergo nucleophilic attack to form 1-fluoroethan-1-ol, with the nucleophile being an HO− group. In this case, if the reactant is levorotatory, then the product would be dextrorotatory, and vice versa.[3]
The four factors that affect the rate of the reaction, in the order of decreasing importance, are:[4][5]
The substrate plays the most important part in determining the rate of the reaction. For SN2 reaction to occur more quickly, the nucleophile must easily access the sigma antibonding orbital between the central carbon and leaving group.
SN2 occurs more quickly with substrates that are moresterically accessible at the central carbon, i.e. those that do not have as much sterically hindering substituents nearby. Methyl and primary substrates react the fastest, followed by secondary substrates. Tertiary substrates do not react via the SN2 pathway, as the greater steric hindrance between the nucleophile and nearby groups of the substrate will leave the SN1 reaction to occur first.
Substrates with adjacent pi C=C systems can favor both SN1 and SN2 reactions. In SN1, allylic and benzylic carbocations are stabilized by delocalizing the positive charge. In SN2, however, theconjugation between the reaction centre and the adjacent pi system stabilizes the transition state. Because they destabilize the positive charge in the carbocation intermediate, electron-withdrawing groups favor the SN2 reaction. Electron-donating groups favor leaving-group displacement and are more likely to react via the SN1 pathway.[1]
Like the substrate, steric hindrance affects the nucleophile's strength. Themethoxide anion, for example, is both a strong base and nucleophile because it is a methyl nucleophile, and is thus very much unhindered.tert-Butoxide, on the other hand, is a strong base, but a poor nucleophile, because of its three methyl groups hindering its approach to the carbon. Nucleophile strength is also affected by charge andelectronegativity: nucleophilicity increases with increasing negative charge and decreasing electronegativity. For example, OH− is a better nucleophile than water, and I− is a better nucleophile than Br− (in polar protic solvents). In a polar aprotic solvent, nucleophilicity increases up a column of the periodic table as there is no hydrogen bonding between the solvent and nucleophile; in this case nucleophilicity mirrors basicity. I− would therefore be a weaker nucleophile than Br− because it is a weaker base. Verdict - A strong/anionic nucleophile always favours SN2 manner of nucleophillic substitution.
Good leaving groups on the substrate lead to faster SN2 reactions. A good leaving group must be able to stabilize theelectron density that comes from breaking its bond with the carbon center. This leaving group ability trend corresponds well to thepKa of the leaving group's conjugate acid (pKaH); the lower its pKaH value, the faster the leaving group is displaced.
Leaving groups that are neutral, such aswater,alcohols (R−OH), andamines (R−NH2), are good examples because of their positive charge when bonded to the carbon center prior to nucleophilic attack. Halides (Cl−,Br−, andI−, with the exception ofF−), serve as good anionic leaving groups because electronegativity stabilizes additional electron density; the fluoride exception is due to its strong bond to carbon.
Leaving group reactivity of alcohols can be increased withsulfonates, such astosylate (−OTs),triflate (−OTf), andmesylate (−OMs). Poor leaving groups includehydroxide (−OH),alkoxides (−OR), andamides (−NR2).
TheFinkelstein reaction is one SN2 reaction in which the leaving group can also act as a nucleophile. In this reaction, the substrate has a halogen atom exchanged with another halogen. As the negative charge is more-or-less stabilized on both halides, the reaction occurs at equilibrium.
The solvent affects the rate of reaction because solvents may or may not surround a nucleophile, thus hindering or not hindering its approach to the carbon atom.[6]Polar aprotic solvents, liketetrahydrofuran, are better solvents for this reaction than polarprotic solvents because polar protic solvents willhydrogen bond to the nucleophile, hindering it from attacking the carbon with the leaving group. A polar aprotic solvent with low dielectric constant or a hindered dipole end will favour SN2 manner of nucleophilic substitution reaction. Examples:dimethylsulfoxide,dimethylformamide,acetone, etc. In parallel, solvation also has a significant impact on the intrinsic strength of the nucleophile, in which strong interactions between solvent and the nucleophile, found for polarprotic solvents, furnish a weaker nucleophile. In contrast, polar aprotic solvents can only weakly interact with the nucleophile, and thus, are to a lesser extent able to reduce the strength of the nucleophile.[7][8]
The rate of an SN2 reaction issecond order, as therate-determining step depends on the nucleophile concentration, [Nu−] as well as the concentration of substrate, [RX].[1]
This is a key difference between the SN1 and SN2 mechanisms. In the SN1 reaction the nucleophile attacks after the rate-limiting step is over, whereas in SN2 the nucleophile forces off the leaving group in the limiting step. In other words, the rate of SN1 reactions depend only on the concentration of the substrate while the SN2 reaction rate depends on the concentration of both the substrate and nucleophile.[1]
It has been shown[9] that except in uncommon (but predictable cases) primary and secondary substrates go exclusively by the SN2 mechanism while tertiary substrates go via the SN1 reaction. There are two factors which complicate determining the mechanism of nucleophilic substitution reactions at secondary carbons:
The examples in textbooks of secondary substrates going by the SN1 mechanism invariably involve the use of bromide (or other good nucleophile) as the leaving group have confused the understanding of alkyl nucleophilic substitution reactions at secondary carbons for 80 years[3]. Work with the 2-adamantyl system (SN2 not possible) by Schleyer and co-workers,[11] the use of azide (an excellent nucleophile but very poor leaving group) by Weiner and Sneen,[12][13] the development of sulfonate leaving groups (non-nucleophilic good leaving groups), and the demonstration of significant experimental problems in the initial claim of an SN1 mechanism in the solvolysis of optically active 2-bromooctane by Hughes et al.[14][3] have demonstrated conclusively that secondary substrates go exclusively (except in unusual but predictable cases) by the SN2 mechanism.
A commonside reaction taking place with SN2 reactions isE2 elimination: the incoming anion can act as a base rather than as a nucleophile, abstracting a proton and leading to formation of thealkene. This pathway is favored with sterically hindered nucleophiles. Elimination reactions are usually favoured at elevated temperatures[15] because of increasedentropy. This effect can be demonstrated in the gas-phase reaction between aphenolate and a simplealkyl bromide taking place inside amass spectrometer:[16][17]
Withethyl bromide, the reaction product is predominantly the substitution product. Assteric hindrance around the electrophilic center increases, as withisobutyl bromide, substitution is disfavored and elimination is the predominant reaction. Other factors favoring elimination are the strength of the base. With the less basicbenzoate substrate, isopropyl bromide reacts with 55% substitution. In general, gas phase reactions and solution phase reactions of this type follow the same trends, even though in the first,solvent effects are eliminated.
A development attracting attention in 2008 concerns a SN2roundabout mechanism observed in a gas-phase reaction between chloride ions andmethyl iodide with a special technique calledcrossed molecular beam imaging. When the chloride ions have sufficient velocity, the initial collision of it with the methyl iodide molecule causes the methyl iodide to spin around once before the actual SN2 displacement mechanism takes place.[18][19][20]
{{cite book}}: CS1 maint: multiple names: authors list (link)