Alcohols Biological Activity Nomenclature Preparation Reactions Some Alcohols CH3CH2OH HO OH OH CHCH2NH2 CHCHNHCH3 CH3 ethanol HO adrenaline (epinephrine) OH H HOCH2CHCH2OH glycerol H HO H cholesterol pseudephedrine Alcohols are Found in Many Natural Products HO N CH3 O H HO Morphine most abundant of opium's alkaloids Paralytic Shellfish Poisoning NH2 O O H HN H N N NH N A possible chemical warfare agent roughly 1000 times more toxic than saran gas or cyanide N H OH The toxin blocks entry of sodium OH required by cells to make "action potentials" Saxitoxin (STX) LD 50 = 2 g/kg OH O O OH OH HO OH O H2N OH OH OH OH HO PALYTOXIN LD 50 = 0.15 g/kg OH OH OH OH OH OH O HO O N N H H HO OH OH OH OH OH O OH OH OH OH HO OH O O O OH HO OH OH OH OH HO OH OH OH OH OH Ethanol: the Beverage Ethanol is a central nervous system depressant - depresses brain areas responsible for judgement (thus the illusion of stimulation) alcohol dehydrogenase CH 3CH 2OH ethanol NAD + O CH 3CH + NADH + H acetaldehyde LD 50 = 1.9 g/Kg NAD enz. + CH 3CO 2H + NADH + H acetic acid + + Methanol: Not a Beverage CH3OH methanol ADH NAD + O + HCH + NADH + H formaldehyde LD 50 = 0.07 g/Kg Oxidation levels of oxygen- halogen- and nitrogencontaining molecules CH2=CH2 CH3CH3 [O] CH3CH2OH HC [O] CH CH3CH=O [O] CH3CO2H CH3CH2Cl CH 3CHCl2 CH3CCl3 CH3CH2NH2 CH3CH=NH CH3CN Oxidation Reduction Acidity of Alcohols • Due to the electronegativity of the O atoms, alcohols are slightly acidic (pKa 16-18). • The anion dervived by the deprotonation of an alcohol is the alkoxide. • Alcohols also react with Na (or K) as water does to give the alkoxide (red-ox): CH3CH2OH + Na CH3CH2O Na + 1/2 H2 Withdrawing Groups Enhance Acidity CF3 CF3 CF3 C OH + NaHCO3 CF3 CF3 alcohol CH3OH CH3CH2OH CF3CH2OH (CH3)3COH (CF3)3COH C O Na + H2CO3 CF3 pKa 15.54 16.00 12.43 18.00 5.4 Phenols are more acidic than alcohols Physical Properties b.p. oC D sol. in H2O CH3CH2CH3 -42 0.08 i CH3OCH3 -25 1.3 ss CH3CH2OH 78 1.7 vs Intermolecular H-Bonding O H H H O H O H O associated liquid intermolecular H bonding O H H H O Alcohol Nomenclature OH 3 3-heptanol 6 2 5 5-methyl-6-hepten-2-ol OH 2 OH 1 1 3 CH3 CH3 3,3-dimethylcyclohexanol OH CH3 5 CH3 5,5-dimethylcyclohex-2-enol Nomenclature OH OH (E) 3-methyl-3-penten-2-ol (S) 2-hexanol OH OH trans 3-isopropylcyclopentanol H OH (R) 2-butyl-1,4-butanediol (R) 2-butylbutane-1,4-diol Preparation of Alcohols • • • • Reduction of ketones and aldehydes Reduction of esters and carboxylic acids Hydration of Alkenes Nucleophilic addition – Grignard reaction – Acetylide addition • Substitution • Epoxide opening NaBH4 Reduction O R 1) NaBH4, ethanol R' 2) H3O + H H OH R R' H 3O H R O R' + Some Examples O OH 1) NaBH 4, ether 2) H3O O CH + " CH2OH Two Alcohol Products Form in Lab O H axial approach NaBH4 (CH3)3C H O Na (CH3)3C trans O Na O NaBH4 (CH3)3C H (CH3)3C H equatorial approach cis LiAlH4 Reduction a Stronger Reducing Agent OH O 1) LiAlH 4, THF 2) H3O + LiAlH 4 will reduce: o ketones to 2 alcohols o aldehydes to 1 alcohols o carboxylic acids and esters to 1 alcohols LiAlH4 is a much stronger reducing agent 1) LiAlH 4 O OH + 2) H3O + CH3OH O 1) NaBH4 + 2) H3O no reaction NaBH4 is More Selective O O 1) NaBH4 OH OH + 2) H3O O OH OH 1) LiAlH 4 + 2) H3O OH Oxymercuration Hydration Markovnikov 1) Hg(OAc) 2 in THF/H2O 2) NaBH4 OH H Hydroboration Hydration Anti-Markovnikov 3 1) BH3-THF 2) H2O2, NaOH H OH 3 Base Catalyzed Ring-Opening of Epoxides Acid Catalyzed Ring-Opening Aqueous and in Alcohol Nucleophilic addition to Carbonyl Compounds Acetylides O H O C CH3 CH3CH2C CH3 CH3 CH3CH2C C CH3 C C H3O + OH CH3 CH3CH2C C C CH3 Organometallic Chemistry Grignard Reaction CH3 Br + Mg "CH3 MgBr " excellent nucleophile very strong base CH3 MgBr Grignard Reagent Grignard Reagents React With Ketones to form tertiary alcohols O CH3 1) CH3MgBr in ether 2) H3O HO + MgBrOH + o a 3 alcohol H3O MgBrO CH3 CH3 + Grignard Reagents React With Aldehydes to form secondary alcohols O MgBr in ether 1) H OH + 2) H3O H Grignard Reagents React With Formaldehyde to form primary alcohols CH2CH2O MgBr CH2CH2OH H3O + O C H H formaldehyde CH2 MgBr CH2Br Mg, ether, Grignard Reagents react (twice) with Esters to form 3o Alcohols O OH C C CH 3 CH3 OCH3 1) 2 CH3MgBr 2) H3O + CH3 O C OCH 3 CH3 2nd eq. 1) CH3MgBr + 2) H3O O C CH3 ketone (more reactive than ester) Grignard Summary H H R MgX + + C O H3O workup R H formaldehyde R MgX R' + O R' H3O workup R H aldehyde R MgX R' + C R'' ketone C OH H R' + O OH H + C C H3O workup R C R'' OH Grignard Summary R O H3O workup R' MgX + epoxide R'' R R' 2 R MgX + OH + R' + C O RO ester H3O workup R C OH R + ROH Grignard Reagents are exceptionally strong bases H2O CH3OH CH3CH2CH2MgBr + CH3CO2H HC CH CH3NH2 CH3CH2CH3 Synthesis OH ? Retrosynthetic Analysis OH ? Br MgBr 4-Step Synthesis OH 1) HCHO + 2) H3O Br 2, h Br Mg in ether MgBr Synthesize Using Only 1,2, or 3-Carbon Reagents OH HC CH Retrosynthesis + OH O MgBr HC Mg Br CH HBr CH3X CH3X reduce Reactions of Alcohols Oxidation R-X, Ether, and Ester Preparation Protection of Alcohols Synthesis The Logic of Mechanisms Alcohols are Synthetically Versatile Oxidation - Reduction Oxidation of 2o Alcohols with Cr(VI) Mechanism Na2Cr2O7 + H2O + 2 H2SO4 O OH + HO o 2 alcohol O Cr OCrO3H OH O Chromic Acid (Cr VI) CrO3H H 2 H2CrO 4 + 2 NaHSO4 + H 2O Chromate ester O OH2 + H3O + HCrO3 ketone (Cr IV) Oxidation of 1o Alcohols PCC oxidizes 1o Alcohols to Aldehydes CrO3Cl N PCC H pyridinium chlorochromate Oxidation of 1o Alcohols to Aldehydes: PCC Oxidation Summary CH2CO2H Na2Cr2O7 H2SO4 CH2CH2OH NH CrO3Cl OO DMSO, ClCCCl (CH3CH2)3N, in CH 2Cl2 CH2CHO CH2CHO Reduction Summary CH2CO2H 1) LiAlH 4 2) H3O + CH2CH2OH 1) NaBH 4 2) H3O CH2CHO + or H2, Raney Ni CH2CHO Conversion of Alcohol into a Leaving Group • Form Tosylate (p-TsCl, pyridine) • Use strong acid (H3O+) • Convert to Alkyl Halide (HX, SOCl2, PBr3) Formation of p-Toluenesulfonate Esters Best to use p-TsCl with pyridine CH3 OH CH3 O CH3 + ClS O p-toluenesulfonyl chloride OS N pyridine reacts with HCl as it forms O O N H Cl CH3 Reactions of Tosylates: Reduction, Substitution, Elimination CH3 OH CH3 O + ClS O CH3 O OS pyr: CH3 O 1) LiAl H4 KI NaOCH3 CH3 CH3 CH3 I H + LiOTs Alcohols to Alkyl Halides OH HX (HCl or HBr) X rapid S N1 + HOH o 3 alcohol OH o 2 alcohol HX moderate S N1 X + HOH Lucas Test CH3 ZnCl 2 12M HCl CH3COH CH3 CH3CCl forms in seconds CH3 + HOZnCl 2 CH3 CH3 CH3C CH3 OZnCl2 CH3 H CH3C CH3 Cl Qualitative test for Alcohol Characterization primary OH >10 minutes (if at all) OH ZnCl 2, HCl secondary OH tertiary Cl <5 minutes Cl 1-2 seconds Cl Other Simple Qualitative Tests Alkenes Br Br 2 reddish-brown OH colorless Br O Alcohols Na2Cr2O7 OH H2SO4 orange Cr(VI) green Cr(IV) CO2H 1o and 2o Alcohols: best to use SOCl2, PBr3, or P/I2 All are SN2 Reactions SOCl2 pyridine OH PBr 3 P, I2 (in situ prep. of PI3) Cl Br I Thionyl chloride mechanism in Pyridine – SN2, Inversion O Cl S Cl SOCl2 OH Cl + SO2 + HCl pyridine O O O H S Cl O Cl H N S + Cl -H O Cl O S Cl Dehydration of Alcohols – E1 OH H H2SO4 (aq) cat. + H 2O H regenerated H O HSO 4 or H2O H -H2O H Propose a Mechanism OCH2CH3 + H3O Where do you protonate? O + CH3CH2OH Both approaches seem logical H H OCH2CH3 + OCH2CH3 OCH2CH3 H + H OCH2CH3 H Take the Blue Route OCH2CH3 H3O H O + + CH3CH2OH + OCH2CH3 H2O H H O OH2 O H CH2CH3 HOCH2CH3 H Problem Set: Road Map Problem Br A MgBr B O 1) CH3CH2CH + 2) H3O C Na2Cr2O7 H2SO4 D 1) CH3MgBr + 2) H3O E Ethers Dimerization of Alcohols: Symmetrical Ethers Dehydration o 2 CH3CH2CH2OH H2SO4, 125-140 C CH3CH2CH2OCH2CH2CH3 + H2O Mechanism Dehydration, Acid-Catalyzed o H2SO4, 125-140 C 2 CH3CH2CH2OH CH3CH2CH2OCH2CH2CH3 + H2O H CH3CH2CH2-OH CH3CH2CH2OH loss of H 2O CH3CH2CH2OCH2CH2CH3 H2O H Williamson Ether Synthesis Preparation of Unsymmetrical Ethers Mechanism, SN2 Na O OH Na, THF + I o 1 alkyl halide SN2 O Alkoxides are strong bases so there is competition with E2 reactions. Bulky alkoxides reacting with primary alkyl halides favor Williamson ether synthesis(SN2). How would you prepare the following ethers starting from an alcohol and an alkyl halide? O O O Alkene Oxides, Oxiranes or Epoxides O CH2=CH2 ethylene [O] CH2 CH2 ethylene oxide oxirane 1,2-epoxyethane Epoxides are Extremely Reactive Cleavage of Unsymmetrical Ethers H Br HBr O OH Br + HBr H O Br SN2 Br Size 1, Pairwork 8.28 b,d 8.29 a,d 8.33 e,f 8.44 a-e 8.45 8.47 8.51 8.57 8.61 8.64