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 (i.e. simultaneous) fashion. The name SN2 refers to the Hughes-Ingold symbol of the mechanism: "SN" indicates that the reaction is a nucleophilic substitution, and "2" that it proceeds via a bimolecular mechanism, which means both the reacting species are involved in the rate-determining step. What distinguishes SN2 from the other major type of nucleophilic substitution, the SN1 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 the associative substitution from the field of inorganic chemistry.
Reaction mechanism The reaction most often occurs at an aliphatic sp3 carbon center with an electronegative, stable leaving group attached to it, which is frequently a halogen (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 a transition state in which the reaction center is pentacoordinate and approximately sp2-hybridised.
The SN2 reaction can be viewed as a HOMO–LUMO interaction between the nucleophile and substrate. The reaction occurs only when the occupied lone pair orbital of the nucleophile donates electrons to the unfilled σ* antibonding orbital between the central carbon and the leaving group. Throughout the course of the reaction, a p orbital forms at the reaction center as the result of the transition from the molecular orbitals of the reactants to those of the products.
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 with inversion of tetrahedral geometry at the central atom. For example, the synthesis of macrocidin A, a fungal metabolite, involves an intramolecular ring closing step via an SN2 reaction with a phenoxide group as the nucleophile and a halide as the leaving group, forming an ether. Reactions such as this, with an alkoxide as the nucleophile, are known as the Williamson ether synthesis.
If the substrate that is undergoing SN2 reaction has a chiral centre, then inversion of configuration (stereochemistry and optical activity) may occur; this is called the Walden 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.
Factors affecting the rate of the reaction The four factors that affect the rate of the reaction, in the order of decreasing importance, are:
Substrate 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 more sterically 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, the conjugation 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.
Nucleophile Like the substrate, steric hindrance affects the nucleophile's strength. The methoxide 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 and electronegativity: 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.
Leaving group Good leaving groups on the substrate lead to faster SN2 reactions. A good leaving group must be able to stabilize the electron density that comes from breaking its bond with the carbon center. This leaving group ability trend corresponds well to the pKa 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 as water, alcohols (R−OH), and amines (R−NH2), are good examples because of their positive charge when bonded to the carbon center prior to nucleophilic attack. Halides (Cl−, Br−, and I−, with the exception of F−), 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 with sulfonates, such as tosylate (−OTs), triflate (−OTf), and mesylate (−OMs). Poor leaving groups include hydroxide (−OH), alkoxides (−OR), and amides (−NR2).
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