8.11 Substitution And Elimination As Competing Reactions

1. 8.11Substitution And Elimination As Competing Reactions

2. – + : H Y X C C – : Y C C – + : X C C We have seen that alkyl halides can react with Lewisbases in two different ways. They can undergonucleophilic substitution or elimination. b-elimination + H + H X Y nucleophilic substitution

3. – + : H Y X C C – : Y C C – + : X C C How can we tell which reaction pathway is followedfor a particular alkyl halide? b-elimination + H + H X Y nucleophilic substitution

4. A systematic approach is to choose as a referencepoint the reaction followed by a typical alkyl halide(secondary) with a typical Lewis base (an alkoxideion). The major reaction of a secondary alkyl halidewith an alkoxide ion is elimination by the E2 mechanism.

5. CH3CHCH3 Br CH3CHCH3 OCH2CH3 Example NaOCH2CH3 ethanol, 55°C + CH3CH=CH2 (87%) (13%)

6. Figure 8.11 E2 .. O: CH3CH2 .. Br –

7. – .. O: CH3CH2 .. Figure 8.11 SN2 Br

8. Given that the major reaction of a secondaryalkyl halide with an alkoxide ion is elimination by the E2 mechanism, we can expect the proportion of substitution to increase with: 1) decreased crowding at the carbon that bears the leaving group

9. Decreased crowding at carbon that bears the leaving group increases substitution relative to elimination. primary alkyl halide CH3CH2CH2Br NaOCH2CH3 ethanol, 55°C + CH3CH2CH2OCH2CH3 CH3CH=CH2 (9%) (91%)

10. But a crowded alkoxide base can favor elimination even with a primary alkyl halide. primary alkyl halide + bulky base CH3(CH2)15CH2CH2Br KOC(CH3)3 tert-butyl alcohol, 40°C CH3(CH2)15CH2CH2OC(CH3)3 + CH3(CH2)15CH=CH2 (13%) (87%)

11. Given that the major reaction of a secondaryalkyl halide with an alkoxide ion is elimination by the E2 mechanism, we can expect the proportion of substitution to increase with: 1) decreased crowding at the carbon that bears the leaving group 2) decreased basicity of nucleophile

12. CH3CH(CH2)5CH3 Cl CH3CH(CH2)5CH3 CN Weakly basic nucleophile increases substitution relative to elimination secondary alkyl halide + weakly basic nucleophile KCN pKa (HCN) = 9.1 SN2 DMSO (70%)

13. I N3 Weakly basic nucleophile increases substitution relative to elimination secondary alkyl halide + weakly basic nucleophile pKa (HN3) = 4.6 NaN3 SN2 (even weaker base) (75%)

14. Tertiary alkyl halides are so sterically hinderedthat elimination is the major reaction with allanionic nucleophiles. Only in solvolysis reactionsdoes substitution predominate over eliminationwith tertiary alkyl halides.

15. (CH3)2CCH2CH3 Br CH3 CH3 CH3 CH3CCH2CH3 CH3C=CHCH3 CH2=CCH2CH3 OCH2CH3 ethanol, 25°C 36% 64% Example + + 2M sodium ethoxide in ethanol, 25°C 1% 99%

16. Under 2nd order conditions….. STRONG base/nucleophile eg. -OH, -OR ELIMINATION favored with 30 , 20, (and 10 with bulky base eg. -OtBu) SUBSTITUTION favored with 10 (aprotic solvent helps) Mechanism SummarySN1 and SN2 and E1 and E2 With WEAK base but good nucleophile e.g. -CN, -N3 Or Under 1st order conditions….. WEAK base/nucleophile (solvolysis) e.g. H2O, ROH, SUBSTITUTION favored (increased solvent polarity helps)

17. 8.12Nucleophilic Substitution of Alkyl Sulfonates

18. 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

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

20. + 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

21. H H CH2OTs CH2CN Tosylates undergo typical nucleophilic substitution reactions KCN ethanol-water (86%) SN2

22. The best leaving groups are weakly basic

23. Table 8.8Approximate 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 wk acid • Cl– 1 HCl 107 • Br– 10 HBr 109 • I– 102 HI 1010 • H2O101 H3O+ 56 • TsO– 105 TsOH 600 • CF3SO2O– 108 CF3SO2OH 106

24. Table 8.8Approximate 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 • H2O101 H3O+ 56 • TsO– 105 TsOH 600 • CF3SO2O– 108 CF3SO2OH 106 Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.

25. CH3CHCH2CH3 CH3CHCH2CH3 OTs Br Tosylates can be converted to alkyl halides • Tosylate is a better leaving group than bromide. NaBr DMSO SN2 (82%)

26. H H 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 stereogenic center, so configuration and optical purity of tosylate is the same as the alcohol from which it was formed. CH3(CH2)5 TsCl pyridine

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

28. 8.13Looking Back: Reactions of AlcoholswithHydrogen Halides

29. H H3C C OH H CH3(CH2)5 H3C C Br CH3(CH2)5 Secondary alcohols H react with hydrogen halides with net inversion of configuration CH3 C Br 87% (CH2)5CH3 HBr 13% Since some racemization, can’t be SN2

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

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

32. OH + + Br Br Rearrangements HBr 7% 93% Br – Br – +

33. End of Chapter 8