Chapter 8 Substitution Reactions of Alkyl Halides

1. Organic Chemistry 6th Edition Paula Yurkanis Bruice Chapter 8 Substitution Reactions of Alkyl Halides

2. What is a substitution reaction? The atom or group that is substituted or eliminated in these reactions is called a leaving group.

3. Alkyl halides have relatively good leaving groups How do alkyl halides react?

4. Alternatively…

5. The substitution is more precisely called a nucleophilic substitution because the atom or group replacing the leaving group is a nucleophile The reaction mechanism which predominates depends on the following factors: • the structure of the alkyl halide • the reactivity of the nucleophile • the concentration of the nucleophile • the solvent of the reaction

6. Experimental Evidence for the SN2 Reaction Mechanism 1. The rate of the reaction is dependent on the concentration of both the alkyl halide and the nucleophile. 2. The rate of the reaction with a given nucleophile decreases with increasing branching of the alkyl halide at the reacting center. 3. The configuration of the substituted product is inverted compared to the configuration of the reacting chiral alkyl halide.

7. Rate law includes both the alkyl halide and the nucleophile, a second-order process The Rate Law of an SN2 Reaction Obtained experimentally:

8. The Influence of Branching on the SN2 Rate

9. Tertiary alkyl halides cannot undergo SN2 reactions Why Does Branching Lower the SN2 Rate? Because the nucleophile attacks the back side of the carbon that is bonded to the leaving group:

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

11. Reaction coordinate diagrams for (a) the SN2 reaction of methyl bromide and (b) an SN2 reaction of a sterically hindered alkyl bromide

12. Inversion of configuration (Walden inversion) in an SN2 reaction is due to back-side attack

13. SN2 Reactions Are Affected by the Leaving Group

14. Good leaving groups are the conjugate bases of strong acids, i.e., they are weak bases:

15. List of Common Good Leaving Groups Anionic Leaving Groups: Neutral Leaving Groups:

17. Second-Row Nucleophiles in the SN2 Reaction • Second-row nucleophiles: • Are approximately the same size. • The stronger the base, the better the nucleophile. stronger base, better nucleophile weaker base, poorer nucleophile OH– > H2O CH3O– > CH3OH H2N– > NH3 CH3CH2NH– > CH3CH2NH2

18. Therefore the strength of second-row nucleophiles is determined by conjugate acid strength:

19. An SN2 reaction proceeds in the direction that allows the stronger base to displace the weaker base: Chloride is a weaker base than hydroxide and the reaction is not reversible.

20. Because of their small size, second-row nucleophiles are solvated by polar solvents hindering back-side attack: Therefore water and alcohol solvents are not suitable for SN2 reactions with second-row nucleophiles.

21. Consequently, the anionic nucleophile is unsolvated and reactive SN2 reactions with second-row nucleophiles are carried out in polar aprotic solvents: Includes DMSO, DMF, and acetonitrile (CH3CN)

22. Non-nucleophilic bases: Uncoupling basicity from nucleophilicity Bulk decreases nucleophilicity, but not basicity. Why? Nucleophilic attack more sterically congested than proton abstraction.

23. Polarizability means that the loosely held electron cloud of iodide is readily distorted The tightly held electron cloud of fluoride is less polarizable. Higher-Row Nucleophiles in the SN2 Reaction Down a column of the periodic table: nucleophiles become larger and more polarizable, but less solvated and less basic.

24. The Influence of Solvent on Higher-Row Nucleophiles In an aprotic medium, fluoride is the best nucleophile by virtue of its basicity and lack of solvation. In an aprotic medium, iodide is the best nucleophile by virtue of its polarizability and lack of solvation.

25. Synthetic Utility of the SN2 Reaction A variety of functional groups can be prepared employing a good nucleophile and an electrophile with a good leaving group:

26. Insoluble in acetone, reaction goes to completion. Soluble in acetone Iodide SN2 reactions are reversible because the basicities of the nucleophile and leaving group are similar. Solution: Use acetone as a reaction solvent.

27. Fluoride SN2 reactions are problematic because fluoride salts are too ionic to dissolve in aprotic solvents. Solution, use a crown ether:

28. Intermolecular Versus Intramolecular SN2 Reactions

29. An intramolecular reaction is favored when a five- or six- membered ring product is formed:

30. A nucleophilic base would displace chloride directly. Carrying out an internal SN2 reaction: Use sodium metal to generate the oxygen anion. Use a non-nucleophilic base to generate the oxygen anion.

31. Experimental Evidence for an SN1 Reaction 1. The rate of the reaction depends only on the concentration of the alkyl halide. 2. The rate of the reaction increases with branching of the alkyl halide at the reacting center. 3. An SN1 reaction with an enantiomeric pure alkyl halide affords a racemic or partially racemic product.

32. Reaction Coordinate Diagram for an SN1 Reaction

33. An SN1 is a two-step reaction and the leaving group departs before the nucleophile approaches:

34. Influence of Alkyl Halide Branching at the Reacting Center

35. The Stereochemistry of SN1 Reactions The carbocation reaction intermediate leads to the formation of a racemic mixture:

36. CH3OH The SN1 reaction of an enantiomeric pure alkyl halide affords a racemic mixture:

37. Sometimes extra inverted product is formed in an SN1 reaction because…

38. The products resulting from substitution of cyclic compounds: Inversion versus racemization

39. The Rate of an SN1 Reaction The rate of the reaction is affected by: 1) The better the leaving group, the larger the rate. 2) The more stable the carbocation, the larger the rate. 3) The higher the polarity of the solvent, the larger the rate. The nucleophile concentration has no effect on the rate of an SN1 reaction because it is not in the rate-determining step.

40. The effect of a solvent on the rate of an SN1 reaction:

41. The dielectric constant is a measure of how the solvent can insulate opposite charges from one another:

42. If the charge on the transition state is greater than the charge on the reactants, a polar solvent will stabilize the transition state more…

43. SN1 Side Reactions Rearrangement of the carbocation intermediate can occur: The carbocation intermediate can also lose a proton: Called an E1 reaction

44. Benzylic and Allylic Halides Benzylic and allylic halides can undergo SN2 or SN1 reactions: SN2 conditions: Aprotic solvent and good nucleophile. Tertiary benzylic and tertiary allylic halides are unreactive in the SN2 reaction because of steric hindrance.

45. Benzylic and allylic halides can undergo SN1 reactions because benzylic and allylic carbocations are stable. SN1 conditions: Protic solvent and poor nucleophile.

46. More than one product may result from an SN1 reaction of an allylic halide:

47. Vinyl and aryl halides do not undergo SN2 because:

48. Vinyl and aryl halides do not undergo SN1 because: