Chapter 12 - Reactions of Benzene - EAS 12.1 Introduction to benzene vs. alkenes 12.2 Mechanistic principles of Electrophilic Aromatic Subsitution 12.3 Nitration of benzene, reduction to aminobenzenes 12.4 Sulfonation of benzene 12.5 Halogenation of benzene 12.6 Friedel-Crafts alkylation of benzene 12.7 Friedel-Crafts alkylation of benzene 12.8 Alkylbenzenes via acylation then reduction 12.9 Rate and regioselectivity in EAS 12.10 Nitration of toluene - rate and regioselectivity 12.11 Nitration of CF3-benzene - rate and regioselectivity 12.12 Substituent effects in EAS: Activating Substituents 12.13 Substituent effects in EAS: Strongly Deactivating Substituents 12.14 Substituent effects in EAS: Halogens 12.15 Multiple substituent effects in EAS 12.16 Regioselective synthesis of disubstituted aromatic compounds 12.17 Substitution in Naphthalene 12.18 Substitution in heterocyclic aromatic compounds 1 Introduction – Benzene vs. Alkenes Br Br Br no heat Br dark Br Br no colour change no heat (no reaction) dark Completely delocalized (6) pi system lends stability (aromatic) 12.2 Mechanistic Principles of EAS Alkenes react by addition E Y E E Y Y Benzene reacts by substitution Y E Y H E E - H Y Resonance-stabilized cation 2 General Mechanism of EAS on Benzene Energy diagram for EAS in benzene Figure 12.1 Electrophilic Aromatic Substitutions on Benzene H NO HNO3, H2SO4 2 12.3 Nitration H SO , H SO SO3H 12.4 Sulfonation 3 2 4 H Br , Fe Br 12.5 Halogenation 2 3 12.6 Friedel-Crafts Alkylation of Benzene H CH2CH3 CH3CH2Cl AlCl3 CH3 H C CH3 (CH3)3CCl CH3 AlCl3 H3C CH Cl 3 H C CH3 CH3 CH3 AlCl3 Problems: Alkyl groups may rearrange during reaction Products are more reactive than benzene Uses: Alkyl benzenes readily oxidized to benzoic acids using KMnO4 12.7 Friedel-Crafts Acylation of Benzene O O H C RCCl R AlCl3 O O O H CCH3 H3C O CH3 AlCl3 O AlCl3 O RCCl RC RCO Products react more slowly than benzene - cleaner reaction No carbocation rearrangements 4 12.8 Alkylbenzenes via Acylation/Reduction O Zn, HCl H H C (Clemmensen) C R R or NH2NH2, KOH heat (Wolff-Kischner) O Cl AlCl3 Zn, HCl O Make the acyl benzene first (clean, high yielding reaction) Reduce the ketone group down to the methylene (C=O to CH2) Avoids rearrangement problems, better yields Aminobenzenes via Nitration/Reduction (not in text) O H Sn, HCl N N O H H H HNO , H SO NO2 Sn, HCl N 3 2 4 H Make the nitro benzene first, clean high yielding reaction Reduce the nitro group down to the amine Difficult to introduce the amino group by other methods 5 12.9 Activation and Deactivation by Substituents (Rates) X X HNO3, H2SO4 NO2 CF3 H CH3 0.000025 1.0 25 Relative rates in nitration reaction now bringing in a second substituent 12.9 Nitration of Toluene vs Nitration of (Trifluoromethyl)benzene CH3 CH3 CH3 CH3 HNO3, H2SO4 NO2 ++ NO2 NO2 63%3%34% CH3 is said to be an ortho/para director (o/p director) - Regioselectivity CF3 CF3 CF3 CF3 HNO3, H2SO4 NO2 ++ NO2 NO2 6% 91% 3% CF3 is said to be a meta director (m director) - Regioselectivity 6 12.10 Rate and Regioselectivity in Nitration of Toluene CH3 CH3 CH3 CH3 HNO3, H2SO4 NO2 ++ NO2 NO2 63% 3% 34% Fig. 12.5 – Energy diagrams for toluene nitration (vs. benzene) 12.11 Rate and Regioselectivity in Nitration of CF3C6H5 CF3 CF3 CF3 CF3 HNO3, H2SO4 NO2 ++ NO2 NO2 6% 91% 3% Fig. 12.6 – Energy diagrams for CF3C6H5 nitration (vs. benzene) 7 12.12 Substituent Effects – Activating Substituents General : all activating groups are o/p directors halogens are slightly deactivating but are o/p directors strongly deactivating groups are m directors Activating Substituents O R HO RO RCO alkyl hydroxyl alkoxy acyloxy OCH3 OCH3 OCH3 HNO3, H2SO4 Example: NO2 + NO2 Alkyl groups stabilize carbocation by hyperconjugation Lone pairs on O (and others like N) stabilize by resonance 12.13 Subst. Effects – Strongly Deactivating Substituents O O O O O HC R C HO C Cl C RO C aldehyde ketone carboxylic acid acyl chloride ester O N C HO S O2N O nitrile sulfonic acid nitro NO2 NO2 Br2, Fe Example: Br Second substituent goes meta by default – best carbocation 8 12.14 Substituent Effects – Halogens X X X X = F, Cl, Br X = F, Cl, Br Reactivity (i.e. rate) is a balance between inductive effect (EW) and resonance effect (ED) – larger Cl, Br, I do not push lone pair into pi system as well as F, O, N, which are all first row (2p) Example: Cl Cl Cl Cl HNO3, H2SO4 NO2 ++ NO2 NO2 30% 1% 69% Regioselectivity - second substituent goes o/p – better carbocations 12.15 Multiple Substituent Effects CH3 O O CH3 O NHCH3 NHCH3 H3C O CH3 Br2, acetic acid Br CH3 AlCl3 CH3 CH3 Cl Cl 99% 87% CH3 CH3 CH3 CH3 Br2, Fe Br HNO3, H2SO4 NO2 NO2 NO2 C(CH3)3 C(CH3)3 86% 88% Interplay between power of directing group and size of substituents 9 12.16 Regioselective Synthesis of Disubstituted Derivs. O O O CH3 CH3 CH3 Br Br NO2 CO2H CH2CH3 Br NO2 Have to be careful about when to introduce each substituent Remember – isomers (e.g. o/p mixtures) may be separated 12.17-12.18 Substitution in Other Aromatic Systems 12.17 Naphthalene O CH3 O O CH3CCl CH but not 3 AlCl3 90% 12.18 Heterocycles SO3H SO3, H2SO4 o N HgSO4, 230 C N O O H3C O CH3 CH3 O BF3 O O 10.