1 Chapter 16: Reactions of Substituted Benzenes Learning Objectives: 1. Be able to recognize and utilize the oxidative and reductive reactions involving the substituents on benzene. 2. Recognize whether a substituent on a benzene ring is activating or deactivating toward electrophilic aromatic substitution reaction, and why it is so. 3. Predict the effect a substituent will have on the regioselectivity of an electrophilic substitution reaction. 4. Predict the effect a substituent will have on pKa. 5. Be able to design the synthesis of a multisubstituted benzene. 6. Be able to recognize and utilize the reactions involving arenediazonium salts. 7. Recognize and be able to write the mechanism of nucleophilic aromatic substitution. 8. Recognize the structure of benzyne, be able to explain how it is formed, and how it reacts. Sections: 16.1 Nomenclature of Disubstituted and Polysubstituted Benzenes 16.2 Reactions of Substituents on Benzene 16.3 The Effect of Substituents on Reactivity* 16.4 The Effect of Substituents on Orientation (Regioselectivity)* 16.5 The Effect Substituent on pKa 16.6 The Ortho-para ratio 16.7 Additional Considerations Regarding Substituent Effects 16.8 Designing a Synthesis III: Synthesis of monosubstituted and Disubstituted Benzenes* 16.9 Synthesis of Trisubstituted Benzenes 16.10 Synthesis of Substituted Benzenes Using Arenediazonium Salts* 16.11 The Arenediazonium Ion as an Electrophile* 16.12 Mechanism for the Reaction of Amines with Nitrous Acid* 16.13 Nucleophilic Aromatic Substitution Reactions* 16.14 Benzyne 16.15 Polycyclic Benzenoid Hydrocarbons# 16.16 Electrophilic Substitution Reactions of Naphthalene and Substituted Naphthalene# * Sections that will be focused # Sections that will be skipped Recommended additional problems 16.36 – 6.41, 6.43 – 6.55, 6.57 – 6.60, 6.62 – 6.682 Class Note 16.1 Nomenclature of Disubstituted and Polysubstituted Benzenes BrBrBrNO2NO2H2NBrOHNO2BrClBrNO2ClCH3BrClBrNH2ClBrCH33 16.2 Reactions of Substituents on Benzene A. Reactions of Alkyl Substituents NBSperoxideor hνBrOHCNtert-BuO4 H2, PtNOH2, PtH2, Pt B. Oxidations of Alkyl Substituents 1. KMnO4, heat (reflux)2. H+Na2Cr2O7, H+, heat5 Na2Cr2O7, H+, heatNa2Cr2O7, H+, heatNa2Cr2O7, H+, heatOHMnO2 (no heating needed)OHNa2Cr2O7, H+, heat6 C. Reduction of Nitro Group H2, PtNO2NO2Sn, HClNO2Fe, HCl 16.3 The Effect of Substituents on Reactivity and 16.4 The Effect of Substituents on Orientation (Regioselectivity) EDGEWGelectron donation group (EDG)electron withdrawing group (EWG)7 A. Relative rate of electrophilic aromatic substitution Examples: OCH3NO2 • Rate-determining step (r.d.s) • Resonance effect and inductive effect8 B. Relative reactivity and regioselectivity of substituted benzenes Strong activating groups (substituents) NH2OHOR Moderate activating groups (substituents) HNOOROR9 Weak activating groups (substituents) R Weak deactivating groups (substituents) F Cl Br I10 Moderate deactivating groups (substituents) OHOROOROHNR11 Strong deactivating groups (substituents) SO3H NO2CN NR312 C. Examples (combined with 16.6 The Ortho-para ratio and 16.7 Additional Considerations Regarding Substituent Effects) (i) CH3Br2, FeCl3 (ii) CH3HNO3H2SO4CH2CH3HNO3H2SO4C(CH3)3HNO3H2SO413 (iii) BrCl2, FeCl3 (iv) ORBr2 (1 equivalent) FeCl3ORBr2 (excess) FeCl314 (v) NH2HNORCH3COClAlCl3CH3COClAlCl3 (vi) ORNO2HNO3H2SO4HNO3H2SO415 (vii) Synthesis of trinitrotoluene CH3HNO3H2SO416 16.5 The Effect Substituent on pKa OHOHCH3OHOCH3OHCHOOHClOHNO2IIIIII IVVVI CO2HCO2HCH3CO2HOCH3CO2HCHOCO2HBrCO2HNO2IIIIII IVVVI NH3NH3CH3NH3OCH3NH3CHONH3BrNH3NO2IIIIIIIVVVI17 16.8 Designing a Synthesis III: Synthesis of monosubstituted and Disubstituted Benzenes and 16.9 Synthesis of Trisubstituted Benzenes Design multiple-step synthesis: * Selectivity: chemoselectivity, regioselectivity, and stereoselectivity * Retrosynthetic analysis: breaking and formation of chemical bonds18 A. Examples (i) fromOH19 (ii) fromCH3OO2N (iii) fromCH3NO2O20 16.12 Mechanism for the Reaction of Amines with Nitrous Acid and 16.10 Synthesis of Substituted Benzenes Using Arenediazonium Salts A. Formation of diazonium salt R NH2NaNO2, HCl0oCR N N Cl diazonium salt Mechanism:21 B. Reaction of arenediazonium salt with nucleophiles Sandmeyer reation (CuBr, CuCl, and CuCN) Reaction with KI, HBF4, H3O+, and H3PO222 16.11 The Arenediazonium Ion as an Electrophile NNNu * Nucleophile better be bulky * Terminal nitrogen reacts with nucleophile23 16.13 Nucleophilic Aromatic Substitution (SNAr) Reactions A. Comparison of SNAr, SN1, and SN2 B. General mechanism24 C. Examples (i) ClNO2ClNO2ClNO2NO2NO2O2NOHOHOHOHNO2OHNO2OHNO2NO2NO2O2N (ii) BrNO2NO2NHCH2CH3NO2NO2CH3CH2NH2then OH25 16.14