8.14 Sulfonate Esters as Substrates in Nucleophilic Substitution 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

Alkyl methanesulfonate (mesylate) Alkyl p-toluenesulfonate (tosylate) Other RX compounds ROSCH3 O ROS O CH3 Alkyl methanesulfonate (mesylate) Alkyl p-toluenesulfonate (tosylate) undergo same kinds of reactions as alkyl halides

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

Tosylates undergo typical nucleophilic substitution reactions KCN H CH2OTs H CH2CN ethanol- water (86%)

The best leaving groups are weakly basic

Table 8.8 Approximate Relative Reactivity of Leaving Groups Leaving Group Relative Conjugate acid Ka of Rate of leaving group conj. acid F– 10-5 HF 3.5 x 10-4 Cl– 1 HCl 107 Br– 10 HBr 109 I– 102 HI 1010 H2O 101 H3O+ 56 TsO– 105 TsOH 600 CF3SO2O– 108 CF3SO2OH 106

Table 8.8 Approximate Relative Reactivity of Leaving Groups Leaving Group Relative Conjugate acid Ka of Rate of leaving group conj. acid F– 10-5 HF 3.5 x 10-4 Cl– 1 HCl 107 Br– 10 HBr 109 I– 102 HI 1010 H2O 101 H3O+ 56 TsO– 105 TsOH 600 CF3SO2O– 108 CF3SO2OH 106 Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.

Tosylates can be converted to alkyl halides NaBr OTs CH3CHCH2CH3 Br CH3CHCH2CH3 DMSO (82%) Tosylate is a better leaving group than bromide.

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

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. C H CH3 (CH2)5CH3 H CH3(CH2)5 Nu– C OTs Nu SN2 H3C

8.15 Looking Back: Reactions of Alcohols with Hydrogen Halides 2

Secondary alcohols react with hydrogen halides with net inversion of configuration CH3 C Br 87% C H H3C OH CH3(CH2)5 (CH2)5CH3 HBr C H H3C Br CH3(CH2)5 13%

Secondary alcohols react with hydrogen halides with net inversion of configuration CH3 C Br 87% C H H3C OH CH3(CH2)5 (CH2)5CH3 Most reasonable mechanism is SN1 with front side of carbocation shielded by leaving group HBr C H H3C Br CH3(CH2)5 13%

Rearrangements can occur in the reaction of alcohols with hydrogen halides HBr Br + Br 93% 7%

Rearrangements can occur in the reaction of alcohols with hydrogen halides HBr 7% + + 93% Br – Br – Br + Br