Lecture 13 Reactions of Benzene C F C F 3 3 C l NH3(l) NaNH2 NH2 March 5, 2019 Chemistry 328N Electrophilic Aromatic Substitution H + + E H + H+ E E Please be sure All EAS reactions H follow this path so we that you can do + H this and that it only need to learn E makes sense to how to make different + you!! electrophiles, E H + E H Chemistry 328N The Energetics H H E H + H H H H H H H H H + E+ H E + H+ H H H H Chemistry 328N H E d+ d– + E Y + H Y Electrophilic aromatic substitutions include: Nitration Sulfonation Halogenation Friedel-Crafts Alkylation Friedel-Crafts Acylation Chemistry 328N Relative rates of Nitration OH H Cl NO2 1000 1.0 0.033 6x10-8 Reactivity Chemistry 328N Real Fast Pretty fast Kinda slow Pretty slow Slow Real Slow Chemistry 328N Adding a Second Substiuent Methoxy is is therefore an “o-p director” Chemistry 328N Adding a Second Substiuent Nitro is therefore a “meta director” Chemistry 328N Generalization regioselectivity is controlled by the most activating substituent Chemistry 328N The “Best Man Wins” strongly NHCH3 NHCH3 activating Br Br2 FeBr3 Cl Cl 87% Chemistry 328N Reduction of the Nitro Group NO NH HNO3 2 2 Zn HSO 2 4 HCl Aniline ! The Nitro group is easily reduced. Many reducing agents can be employed for this transformation including Sn or Fe in HCl, H2 with Pd/C, etc Chemistry 328N Aniline dyes (Tyrian Purple) Royal Purple Previously from shell fish secretions Aniline Dye Chemistry 328N Diazonium Salts Diazonium Salt Acts like Chemistry 328N Mechanism of Diazonium Salt formation H + H O N O + H + O N O H H + + O N O H 2O + N O H nitrosonium ion H + + R NH 2 + N O R N N O H N-nitrosoammonium ion H + + R N N O + H 2O R N N O + H 3O H H N-nitrosamine R N N O R N N OH tautomerization H a diazenol + H R N N OH + H + R N N O H + H + R N N O R N N + H 2O H a diazonium ion Chemistry 328N Reactions of Diazonium Salts Chemistry 328N Diazonium Salts + ⚫ The -N2 group of an arenediazonium salt can be replaced in a regioselective manner by these groups H O 2 Ar-OH HBF 4 Ar-F Schiemann reaction HCl, CuCl Ar-Cl + (-N ) HBr, CuBr Sandmeyer Ar-N 2 Ar-Br 2 reaction KCN, CuCN Ar-CN KI Ar-I H PO 3 2 Ar-H Chemistry 328N Practice CH3 Cl CH3 CH3 CH3 NH2 C N CH2 NH2 CH3 CH3 NH2 Cl Cl Cl Cl Chemistry 328N Practice…work backwards Oh No….two o,p directors meta to one another??? B r ????? C l Chemistry 328N Synthesis Strategy ? ? Chemistry 328N Substitution Reactions ⚫ Aryl halides do not undergo nucleophilic substitution by either SN1 or SN2 pathways! But….. Chemistry 328N But….this is fact ⚫ When heated under pressure with aqueous NaOH, chlorobenzene is converted to sodium phenoxide - + Cl O Na H2 O + 2 NaOH + NaCl + H2 O pressure, 300oC Chloro- Sodium benzene phenoxide – neutralization with HCl gives phenol????? What is this?? Chemistry 328N Also fact…. ⚫ The same reaction with 2-chlorotoluene gives a mixture of ortho- and meta-cresol???? Ortho and meta….huh???? CH CH3 3 CH3 Cl OH 1 . NaOH , heat, pressure + 2. HCl, H2O OH 2-Methylphenol 3-Methylphenol (o-Cresol) (m-Cresol) Chemistry 328N Also true ⚫ The same type of reaction can be brought about by the use of sodium amide in liquid ammonia CH 3 CH 3 CH 3 NH 3 (l) + NaNH + NaCl 2 (-33 oC) + NH Cl 2 NH 2 Chemistry 328N Proposed Benzyne Intermediate ⚫ -elimination of HX gives a “benzyne” intermediate, that then adds the nucleophile to give products CH3 CH3 NaNH 2 -elimin- H Cl ation A benzyne intermediate Chemistry 328N Proposed Benzyne Intermediate CH3 CH3 CH3 - + NH2 CH3 - NH2 NH2 NH2 H H NH2 - NH2 CH CH3 H CH3 3 Cl - + NH2 H NH2 H NH - NH2 2 NH2 Chemistry 328N Proposed Benzyne Intermediate Another Mystery?? CF3 CF3 Cl NH3(l) NaNH2 NH2 More than 95% of the product is the meta isomer?? Chemistry 328N Nucleophilic Addition-Elimination ⚫ When an aryl halide contains strongly electron- withdrawing -NO2 groups ortho and/or para to X, nucleophilic aromatic sub. takes place readily - + Cl O Na NO NO 2 Na 2 CO3 , H 2 O 2 100 oC NO2 NO2 1-Chloro-2,4- dinitrobenzene Sodium 2,4-dinitrophenoxide Chemistry 328N Meisenheimer Complex •• •• O slow, rate- •• - +N Cl + Nu limiting •• •• (1) O - •• NO2 •• - •• •• •• •• O O Cl fast - + N + N Nu + Cl •• •• (2) •• Nu •• O O -•• NO2 - •• NO2 A Meisenheimer complex Chemistry 328N Addition Elimination F OCH3 - CH3O CH3OH NO2 NO2 Chemistry 328N.