1. Dr. Wolf's CHM 201 & 202 8-1 8.11 Substitution And Elimination As Competing Reactions

2. Dr. Wolf's CHM 201 & 202 8-2 We have seen that alkyl halides can react with Lewis bases in two different ways. They can undergo nucleophilic substitution or elimination. C C H X + Y :– C C Y H X :–+ C C +HY X :–+  -elimination nucleophilic substitution

3. Dr. Wolf's CHM 201 & 202 8-3 How can we tell which reaction pathway is followed for a particular alkyl halide? C C H X + Y :– C C Y H X :–+ C C +HY X :–+  -elimination nucleophilic substitution

4. Dr. Wolf's CHM 201 & 202 8-4 A systematic approach is to choose as a reference point the reaction followed by a typical alkyl halide (secondary) with a typical Lewis base (an alkoxide ion). The major reaction of a secondary alkyl halide with an alkoxide ion is elimination by the E2 mechanism.

5. Dr. Wolf's CHM 201 & 202 8-5 ExampleExample CH 3 CHCH 3 Br NaOCH 2 CH 3 ethanol, 55°C CH 3 CHCH 3 OCH 2 CH 3 CH 3 CH=CH 2 + (87%) (13%)

6. Dr. Wolf's CHM 201 & 202 8-6 CH 3 CH 2 O:O:O:O:.... – Br E2 Figure 8.11

7. Dr. Wolf's CHM 201 & 202 8-7 CH 3 CH 2 O:O:O:O:....–Br SN2SN2SN2SN2 Figure 8.11

8. Dr. Wolf's CHM 201 & 202 8-8 Given that the major reaction of a secondary alkyl 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. Dr. Wolf's CHM 201 & 202 8-9 Decreased crowding at carbon that bears the leaving group increases substitution relative to elimination. primary alkyl halide CH 3 CH 2 CH 2 Br NaOCH 2 CH 3 ethanol, 55°C CH 3 CH=CH 2 + CH 3 CH 2 CH 2 OCH 2 CH 3 (9%) (91%)

10. Dr. Wolf's CHM 201 & 202 8-10 But a crowded alkoxide base can favor elimination even with a primary alkyl halide. primary alkyl halide + bulky base CH 3 (CH 2 ) 15 CH 2 CH 2 Br KOC(CH 3 ) 3 tert-butyl alcohol, 40°C + CH 3 (CH 2 ) 15 CH 2 CH 2 OC(CH 3 ) 3 CH 3 (CH 2 ) 15 CH=CH 2 (87%)(13%)

11. Dr. Wolf's CHM 201 & 202 8-11 Given that the major reaction of a secondary alkyl 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. Dr. Wolf's CHM 201 & 202 8-12 Weakly basic nucleophile increases substitution relative to elimination KCN CH 3 CH(CH 2 ) 5 CH 3 Cl pK a (HCN) = 9.1 (70%) DMSO CH 3 CH(CH 2 ) 5 CH 3 CN secondary alkyl halide + weakly basic nucleophile SN2SN2SN2SN2

13. Dr. Wolf's CHM 201 & 202 8-13 secondary alkyl halide + weakly basic nucleophile NaN 3 I (75%) N3N3N3N3 Weakly basic nucleophile increases substitution relative to elimination pK a (HN 3 ) = 4.6 (even weaker base) SN2SN2SN2SN2

14. Dr. Wolf's CHM 201 & 202 8-14 Tertiary alkyl halides are so sterically hindered that elimination is the major reaction with all anionic nucleophiles. Only in solvolysis reactions does substitution predominate over elimination with tertiary alkyl halides.

15. Dr. Wolf's CHM 201 & 202 8-15 ExampleExample (CH 3 ) 2 CCH 2 CH 3 Br + CH 3 CCH 2 CH 3 OCH 2 CH 3 CH 3 CH 2 =CCH 2 CH 3 CH 3 CH 3 C=CHCH 3 CH 3 + ethanol, 25°C 64% 36% 2M sodium ethoxide in ethanol, 25°C 1%99%

16. Dr. Wolf's CHM 201 & 202 8-16 Mechanism Summary S N 1 and S N 2 and E1 and E2 Under 2 nd order conditions….. STRONG base/nucleophile eg. - OH, - OR ELIMINATION favored with 3 0, 2 0, (and 1 0 with bulky base eg. - OtBu) SUBSTITUTION favored with 1 0 (aprotic solvent helps) With WEAK base but good nucleophile e.g. - CN, - N 3 Or Under 1 st order conditions….. WEAK base/nucleophile (solvolysis) e.g. H 2 O, ROH, SUBSTITUTION favored (increased solvent polarity helps)

17. Dr. Wolf's CHM 201 & 202 8-17 8.12 Nucleophilic Substitution of Alkyl Sulfonates

18. Dr. Wolf's CHM 201 & 202 8-18 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. Dr. Wolf's CHM 201 & 202 8-19 Other RX compounds ROSCH 3 OO ROSOO CH 3 Alkyl methanesulfonate (mesylate) Alkyl p-toluenesulfonate (tosylate) undergo same kinds of reactions as alkyl halides HOSOHOO Sulfuric acid

20. Dr. Wolf's CHM 201 & 202 8-20 Preparation (abbreviated as ROTs) ROH + CH 3 SO 2 Cl pyridine ROSOO CH 3 Tosylates are prepared by the reaction of alcohols with p-toluenesulfonyl chloride (usually in the presence of pyridine)

21. Dr. Wolf's CHM 201 & 202 8-21 Tosylates undergo typical nucleophilic substitution reactions H CH 2 OTs KCN ethanol- water H CH 2 CN (86%) SN2SN2SN2SN2

22. Dr. Wolf's CHM 201 & 202 8-22 The best leaving groups are weakly basic

23. Dr. Wolf's CHM 201 & 202 8-23 Table 8.8 Approximate Relative Reactivity of Leaving Groups Leaving GroupRelative Conjugate acidK a of Rateof leaving group conj. acid F – 10 -5 HF3.5 x 10 -4 wk acid Cl – 1HCl10 7 Br – 10HBr10 9 I – 10 2 HI10 10 H 2 O10 1 H 3 O + 56 TsO – 10 5 TsOH600 CF 3 SO 2 O – 10 8 CF 3 SO 2 OH 10 6

24. Dr. Wolf's CHM 201 & 202 8-24 Table 8.8 Approximate Relative Reactivity of Leaving Groups Leaving GroupRelative Conjugate acidK a of Rateof leaving group conj. acid F – 10 -5 HF3.5 x 10 -4 Cl – 1HCl10 7 Br – 10HBr10 9 I – 10 2 HI10 10 H 2 O10 1 H 3 O + 56 TsO – 10 5 TsOH600 CF 3 SO 2 O – 10 8 CF 3 SO 2 OH 10 6 Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.

25. Dr. Wolf's CHM 201 & 202 8-25 Tosylates can be converted to alkyl halides NaBr DMSO (82%) OTs CH 3 CHCH 2 CH 3 Br Tosylate is a better leaving group than bromide. SN2SN2SN2SN2

26. Dr. Wolf's CHM 201 & 202 8-26 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. CH H3CH3CH3CH3C OHOHOHOH CH 3 (CH 2 ) 5 TsCl pyridine CH H3CH3CH3CH3C OTs CH 3 (CH 2 ) 5

27. Dr. Wolf's CHM 201 & 202 8-27 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 S N 2 processes. Nu – SN2SN2SN2SN2 C H H3CH3CH3CH3C OTs CH 3 (CH 2 ) 5 CH CH 3 (CH 2 ) 5 CH 3 Nu

28. Dr. Wolf's CHM 201 & 202 8-28 8.13 Looking Back: Reactions of Alcohols with Hydrogen Halides

29. Dr. Wolf's CHM 201 & 202 8-29 Secondary alcohols CH H3CH3CH3CH3C OH CH 3 (CH 2 ) 5 CH H3CH3CH3CH3C Br C H CH 3 (CH 2 ) 5 CH 3 Br HBr 87% 13% react with hydrogen halides with net inversion of configuration Since some racemization, can’t be S N 2

30. Dr. Wolf's CHM 201 & 202 8-30 Secondary alcohols CH H3CH3CH3CH3C OH CH 3 (CH 2 ) 5 CH H3CH3CH3CH3C Br C H CH 3 (CH 2 ) 5 CH 3 Br HBr 87% 13% Most reasonable mechanism is S N 1 with front side of carbocation shielded by leaving group react with hydrogen halides with net inversion of configuration

31. Dr. Wolf's CHM 201 & 202 8-31 Rearrangements OH Br Br+ 93%7% HBr can occur in the reaction of alcohols with hydrogen halides

32. Dr. Wolf's CHM 201 & 202 8-32 Rearrangements OH Br Br + ++ 93% 7% Br – HBr

33. Dr. Wolf's CHM 201 & 202 8-33 End of Chapter 8