SN2 reaction

The S_N2 reaction (also known as bimolecular nucleophilic substitution) is a type of nucleophilic substitution, where a lone pair from a nucleophile attacks an electron deficient electrophilic center and bonds to it, expelling another group called a leaving group. Thus the incoming group replaces the leaving group in one step. Since two reacting species are involved in the slow, rate-determining step of the reaction, this leads to the name "bimolecular nucleophilic substitution", or "S_N2". Among inorganic chemists, the S_N2 reaction is often known as the "interchange mechanism".

Reaction mechanism

The reaction most often occurs at an aliphatic sp³ carbon center with an electronegative, stable leaving group attached to it - 'X' - frequently a halide atom. The breaking of the C-X bond and the formation of the new C-Nu bond occur simultaneously to form a transition state in which the carbon under nucleophilic attack is pentacoordinate, and approximately sp² hybridised. The nucleophile attacks the carbon at 180° to the leaving group, since this provides the best overlap between the nucleophile's lone pair and the C-X σ* antibonding orbital. The leaving group is then pushed off the opposite side and the product is formed.

If the substrate under nucleophilic attack is chiral, this leads to an inversion of stereochemistry, called the Walden inversion.In an example of the S_N2 reaction, the attack of OH⁻ (the nucleophile) on a bromoethane (the electrophile) results in ethanol, with bromide ejected as the leaving group.

S_N2 attack occurs if the backside route of attack is not sterically hindered by substituents on the substrate. Therefore this mechanism usually occurs at an unhindered primary carbon centre. If there is steric crowding on the substrate near the leaving group, such as at a tertiary carbon centre, the substitution will involve an S_N1 rather than an S_N2 mechanism, (an S_N1 would also be more likely in this case because a sufficiently stable carbocation intermediary could be formed.)

Factors affecting reaction

The Basicity of the Leaving Group. By comparing the relative S_N2 reaction rates of compounds with atoms in the same periodic group (the halides, for example), results show that the ability as a leaving group during an S_N2 reaction depends on its basicity. In general, "the weaker the basicity of a group, the greater its leaving ability". For example, the iodide ion is a very weak base and because it is so, it is the most reactive. Weak bases do not share their electrons well because their electrons are farther away from the nucleus, making it easier for their bonds to be broken. In contrast, the fluoride ion is a strong base and, therefore, the least reactive. In fact, the fluoride ion is such a strong base that compounds involving them essentially do not undergo S_N2 reaction. Looking at the periodic table, relative basicity decreases down a group.

:(Stronger Base) F^- > Cl^- > Br^- > I^- (Weaker Base)

The Size of the Nucleophile. How readily a compound attacks an electron-deficient atom also affects an S_N2 reaction. As a rule, a negatively charged species (e.g. OH ^-) are better nucleophiles than neutral species (e.g. H₂O, water). There is a direct relationship between basicity and nucleophilicity: "stronger bases are better nucleophiles". Acidity, the ability of an atom to give up a proton (H⁺), is comparatively relative when molecules whose "attacking atoms are approximately the same in size", the weakest going toward the left side of the periodic table. If hydrogen were attached to second-row elements of the periodic table, the resulting compounds would have the following relative acidities:

:(Weaker Acid) NH₃ < H₂O < HF (Stronger Acid)

If each of these acids were to give up a hydrogen, the result would be its conjugate base, and the relative strengths will reverse. The stronger base now moves toward the left side of the periodic table.

:(Stronger Base) ^-NH₂ > OH^- > F^- (Weaker Base)

Elements increase in size down the periodic table. Although basicity decreases down the periodic table, nucleophilicity increases as size increases "depending on the solvent used".

Solvent. If a reaction is carried out in a protic solvent, whose molecules have a hydrogen bonded to an oxygen or to a nitrogen, the larger atom is a better nucleophile in an S_N2 reaction. In other words, the weaker base is the better nucleophile in a protic solvent. For example, the iodide ion is better than a fluoride ion as a nucleophile. However, if the reaction is carried out in an aprotic solvent, whose molecules do not have hydrogen bonded to an oxygen or to a nitrogen, then the stronger base is the better nucleophile. In this case, the fluoride ion is better than the iodide ion as a nucleophile. Sterics. Steric hindrance is any effect of a compound due to the size and/or arrangement of its substituent groups. Steric effects affect nucleophilicity but "does not affect base strength". A bulky nucleophile, such as a tert-butoxide ion with its specific arrangement of methyl groups, is a poorer nucleophile than an ethoxide ion with a straighter chain of carbons, even though "tert"-butoxide is a stronger base.

Reaction kinetics

The rate of an S_N2 reaction is second order, as the rate-determining step depends on the nucleophile concentration, [Nu⁻] as well as the concentration of substrate, [RX] .

:r = k [RX] [Nu⁻]

This is a key difference between the S_N1 and S_N2 mechanisms. In the S_N1 reaction the nucleophile attacks after the rate-limiting step is over, whereas in S_N2 the nucleophile forces off the leaving group in the limiting step. In other words, the rate of S_N1 reactions depend only on the concentration of the substrate while the S_N2 reaction rate depends on the concentration of both the substrate and nucleophile. In cases where both mechanisms are possible (for example at a secondary carbon centre), the mechanism depends on solvent, temperature, concentration of the nucleophile or on the leaving group.

S_N2 reactions are generally favoured in primary alkyl halides or secondary alkyl halides with an aprotic solvent. They occur at a negligible rate in tertiary alkyl halides due to steric hindrance.

It is important to understand that S_N2 and S_N1 are two extremes of a sliding scale of reactions, it is possible to find many reactions which exhibit both S_N2 and S_N1 character in their mechanisms. For instance, it is possible to get a contact ion pairs formed from an alkyl halide in which the ions are not fully separated. When these undergo substitution the stereochemistry will be inverted (as in S_N2) for many of the reacting molecules but a few may show retention of configuration.

E2 competition

A common side reaction taking place with S_N2 reactions is E2 elimination: the incoming anion can act as a base rather than as a nucleophile, abstracting a proton and leading to formation of the alkene. This effect can be demonstrated in the gas-phase reaction between a sulfonate and a simple alkyl bromide taking place inside a mass spectrometer: ["Gas Phase Studies of the Competition between Substitution and Elimination Reactions" Scott Gronert Acc. Chem. Res.; 2003; 36(11) pp 848 - 857; (Article) DOI|10.1021/ar020042n] [The technique used is electrospray ionization and because it requires charged reaction products for detection the nucleophile is fitted with an additional sulfonate anionic group, non-reactive and well separated from the other anion. The product ratio of substitution and elimination product can be measured from the intensity their relative molecular ions ]

:

With ethyl bromide, the reaction product is predominantly the substitution product. As steric hindrance around the electrophilic center increases, as with isobutyl bromide, substitution is disfavored and elimination is the predominant reaction. Other factors favoring elimination are the strength of the base. With the less basic benzoate 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.

Roundabout mechanism

A development attracting attention in 2008 concerns a S_N2 roundabout mechanism observed in a gas-phase reaction between chloride ions and methyl iodide with a special technique called "crossed molecular beam imaging". When the chloride ions have sufficient velocity the energy of the resulting iodide ions after the collision is much lower than expected and it is theorized that energy is lost as a result of a full roundabout of the methyl group around the iodine atom before the actual displacement takes place ["Imaging Nucleophilic Substitution Dynamics" J. Mikosch, S. Trippel, C. Eichhorn, R. Otto, U. Lourderaj, J. X. Zhang, W. L. Hase, M. Weidemüller, and R. Wester Science 11 January 2008 319: 183-186 DOI| 10.1126/science.1150238 (in Reports) ] ["PERSPECTIVES CHEMISTRY: Not So Simple " John I. Brauman (11 January 2008) Science 319 (5860), 168. DOI|10.1126/science.1152387] ["Surprise From SN2 Snapshots Ion velocity measurements unveil additional unforeseen mechanism" Carmen Drahl Chemical & Engineering News January 14, 2008 Volume 86, Number 2 p. 9 http://pubs.acs.org/cen/news/86/i02/8602notw1.html , video included] .

See also

*Substitution reaction
*S_N1 reaction
*S_Ni
*Nucleophilic aromatic substitution
*Nucleophilic acyl substitution
*Neighbouring group participation
*Finkelstein reaction

References