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8.12 Nucleophilic Substitution of Alkyl Sulfonates

8.12 Nucleophilic Substitution of Alkyl Sulfonates. Leaving Groups. We have seen numerous examples of nucleophilic substitution in which X in R X is a halogen. Halogen is not the only possible leaving group, though. O. O. CH 3. ROSCH 3. ROS. O. O. Other RX Compounds.

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8.12 Nucleophilic Substitution of Alkyl Sulfonates

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  1. 8.12Nucleophilic Substitution of Alkyl Sulfonates

  2. Leaving Groups • We have seen numerous examples of nucleophilic substitution in which X in RX is a halogen. • Halogen is not the only possible leaving group, though.

  3. O O CH3 ROSCH3 ROS O O Other RX Compounds • undergo same kinds of reactions as alkyl halides Alkylmethanesulfonate(mesylate) Alkylp-toluenesulfonate(tosylate)

  4. + SO2Cl CH3 ROH O CH3 ROS O Preparation Tosylates are prepared by the reaction of alcohols with p-toluenesulfonyl chloride(usually in the presence of pyridine). • (abbreviated as ROTs) pyridine

  5. H H CH2OTs CH2CN (86%) Tosylates Undergo Typical Nucleophilic Substitution Reactions KCN ethanol-water

  6. The best leaving groups are weakly basic.

  7. Table 8.8Approximate Relative Reactivity of Leaving Groups • Leaving Relative Conjugate acid pKa ofGroup Rate of leaving group conj. acid • F– 10-5 HF 3.5 • Cl– 1 HCl -7 • Br– 10 HBr -9 • I– 102 HI -10 • H2O101 H3O+ -1.7 • TsO– 105 TsOH -2.8 CF3SO2O– 108 CF3SO2OH -6

  8. Table 8.8Approximate Relative Reactivity of Leaving Groups • Leaving Relative Conjugate acid pKa ofGroup Rate of leaving group conj. acid • F– 10-5 HF 3.5 • Cl– 1 HCl -7 • Br– 10 HBr -9 • I– 102 HI -10 • H2O101 H3O+ -1.7 • TsO– 105 TsOH -2.8 CF3SO2O– 108 CF3SO2OH -6 Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.

  9. CH3CHCH2CH3 CH3CHCH2CH3 OTs Br Tosylates can be Converted to Alkyl Halides • Tosylate is a better leaving group than bromide. NaBr DMSO (82%)

  10. H H CH3(CH2)5 CH3(CH2)5 C C OTs OH H3C H3C Tosylates Allow Control of Stereochemistry • Preparation of tosylate does not affect any of the bonds to the chirality center, so configuration and optical purity of tosylate is the same as the alcohol from which it was formed. TsCl pyridine

  11. H CH3(CH2)5 H Nu– C Nu OTs (CH2)5CH3 SN2 C H3C CH3 Tosylates Allow Control of Stereochemistry • Having a tosylate of known optical purity and absolute configuration then allows the preparation of other compounds of known configuration by SN2 processes.

  12. 8.13Looking Back: Reactions of AlcoholswithHydrogen Halides

  13. H CH3 C Br 87% H (CH2)5CH3 H3C HBr C OH H CH3(CH2)5 13% H3C C Br CH3(CH2)5 Secondary Alcohols React with Hydrogen Halides with Net Inversion of Configuration

  14. H H3C C OH H CH3(CH2)5 H3C C Br CH3(CH2)5 Secondary Alcohols React with Hydrogen Halides with Net Inversion of Configuration H CH3 • Most reasonable mechanism is SN1 with front side of carbocation shielded by leaving group C Br 87% (CH2)5CH3 HBr 13%

  15. OH Br Br Rearrangements can Occur in the Reaction of Alcohols with Hydrogen Halides HBr + 93% 7%

  16. OH + + Br Br Rearrangements can Occur in the Reaction of Alcohols with Hydrogen Halides HBr 7% 93% Br – Br– +

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