Chapter 21 ● Phenols and Aryl Halides Nucleophilic Aromatic Substitution Ch. 21 - 1 1. Structure and Nomenclature of Phenols OH OH OH Phenol 1-Naphthol 9-Phenanthrol (α-naphthol) Ch. 21 - 2 1A. Nomenclature of Phenols Cl CH3 NO2 OH OH OH 4-Chlorophenol 2-Nitrophenol 3-Methylphenol (p-chlorophenol) (o-nitrophenol) (m-cresol) Ch. 21 - 3 The benzenediols also have common names OH OH OH OH OH OH 1,2-Benzenediol 1,3-Benzenediol 1,4-Benzenediol (catechol) (resorcinol) (hydroquinone) Ch. 21 - 4 2. Naturally Occurring Phenols O CO2CH3 OH O− H + NH3 HO L-Tyrosine Methyl salicylate (oil of wintergreen) OH OH CH3 OCH3 H H H HO Eugenol Estradiol (oil of cloves) Ch. 21 - 5 3. Physical Properties of Phenols OH CH3 Phenol Toluene M.W. 94 92 B.P. (oC) 182 110 Ch. 21 - 6 4. Synthesis of Phenols 4A. Laboratory Synthesis NH 2 N2 2+ OH Cu2O, Cu HONO H2O R R R e.g. NH2 OH o 1. NaNO2, HCl, 0-5 C 2+ 2. Cu2O, Cu , H2O Cl CH3 Cl CH3 Ch. 21 - 7 4B. Industrial Syntheses Hydrolysis of chlorobenzene (Dow Process) Cl O Na 2 NaOH + NaCl + H2O 350oC high pressure HCl OH + NaCl Ch. 21 - 8 From cumene hydroperoxide H3PO4 + 250oC (Cumene) high pressure O2 95-135oC O OH + H3O + O 50-90oC OH (Cumene hydroperoxide) Ch. 21 - 9 Mechanism ● Chain initiation Step 1 H R + R H Ch. 21 - 10 ● Chain propagation Step 2 O O + O O Step 3 O O H + O O H + Ch. 21 - 11 ● Chain propagation H O O H O O + H OH2 H - H2O H O O H2O O H OH2 + + H - H3O O O O HO H Ch. 21 - 12 5. Reactions of Phenols as Acids pKa pKa OH 9.89 O2N OH 7.15 NO2 H3C OH 10.17 O2N OH 3.96 NO2 Cl OH 9.20 O2N OH 0.38 NO2 Ch. 21 - 13 OH OH pKa 18 9.89 O O H + + H2O + H3O (NO resonance stabilization) Ch. 21 - 14 O O H + + H3O + H2O O O O Ch. 21 - 15 5B. Distinguishing and Separating Phenols from Alcohols and Carboxylic Acids Question If you are given three unknown samples: one is benzoic acid; one is phenol; and one is cyclohexyl alcohol; how would you distinguish them by simple chemical tests? ● Recall: acidity of H H O O O H O > > Ch. 21 - 16 O O H + Na OH + H2O R O R O Na (soluble in water) O O Na H + NaOH (soluble in water) O H + NaOH No Reaction (immiscible with H O) 2 Ch. 21 - 17 O O H O O Na + NaHCO3 + CO2(g) + H2O (gas evolved) O H + NaHCO3 No Reaction O H + NaHCO3 No Reaction Ch. 21 - 18 6. Other Reactions of the O–H Group of Phenols O O R O R base O OH O O R R Cl base Ch. 21 - 19 6A. Phenols in the Williamson Synthesis OH O Na NaOH R R R X (X = halides, OTs, OMs) OR R e.g. OH O 1. NaOH 2. Br Ch. 21 - 20 7. Cleavage of Alkyl Aryl Ethers O OH R conc. HX + RX heat R R e.g. O OH conc. HCl + Cl heat Ch. 21 - 21 8. Reactions of the Benzene Ring of Phenols Bromination OH Br Br 3 Br2 + 3 HBr OH H2O Br (NO Lewis acid required for the OH brominations) Br2 + HBr o CS2, 5 C Br Ch. 21 - 22 Nitration OH OH OH NO2 20% HNO3 + 25oC NO2 (30-40%) (15%) Ch. 21 - 23 Sulfonation OH SO3H conc. H2SO4 25oC OH conc. H2SO4 100oC OH conc. H2SO4 100oC SO3H Ch. 21 - 24 Kolbe reaction O Na OH COOH 1. CO2 + 2. H3O (Salicylic acid) Ch. 21 - 25 ● Mechanism Na O O H O O C C Na O O tautomerization H H O OH O O + O H3O O Na Salicylic acid Sodium salicylate Ch. 21 - 26 O OH O O O COOH COOH O R O R + CH3COOH OH (Salicylic acid) Acetylsalicylic acid (Aspirin) Ch. 21 - 27 9. The Claisen Rearrangement OH O 1. NaH 2. Br 200oC OH Ch. 21 - 28 Via a [3,3] sigmatropic rearrangement 1 2 O O 1' 3 2' 3' H keto-enol tautomerization OH Ch. 21 - 29 10. Quinones OH O - 2 e− + 2 H+ + 2 e− OH O Hydroquinone p-Benzoquinone Ch. 21 - 30 O H3CO CH3 + 2 e−, + 2 H+ - 2 e−, - 2 H+ H3CO H n O CH3 OH Ubiquinones (n = 6-10) H3CO CH3 (coenzymes Q) H3CO H n OH CH3 Ubiquinol (hydroquinone form) Ch. 21 - 31 O O 1,4-Naphthoquinone O 3 CH3 O Vitamin K1 Ch. 21 - 32 11. Aryl Halides and Nucleophilic Aromatic Substitution Cl H2O + NaOH NO substitution heat H2O Cl + NaOH NO substitution heat X Nu: X NO reaction Ch. 21 - 33 X X X X X Ch. 21 - 34 11A. Nucleophilic Aromatic Substitution by Addition–Elimination: The SNAr Mechanism Nucleophilic aromatic substitution can occur when strong electron-withdrawing groups are ortho or para to the halogen atom Cl OH NO2 + NO2 aq. NaHCO3 H3O + OH 130oC Ch. 21 - 35 Cl OH NO2 + NO2 aq. NaHCO3 H3O + OH 130oC NO2 NO2 Cl O2N NO2 aq. NaHCO3 + OH o 130 C OH + O2N NO2 NO2 H3O NO2 Ch. 21 - 36 The mechanism that operates in these reactions is an addition–elimination mechanism involving the formation of a carbanion with delocalized electrons, called a Meisenheimer intermediate. The process is called nucleophilic aromatic substitution (SNAr) Ch. 21 - 37 The SNAr mechanism Cl Cl OH addition + OH slow elimination NO2 NO2 fast O OH OH HOH + Cl + NO2 NO2 Ch. 21 - 38 HO Cl HO Cl HO Cl N N N O O O O O O HO Cl N O O Ch. 21 - 39 11B. Nucleophilic Aromatic Substitution through an Elimination–Addition Mechanism: Benzyne Cl ONa OH + NaOH H3O 350oC Phenol Br NH2 K :NH2 + KBr -33oC Aniline Ch. 21 - 40 The benzyne elimination–addition mechanism Br Br − (-NH3) (-Br ) H Benzyne (or dehydrobenzene) NH2 NH2 NH2 NH2 NH2 + NH3 H Ch. 21 - 41 * NH2 Cl 50% * + − * − K NH2 NH2 NH3 * NH elimination addition 50% 2 Ch. 21 - 42 CF3 CF3 Cl NaNH2 NH3 (-NaCl) NH2 m-(Trifluoromethyl)aniline CF3 Ch. 21 - 43 CF3 > NH2 X CF3 less stable carbanion NH2 CF3 CF3 > NH3 NH2 NH2 more stable + NH carbanion 2 Ch. 21 - 44 Benzyne intermediates have been “trapped” through the use of Diels– Alder reactions O O C C O diazotization O NH3 N N Anthranilic acid -CO2 O -N2 O Benzyne (trapped in situ) Ch. 21 - 45 11C. Phenylation O O Br O O 2 NaNH2 + liq. NH OEt 3 OEt Ch. 21 - 46 12. Spectroscopic Analysis of Phenols and Aryl Halides Infrared spectra (IR) OH ● O H stretching: 3400-3600 cm-1 R OH X ● and : characteristic absorptions of the benzene rings R R Ch. 21 - 47 1H NMR spectra δ (ppm) of H O H pure phenol: 2.55 in CCl4 (1%) 5.63 δ 0.5 – 1.0 ppm O H O intramolecular hydrogen bonding OH Ch. 21 - 48 H H Y (Y = OH or halides) H H H δ 7 – 9 ppm Ch. 21 - 49 13C NMR spectra Y (Y = OH or halides) δ 135 – 170 ppm Ch. 21 - 50 Mass spectra ● Mass spectra of phenols often display a prominent molecular ion peak, M ● Phenols that have a benzylic hydrogen produce an M – 1 peak that can be larger than the M peak Ch. 21 - 51 END OF CHAPTER 21 Ch. 21 - 52.