Reactions of Alcohols and Epoxides Keeping it All Straight

Reactions of Alcohols and Epoxides: Keeping it all straight Dehydration of alcohols under strongly acidic conditions OH -Protonation turns -OH into -OH2+, a good leaving group -Slow for 1° R-OH, faster for 2° and 3° R-OH. -Mechanism is E2 for 1° R-OH; E1 for 2° and 3° R-OH -This reaction is reversible (alkene is in equilibrium with alcohol) -More substituted alkene is the major dehydration product (Zaitsev rule), because it is more stable (due to ! to "* hyperconjugation). -Watch out for carbocation rearrangement! -We don't observe any competing substitution products, presumably because HSO4- and TsO- are very poor nucleophiles (their minus charges are spread out via resonance). H2SO4 H2O TsOH OH H2O Dehydration of alcohols with POCl3 / pyridine -Reaction with POCl3 turns -OH into a good leaving group -Mechanism is E2 for 1°, 2° and 3° R-OH -More substituted alkene is the major dehydration product (Zaitsev OH POCl3 rule), because it is more stable (due to ! to "* hyperconjugation). -No carbocationic intermediate, no rearrangement! pyridine O -We don't observe any competing SN2 products P for reasons that are unclear Cl Cl Cl Substitution of alcohols with halides, using H-X (X= Cl, Br, I) POCl3 ZnCl2 -ZnCl2 is a Lewis Acid catalyst that makes OH a good enough L.G. Cl for Cl- to displace in an SN2 mechanism. Cl- is not a good enough HCl nucleophile to displace a primary OH2+ group. HBr -HBr protonates the OH, turning it into a good L.G. Br- displaces OH Br the OH2+ group in an SN2 mechanism. HI I -HI protonates the OH, turning it into a good L.G. I- displaces the OH2+ group in an SN2 mechanism. HCl Cl HBr OH Br HI -HCl, HBr, or HI protonate the 2° R-OH and turn it into a good L.G. -Cl-, Br-, or I- replace the the OH2+ group in an SN1 mechanism. -Watch out for loss of stereochemistry and carbocation rearrangement -We don't observe any competing E1 products, presumably because I-, Br-, and Cl- are such weak bases. I HCl Cl HBr OH Br HI I -HCl, HBr, or HI protonate the 3° R-OH and turn it into a good L.G. -Cl-, Br-, or I- replace the the OH2+ group in an SN1 mechanism -Watch out for loss of stereochemistry and carbocation rearrangement -We don't observe any competing E1 products, presumably because I-, Br-, and Cl- are such weak bases. Reactions of Alcohols and Epoxides: Keeping it all straight (page 2) Substitution of 1° and 2° alcohols with halides under conditions that do not allow carbocation rearrangement OH OH SOCl2 Cl pyridine Cl SOCl2 pyridine OH OH PBr3 Br Br PBr3 -SOCl2 and pyridine (a base) turn -OH into -OSOCl, a good L.G. -Cl- displaces the L.G. in an SN2 mechanism -We observe inversion of configuration at stereocenters O -The L.G. decomposes into SO2 (gas) and ClS Cl Cl -We only observe the SN2 product in this reaction. E2 does not compete (for reasons that are unclear) SOCl2 -PBr3 turns -OH into -+OHPBr2, a good L.G. -No base necessary (for reasons that are unclear) -Br- displaces the L.G. in an SN2 mechanism -We observe inversion of configuration at stereocenters -We only observe the SN2 product in this reaction. E2 does not compete (Br- is too weak of a base) Br P Br Br PBr3 Conversion of alcohols into alkyl tosylates (tosylate is a good L.G.; more or less equivalent to a halide) TsCl OH OH OTs pyridine OTs TsCl pyridine TsCl OH OTs pyridine -The -OH group attacks TsCl, generating a protonated tosylate; pyridine removes the proton. -Tosylates are very good leaving groups; alkyl tosylates will react like alkyl halides in substitution and elimination reactions, depending on the identity of the nucleophile/base you use. -Conversion of the alcohol into the alkyl tosylate does not change the configuration of stereocenters. O TsCl Cl S O Opening of epoxides with strong nucleophiles (-OH, -OR, -CN, -N3, -SR, NH3) OH 1. Nu:- O 2. H2O -Strong nucleophiles open epoxides via backside attack (an SN2 mechanism) at the least substituted carbon, presumably due to sterics---this is an example of regioselectivity Nu OH O Nu 1. Nu:- Nu 2. H2O -Achiral symmetrical epoxides must give a racemic mixture of enantiomers -Note that in opening of epoxides attached to a ring, the OH group and the nucleophile are always trans, never cis! OH Opening of epoxides with H-Z (Z = Cl, Br, I, H2O, ROH) O H-Br O MeOH H2SO4 Br HO OMe OH -Under acidic conditions, nucleophiles open epoxides via backside attack at the more substituted carbon -In the TS for this reaction, the L.G. (ROH) has already left enough that a significant amount of partial positive charge builds up on the more substituted carbon, where it is more stabilized by hyperconjugation. However, the L.G. is still close enough to block attack from the front side.