23.6 The Addition-Elimination Mechanism of Nucleophilic Aromatic Substitution In contrast to nucleophilic substitution in alkyl halides, where alkyl fluorides are exceedingly unreactive, aryl fluorides undergo nucleophilic substitution readily when the ring bears an o-or a p-nitro group The compound 1-fluoro-2,4- CH:OH gly reactive toward KOCH determination of the struG. p-Fluoronitrobenzene Potassium methoxide Nitroanisole (93%) Potassium fluoride ture of insulin Indeed, the order of leaving-group reactivity in nucleophilic aromatic substitution is the opposite of that seen in aliphatic substitution. Fluoride is the most reactive leaving group in nucleophilic aromatic substitution, iodide the least reactive. Relative reactivity toward sodium methoxide in methanol(50°C X=F 312 X= Br 0.8 0.4 Kinetic studies of these reactions reveal that they follow a second-order rate law Rate= k[Aryl halide] [Nucleophile] Second-order kinetics is usually interpreted in terms of a bimolecular rate-determinin step. In this case, then, we look for a mechanism in which both the aryl halide and the nucleophile are involved in the slowest step. Such a mechanism is described in the fol- 23.6 THE ADDITION-ELIMINATION MECHANISM OF NUCLEOPHILIC AROMATIC SUBSTITUTION The generally accepted mechanism for nucleophilic aromatic substitution in nitro- substituted aryl halides, illustrated for the reaction of p-fluoronitrobenzene with sodium methoxide, is outlined in Figure 23. 3. It is a two-step addition-elimination mechanism, in which addition of the nucleophile to the aryl halide is followed by elimination of the halide leaving group. Figure 23. 4 shows the structure of the key intermediate. The mech anism is consistent with the following experimental observations: 1. Kinetics: As the observation of second-order kinetics requires, the rate-determining step(step 1)involves both the aryl halide and the nucleophile. 2. Rate-enhancing effect of the nitro group: The nucleophilic addition step is rate- determining because the aromatic character of the ring must be sacrificed to form the cyclohexadienyl anion intermediate. Only when the anionic intermediate is sta- bilized by the presence of a strong electron-withdrawing substituent ortho or para to the leaving group will the activation energy for its formation be low enough to provide a reasonable reaction rate. We can illustrate the stabilization that a p-nitro group provides by examining the resonance structures for the cyclohexadienyl anion formed from methoxide and p-fluoronitrobenzene Back Forward Main MenuToc Study Guide ToC Student o MHHE WebsiteIn contrast to nucleophilic substitution in alkyl halides, where alkyl fluorides are exceedingly unreactive, aryl fluorides undergo nucleophilic substitution readily when the ring bears an o- or a p-nitro group. Indeed, the order of leaving-group reactivity in nucleophilic aromatic substitution is the opposite of that seen in aliphatic substitution. Fluoride is the most reactive leaving group in nucleophilic aromatic substitution, iodide the least reactive. Kinetic studies of these reactions reveal that they follow a second-order rate law: Rate  k[Aryl halide] [Nucleophile] Second-order kinetics is usually interpreted in terms of a bimolecular rate-determining step. In this case, then, we look for a mechanism in which both the aryl halide and the nucleophile are involved in the slowest step. Such a mechanism is described in the fol￾lowing section. 23.6 THE ADDITION–ELIMINATION MECHANISM OF NUCLEOPHILIC AROMATIC SUBSTITUTION The generally accepted mechanism for nucleophilic aromatic substitution in nitro￾substituted aryl halides, illustrated for the reaction of p-fluoronitrobenzene with sodium methoxide, is outlined in Figure 23.3. It is a two-step addition–elimination mechanism, in which addition of the nucleophile to the aryl halide is followed by elimination of the halide leaving group. Figure 23.4 shows the structure of the key intermediate. The mech￾anism is consistent with the following experimental observations: 1. Kinetics: As the observation of second-order kinetics requires, the rate-determining step (step 1) involves both the aryl halide and the nucleophile. 2. Rate-enhancing effect of the nitro group: The nucleophilic addition step is rate￾determining because the aromatic character of the ring must be sacrificed to form the cyclohexadienyl anion intermediate. Only when the anionic intermediate is sta￾bilized by the presence of a strong electron-withdrawing substituent ortho or para to the leaving group will the activation energy for its formation be low enough to provide a reasonable reaction rate. We can illustrate the stabilization that a p-nitro group provides by examining the resonance structures for the cyclohexadienyl anion formed from methoxide and p-fluoronitrobenzene: X NO2 Relative reactivity toward sodium methoxide in methanol (50°C): X  F X  Cl X  Br X  I 312 1.0 0.8 0.4 23.6 The Addition–Elimination Mechanism of Nucleophilic Aromatic Substitution 923 F NO2 p-Fluoronitrobenzene KOCH3 Potassium methoxide OCH3 NO2 p-Nitroanisole (93%) KF Potassium fluoride CH3OH 85°C The compound 1-fluoro-2,4- dinitrobenzene is exceed￾ingly reactive toward nucleophilic aromatic substi￾tution and was used in an imaginative way by Frederick Sanger (Section 27.10) in his determination of the struc￾ture of insulin. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website