1. The S N 2 Mechanism of Nucleophilic Substitution

4. Many nucleophilic substitutions follow a second-order rate law. CH 3 Br + HO – CH 3 OH + Br – rate = k [CH 3 Br] [HO – ] What is the reaction order of each starting material? What can you infer on a molecular level? What is the overall order of reaction? Kinetics

5. HO – CH 3 Br + HOCH 3 Br – + one step concerted Bimolecular mechanism

6. HO – CH 3 Br + HOCH 3 Br – + one step concerted Bimolecular mechanism

7. HO – CH 3 Br + HOCH 3 Br – + one step concerted HO CH 3 Br  transition state Bimolecular mechanism

8. Stereochemistry of S N 2 Reactions

9. Generalization Nucleophilic substitutions that exhibit second-order kinetic behavior are stereospecific and proceed with inversion of configuration.

10. nucleophile attacks carbon from side opposite bond to the leaving group Inversion of Configuration

11. nucleophile attacks carbon from side opposite bond to the leaving group three-dimensional arrangement of bonds in product is opposite to that of reactant Inversion of Configuration

12. Inversion of configuration (Walden inversion) in an S N 2 reaction is due to back side attack

13. A stereospecific reaction is one in which stereoisomeric starting materials give stereoisomeric products. The reaction of 2-bromooctane with NaOH (in ethanol-water) is stereospecific. (+)-2-Bromooctane (–)-2-Octanol (–)-2-Bromooctane  (+)-2-Octanol Stereospecific Reaction

14. CH CH 3 Br CH 3 (CH 2 ) 5 CH CH 3 HO (CH 2 ) 5 CH 3 NaOH (S)-(+)-2-Bromooctane (R)-(–)-2-Octanol Stereospecific Reaction

15. H Br CH 3 CH 2 (CH 2 ) 4 CH 3 1) Draw the Fischer projection formula for (+)-S-2-bromooctane. 2) Write the Fischer projection of the (–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration. 2) Write the Fischer projection of the (–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration. HOH CH 3 CH 2 (CH 2 ) 4 CH 3 R- or S- ?

16. A conceptual view of S N 2 reactions

17. Why does the nucleophile attack from the back side?

18. : Br C H.... –.... HO CH 3 (CH 2 ) 5 H3CH3CH3CH3C

19. : Br C H.... –.... HO C H Br  –.... HO :.... CH 3 (CH 2 ) 5 H3CH3CH3CH3C CH 3

20. : Br C H.... –.... HO C H Br  –.... HO :.... C H HO.... –.... : Br CH 3 (CH 2 ) 5 H3CH3CH3CH3C (CH 2 ) 5 CH 3 CH 3 (CH 2 ) 5 CH 3

21. Steric Effects in S N 2 Reactions

22. The rate of nucleophilic substitution by the S N 2 mechanism is governed by steric effects. Crowding at the carbon that bears the leaving group slows the rate of bimolecular nucleophilic substitution. Crowding at the Reaction Site

23. RBr + LiI RI + LiBr AlkylClassRelative bromiderate CH 3 BrMethyl221,000 CH 3 CH 2 BrPrimary1,350 (CH 3 ) 2 CHBrSecondary1 (CH 3 ) 3 CBrTertiarytoo small to measure Reactivity toward substitution by the S N 2 mechanism

24. A bulky substituent in the alkyl halide reduces the reactivity of the alkyl halide: steric hindrance

25. CH 3 Br CH 3 CH 2 Br (CH 3 ) 2 CHBr (CH 3 ) 3 CBr Decreasing S N 2 Reactivity

26. CH 3 Br CH 3 CH 2 Br (CH 3 ) 2 CHBr (CH 3 ) 3 CBr Decreasing S N 2 Reactivity

27. Reaction coordinate diagrams for (a) the S N 2 reaction of methyl bromide and (b) an S N 2 reaction of a sterically hindered alkyl bromide

28. The rate of nucleophilic substitution by the S N 2 mechanism is governed by steric effects. Crowding at the carbon adjacent to the one that bears the leaving group also slows the rate of bimolecular nucleophilic substitution, but the effect is smaller. Crowding Adjacent to the Reaction Site

29. RBr + LiI RI + LiBr AlkylStructureRelative bromiderate EthylCH 3 CH 2 Br1.0 PropylCH 3 CH 2 CH 2 Br0.8 Isobutyl(CH 3 ) 2 CHCH 2 Br0.036 Neopentyl(CH 3 ) 3 CCH 2 Br0.00002 Effect of chain branching on rate of S N 2 substitution