Substitution by the Sn2 Mechanism

Substitution reactions at 1° and 2° (but not 3°) C(sp3) usually proceed by the SN2 mechanism under basic or neutral conditions. In the Sn2 mechanism, the nucleophile Nu approaches the electrophilic center opposite X and in line with the C-X bond. The lone pair on Nu is used to form the C-Nu bond, and the pair of electrons in the C-X bond simultaneously leaves with X as the bond breaks. The other three groups on C move away from Nu and toward X as the reaction proceeds, so that when the reaction is complete, the stereochemistry of C is inverted. The charges do not have to be as shown the nucleophile may be anionic or neutral, and the electrophile may be neutral or cationic. 

The curved arrow shows how the pair of electrons moves from the nucleophile to the electron-deficient center. The nucleophilic atom increases its formal charge by 1, and the leaving group decreases its formal charge by 1. The minus sign on Nu indicates both a formal charge and a pair of electrons. When the nucleophile is uncharged, the lone pair is usually drawn. 

Lone-pair nucleophiles are by far the most enthusiastic participants in Sn2 substitution reactions. Sigma-bond nucleophiles may also participate in Sn2 reactions, but they do not do so as often as lone-pair nucleophiles. By contrast, 7r-bond nucleophiles do not usually have sufficiently high energy to react with an atom that already has an octet. The major exceptions to this rule are the enam-ines (R2N-CR=CR2 — R2N=CR-CR2), which are sufficiently nucleophilic at the j8 position to attack particularly reactive alkyl halides such as CH3I and al-lylic and benzylic bromides, and enolates (0-CR=CR2 — 0=CR-CR2), which react with many alkyl halides. 

S 2 substitution can occur at elements other than C. For example, substitution at a stereogenic S atom leads to inversion of configuration, suggesting an S 2 mechanism for this process. 

In contrast with first-row main-group elements, second-row and heavier atoms such as P and S can extend their octet, so substitution at these atoms can occur either by an Sn2 mechanism or by a two-step addition-elimination mechanism. In the first step, the nucleophile adds to the electrophilic heavy atom to give a hypervalent, 10-electron in- 

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FIGURE 8 2 Hybrid orbital description of the bonding changes that take place at carbon during nucleophilic substitution by the Sn2 mechanism... 

Reactivity of Some Alkyl Bromides Toward Substitution by the Sn2 Mechanism ... 

Having just learned that tertiary alkyl halides are practically inert to substitution by the Sn2 mechanism because of steric hindrance we might wonder whether they undergo nucleophilic substitution at all We 11 see m this section that they do but by a mecha nism different from 8 2... 

Section 8 13 When nucleophilic substitution is used for synthesis the competition between substitution and elimination must be favorable However the normal reaction of a secondary alkyl halide with a base as strong or stronger than hydroxide is elimination (E2) Substitution by the Sn2 mechanism predominates only when the base is weaker than hydroxide or the alkyl halide is primary Elimination predominates when tertiary alkyl halides react with any anion... 

Aryl halides react too slowly to undergo substitution by the Sn2 mechanism with the sodium salt of diethyl malonate and so the phenyl substituent of phenobarbital cannot be introduced in the way that alkyl substituents can... 

Solvent Effects on the Rate of Substitution by the SN2 Mechanism. Polar solvents are required in typical bimolecular substitutions because ionic substances, such as the sodium and potassium salts cited earlier in Table 8.1, are not sufficiently soluble in nonpolar solvents to give a high enough concentration of the nucleophile to allow the reaction to occur at a rapid rate. Other than the requirement that the solvent be polar enough to dissolve ionic compounds, however, the effect of solvent polarity on the rate of Sn2 reactions is small. What is most important is whether or not the polar solvent is protic or aprotic. 

Iodide and bromide ions are good nucleophiles but weak bases, so they are more likely to substitute by the Sn2 mechanism than to promote elimination by the E2 mechanism. Mechanism 14-1 shows how bromide ion cleaves the protonated ether by displacing an alcohol. In the following example, cyclopentyl ethyl ether reacts with HBr to produce cyclopentanol by this displacement. Cyclopentanol reacts further with HBr, though, so the final products are ethyl bromide and bromocyclopentane. 

Common error alert Intermolecular substitution by the Sn2 mechanism occurs only at 1° and 2° C(sp3). Under basic conditions, intramolecular substitution at 3° C(sp3) may occur by the SN2 mechanism, but substitution at C(sp2) never occurs by the SN2 mechanism at all. Substitution at an electrophilic C(sp2) or intermolecular substitution at 3° C(sp3) must proceed by a mechanism other than Sn2 (see below). 

Common error alert C(sp2) electrophiles never, ever, ever undergo substitution by the SN2 mechanism. The two-step mechanism for substitution at car-... 

Substitution by the SN2 mechanism and -elimination by the E2 and Elcb mechanisms are not the only reactions that can occur at C(sp3)-X. Substitution can also occur at C(sp3)-X by the SRN1 mechanism, the elimination-addition mechanism, a one-electron transfer mechanism, and metal insertion and halogen-metal exchange reactions. An alkyl halide can also undergo a-elimination to give a carbene. 

SAMPLE SOLUTION (a) Compare the structures of the two chlorides. 1-Chloro-hexane is a primary alkyl chloride cyclohexyl chloride is secondary. Primary alkyl halides are less crowded at the site of substitution than secondary ones and react faster in substitution by the Sn2 mechanism. 1-Chlorohexane is more reactive. 

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