Bài giảng Organic Chemistry - Chapter 9: Reactions of Alcohols

DeprotonationSN1 / SN2E1 / E2OxidationChapter 9: Reactions of AlcoholspKa (ROH) ~ 15-18. Need base stronger than RO :a. RLi , e.g., CH3Li [pKa(CH4) ~ 50]; b. Na NH2 ( NH3, 35); LDA [(i-Pr)2NH, 40); K H or Li H (H2, 38); d. (CH3)3CO [(CH3)3COH, 18]-:::::-+:::-:::-+:-+DeprotonationH2Oa.Rprim::OH::HXRprimOH2:+XSN2-::RX:::b.Rsec/tertOH::H+:R+SN1E1R NuAlkeneOHBrOHIHBrHIProblem: mixturesDehydrationNote: Needs H+ with a good Nu (X)SN1/SN2 Via Protonation:Bad leaving groupGood leaving groupBest when Rsec Rtert (exothermic), but “degenerate” shifts possible Rsec Rsec, Rtert Rtert There is another general problem with SN1: H shifts-:+++++HCCOHH+H2OCC+HCCH+SN1E1+Carbocation RearrangementsHydride shiftMechanism of Hydride ShiftThe Hydride Shift Transition StateShiftLipshBeachBCH2CH3+Br::HHBr::::CH3+HBr::::-CH3CH2CH3CH3CH2CH3Br:::Cis/transCH2CH3-HNote: stereospecific; H stays on same sideCH3:Attack from either sideOther Carbocation PrecursorsExample: All steps reversible  thermodynamic equilibration possible, but hydride shift is fast, therefore some selectivity at relatively lower temperatures and short reaction times. Bottom line: mixtures to be expectedNote: proton loss is reversible, i.e. double bonds can be protonated to carbocations (Chapter 11).++OHH2SO4H2O+H- shiftsH- shift H+H+H+More Complications: E1becomes prevalent at higher temperaturesProton lossMost stable carbocationHCC+RCCR+Best Rsec Rtert++More Complications: Alkyl ShiftsEspecially when there are no hydrogens to shift:Slower than H- shifts, but compete.R+secR+tertAlkyl shifts are fast when they relieve ring strain:OH::H2O::++OH::HH2O::+Mechanism Of Alkyl Shift H+ By concerted shifts, bypassing cations: H+, needs Δ+CCRCCR+HHHHOH2δ++:Especially with neopentyl alcohols:CCH2OHRRRquaternaryEven Rprim-OH RearrangeTurning ROH Into RNu Without The Use of AcidA mild way to convert ROH RNu without H+ Reagents: PBr3 for RBr; PCl3 or ClSCl for RCl, e.g.:O3 ROH + PBr3 3 RBr + H3PO3 [“P(OH)3”]Phosphorous acidMechanisms go through inorganic esters as reactive intermediates (not isolated).RprimOH::HXRprimOH2:+Bad leaving groupGood leaving groupWe have learned:Can have problems with strong acid and carbocationformation Solution: inorganic derivatives as reactive or isolable intermediates: Mechanism:Step 1Step 2RepeatMechanism Of PBr3 Reaction With ROHExample:Bad leaving groupGood leaving groupSN2Chloroalkane Synthesis Using SOCl2CH3CH2CH2OHCH3CH2CH2ClOSN++SO2NHCl-+NPyridine acts simply as a baseH Cl+-NHCl-++“Mops up” acid:91%+ClClThionyl chlorideMechanism of SOCl2 ReactionBad leaving groupGood leaving groupReactive intermediate;not isolable“Suicide” leaving groupGasGasIsolable Sulfonates R L +ROHCH3SO2ClR O SCH3OOMethane-sulfonate, “mesylate”CH3 SO2ClR O SO2 CH34-Methylbenzenesulfonate, “tosylate”React by SN1/SN2: substitution of OH function by Nu+ROHNNEthersNo hydrogen bonds, therefore relatively low b.p.sO::O::O::RRRHHH‘Water Alcohol EtherNames: As substituted alkanes, alkoxyalkanes. Ethoxyethane (IUPAC) Diethylether (common) “Ether” (colloquial) OO1,2-Dimethoxyethane, “glyme”CH3OOCH3Tetrahydrofuran(THF)No acidic hydrogens: Relatively unreactive Ù used as solventsCyclic polyethers can bind metal cations and dissolve salts in organic media: crown ethersHole size perfect for K+Ethers Are Inert18-Crown-6In nature, ionophores transport ions across cell membrane.ValinomycinSN2Rprim X + R’O R OR’:::Alkoxide is a strong base (E2!), therefore best for unhindered primary R; primary or secondary R’; polar aprotic solvent (although R’OH is OK); X = good leaving group.-The Williamson Ether SynthesisAlexander W. Williamson (1824–1904)::Cyclic Ethers Intramolecular Williamson synthesisRemember rules for the SN2 reaction: backside attack with inversion.High Dilution Favors Intramolecular ReactionThere is a trade off between ΔH and ΔS in the various transition states.Relative rates of ring closure: 3 > 5 > 6 > 4 > 7 > 8Proximity beats strainStrained and distantProximity effect: enthalpic ground state activation SuperfastFastFastSlowOOBrBrEthers From Alcohols And H+SN2 and SN1RprimOHH2SO4H2OR O RMechanism SN2 via:ROH::R O:HH+Needs heat!SymmetricalPoor NuRsec/tert OH : SN1 via R+OH::H-H2OO::Via:++HO::ProductOH2:++OHH+R O C CH3CH3CH3SymmetricalUnymmetricalWhy?Can be used for “protection” of alcohols as t-butyl ethers:ROHReactive OH groupUnreactive OtBu groupCH3CH3H3CEthers by Alcoholysis of Rsec/tert X: SN1ClOCH3CH3OHSN1+RCH2OHH+CH3CH3H3CC+RCH2OH::-H+RCH2OExcessThis works because the t-Bu cation is formed fast:CH3CH3CH3OHCH3CH3H3CRprim O Rprim: quite unreactiveStable to base, RLi, RMgBr, dilute aqueous H+But, strong H X- : SN2Examples:+OHBrBrHOBrBrHBrReactions of EthersRprim O Rsec mixed ethers: both SN1 and SN2O::HIO+HI::-::I+OH::Less hinderedGood NuIn the presence of good Nu: SN2O::H+, H2OO+H+:: OHHO-Poor NuH2O-H+Example:In the absence of good Nu: SN1Htert-Bu ether hydrolysis: H , H2O mild: “deprotection”+R O::H+ROH++R :H+O Δ+Protecting group strategy for alcohols:ROHR OROHProtectionDeprotectionGasTert-Bu Ether Hydrolysis HO, H+H+, H2O Tert-butyl Protection Of AlcoholsStrained EthersBasic conditions: Nu attacks directly! O:CH3S+:::-H2OWork-upSCH3HO::::Hydroxyethylation of Nu ::HONu:-:React by ring opening, release ring strain (~ 27 kcal mol-1).CH3LiCH3HCH3OHRegio- and stereocontrolMany Nu work::-OLiALD4CH3HCH3HDOHRegioselective: SN2 at less hindered siteRecall: RLi or RMgX do not react with RX normally!With neutral Nu, we need acidic conditions to activate the ether to nucleophilic attack.:O::O+CH3OHH+OCH3HONo reaction without H++H+O:+HCH3OH::OHOCH3H+:HOOCH3H+Mechanism:::For unsymmetrical systems, mixtures ensue, but reaction is often regioselective to more hindered side!OHHCH3CH3+CH3OHOCH3HOH+!Selectivity is induced by electronic effect: the more substituted carbon bears δ better Coulomb’s Law wins over steric hindrance+RegioselectiveMechanism:ProtonatedoxygenSulfur Analogs Of ROH And ROR’: Alkanethiols And Alkyl SulfidesR SH::andR S R’::Names:CH3SHMethanethiolSH12342-Methyl-1-butanethiolSH321Sulfides:3-PentanethiolCH3SCH2CH3Ethyl methyl sulfideSubstituents:SHMercapto,SRAlkylthioPriority:HOHS>2-MercaptoethanolHSOH21RSHH2ORSHOH2+++:::::-Less hydrogen bonding than ROH: R S H less polar, S less e-negative. H2S is a gas (b.p. -60°C)!:::-δ+δ-CH3SH: pKa = 10, b.p. 6.2 °C:pKa ~ 9-12More acidic than ROH, because RS H weaker and RS more polarizableCH3OH: pKa = 15.5, b.p. 65 °CAcidity Of ThiolsRS much better than RO , less basic, more polarizable. No E2 problem with RsecX.Nucleophilicity Of Thiols And SulfidesRSR’R’ XRS++:::::-::X::::-SN2Even neutral RSR’ undergo SN2 (like NH3, PR3)CH3 S CH3 ::CH3 I+:::(CH3)2SCH3+:I::::-+:::::-:Compare: CH3OCH3 no reaction. ROH only in SN1. :::-(CH3)2S CH3 +:Nu::(CH3)2SCH3 Nu++:+Oxidation to disulfides (reversible by reduction)2 R S H::I2Li, NH3 liqR S S R+2 HINature: polypeptide cross linking. S SSHSHenzymeNeutral sulfides are good leaving groups (like H2O) = Sulfonium salts are alkylating agents.H2O2H3CCH3O::SO::H3CCH3S::H2O2Dimethyl sulfideDimethylsulfoxide, (DMSO; used as polar nonprotic solvent)DimethylsulfoneBeyond second row, the presence of d orbitals allows for valence shell expansion. -H3CCH3O::S::+Strong contributorsOH3CCH3::S:10e12e-H3CCH3O::S::+2O::-Oxidation To Sulfuroxide SpeciesWe can still write dipolar octet forms:Sulfonic acid