2. © 2011 Pearson Education, Inc. 1 Chapter 8 Substitution Reactions of Alkyl Halides Organic Chemistry 6 th Edition Paula Yurkanis Bruice

3. © 2011 Pearson Education, Inc. 2 What is a substitution reaction? The atom or group that is substituted or eliminated in these reactions is called a leaving group.

4. © 2011 Pearson Education, Inc. 3 Alkyl halides have relatively good leaving groups How do alkyl halides react?

5. © 2011 Pearson Education, Inc. 4 Alternatively…

6. © 2011 Pearson Education, Inc. 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

7. © 2011 Pearson Education, Inc. 6 Experimental Evidence for the S N 2 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.

8. © 2011 Pearson Education, Inc. 7 The Rate Law of an S N 2 Reaction Obtained experimentally: Rate law includes both the alkyl halide and the nucleophile, a second- order process

9. © 2011 Pearson Education, Inc. 8 The Influence of Branching on the S N 2 Rate

10. © 2011 Pearson Education, Inc. 9 Because the nucleophile attacks the back side of the carbon that is bonded to the leaving group: Why Does Branching Lower the S N 2 Rate? Tertiary alkyl halides cannot undergo S N 2 reactions

11. © 2011 Pearson Education, Inc. 10 Why does the nucleophile attack from the back side?

12. © 2011 Pearson Education, Inc. 11 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

13. © 2011 Pearson Education, Inc. 12 Inversion of configuration (Walden inversion) in an S N 2 reaction is due to back-side attack

14. © 2011 Pearson Education, Inc. 13 S N 2 Reactions Are Affected by the Leaving Group

15. © 2011 Pearson Education, Inc. 14 Good leaving groups are the conjugate bases of strong acids, i.e., they are weak bases:

16. © 2011 Pearson Education, Inc. 15 List of Common Good Leaving Groups Anionic Leaving Groups: Neutral Leaving Groups:

17. © 2011 Pearson Education, Inc. 16

18. © 2011 Pearson Education, Inc. 17 Second-Row Nucleophiles in the S N 2 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 – >H 2 O CH 3 O – >CH 3 OH H 2 N – >NH 3 CH 3 CH 2 NH – >CH 3 CH 2 NH 2

19. © 2011 Pearson Education, Inc. 18 Therefore the strength of second-row nucleophiles is determined by conjugate acid strength:

20. © 2011 Pearson Education, Inc. 19 An S N 2 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.

21. © 2011 Pearson Education, Inc. 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 S N 2 reactions with second- row nucleophiles.

22. © 2011 Pearson Education, Inc. 21 S N 2 reactions with second-row nucleophiles are carried out in polar aprotic solvents: Includes DMSO, DMF, and acetonitrile (CH 3 CN) Consequently, the anionic nucleophile is unsolvated and reactive

23. © 2011 Pearson Education, Inc. 22 Bulk decreases nucleophilicity, but not basicity. Non-nucleophilic bases: Uncoupling basicity from nucleophilicity Why? Nucleophilic attack more sterically congested than proton abstraction.

24. © 2011 Pearson Education, Inc. 23 Higher-Row Nucleophiles in the S N 2 Reaction Down a column of the periodic table: nucleophiles become larger and more polarizable, but less solvated and less basic. Polarizability means that the loosely held electron cloud of iodide is readily distorted The tightly held electron cloud of fluoride is less polarizable.

25. © 2011 Pearson Education, Inc. 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.

26. © 2011 Pearson Education, Inc. 25 Synthetic Utility of the S N 2 Reaction A variety of functional groups can be prepared employing a good nucleophile and an electrophile with a good leaving group:

27. © 2011 Pearson Education, Inc. 26 Iodide S N 2 reactions are reversible because the basicities of the nucleophile and leaving group are similar. Solution: Use acetone as a reaction solvent. Soluble in acetone Insoluble in acetone, reaction goes to completion.

28. © 2011 Pearson Education, Inc. 27 Fluoride S N 2 reactions are problematic because fluoride salts are too ionic to dissolve in aprotic solvents. Solution, use a crown ether:

29. © 2011 Pearson Education, Inc. 28 Intermolecular Versus Intramolecular S N 2 Reactions

30. © 2011 Pearson Education, Inc. 29 An intramolecular reaction is favored when a five- or six- membered ring product is formed:

31. © 2011 Pearson Education, Inc. 30 Carrying out an internal S N 2 reaction: Use sodium metal to generate the oxygen anion. Use a non-nucleophilic base to generate the oxygen anion. A nucleophilic base would displace chloride directly.

32. © 2011 Pearson Education, Inc. 31 Experimental Evidence for an S N 1 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 S N 1 reaction with an enantiomeric pure alkyl halide affords a racemic or partially racemic product.

33. © 2011 Pearson Education, Inc. 32 Reaction Coordinate Diagram for an S N 1 Reaction

34. © 2011 Pearson Education, Inc. 33 An S N 1 is a two-step reaction and the leaving group departs before the nucleophile approaches:

35. © 2011 Pearson Education, Inc. 34 Influence of Alkyl Halide Branching at the Reacting Center

36. © 2011 Pearson Education, Inc. 35 The carbocation reaction intermediate leads to the formation of a racemic mixture: The Stereochemistry of S N 1 Reactions

37. © 2011 Pearson Education, Inc. 36 The S N 1 reaction of an enantiomeric pure alkyl halide affords a racemic mixture: CH 3 OH

38. © 2011 Pearson Education, Inc. 37 Sometimes extra inverted product is formed in an S N 1 reaction because…

39. © 2011 Pearson Education, Inc. 38 The products resulting from substitution of cyclic compounds: Inversion versus racemization

40. © 2011 Pearson Education, Inc. 39 The Rate of an S N 1 Reaction The nucleophile concentration has no effect on the rate of an S N 1 reaction because it is not in the rate- determining step. 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.

41. © 2011 Pearson Education, Inc. 40 The effect of a solvent on the rate of an S N 1 reaction:

42. © 2011 Pearson Education, Inc. 41 The dielectric constant is a measure of how the solvent can insulate opposite charges from one another:

43. © 2011 Pearson Education, Inc. 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…

44. © 2011 Pearson Education, Inc. 43 Rearrangement of the carbocation intermediate can occur: S N 1 Side Reactions The carbocation intermediate can also lose a proton: Called an E1 reaction

45. © 2011 Pearson Education, Inc. 44 Benzylic and allylic halides can undergo S N 2 or S N 1 reactions: Tertiary benzylic and tertiary allylic halides are unreactive in the S N 2 reaction because of steric hindrance. Benzylic and Allylic Halides S N 2 conditions: Aprotic solvent and good nucleophile.

46. © 2011 Pearson Education, Inc. 45 Benzylic and allylic halides can undergo S N 1 reactions because benzylic and allylic carbocations are stable. S N 1 conditions: Protic solvent and poor nucleophile.

47. © 2011 Pearson Education, Inc. 46 More than one product may result from an S N 1 reaction of an allylic halide:

48. © 2011 Pearson Education, Inc. 47 Vinyl and aryl halides do not undergo S N 2 because:

49. © 2011 Pearson Education, Inc. 48 Vinyl and aryl halides do not undergo S N 1 because:

50. © 2011 Pearson Education, Inc. 49

51. © 2011 Pearson Education, Inc. 50

52. © 2011 Pearson Education, Inc. 51 S-Adenosyl methionine (SAM) SAM, a Biological Methylating Agent A sulfide leaving group

53. © 2011 Pearson Education, Inc. 52 Methyltetrahydrofolate, Another Biological Methylating Agent An amine leaving group

54. © 2011 Pearson Education, Inc. 53 Hypoxanthine Guanine Phosphoribo Transferase (HGPRTase): An S N 2-Type Enzymatic Reaction HGPRTase deficiency: severe mental retardation (Lesch Nyhan Syndrome) A pyrophosphate leaving group

55. © 2011 Pearson Education, Inc. 54 Glutathione Most nucleophilic site in an aqueous media This is the biological nucleophile that protects us from electrophiles that react with proteins and DNA: Highly solvated and not nucleophilic The glutathione S N 2 product is highly polar and readily excreted.

56. © 2011 Pearson Education, Inc. 55 Alkylating Agents: Cancer Drugs These agents add alkyl groups to DNA by an S N 2 reaction. Leaving groups: The presence of two leaving groups results in DNA crosslinking, a toxic event.

57. © 2011 Pearson Education, Inc. 56 Mechlorethamine, a Nitrogen Mustard Mustard: refers to odor and color of the impure warfare agent. Now used to treat lymphomas, breast and lung cancers. Affects only rapidly dividing cells, both normal and cancerous.

58. © 2011 Pearson Education, Inc. 57 Triethylenemelamine, an Aziridinyl Triple Alkylating Agent Used to treat Hodgkin’s lymphoma Requires protonation to be activated as an alkylating agent Protonation and ring opening: Ring opening driven by: Amine leaving group Relief of ring strain

59. © 2011 Pearson Education, Inc. 58 Sulfur Mustard, Chemical Warfare Agent

60. © 2011 Pearson Education, Inc. 59 Temozolomide: Used to Treat Senator Kennedy’s Brain Tumor Crosses the Blood- Brain Barrier