1. 8.14 Sulfonate Esters as Substrates in Nucleophilic Substitution2

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. 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

4. 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)

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

6. The best leaving groups are weakly basic

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

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

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

10. 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

11. 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

12. 8.15 Looking Back: Reactions of Alcohols with Hydrogen Halides2

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
HBr C H
H3C Br
CH3(CH2)5
13%

14. 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%

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

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