Bài giảng Organic Chemistry - Chapter 8: Alcohols

OChapter 8: AlcoholsR OHHHO CH3CH3 δ+OHCH3δ+δ+δ+δ+δ+δ--δ--δ--WaterAn alcoholAn etherEthanolIndustrial Building Block, FuelBeverageEthanol plant in West Burlington, IowaAbuseInitial dose causes euphoria, but alcohol is a general CNS active depressant drug.Absorption: 20% stomach, 80% gastrointestinal.Food slows it, but what is in, stays inDistribution through the body and brain is fast.Intravenous can be lethal: sudden depression of the respiratory system, brain centers.Excretion: Lungs Alcoholic breath; 5% in urine.Metabolism: Zero order in ROH! Linear with time; 10 mL/h (cocktail/hour); by oxidation: CH3CH2OHCH3CHCO2PoisonousSecond step is prevented by antabuse (disulfiram):OEnzymeEnzymeCommon misconceptions:1. Not a stimulant2. Doesn’t warm you3. Doesn’t help your sleep4. Not an aphrodisiac1. Find the longest chain containing the –OH function: alkane  alkanol. Note: This may not be the longest chain in the molecule!2. Number from the end closest to HO-C 3. Other rules same as in alkanes4,4-Dimethyl-1-nonanol5-Bromo-3-propyl-2-heptanolOHOHBr123456789123456Names7OHOHCH3HOCyclohexanolcis-3-Methyl-cyclohexanol1-Ethylcyclo-pentanol-OH as a substituent is called hydroxy-OR is alkoxy: ethers R-O-R’ = alkoxyalkanesRCH2OH RCHOHR’RCOHR’R’’PrimarySecondaryTertiary alcoholDefined as C1, # is not necessary in name113Cyclic Alcohols Are Called CycloalkanolsStructureO can be thought of as sp3-hybridized, “tetrahedral”, i.e. bent, not linear. Due to electron repulsion by lone pairs. O is relatively e-negative, draws bonding electrons: short = strong bonds. HH3CODHº = 119 kcal mol-1Most striking: Relatively high melting and boiling points, and water solubility. Why?Physical PropertiesHydrogen BondingORHHORδ-δ-δ+δ+5 kcalmol-1Extensive network:Increases intermolecular interactions. Allows for solvation by water.Hydrophobic-HydrophilicWater solubility: Decreases with size of R is hydrophobic; –OH is hydrophilic R OHalkyl chainROH + H2O RO- + H3O+ pKa’sH2OCH3OHCH3CH2OH(CH3)2CHOH15.715.515.917.1(CH3)3COHClCH2CH2OHCF3CH2OHCF3CH2CH2OH1814.312.415.4Steric effect“Inductive” electronic effect. Tapers off with distance.KSterics andsolvationAcidityAlkoxides RO CH3OH + Na NH2 CH3O Na + NH3CH3CH2OH + Na OH CH3CH2O Na + H2OK ~ 1 pKa 15.5 35K 15.9 15.7+-+-+-+-KK = 1019.5Preparation:When CH3CH2OH is solvent, equilibrium is displaced to the right.Lone e-pairs can be protonated. Molecules that are both acids and bases are called amphoteric. HHR-O-H + H2SO4 R-O + HSO4Oxonium ion pKa ~ -3Compare R NH2 + H R NH3Ammonium ion pKa ~10Alcohols Are Also Basic+-++Synthesis of Alcohols R-OH1. R-X R-OH Review: SNBy SN2: Rprim-X IOHOHOHIProblem: β-Branching  E2 ( OH = base)---By SN1: Rsec X, Rtert XOHH-OH+BrClOHMinimize at low THBrH-OHHCl+Problem: E1Solution for E2 problem: Use a relatively nonbasic, “masked” OH–equivalent:CH3 COOAcetate (works for Rprim, β-branched, or Rsec) Br+O CCH3OO CCH3OSN2H2O, OHOH+CH3CO, removed in aqueous work upO“Ester”Hydrolysis-Mechanism preview: Ester Hydrolysis (Chapter 20)2. Reduction of aldehydes and ketones . OR C R’OR C HCOCOCOδ+2e reductionCOCHOH2 e + 2 H equals H2. There are two practical ways to add H2: a. as such, or b. as H-, then H+.-2 H++2 H++δ++Redox Relationship-2e oxidationNa+H:- + BH3 Na+BH4- Sodium borohydridesp2sp3 Li+H- + AlH3 Li+AlH4- Lithium aluminumhydride (LAH)Ketones Rsec-OHAldehydes Rprim-OHredredoxoxWhat are the reagents?Hydrogenation is possible, but is cumbersome: Needs H2 pressure and catalysts (e.g., Pd, Pt). Better: Use reagent that is equivalent to H:-, but not as basic, such as “complex” hydrides, prepared simply by: sp2sp3Reduction Of Aldehydes and KetonesNaBH4 is less reactive, more selective:Na+BH4 4 H2 + NaB(OH)4Li+ AlH4 4 H2 + LiAl(OH)4RX + LiAlH4 R-H H-OHH-OH--These reagents are still somewhat basic and will undergo protonation by alcohols or water to give H2. Reactivity differs greatly: --LiAlH4 (but not NaBH4) will reduce even halides:slow, allowing for alcohol solventsBut:violent, needs aprotic and rigorously dry solvents (e.g., ethers)Nucleophilic attack of hydride COOHHOO Li+H3AlOHHOHNaBH4, CH3OHLiAlH4etherH+, H2OWork up-Electrophiliccarbonyl carbonHydrideThe resulting alkoxide is protonated by alcohol solvent, in the case of NaBH4, or on aqueous work up, in the case of LiAlH4 The aqueous work-up step is normally not shown in eqns.HHHNaBH4: termolecular, concerted. Simultaneous addition of H- (from NaBH4) and H+ (from CH3OH): CH3O HH BH3CH OHLiAlH4: Stepwise delivery of first H:- then H+, H2O (work-up)COCH3O BH3+MechanismsAnimCrVI reagents CrIIITypically, use Na2Cr2O7 or CrO3 in H2O, H2SO4 CrOOHOHOChromic acid+3eOxidation Of Aldehydes and KetonesOH+ Na2Cr2O7OH2SO4H2OExample:Best for secondary alcohols giving ketones. Primary alcohols are overoxidized in aqueous medium.PyridinePyridinium chlorochromate : “PCC” OHOHOHOMechanism of Cr oxidation:NH +RCH2OHHO Cr OHOOR CH O Cr OHHOO RCH + OCrOHOOa chromate esterNPCCHOHVIIVRprim–OH: Use CrO3Cl-Avoids overoxidation with aqueous Cr reagents.E2VI3. Alcohols from Organometallics R:-M+ Hexaneor etherR-X + Li RLi + LiXR-X + MgR-Mg-XOOOEther needed“Grignard reagent” “RMgX”MeLiMeMgBrAlkyllithium R-M Franỗois Auguste Victor Grignard1871-1935Reverse Polarization RX RMRM are basic and nucleophilic MgBrDMgD2OBasicity BrHydrolysis:Not strong enough for the reaction R:– M+ + R’X R-R’ (obviously, since they are made from RX). But, carbonyl group is more reactive than RX:OR M O Rδ-δ-δ+δ++-RM as Nucleophiles+Works with ketones, aldehydes, including formaldehyde, CH2=OH2OOHRMO+ CH3MgBrHOCH3H2Otert+LiHOHOHMgBrOHCH2 O +FormaldehydeprimsecKetones:Aldehydes:GrignardSynthesis: How To Assemble Complex Molecules From Simple Starting MaterialsPrerequisites: Vocabulary = Reactions and Grammar = Mechanisms1. ReactionsRoadmaps Of VocabularyWhat does the function do?How is the function made?Mechanisms1. Can we make 1-chloro-1-methylcyclohexane by radical chlorination of methylcyclohexane in high yield?Not really. The selectivity tertiary/secondary is 4:1, but the statistical ration is 1:10: We will get mixtures.Possible solution: Radical bromination, followed by SN1 with excess chloride. 2. What will be the result of the following reaction?Retrosynthetic AnalysisWork backwards! Break up into even pieces!Forward scheme:MakeSynthetic Planning: Know your reactions, forward and backward (vocabulary) Know your mechanisms, forward and backward (grammar)HOOLifrom starting materials 4 carbons or lessOHLiHHO++Another example:Problem:Which retrosynthesis is best: a, b, or c?