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ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 21.11 Aryl Halide and Nucleophilic Aromatic Substitution ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 Simple aryl halides are much less reactive than alkyl halides in nucleophilic substitution reactions. Cl + NaOH H2O reflux no substitution The C–X bonds of aryl halides are stronger and shorter than those of alkyl halides. Aryl cations are very unstable. SN1 do not occur. The optimal transition-state geometry required for SN2 processes cannot be achieved. XNu × no reaction ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 21.11A Nucleophilic Aromatic Substitution by Addition-Elimination: The SNAr Mechanism Nucleophilic substitution can occur when strong electron-withdrawing groups are ortho or para to the halogen atom. N2 N NO NO2 CO2H CF3 CR CN O SO3 Cl Br I CO2 C6H5 ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 pressur, 135~160? Cl OH NO2 10% NaOH NO2 H+ 100? Cl OH NO2 Na2CO3, H2O NO2 NO2 NO2H+ Cl NO2 NO2O2N OH NO2 NO2O2N H2O H+ 35°C ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 MechanismMechanism L N O O + Nu slow L N O O Nu Nu N O O fast addition elimination L N O O Nu L N O O Nu L N O O Nu L N O O Nu Addition-elimination mechanism (????? ??) ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 21.11B Nucleophilic Aromatic Substitution through an Elimination-Addition Mechanism: Benzyne Chlorobenzene can be converted to phenol by heating it with aqueous NaOH in a pressurized reactor at 350°C. Bromobenzene reacts with KNH2 in liquid ammonia. Cl 10%NaOH , Cu 350? , 28MPa OH H3O+ Br KNH2+ NH3 33°C NH2 ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 2-Iodo-1,3-dimethylbenzene do not react with NaNH2: p-Chlorotoluene reacts with NaNH2 to yield a mixture of p- and m-toluidine: I CH3CH3 NH3(l) NaNH2 no substitution 2-Iodo-1,3-dimethylbenzene CH3 Cl CH3 NH2 NH3(l) CH3 NH2 + NaNH2 p-Chlorotoluene p-Toluidine m-Toluidine ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 MechanismMechanism These reaction take place through an elimination- addition mechanism that involves the formation of an intermediate called benzyne. Cl H Cl NH2+ BenzyneElimination + NH2 NH2 NH2NH3 H+ NH3 Addition ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 Benzyne SP2 The first piece of clear-cut evidence was an experiment done by J. D. Roberts in 1953. Br KNH2* * NH2- NH2 NH2* * + (50%) (50%) ? ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 Benzyne intermediates have been “trapped” though the use of Diels-Alder reactions. CO2H NH2 + CH3(CH2)4ONO H+ CH2Cl2 C N2+ O O CO2 N2 O O Br KNH2* O O ** ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 An even striking illustration can be seen in the following reaction. CF3 Cl NaNH2 NH3 CF3 NH2 CF3CF3 Cl H NaNH2 NH3 NH2 CF3 NH2 CF3 NH2 Less stable carbanion More stable carbanion NH3 CF3 NH2 ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 G G X X G G G X H H H H ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 Regioselectivity in the nucleophilic addition of arynes G NH3(l) G NH2 NaNH2 G = electro-withdrawing groups G NH3(l) G NH2NaNH2 G = electro-donating groups ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 CH3 Cl KNH2 NH3(l) CH3 NH2 CH3 NH2 + 38% 62% F3C OCH3 Br F3C OCH3 NH2 NaNH2 NH3(l) 100% ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 21.12 Spectroscopic Analysis of Phenols and Aryl Halides ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 IR Phenols: O–H 3400 – 3600 cm-1 Phenols and aryl halides: benzene rings NMR 1H NMR: O–H phenol(1% in CCl4) δ 2.55–5.63 , D2O exchangeable. Ar–H δ 7–9 . 13C NMR: aromatic ring δ 135–170 MS Phenols often display a prominent M+· Phenols : M+· –1> M+· ORGANIC CHEMISTRY Department of Chemistry, Xiamen University Chapter 21 Exercises 21.12, 21.13, 21.14, 21.15, 21.16 21.19, 21.21, 21.22, 21.23 21.11 Aryl Halide and Nucleophilic Aromatic Substitution 21.11A Nucleophilic Aromatic Substitution by Addition-Elimination: The SNAr Mechanism Mechanism 21.11B Nucleophilic Aromatic Substitution through an Elimination-Addition Mechanism: Benzyne Mechanism 21.12 Spectroscopic Analysis of Phenols and Aryl Halides IR Exercises
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