CHAPTER TWENTY-THREE Aryl Halides 23.5 NUCLEOPHILIC SUBSTITUTION IN NITRO-SUBSTITUTED ARYL HALIDES One group of aryl halides that do undergo nucleophilic substitution readily consists of those that bear a nitro group ortho or para to the halogen OCH NaoCH3 Nacl p-Nitroanisole(92%) Sodium chloride An ortho-nitro group exerts a comparable rate-enhancing effect. m-Chloronitrobenzene, although much more reactive than chlorobenzene itself, is thousands of times less reac- tive than either o-or p-chloronitrobenzene The effect of o- and p-nitro substituents is cumulative, as the following rate data demonstrate Increasing rate of reaction with sodium methoxide in methanol (50C O2N、 Chlorobenzene 1-chloro- 1-chloro- 2-chloro- 4-nitrobenzene 2. 4-dinitrobenzene 1.3, 5-trinitrobenzene Relative rate 1.0 7×10 24×1015 (too fast to measure) PROBLEM 23.2 Write the structure of the expected product from the reaction of 1-chloro-2, 4-dinitrobenzene with each of the following reagen (aCH3 CH2ON (b)CHSCH2 SNa ( d)CH SAMPLE SoLUTION (a)Sodium ethoxide is a source of the nucleophile CH3,O, which displaces chloride from 1-chloro-2, 4-dinitrobenzene OCHCH +CH3CH2O一 NO 1-Chloro-2 4-dinitrobenzene Ethoxide 1-Ethoxy-2, 4-dinitrobenzene Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
23.5 NUCLEOPHILIC SUBSTITUTION IN NITRO-SUBSTITUTED ARYL HALIDES One group of aryl halides that do undergo nucleophilic substitution readily consists of those that bear a nitro group ortho or para to the halogen. An ortho-nitro group exerts a comparable rate-enhancing effect. m-Chloronitrobenzene, although much more reactive than chlorobenzene itself, is thousands of times less reactive than either o- or p-chloronitrobenzene. The effect of o- and p-nitro substituents is cumulative, as the following rate data demonstrate: PROBLEM 23.2 Write the structure of the expected product from the reaction of 1-chloro-2,4-dinitrobenzene with each of the following reagents: (a) CH3CH2ONa (b) C6H5CH2SNa (c) NH3 (d) CH3NH2 SAMPLE SOLUTION (a) Sodium ethoxide is a source of the nucleophile CH3CH2O, which displaces chloride from 1-chloro-2,4-dinitrobenzene. Cl NO2 NO2 1-Chloro-2,4-dinitrobenzene CH3CH2O Ethoxide anion OCH2CH3 NO2 NO2 1-Ethoxy-2,4-dinitrobenzene Cl Increasing rate of reaction with sodium methoxide in methanol (50°C) Cl Chlorobenzene Relative rate: 1.0 Cl NO2 1-Chloro- 4-nitrobenzene 7 1010 NO2 Cl NO2 1-Chloro- 2,4-dinitrobenzene 2.4 1015 NO2 Cl O2N NO2 2-Chloro- 1,3,5-trinitrobenzene (too fast to measure) NO2 OCH3 p-Nitroanisole (92%) CH3OH 85°C Cl NO2 p-Chloronitrobenzene NaOCH3 Sodium methoxide NaCl Sodium chloride 922 CHAPTER TWENTY-THREE Aryl Halides Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
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 Website
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. 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 following section. 23.6 THE ADDITION–ELIMINATION MECHANISM OF NUCLEOPHILIC AROMATIC SUBSTITUTION The generally accepted mechanism for nucleophilic aromatic substitution in nitrosubstituted 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 mechanism 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 ratedetermining because the aromatic character of the ring must be sacrificed to form the cyclohexadienyl anion intermediate. Only when the anionic intermediate is stabilized 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 exceedingly reactive toward nucleophilic aromatic substitution and was used in an imaginative way by Frederick Sanger (Section 27.10) in his determination of the structure of insulin. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CHAPTER TWENTY-THREE Aryl Halides Overall reaction NaOCH3 p-Fluoronitrobenzene Sodium methoxide Sodium fluoride Step 1: Addition stage. The nucleophile, in this case methoxide ion, adds to the carbon atom that bears the leaving group to give a cyclohexadienyl anion intermediate OCH3 H O2 O, p-Fluoronitrobenzene Methoxide ion Cyclohexadienyl Step 2: Elimination stage. Loss of halide from the cyclohexadienyl intermediate restores the aromaticity of the ring and gives the product of nucleophilic aromatic substitution OCI H H O N p-Nitroanisole FIGURE 23. 3 The addition-elimination mechanism of nucleophilic aromatic substitution FIGURE 23. 4 Stru ture of the rate-dete ntermediate in the of 1-fluoro-4-nitrobenzene Back Forward Main MenuToc Study Guide ToC Student o MHHE Website
924 CHAPTER TWENTY-THREE Aryl Halides FIGURE 23.4 Structure of the rate-determining intermediate in the reaction of 1-fluoro-4-nitrobenzene with methoxide ion. Overall reaction: Step 1: Addition stage. The nucleophile, in this case methoxide ion, adds to the carbon atom that bears the leaving group to give a cyclohexadienyl anion intermediate. NO2 NO2 NO2 NO2 F p-Fluoronitrobenzene NaOCH3 Sodium methoxide OCH3 OCH3 OCH3 OCH3 OCH3 p-Nitroanisole NaF Sodium fluoride H H H H F F p-Fluoronitrobenzene Methoxide ion slow H H H H Step 2: Elimination stage. Loss of halide from the cyclohexadienyl intermediate restores the aromaticity of the ring and gives the product of nucleophilic aromatic substitution. fast H H H H NO2 F H H H H NO2 p-Nitroanisole F Fluoride ion Cyclohexadienyl anion intermediate Cyclohexadienyl anion intermediate FIGURE 23.3 The addition–elimination mechanism of nucleophilic aromatic substitution. Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website