1 Chapter 15: 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: 15.1 Nomenclature of Disubstituted and Polysubstituted Benzenes 15.2 Some Substituents Increase the Reactivity of a Benzene Ring and Some Decrease Its Reactivity* 15.3 The Effect of Substituents on Orientation (Regioselectivity)* 15.4 The Effect Substituent on pKa 15.5 The Ortho-Para ratio 15.6 Additional Considerations Regarding Substituent Effects 15.7 Designing a Synthesis III: Synthesis of monosubstituted and Disubstituted Benzenes* 15.8 Synthesis of Trisubstituted Benzenes 15.9 Synthesis of Substituted Benzenes Using Arenediazonium Salts* 15.10 The Arenediazonium Ion as an Electrophile* 15.11 Mechanism for the Reaction of Amines with Nitrous Acid* 15.12 Nucleophilic Aromatic Substitution Reactions: An Addition-Elimination Mechanism* 15.13 Nucleophilic Aromatic Substitution Reactions: An Elimination-Addition Mechanism That Forms a Benzyne Intermediate 15.14 Polycyclic Benzenoid Hydrocarbons# * Sections that will be focused # Sections that will be skipped Recommended additional problems 15.34 – 15.692 Class Note 15.1 Nomenclature of Disubstituted and Polysubstituted Benzenes BrBrBrNO2NO2H2NBrOHNO2BrClBrNO2ClCH3BrClBrNH2ClBrCH33 15.2 Some Substituents Increase the Reactivity of a Benzene Ring and Some Decrease Its Reactivity* and 15.3 The Effect of Substituents on Orientation (Regioselectivity)* EDGEWGelectron donation group (EDG)electron withdrawing group (EWG) A. Relative rate of electrophilic aromatic substitution Examples: OCH3NO2 • Rate-determining step (r.d.s) • Resonance effect and inductive effect4 B. Relative reactivity and regioselectivity of substituted benzenes Strong activating groups (substituents) NH2OHOR Moderate activating groups (substituents) HNOOROR5 Weak activating groups (substituents) R Weak deactivating groups (substituents) F Cl Br I6 Moderate deactivating groups (substituents) OHOROOROHNR7 Strong deactivating groups (substituents) SO3H NO2CN NR38 C. Examples (combined with 15.5 The Ortho-Para ratio and 15.6 Additional Considerations Regarding Substituent Effects) (i) CH3Br2, FeCl3 (ii) CH3HNO3H2SO4CH2CH3HNO3H2SO4C(CH3)3HNO3H2SO49 (iii) BrCl2, FeCl3 (iv) ORBr2 (1 equivalent) FeCl3ORBr2 (excess) FeCl310 (v) NH2HNORCH3COClAlCl3CH3COClAlCl3 (vi) ORNO2HNO3H2SO4HNO3H2SO411 (vii) Synthesis of trinitrotoluene CH3HNO3H2SO412 15.4 The Effect Substituent on pKa OHOHCH3OHOCH3OHCHOOHClOHNO2IIIIII IVVVI CO2HCO2HCH3CO2HOCH3CO2HCHOCO2HBrCO2HNO2IIIIII IVVVI NH3NH3CH3NH3OCH3NH3CHONH3BrNH3NO2IIIIIIIVVVI13 15.7 Designing a Synthesis III: Synthesis of monosubstituted and Disubstituted Benzenes* and 15.8 Synthesis of Trisubstituted Benzenes Design multiple-step synthesis: * Selectivity: chemoselectivity, regioselectivity, and stereoselectivity * Retrosynthetic analysis: breaking and formation of chemical bonds14 A. Examples (i) fromOH15 (ii) fromCH3OO2N (iii) fromCH3NO2O16 15.9 Synthesis of Substituted Benzenes Using Arenediazonium Salts and 15.11 Mechanism for the Reaction of Amines with Nitrous Acid* A. Formation of diazonium salt R NH2NaNO2, HCl0oCR N N Cl diazonium salt Mechanism:17 B. Reaction of arenediazonium salt with nucleophiles Sandmeyer reation (CuBr, CuCl, and CuCN) Reaction with KI, HBF4, H3O+, and H3PO218 15.10 The Arenediazonium Ion as an Electrophile* NNNu * Nucleophile better be bulky * Terminal nitrogen reacts with nucleophile19 15.12 Nucleophilic Aromatic Substitution Reactions (SNAr): An Addition-Elimination Mechanism* A. Comparison of SNAr, SN1, and SN2 B. General mechanism20 C. Examples (i) ClNO2ClNO2ClNO2NO2NO2O2NOHOHOHOHNO2OHNO2OHNO2NO2NO2O2N (ii) BrNO2NO2NHCH2CH3NO2NO2CH3CH2NH2then OH21 15.13 Nucleophilic Aromatic Substitution Reactions: An Elimination-Addition Mechanism That Forms a Benzyne