Chapter 9

Chapter 9 - Chapter 9: Reactions of Alcohols Deprotonation...

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Unformatted text preview: Chapter 9: Reactions of Alcohols Deprotonation SN1 / SN2 E1 / E2 Oxidation 1. Deprotonation: pKa (ROH) ~ 15-18. Need base stronger than +: RO: : : : : : a. RLi , e.g., CH3Li [pKa(CH4) ~ 50]; b. Na :NH2 (: NH3, 35); LDA (R2NH, 40); c. K + : : : : H: or Li : : : : + : -(H H 2, 38); 18] d. (CH3)3 CO: [(CH 3)3COH, 2. Protonation a. Rprim OH : : : : HX HBr HI + Rprim OH2 Oxonium ion :X:- SN2 Br I : : : : R X: : : : : : : OH OH Note: Needs H+ with a good Nu (X) b. Rsec/tert OH : : : : + H H2O: : : + SN1 R E1 RNu Dehydration Problem: Mixtures Alkene There is another general problem with SN1: 3. Carbocation Rearrangement by H :Shift H C C OH + H H C H2O sec : + C + C + Best when Rsec possible R+ sec + , but "degenerate" shifts Rtert + + R+ , R R . tert tert H SN1 C E1 Mechanism of Carbocation Rearrangement Step 1 Step 2 Fast! Step 3 Step 4 The Hydride Shift Br -BrCH3 CH2CH3 H H CH3 Br CH2CH3 OH HBr 13C + CH3 CH2CH3 H H + CH3 + Br- CH2CH3 Note: H stays on same side Cis/trans mixture, in addition to H shift Br Br Br 1 Statistical distribution 2 2 Br 1 In other words: Complete scrambling of label E1 from rearranged carbocations: More substituted double bond more stable. OH H2SO4 H 2O + H shift H+ + Intermediate cations can be trapped by SN1, but this is reversible with strong H+ H H+ + + + H ! ` OH H shift + Reversibility means thermodynamic control. Thermodynamic products may need prolonged reaction time (or heat) to form. Intermediate SN1 or E1 products may be isolated in the early stages of a reaction (or at low temperature). Note 4. Carbocations Also Rearrange by Alkyl Shifts (Slower Than H Shifts) R C + C + C R C + Best Rsec + Rtert Especially when there are no hydrogens to shift: Mechanism of Alkyl Shift Rsec Rtert Good! Alkyl shifts are fast when they relieve ring strain: Rprim OH rearrange by concerted shifts R C C H H : : H OH2 H + R Especially with neopentyl alcohols: R C CH2OH R + C R C 5. Esters from ROH and Acids General "esterification": O A Acid O A Ester OH + HOR OR + H2O A = C, N, S, P, Cr, etc. Organic esters: Equilibria O RCOH + ROH H2SO4 cat. K~1 O RCOR + HOH Use of Inorganic Esters Mild way to convert ROH RX without H+ O Reagents: PBr3 for RBr; PCl3 or ClSCl for RCl. 3ROH + PBr3 3RBr + H3PO3 ["P(OH)3"] Phosphorous acid Mechanisms go through inorganic esters as reactive intermediates (not isolated). Mechanism: Step 1 Step 2 Repeat Chloroalkane Synthesis Using SOCl2 O CH3CH2CH2OH + ClSCl 91% N CH3CH2CH2Cl + OSO + N+ H Cl Pyridine "Mops up" acid Isolable Sulfonates R L ROH + CH3SO2Cl N O R O SCH3 O Alternatively: 4-Methylbenzenesulfonate, "tosylate" Methanesulfonate, "mesylate" React by SN1/2: Substitution of OH function Ethers H O H R O H R O R` No hydrogen bonds: relatively low b.p.s No acidic hydrogens: Relatively unreactive, hence used as solvents O "Ether" Tetrahydrofuran (THF) O CH3O OCH3 Dimethoxyethane, "glyme" Cyclic polyethers: Crown ethers Hole perfect for K+ Crown Ethers Solvate Cations Names: Alkoxyalkane. Same rules as for RH. O Ethoxyethane OCH3 OCH2CH3 O 1 2 3 4 1-Methoxybutane Cis-1-ethoxy-2-methoxycyclopentane Synthesis: Williamson ether synthesis Rprim X + : R'O : : : : SN2 R OR' Best: good X = L, unhindered R, R'; polar aprotic solvent; otherwise E2! (Use 1-butanol + NaOH) - + O Cl 60% yield in butanol solvent 95% in DMSO (CH3SOCH3) O Rsec O is O.K.: - + O Br HMPA 85% O 2-Ethoxypropane Other way no good: Br + O E2 Cyclic Ethers Intramolecular Williamson synthesis High Dilution Favors Intramolecular Reaction Relative rates: 3 > 5 > 6 > 4 > 7 > 8 Proximity beats strain Strained and distant Trading off H and S effects in the various transition states: LO-LO-L-OL-O Fast Superfast Proximity effect: enthalpic ground state activation Fast Slow Remember: SN2 is stereospecific. Good! Not good Backside displacement with inversion. Ethers from Alcohols SN2 and SN1 Rprim OH R O R Symmetrical H2O H ROH R O + Needs heat! Mechanism SN2 via: H Poor Nu : : : : : : H2SO4 + Rsec/tert OH : SN1 via R H+ OH -H2O O + OH2 : : Via: Can be used for "protection" of alcohols as t-butyl ethers: + CH3 H ROH + OH R O C CH3 CH3 Unreactive Unsymmetrical Reactive : : : : : : : : Symmetrical + HO : : : : Product This works because the t-Bu cation is formed fast: Excess OH + RCH2OH RCH2O + H CH3 H3C C+ CH3 RCH2OH + -H Ethers by Alcoholysis of Rsec/tert X: sec/ Cl CH3OH SN1 OCH3 Reactions of Ethers Rprim ethers: Stable to base, RLi, RMgBr, dilute aqueous H+ But, strong H + : SN2 HBr O HO Br HBr Br Br Mixed prim/sec ethers: Both SN1/2 SN2: HI Less hindered; Inversion Good Nu O + O H :I: : : : : OH + I : : : : SN1: O : : : : : : : : Poor Nu H + , H2 O + O H - HO + H 2O -H+ OH : : : : Useful Application: tert-Bu ether hydrolysis: H+, H2O mild R O H+ + R O H ROH + + H+ Sequence: ROH Protection Gas R O Deprotection ROH Tert-Butyl Protection of Alcohols Strained Ethers React by ring opening, release ring strain (~ 27 kcal mol-1). Basic conditions: :Nu -attacks directly! O : + CH3S : : : : H 2O Work-up HO SCH3 Nu : : : : Hydroxyethylation of :Nu HO Regioselective: SN2 at less hindered site Many Nu : work: OH CH3 H CH3 O CH3 H LiAlD4 CH3Li OH CH3 H D Regio- and stereocontrol Recall: RLi or RMgX do not react with RX normally! With neutral : Nu, we need acidic conditions to activate the ether to nucleophilic attack. O + CH3OH + H No reaction + without H HO OCH3 Mechanism: O + + H +O OCH3 H CH3OH HO : : : : : : : : + CH3 :O H : : : : : : : : H+ HO For unsymmetrical systems, mixtures ensue, but reaction is often regioselective to more hindered side! O H H Regioselective CH3 CH3 + CH3OH H+ HO OCH3 Selectivity is induced by electronic effect: + the more substituted carbon bears better Coulomb's Law wins Mechanism: Protonated oxygen Sulfur Analogs of ROH and ROR': Alkanethiols and Alkyl Sulfides R SH : : : : : : : : and 3 1 2 R S R' 2 1 3 Names: Methanethiol CH3SH 4 SH 2-Methyl-1-butanethiol 3-Pentanethiol SH Sulfides: CH3SCH2CH3 Ethyl methyl sulfide SH Mercapto, 2 Substituents: Priority: HO SR Alkylthio 1 > HS HS OH 2-Mercaptoethanol Acidity: pKa ~ 9-12 RSH + H2O + - + RS: HOH2 : : : : : : More acidic than ROH, because RS H : more polarizable weaker and RS CH3SH: pKa = 10, b.p. 6.2 C CH3OH: pKa = 15.5, b.p. 65 C : : : : : : : : Much better than RO:- , less basic, more polarizable. No problem with RsecX. : : : : Nucleophilicity: : + R' X RS New: : : : : SN2 RSR' + : : : : X Even neutral RSR' undergo SN2 (like NH3, PR3) CH3 S CH3 + CH3 : : : : Compare: CH3OCH3 no reaction. ROH only in SN1. : : : : I: + (CH3)2SCH3 + :I: : : : : : : : : : : Neutral sulfides are good leaving groups (like H2O): Sulfonium salts are alkylating agents. + + :Nu (CH3)2S CH3 + (CH3)2S + CH3 Nu Oxidation to disulfides (reversible by reduction) 2R S H : : : : I2 Li, NH3 liq New: R S S R + 2 HI Nature: polypeptide cross linking. SH enzyme SH S S New: Oxidation to Sulfoxides and Sulfones H3C S CH3 H2O2 :O : 10e S H2O2 CH3 :O : H3C S 12e CH3 CH : : Dimethyl sulfide H3C Dimethylsulfoxide, (DMSO) :O : Dimethylsulfone Valence shell expansion (d orbitals). Octet forms: :O : :O: 2+ + H3C S CH3 H3C S CH3 :O: : : : : : : : : Strong contributors Thiols (and sulfides) stink.... Decomposing food, passing gas, power plants, natural gas additive methanethiol, stink bombs, waste water, feces, some chemistry departments... . Skunk chemical defense: ...but may be very pleasant in low concentrations. Dimethylsulfide: H3C S CH3 : : : : Black tea Grapefruit Can be tasted at the 10-5 ppb level!! 1 mg in a large swimming pool. Garlic and Onion: Culinary Marvels When cut: Allicin Garlic Antibacterial Antimicrobial Fungicidal Anticancer Cardiovascular Cholesterol reducer Anticoagulant LD50 = 60mg/kg Plants: chemical protection against insects ...
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This note was uploaded on 03/21/2012 for the course CHEM 140A taught by Professor Whiteshell during the Fall '04 term at UCSD.

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