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Transcript
more aromatic chemistry Aromatic substitution Electrophilic Nucleophilic Addition-Elimination Mechanism Benzyne Mechanism Other ring reactions Side-chain reactions 1 Benzyne Mechanism Reactant is halobenzene with no electron-withdrawing groups on the ring. Use a very strong base like NaNH2. => Benzyne Intermediate => 2 Chlorination of Benzene Addition to the benzene ring may occur with high heat and pressure (or light). The first Cl2 addition is difficult, but the next 2 moles add rapidly. The product, benzene hexachloride, is an insecticide. => Catalytic Hydrogenation Elevated heat and pressure is required. Possible catalysts: Pt, Pd, Ni, Ru, Rh. Reduction cannot be stopped at an intermediate stage. CH3 CH3 3 H2, 1000 psi Ru, 100°C CH3 CH3 => 3 Reduction of Aromatic Compounds Aromatic rings are inert to catalytic hydrogenation under conditions that reduce alkene double bonds Can selectively reduce an alkene double bond in the presence of an aromatic ring Reduction of an aromatic ring requires more powerful reducing conditions (high pressure or rhodium catalysts) Birch Reduction: Regiospecific A carbon with an electron-withdrawing group is reduced. O O C C OH Na, NH3 _ O H CH3CH2OH A carbon with an electron-releasing group is not reduced. OCH3 Li, NH3 (CH3)3COH, THF OCH3 => 4 Birch Mechanism => Side-Chain Oxidation Alkyl side chains can be oxidized to CO2H by strong reagents such as KMnO4 and Na2Cr2O7 if they have a C-H next to the ring Converts an alkylbenzene into a benzoic acid, ArR → ArCO2H 5 Side-Chain Oxidation Alkylbenzenes are oxidized to benzoic acid by hot KMnO4 or Na2Cr2O7/H2SO4. CH(CH3)2 _ COO - KMnO4, OH CH CH2 _ COO H2O, heat => Side-Chain Halogenation Benzylic position is the most reactive. Chlorination is not as selective as bromination, results in mixtures. Br2 reacts only at the benzylic position. Br CH2CH2CH3 Br2, hν CHCH2CH3 => 6 Side-Chain Halogenation Reaction of an alkylbenzene with N-bromosuccinimide (NBS) and benzoyl peroxide (radical initiator) introduces Br into the side chain SN1 Reactions Benzylic carbocations are resonancestabilized, easily formed. Benzyl halides undergo SN1 reactions. CH2Br CH3CH2OH, heat CH2OCH2CH3 => 7 SN2 Reactions Benzylic halides are 100 times more reactive than primary halides via SN2. Transition state is stabilized by ring. => Nitrobenzenes: Precursors to Anilines Nitric acid destroys alkenes through [O] In sulfuric acid, nitric acid reacts with benzene giving nitrobenzene Nitrobenzene may be reduced to aniline Aniline useful precursors to many industrially important organic compounds NO 2 SnCl2 /acid NH 2 8 Important Anilines O O O O Et NEt2 NH2 NH2 procaine benzocaine CH3 H N NEt2 O CH3 lidocaine Aromatic Dyes William Henry Perkin, Age 17 (1856) Undergraduate student in medicine Reacted aniline with potassium dichromate obtained a black tarry mess Attempting to synthesize quinine and instead discovered how to make mauveine, a purple dye - the first industrial organic fine-chemical http://www.ch.ic.ac.uk/motm/perkin.html 9 Aromatic Dyes Isolated H3 C N H N CH 3 N NH 2 Mauve - a purple color Dyed white cloth Patented material and process First chemical company Some Aniline Chemistry Anilines readily react with nitrous acid N2 NH2 Diazonium salts Coupling reaction giving an azo compound + HONO aryl diazonium salt N2 + N N X azo compound aryl diazonium salt Dyes and sulfa drugs activated ring 10 Aniline Chemistry N2+ H H3PO3 N2+ I NaI N2+ CN KCN/CuCN N2+ Cu2O/Cu(NO3)2 OH Phenols A phenol is a hydroxyl group directly bonded to a a benzene ring. OH OH OH OH OH OH OH CH3 phenol m-cresol 3-methyl phenol catechol 1,2-benzenediol resorcinol 1,3-benzenediol OH hydroquinone 1,4-benzenediol 11 Phenols Phenol is a low melting solid that is soluble in water. It has antiseptic properties and was used in the 19th century in surgery. Its medical use is now limited as derivatives with fewer side effects have become available Phenols are found in coal tar as well as the cresols (o,m,p). Some important phenols: OH CH3 CH CH3 OH CH3 O H3C 2-isopropyl-5-methylphenol (Thymol an oil in thyme leaves) CHO 4-hydroxy-3-methoxybenzaldehyde (Vanillin an important constituent of the vanilla bean) Modern antiseptic phenols: OH OH OH CH3 O OH H2C C CH2 H Eugenol OH Urishol Urishol is the active oil ingredient in poison ivy. Hexylresorcinol Removing an OH gives a lysol, a useful antiseptic. 12 Acidity of Phenols • Phenols and alcohols both contain hydroxyl groups however they are classified as separate functional groups. • Phenols have different properties than alcohols, most noteworthy is their acidity (pKa difference of 106) O OH H3C H2 C OH + H2O + H2O H3C H2 C O + H3O+ pKa = 9.95 + H3O+ pKa = 15.9 Solutions of alcohols in water are neutral, whereas a solution of 0.1 M phenol is slightly acidic (pH 5.4). • Why are phenols more acidic? O O O O Resonance. The charge is delocalized around the ring. m-cresol and p-cresol are weaker acids than phenol with pKa’s of 10.01 and 10.17 respectively. OH OH CH3 CH3 m-cresol p-cresol 13 Influence of substituents on the acidity of phenol Alkyl groups decrease the acidity of phenol halogens increase the acidity of phenol OH OH O CH3 Cl Electron donating alkyl group destabilizes this resonance structure OH pKa = 10.17 pKa = 8.85 CH3 m-chlorophenol p-cresol O Electron withdrawing halogen groups stabilize the delocalized negative charge X = F, Cl, Br X X Chlorine < fluorine < bromine < chlorine. Nitro groups increase acidity by both inductive and resonance effects. OH OH OH NO2 phenol pKa = 9.95 m-nitrophenol pKa = 8.28 NO2 p-nitrophenol pKa = 7.15 p-Nitrophenol is more acidic than m-nitrophenol, OH O O O2N Delocalization of negative charge onto ocygen futher increases the resonance stabilization of the phenoxide ion O N N O O O NO2 NO2 picric acid 2,4,6-nitrophenol pKa = 0.38 14 Acid-Base Reactions of Phenol When reacted with strong bases phenols are deprotonated to give water-soluble salts. Phenols will not react with weak bases such as sodium bicarbonate. + O Na OH + + NaOH H2O (pKa = 15.7) weaker acid pKa = 9.95 stronger acid + O Na OH + + NaHCO3 H2CO3 (pKa = 6.36) stronger acid pKa = 9.95 weaker acid Separation of alcohols from phenols OH OH OH ether + evaporation NaOH OH OH + H+ CH3 O-Na+ CH3 dissolved in ethyl ether CH3 15 Preparation of Aryl Ethers Aryl ethers can be prepared from phenoxide salts and alkyl halides. The opposite case is not true (aryl halides are not good leaving groups). The phase transfer catalyst transports the phenoxide anion into the organic layer. Cl OH O NaOH, H2O CH2Cl2 + Bu4N+Br- • Anisole can be formed from phenol plus a methylating agent, CH3I or dimethyl sulfate. OH O + H3C O S O CH3 O NaOH, H2O CH2Cl2 O CH3 + Bu4N+Br- +Na-O O S O-Na+ O dimethyl sulfate anisole 16 • Aryl ethers can be cleaved by hydrohalic acids, HX, to form alkyl halides and phenol. O OH + Br + HBr Kolbe Carboxylation; Synthesis of Salicyclic Acid •This industrial method is called the high-pressure carboxylation of sodium phenoxide. OH O NaOH H2O OH O OH O CO2 O-Na+ H2O HCl H2O OH salicylic acid Mech: O O C O O O H keto-enol tautomerism O- OH O O- 17 1,4-diketones Some reactions like aliphatic alcohols: phenol + carboxylic acid → ester phenol + aq. NaOH → phenoxide ion Oxidation to quinones: 1,4-diketones. O OH Na2Cr2O7, H2SO 4 CH3 CH3 => O hydroquinones 18 Quinones Hydroquinone is used as a developer for film. It reacts with lightsensitized AgBr grains, converting it to black Ag. (http://video.uni-regensburg.de:8080/ramgen/Fakultaeten/Chemie/Org_Chemie/Demonstrationsexperimente/benzoquinone_0.rm) Coenzyme Q is an oxidizing agent found in the mitochondria of cells. => 19 hydroquinone 2e(–) Quinone + 2H(+) Hydroquinone –2e(–) The SkinSilk Color Restoration step includes a Skin "Bleach" Cream formulated using the innovative ingredient Hydroquinone 2.0% Orto-Electrophilic Substitution of Phenols Phenols and phenoxides are highly reactive. Only a weak catalyst (HF) required for FriedelCrafts reaction. Tribromination occurs without catalyst. Even reacts with CO2. O _ _ O - CO2, OH O C OH O _ + O C H OH => salicylic acid 20 Biological Halogenation Accomplished during biosynthesis of thyroxine I CO2H NH3 + HO thyroid peroxidase CO2H HO NH3 + I tyrosine Hydroxylation Ipso-substitution Direct hydroxylation is difficult in lab Indirect method uses sulfonic acid O S OH O OH 1. NaOH 2. 300 oC phenol 21 Biological Hydroxylation O HO O O2 FADH 2 HO HO O O o-hydroxyphenylacetate-3-hydroxylase Coenzyme necessary Biological Alkylations No AlCl3 present O O R O P O P O Utilizes an organodiphosphate O O Mg +2 Dissociation is facilitated by Mg Important reaction in biosynthesis of Vitamin K1 R+ +2 22 Oxidation of Benzene Toluene is readily oxidized by reagents Benzene is inert to oxidizing agents Benzene is toxic to humans Benzene is a suspected carcinogen Cytochrom P strong oxidant in Liver Primary detoxification process used Proposed Chemistry Toluene is non-toxic CH3 CO2H [O] in liver water soluble Benzene is toxic O [O] in liver triepoxide O lipid soluble mutagen O 23 Biological Oxidations of Side Chains Biosynthesis of norepinephrine H enzyme HO HO NH2 HO HO OH NH2 enzyme = dopamine-beta-monooxygenase 24