Organic Lecture Series ReactionsReactions ofof BenzeneBenzene && ItsIts DerivativesDerivatives Chapter 22 1 Organic Lecture Series Reactions of Benzene The most characteristic reaction of aromatic compounds is substitution at a ring carbon: Halogenation: FeCl3 H + Cl2 Cl + HCl Chlorobenzene Nitration: H2 SO4 HNO+ HNO3 2 + H2 O Nitrobenzene 2 Organic Lecture Series Reactions of Benzene Sulfonation: H 2 SO4 HSO+ SO3 3 H Benzenesulfonic acid Alkylation: AlX3 H + RX R + HX An alkylbenzene Acylation: O O AlX H + RCX 3 CR + HX An acylbenzene 3 Organic Lecture Series Carbon-Carbon Bond Formations: R RCl AlCl3 Arenes Alkylbenzenes 4 Organic Lecture Series Electrophilic Aromatic Substitution • Electrophilic aromatic substitution: a reaction in which a hydrogen atom of an aromatic ring is replaced by an electrophile H E + + + E + H • In this section: – several common types of electrophiles – how each is generated – the mechanism by which each replaces hydrogen 5 Organic Lecture Series EAS: General Mechanism • A general mechanism slow, rate + determining H Step 1: H + E+ E El e ctro - Resonance-stabilized phile cation intermediate + H fast Step 2: E + H+ E • Key question: What is the electrophile and how is it generated? 6 Organic Lecture Series + + 7 Organic Lecture Series Chlorination Step 1: formation of a chloronium ion Cl Cl + + - - Cl Cl+ Fe Cl Cl Cl Fe Cl Cl Fe Cl4 Cl Cl Chlorine Ferric chloride A molecular complex An ion pair (a Lewis (a Lewis with a positive charge containing a base) acid) on ch lorine ch loronium ion Step 2: attack of the chloronium ion on the ring slow, rate determining + Cl + H H H + Cl Cl Cl + Resonance-stabilized cation intermediate; the positive charge is delocalized onto three atoms of the ring 8 Organic Lecture Series Chlorination Step 3: proton transfer regenerates the aromatic character of the ring + H - + fast Cl-FeCl3 Cl + HCl + FeCl3 Cl Cation Chlorobenzene intermediate 9 Organic Lecture Series Bromination FeBr 3 + H + Br 2 Br HBr Bromobenzene This is the general method for Substitution of halogen onto a benzene ring (CANNOT be halogenated by Free Radical Mechanism) 10 Organic Lecture Series Bromination-Why not addn of Br2? Regains Aromatic Energy 11 Organic Lecture Series Nitration + • Generation of the nitronium ion, NO2 – Step 1: proton transfer to nitric acid O H O HSO3 OH+ HON HSO4 + ON O H O Sulfuric Nitric Co nju gate acid acid pKa= -3 acid pKa= -1.4 of nitric acid – Step 2: loss of H2O gives the nitronium ion, a very strong electrophile H O H ON O + ONO H H O The nitronium ion 12 Nitration Organic Lecture Series Step 1: attack of the nitronium ion (an electrophile) on the aromatic ring (a nucleophile) HNO 2 H NO2 HNO2 + + + + ONO + Resonance-stabilized cation intermediate Step 2: proton transfer regenerates the aromatic ring HHNO NO2 H 2 H O + + + O H H H 13 Organic Lecture Series Nitration • A particular value of nitration is that the nitro group can be reduced to a 1° amino group COOH COOH Ni + 3H + 2H O 2 (3 atm) 2 NO2 NH2 4-Nitrobenzoic acid 4-Aminobenzoic acid 14 Organic Lecture Series Sulfonation • Carried out using concentrated sulfuric acid containing dissolved sulfur trioxide H SO + 2 4 SO3 SO3 H Benzene B enzenesulfonic acid (SO3 in H2SO4 is sometimes called “fuming” sulfuric acid.) 15 Organic Lecture Series Friedel-Crafts Alkylation • Friedel-Crafts alkylation forms a new C-C bond between an aromatic ring and an alkyl group AlCl3 + Cl + HCl Benzene 2-Chloropropane Cumene (Isopropyl chloride) (Isopropylbenzene) The electrophilic partner is a carbocation; it will arrange to the most stable ion: allylic>3o>2o>1o 16 Friedel-Crafts Alkylation Organic Lecture Series Step 1: formation of an alkyl cation as an ion pair Cl + Cl - + - RCl+ Al Cl RClAl Cl R AlCl4 Cl Cl A molecular An ion pair containing comp lex a carbocation Step 2: attack of the alkyl cation on the aromatic ring + H H H + R+ + R R R + A resonance-stabilized cation Step 3: proton transfer regenerates the aromatic ring H + Cl AlCl3 R ++AlCl3 HCl R 17 Friedel-Crafts Alkylation Organic Lecture Series There are two major limitations on Friedel-Crafts alkylations: 1. carbocation rearrangements are common: AlCl3 + Cl +HCl Benzene Isobutyl tert-Butylbenzene chloride CH CH 3 CH3 + 3 - + - CH3 CHCH2 -Cl + AlCl3 CH 3 C- CH2 -Cl-AlCl3 CH3 C AlCl4 H CH 3 I sobutyl chloride amolecular an ion pair complex 18 Organic Lecture Series Friedel-Crafts Alkylation 2. F-C alkylation fails on benzene rings bearing one or more of these strongly electron- withdrawing groups Y AlCl + RX 3 No reacti on When Y Equals Any of These Groups, the Benzene Ring Does Not Undergo Friedel-Crafts Alkylation O O O O O CH CR COH COR CNH2 + SO3 HNOCN 2 NR3 CF3 CCl3 19 Organic Lecture Series 20 Organic Lecture Series The “De-activation” of Aromatic Systems Note: deactivation refers to the rate of EAS 21 Organic Lecture Series Friedel-Crafts Acylation • Friedel-Crafts acylation forms a new C-C bond between a benzene ring and an acyl group: O O AlCl3 + CH3 CCl + HCl BenzeneAcetyl Acetophenone ch loride O Cl O AlCl 3 + HCl 4-Phenylbutanoyl α-Tetralone chlorid e 22 Organic Lecture Series Friedel-Crafts Acylation • The electrophile is an acylium ion O Cl (1) •• •• R-C Cl + Al-Cl •• Cl An acyl Aluminum chloride chloride O O + Cl (2) •• - R-C Cl Al Cl R-C + AlCl - •• 4 Cl A molecular complex A n ion pair with a positive charge containing an charge on chlorine acylium ion 23 Friedel-Crafts Acylation Organic Lecture Series – an acylium ion is a resonance hybrid of two major contributing structures complete valence shells + + : R-C O: : R-C O The more important contributing structure • F-C acylations are free of a major limitation of F-C alkylations; acylium ions do not rearrange. 24 Organic Lecture Series Friedel-Crafts Acylation A special value of F-C acylations is preparation of unrearranged alkylbenzenes: O AlCl + Cl 3 2-Methylpropanoyl chloride O N 2H 4, KOH diethylene 2-Methyl-1- glycol Isobutylbenzene phenyl-1-propanone 25 Organic Lecture Series Di- and Polysubstitution Only a trace 26 Organic Lecture Series Di- and Polysubstitution Orientation on nitration of monosubstituted benzenes: ortho + Substituent ortho meta para para meta - OCH3 44 55 99 trace CH 3 58 4 38 96 4 Cl 70 - 30 100 trace Br 37 1 62 99 1 COOH 18 80 2 20 80 CN 19 80 1 20 80 NO2 6.4 93.2 0.3 6.7 93.2 27 Organic Lecture Series Di- and Polysubstitution • Orientation: –certain substituents direct preferentially to ortho & para positions; others to meta positions –substituents are classified as either ortho-para directing or meta directing toward further substitution 28 Di- and Polysubstitution Organic Lecture Series • Rate –certain substituents cause the rate of a second substitution to be greater than that for benzene itself; others cause the rate to be lower –substituents are classified as activating or deactivating toward further substitution 29 Organic Lecture Series 30 Di- and Polysubstitution Organic Lecture Series – -OCH3 is ortho-para directing: OCH3 OCH3 OCH3 NO2 + HNO3 + + H2 O CH 3 COOH NO2 Anisole o-Nitroanisole p-Nitroanisole (44%) (55%) –-CO2H is meta directing COOH COOH COOH COOH NO H2 SO4 2 ++HNO3 + 100°C NO2 Benzoic NO2 acid o-Nitro- m-Nitro- p-Nitro- benzoic benzoic benzoic acid acid acid (18%) (80%) (2%) 31 Organic Lecture Series Di- and Polysubstitution : : : Strongly : : NH NHR NR OH OR: activating 2 2 : OOOO: : Moderately : : NHCR NHCAr OCR: OCAr activating : Weakly activating R :: :: :: : Ortho-para Directing Weakly F: : : : deactivating Cl: Br I OOO O CH CR COH COR Moderately deactivating O CNH2 SO3 H CN Strongly + Meta Directing deactivating NO2 NH3 CF3 CCl3 32 Di- and Polysubstitution Organic Lecture Series the order of steps is important: CH3 COOH HNO 3 K2 Cr2O7 H SO 2 4 H2SO4 CH 3 NO2 NO2 p-Nitrobenzoic acid COOH COOH HNO K2 Cr 2 O7 3 H SO H2 SO4 2 4 NO2 m-Nitrobenzoic acid 33 Organic Lecture Series Theory of Directing Effects • The rate of EAS is limited by the slowest step in the reaction • For almost every EAS, the rate- determining step is attack of E+ on the aromatic ring to give a resonance- stabilized cation intermediate •The more stable this cation intermediate, the faster the rate- determining step and the faster the overall reaction 34 Organic Lecture Series Theory of Directing Effects • For ortho-para directors, ortho-para attack forms a more stable cation than meta attack – ortho-para products are formed faster than meta products • For meta directors, meta attack forms a more stable cation than ortho-para attack – meta products are formed faster than ortho-para products 35 Theory of Directing Effects Organic Lecture Series Nitration of anisole -OCH3; examine the meta attack: OCH3 slow + + NO2 OCH3 OCH3 OCH3 OCH3 + + fast H H H -H+ NO2 NO2 NO2 + NO2 (a) (b) (c) 36 Organic Lecture Series Nitration of anisole -OCH3: examine the ortho-para attack: OCH3 OCH3 + slow + NO2 : +: : : NO : 2 OCH3 ::OCH3 OCH3 OCH3 fast + -H+ + + NO H 2 HNO2 H NO2 H NO2 (d) (e) (f) (g) This resonance structure accounts for the selectivity 37 Organic Lecture Series Theory of Directing Effects Nitration of benzoic acid -NO2; examine the meta attack: COOH + slow + NO2 COOH COOH COOH COOH fast H H H -H+ NO2 NO2 NO2 NO2 (a) (b) (c) 38 Organic Lecture Series Nitration of benzoic acid -NO2: assume ortho-para attack: COOH + slow + NO2 COOH COOH COOH COOH fast -H+ H NO 2 H NO2 H NO2 NO2 (d) (e) (f) The most disfavored contributing structure This resonance structure accounts for the selectivity 39 Organic Lecture Series Activating-Deactivating • Any resonance effect,effect such as that of - NH2,