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Created by Professor William Tam & Dr. Phillis Chang Chapter 6 Ionic Reactions Nucleophilic Substitution and Elimination Reactions of Alkyl Halides Copyright.

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1 Created by Professor William Tam & Dr. Phillis Chang Chapter 6 Ionic Reactions Nucleophilic Substitution and Elimination Reactions of Alkyl Halides Copyright © 2014 by John Wiley & Sons, Inc. All rights reserved.

2 About The Authors These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang. Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in 1995. He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem. Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew. © 2014 by John Wiley & Sons, Inc. All rights reserved.

3 Table of Contents (hyperlinked) 1. Alkyl Halides Alkyl Halides 2. Nucleophilic Substitution Reactions Nucleophilic Substitution Reactions 3. Nucleophiles Nucleophiles 4. Leaving Groups Leaving Groups 5. Kinetics of a Nucleophilic Substitution Reaction: An S N 2 Reaction Kinetics of a Nucleophilic Substitution Reaction: An S N 2 Reaction 6. A Mechanism for the S N 2 Reaction A Mechanism for the S N 2 Reaction 7. Transition State Theory: Free-Energy Diagrams Transition State Theory: Free-Energy Diagrams 8. The Stereochemistry of S N 2 Reactions The Stereochemistry of S N 2 Reactions 9. The Reaction of tert-Butyl Chloride with Water: An S N 1 Reaction The Reaction of tert-Butyl Chloride with Water: An S N 1 Reaction 10. A Mechanism for the S N 1 Reaction A Mechanism for the S N 1 Reaction 11. Carbocations Carbocations 12. The Stereochemistry of S N 1 Reactions The Stereochemistry of S N 1 Reactions 13. Factors Affecting the Rates of S N 1 and S N 2 Reactions Factors Affecting the Rates of S N 1 and S N 2 Reactions 14. Organic Synthesis: Functional Group Transformations Using S N 2 Reactions Organic Synthesis: Functional Group Transformations Using S N 2 Reactions 15. Elimination Reactions of Alkyl Halides Elimination Reactions of Alkyl Halides 16. The E2 Reaction The E2 Reaction 17. The E1 Reaction The E1 Reaction 18. How to Determine Whether Substitution or Elimination Is Favored How to Determine Whether Substitution or Elimination Is Favored 19. Overall Summary Overall Summary © 2014 by John Wiley & Sons, Inc. All rights reserved.

4 Table of Contents 1. Alkyl Halides 2. Nucleophilic Substitution Reactions 3. Nucleophiles 4. Leaving Groups 5. Kinetics of a Nucleophilic Substitution Reaction: An S N 2 Reaction 6. A Mechanism for the S N 2 Reaction 7. Transition State Theory: Free-Energy Diagrams 8. The Stereochemistry of S N 2 Reactions 9. The Reaction of tert-Butyl Chloride with Water: An S N 1 Reaction 10. A Mechanism for the S N 1 Reaction 11. Carbocations 12. The Stereochemistry of S N 1 Reactions 13. Factors Affecting the Rates of S N 1 and S N 2 Reactions 14. Organic Synthesis: Functional Group Transformations Using S N 2 Reactions 15. Elimination Reactions of Alkyl Halides 16. The E2 Reaction 17. The E1 Reaction 18. How to Determine Whether Substitution or Elimination Is Favored 19. Overall Summary © 2014 by John Wiley & Sons, Inc. All rights reserved.

5 In this chapter we will consider:  What groups can be replaced (i.e., substituted) or eliminated  The various mechanisms by which such processes occur  The conditions that can promote such reactions © 2014 by John Wiley & Sons, Inc. All rights reserved.

6 1.Alkyl Halides  An alkyl halide has a halogen atom bonded to an sp 3 -hybridized (tetrahedral) carbon atom  The carbon–chlorine and carbon– bromine bonds are polarized because the halogen is more electronegative than carbon © 2014 by John Wiley & Sons, Inc. All rights reserved.

7  Iodine does not have a permanent dipole, but the bond is easily polarizable  Iodine is a good leaving group due to its polarizability, i.e. its ability to stabilize a negative charge due to its large atomic size © 2014 by John Wiley & Sons, Inc. All rights reserved.

8  Halogens are more electronegative than carbon X = Cl, Br, I © 2014 by John Wiley & Sons, Inc. All rights reserved.

9 Different Types of Organic Halides  Alkyl halides (haloalkanes) a 1 o chloridea 2 o bromidea 3 o iodide Attached to 1 carbon atom C Attached to 2 carbon atoms C C Attached to 3 carbon atoms C C C sp 3 © 2014 by John Wiley & Sons, Inc. All rights reserved.

10  Vinyl halides (Alkenyl halides)  Aryl halides  Acetylenic halides (Alkynyl halides) © 2014 by John Wiley & Sons, Inc. All rights reserved.

11  Prone to undergo Nucleophilic Substitutions (S N ) and Elimination Reactions (E) (the focus of this Chapter)  Different reactivity than alkyl halides, and do not undergo S N or E reactions © 2014 by John Wiley & Sons, Inc. All rights reserved.

12 The Nu ⊖ donates an e ⊖ pair to the substrate The bond between C and LG breaks, giving both e ⊖ from the bond to LG The Nu ⊖ uses its e ⊖ pair to form a new covalent bond with the substrate C The LG gains the pair of e ⊖ originally bonded in the substrate 2.Nucleophilic Substitution Reactions © 2014 by John Wiley & Sons, Inc. All rights reserved.

13  Two types of mechanisms ●1 st type: S N 2 (concerted mechanism) Timing of The Bond Breaking & Bond Making Process © 2014 by John Wiley & Sons, Inc. All rights reserved.

14 slow r.d.s. k 1 << k 2 and k 3 fast ●2 nd type: S N 1 (stepwise mechanism) © 2014 by John Wiley & Sons, Inc. All rights reserved.

15  A reagent that seeks a positive center  Nucleophile – “nucleus” “loving”  “phile” – derived from the Greek word philia meaning “loving” 3.Nucleophiles © 2014 by John Wiley & Sons, Inc. All rights reserved.

16  Has an unshared pair of e ⊖ e.g.: This is the positive center that the Nu ⊖ seeks © 2014 by John Wiley & Sons, Inc. All rights reserved.

17  Examples: © 2014 by John Wiley & Sons, Inc. All rights reserved.

18  To be a good leaving group, the substituent must be able to leave as a relatively stable, weakly basic molecule or ion e.g.: I ⊖, Br ⊖, Cl ⊖, TsO ⊖, MsO ⊖, H 2 O, NH 3 4.Leaving Groups © 2014 by John Wiley & Sons, Inc. All rights reserved.

19  The rate of the substitution reaction is linearly dependent on the concentration of HO ⊖ and CH 3 Br  Overall, a second-order reaction  bimolecular 5.Kinetics of a Nucleophilic Substitution Reaction: An S N 2 Reaction © 2014 by John Wiley & Sons, Inc. All rights reserved.

20  The rate of reaction can be measured by ●The consumption of the reactants (HO ⊖ or CH 3 Cl) or ●The appearance of the products (CH 3 OH or Cl ⊖ ) over time 5A.How Do We Measure the Rate of This Reaction? © 2014 by John Wiley & Sons, Inc. All rights reserved.

21 Time, t Concentration, M [CH 3 Cl] ↓ [CH 3 OH] ↑ Graphically … Rate = Δ[CH 3 Cl] ΔtΔt = − [CH 3 Cl] t=t − [CH 3 Cl] t=0 Time in seconds [CH 3 Cl] ↓ [CH 3 OH] ↑ © 2014 by John Wiley & Sons, Inc. All rights reserved.

22 Time, t Concentration, M [CH 3 Cl] Initial Rate [CH 3 Cl] t=0 [CH 3 Cl] t=t Initial Rate (from slope) = − [CH 3 Cl] t=t − [CH 3 Cl] t=0 ΔtΔt © 2014 by John Wiley & Sons, Inc. All rights reserved.

23  Example: [OH ⊖ ] t=0 [CH 3 Cl] t=0 Initial rate mole L -1, s -1 Result 1.0 M0.0010 M4.9 × 10 -7 1.0 M0.0020 M9.8 × 10 -7 Doubled 2.0 M0.0010 M9.8 × 10 -7 Doubled 2.0 M0.0020 M19.6 × 10 -7 Quadrupled © 2014 by John Wiley & Sons, Inc. All rights reserved.

24  Conclusion: ●The rate of reaction is directly proportional to the concentration of either reactant. ●When the concentration of either reactant is doubled, the rate of reaction doubles. © 2014 by John Wiley & Sons, Inc. All rights reserved.

25 The Kinetic Rate Expression Rate α [OH ⊖ ][CH 3 Cl] [OH ⊖ ][CH 3 Cl] Initial Rate k = = 4.9 × 10 -7 L mol -1 s -1 Rate = k[OH ⊖ ][CH 3 Cl] © 2014 by John Wiley & Sons, Inc. All rights reserved.

26 5B.What is the Order of This Reaction?  This reaction is said to be second order overall  We also say that the reaction is bimolecular  We call this kind of reaction an S N 2 reaction, meaning substitution, nucleophilic, bimolecular © 2014 by John Wiley & Sons, Inc. All rights reserved.

27 negative HO ⊖ brings an e ⊖ pair to δ+ C; δ – Br begins to move away with an e ⊖ pair O–C bond partially formed; C – Br bond partially broken. Configuration of C begins to invert O–C bond formed; Br ⊖ departed. Configuration of C inverted 6.A Mechanism for the S N 2 Reaction © 2014 by John Wiley & Sons, Inc. All rights reserved.

28  A reaction that proceeds with a negative free-energy change (releases energy to its surroundings) is said to be exergonic  A reaction that proceeds with a positive free-energy change (absorbs energy from its surroundings) is said to be endergonic 7.Transition State Theory: Free-Energy Diagrams © 2014 by John Wiley & Sons, Inc. All rights reserved.

29  At 60 o C (333 K)  G o = -100 kJ/mol ●This reaction is highly exergonic ●This reaction is exothermic  H o = -75 kJ/mol © 2014 by John Wiley & Sons, Inc. All rights reserved.

30 ●Its equilibrium constant (K eq ) is  G o = –RT ln K eq ln K eq = –Go–Go RT = –(–100 kJ/mol) (0.00831 kJ K -1 mol -1 )(333 K) = 36.1 K eq = 5.0 x 10 15 © 2014 by John Wiley & Sons, Inc. All rights reserved.

31 A Free Energy Diagram for a Hypothetical S N 2 Reaction That Takes Place with a Negative  G o © 2014 by John Wiley & Sons, Inc. All rights reserved.

32  The reaction coordinate indicates the progress of the reaction, in terms of the conversion of reactants to products  The top of the energy curve corresponds to the transition state for the reaction  The free energy of activation (  G ‡ ) for the reaction is the difference in energy between the reactants and the transition state  The free energy change for the reaction (  G o ) is the difference in energy between the reactants and the products © 2014 by John Wiley & Sons, Inc. All rights reserved.

33 A Free Energy Diagram for a Hypothetical Reaction with a Positive Free-Energy Change © 2014 by John Wiley & Sons, Inc. All rights reserved.

34  A 10°C increase in temperature will cause the reaction rate to double for many reactions taking place near room temperature 7A.Temperature & Reaction Rate Distribution of energies at two different temperatures. The number of collisions with energies greater than the free energy of activation is indicated by the corresponding shaded area under each curve. © 2014 by John Wiley & Sons, Inc. All rights reserved.

35  The relationship between the rate constant (k) and  G ‡ is exponential : Distribution of energies at two different temperatures. The number of collisions with energies greater than the free energy of activation is indicated by the corresponding shaded area under each curve. e = 2.718, the base of natural logarithms k 0 = absolute rate constant, which equals the rate at which all transition states proceed to products (At 25 o C, k 0 = 6.2 ╳ 10 12 s  1 ) © 2014 by John Wiley & Sons, Inc. All rights reserved.

36  A reaction with a lower free energy of activation (  G ‡ ) will occur exponentially faster than a reaction with a higher  G ‡, as dictated by Distribution of energies at two different temperatures. The number of collisions with energies greater than the free energy of activation is indicated by the corresponding shaded area under each curve. © 2014 by John Wiley & Sons, Inc. All rights reserved.

37 EExothermic (  G o is negative) TThermodynamically favorable process Free Energy Diagram of S N 2 Reactions © 2014 by John Wiley & Sons, Inc. All rights reserved.

38 (R)(R) (S)(S) (inversion) IInversion of configuration 8.The Stereochemistry of S N 2 Reactions © 2014 by John Wiley & Sons, Inc. All rights reserved.

39  Example: Nu ⊖ attacks from the TOP face. (inversion of configuration) © 2014 by John Wiley & Sons, Inc. All rights reserved.

40  Example: Nu ⊖ attacks from the BACK side. (inversion of configuration) © 2014 by John Wiley & Sons, Inc. All rights reserved.

41 9. The Reaction of tert -Butyl Chloride with Water: An S N 1 Reaction © 2014 by John Wiley & Sons, Inc. All rights reserved.

42  The rate of S N 1 reactions depends only on concentration of the alkyl halide and is independent of concentration of the Nu ⊖ Rate = k[ t BuCl] In other words, it is a first-order reaction  unimolecular nucleophilic substitution © 2014 by John Wiley & Sons, Inc. All rights reserved.

43  In a multistep reaction, the rate of the overall reaction is the same as the rate of the SLOWEST step, known as the rate-determining step (r.d.s)  For example: k 1 << k 2 or k 3 9A.Multistep Reactions & the Rate- Determining Step © 2014 by John Wiley & Sons, Inc. All rights reserved.

44  The opening A is much smaller than openings B and C  The overall rate at which sand reaches to the bottom of the hourglass is limited by the rate at which sand falls through opening A  Opening A is analogous to the rate-determining step of a multistep reaction A B C Fig. 6.5 © 2014 by John Wiley & Sons, Inc. All rights reserved.

45  A multistep process slow r.d.s. 10.A Mechanism for the S N 1 Reaction © 2014 by John Wiley & Sons, Inc. All rights reserved.

46 Free Energy Diagram of S N 1 Reactions intermediate © 2014 by John Wiley & Sons, Inc. All rights reserved.

47 fast © 2014 by John Wiley & Sons, Inc. All rights reserved.

48 Free Energy Diagram of S N 1 Reactions intermediate © 2014 by John Wiley & Sons, Inc. All rights reserved.

49 fast © 2014 by John Wiley & Sons, Inc. All rights reserved.

50 Free Energy Diagram of S N 1 Reactions intermediate © 2014 by John Wiley & Sons, Inc. All rights reserved.

51 k 1 << k 2 and k 3 fast © 2014 by John Wiley & Sons, Inc. All rights reserved.

52  2 intermediates and 3 transition states (T.S.)  The most important T.S. for S N 1 reactions is T.S. (1) of the rate- determining step (r.d.s.) © 2014 by John Wiley & Sons, Inc. All rights reserved.

53  Carbocations are trigonal planar  The central carbon atom in a carbocation is electron deficient; it has only six e ⊖ in its valence shell  The p orbital of a carbocation contains no electrons, but it can accept an electron pair when the carbocation undergoes further reaction 11A.The Structure of Carbocations 11.Carbocations © 2014 by John Wiley & Sons, Inc. All rights reserved.

54  General order of reactivity (towards S N 1 reaction) ●3 o > 2 o >> 1 o > methyl  The more stable the carbocation formed, the faster the S N 1 reaction 11B.The Relative Stabilities of Carbocations © 2014 by John Wiley & Sons, Inc. All rights reserved.

55  Stability of cations  Resonance stabilization of allylic and benzylic cations most stable (positive inductive effect) © 2014 by John Wiley & Sons, Inc. All rights reserved.

56 50:50 chance 12.Stereochemistry of S N 1 Reactions (1 : 1) © 2014 by John Wiley & Sons, Inc. All rights reserved.

57  Example: slow r.d.s. (one enantiomer) (carbocation) attack from TOP face attack from BOTTOM face racemic mixture ( 1 : 1 ) © 2014 by John Wiley & Sons, Inc. All rights reserved.

58   Example: slow r.d.s. trigonal planar © 2014 by John Wiley & Sons, Inc. All rights reserved.

59  The structure of the substrate  The concentration and reactivity of the nucleophile (for S N 2 reactions only)  The effect of the solvent  The nature of the leaving group 13. Factors Affecting the Rates of S N 1 and S N 2 Reactions © 2014 by John Wiley & Sons, Inc. All rights reserved.

60 13A.The Effect of the Structure of the Substrate  General order of reactivity (towards S N 2 reaction) ●Methyl > 1 o > 2 o >> 3 o > vinyl or aryl DO NOT undergo S N 2 reactions © 2014 by John Wiley & Sons, Inc. All rights reserved.

61 Relative Rate (towards S N 2) methyl1o1o 2o2o neopentyl3o3o 2  10 6 4  10 4 5001< 1 Most reactive Least reactive  For example: © 2014 by John Wiley & Sons, Inc. All rights reserved.

62  Compare faster slower © 2014 by John Wiley & Sons, Inc. All rights reserved.

63 extremely slow very slow © 2014 by John Wiley & Sons, Inc. All rights reserved.

64  Note NO S N 2 reaction on sp 2 or sp carbons sp 2 sp © 2014 by John Wiley & Sons, Inc. All rights reserved.

65  General order of reactivity (towards S N 1 reaction) ●3 o > 2 o >> 1 o > methyl  The more stable the carbocation formed, the faster the S N 1 reaction Reactivity of the Substrate in S N 1 Reactions © 2014 by John Wiley & Sons, Inc. All rights reserved.

66  Stability of cations most stable (positive inductive effect)  Allylic halides and benzylic halides also undergo S N 1 reactions at reasonable rates © 2014 by John Wiley & Sons, Inc. All rights reserved.

67  Resonance stabilization for allylic and benzylic cations © 2014 by John Wiley & Sons, Inc. All rights reserved.

68  For S N 1 reaction Recall: Rate = k[RX] ●The Nu ⊖ does NOT participate in the r.d.s. ●Rate of S N 1 reactions are NOT affected by either the concentration or the identity of the Nu ⊖ 13B.The Effect of the Concentration & Strength of the Nucleophile © 2014 by John Wiley & Sons, Inc. All rights reserved.

69  For S N 2 reaction Recall: Rate = k[Nu ⊖ ][RX] ●The rate of S N 2 reactions depends on both the concentration and the identity of the attacking Nu ⊖ © 2014 by John Wiley & Sons, Inc. All rights reserved.

70  Identity of the Nu ⊖ ●The relative strength of a Nu ⊖ (its nucleophilicity) is measured in terms of the relative rate of its S N 2 reaction with a given substrate rapid Good Nu ⊖ Very slow Poor Nu: © 2014 by John Wiley & Sons, Inc. All rights reserved.

71  The relative strength of a Nu ⊖ can be correlated with 3 structural features ●A negatively charged Nu ⊖ is always a more reactive Nu ⊖ than its conjugate acid  e.g. HO ⊖ is a better Nu ⊖ than H 2 O and RO ⊖ is better than ROH ●In a group of Nu ⊖ s in which the nucleophilic atom is the same, nucleophilicities parallel basicities  e.g. for O compounds, RO ⊖ > HO ⊖ >> RCO 2 ⊖ > ROH > H 2 O © 2014 by John Wiley & Sons, Inc. All rights reserved.

72 ●When the nucleophilic atoms are different, then nucleophilicities may not parallel basicities  e.g. in protic solvents HS ⊖, NC ⊖, and I ⊖ are all weaker bases than HO ⊖, yet they are stronger Nu ⊖ s than HO ⊖ HS ⊖ > NC ⊖ > I ⊖ > HO ⊖ © 2014 by John Wiley & Sons, Inc. All rights reserved.

73  S N 2 reactions are favored by polar aprotic solvents (e.g., acetone, DMF, DMSO)  S N 1 reactions are favored by polar protic solvents (e.g., EtOH, MeOH, H 2 O) 13C.Solvent Effects in S N 2 & S N 1 Reactions © 2014 by John Wiley & Sons, Inc. All rights reserved.

74 Solvents Non-polar solvents (e.g. hexane, benzene) Polar solvents Polar protic solvents (e.g. H 2 O, MeOH) Polar aprotic solvents (e.g. DMSO, HMPA)  Classification of solvents © 2014 by John Wiley & Sons, Inc. All rights reserved.

75  S N 2 Reactions in Polar Aprotic Solvents ●The best solvents for S N 2 reactions are  Polar aprotic solvents, which have strong dipoles but do not have OH or NH groups  Examples © 2014 by John Wiley & Sons, Inc. All rights reserved.

76  Polar aprotic solvents tend to solvate metal cations rather than nucleophilic anions, and this results in “ naked ” anions of the Nu ⊖ and makes the e ⊖ pair of the Nu ⊖ more available © 2014 by John Wiley & Sons, Inc. All rights reserved.

77 SolventRelative Rate MeOH1 DMF10 6  Tremendous acceleration in S N 2 reactions with polar aprotic solvent © 2014 by John Wiley & Sons, Inc. All rights reserved.

78  S N 2 Reactions in Polar Protic Solvents ●In polar protic solvents, the Nu ⊖ anion is solvated by the surrounding protic solvent which makes the e ⊖ pair of the Nu ⊖ less available and thus less reactive in S N 2 reactions © 2014 by John Wiley & Sons, Inc. All rights reserved.

79  Halide Nucleophilicity in Protic Solvents ●I ⊖ > Br ⊖ > Cl ⊖ > F ⊖  Thus, I ⊖ is a stronger Nu ⊖ in protic solvents, as its e ⊖ pair is more available to attack the substrate in the S N 2 reaction. © 2014 by John Wiley & Sons, Inc. All rights reserved.

80  Halide Nucleophilicity in Polar Aprotic Solvents (e.g. in DMSO) ●F ⊖ > Cl ⊖ > Br ⊖ > I ⊖  Polar aprotic solvents do not solvate anions but solvate the cations  The “ naked ” anions act as the Nu ⊖  Since F ⊖ is smaller in size and the charge per surface area is larger than I ⊖, the nucleophilicity of F ⊖ in this environment is greater than I ⊖ © 2014 by John Wiley & Sons, Inc. All rights reserved.

81  Solvent plays an important role in S N 1 reactions but the reasons are different from those in S N 2 reactions  Solvent effects in S N 1 reactions are due largely to stabilization or destabilization of the transition state © 2014 by John Wiley & Sons, Inc. All rights reserved.

82  Polar protic solvents stabilize the development of the polar transition state and thus accelerate this rate- determining step (r.d.s.): © 2014 by John Wiley & Sons, Inc. All rights reserved.

83 13D.The Nature of the Leaving Group  Leaving groups depart with the electron pair that was used to bond them to the substrate  The best leaving groups are those that become either a relatively stable anion or a neutral molecule when they depart © 2014 by John Wiley & Sons, Inc. All rights reserved.

84  The better a species can stabilize a negative charge, the better the LG in an S N 2 reaction S N 1 Reaction: S N 2 Reaction: © 2014 by John Wiley & Sons, Inc. All rights reserved.

85 CH 3 O  + CH 3 –X  CH 3 –OCH 3 + X  HO , H 2 N , RO  FF Cl  Br  II TsO  ~ 0120010,00030,00060,000 Relative Rate: <<<<<< Worst X ⊖ Best X ⊖  Note:Normally R–F, R–OH, R–NH 2, R–OR’ do not undergo S N 2 reactions.  Examples of the reactivity of some X ⊖ : © 2014 by John Wiley & Sons, Inc. All rights reserved.

86  a strong basic anion a poor leaving group weak base ✔ a good leaving group © 2014 by John Wiley & Sons, Inc. All rights reserved.

87  Other weak bases that are good leaving groups: © 2014 by John Wiley & Sons, Inc. All rights reserved.

88 14.Organic Synthesis: Functional Group Transformation Using S N 2 Reactions © 2014 by John Wiley & Sons, Inc. All rights reserved.

89

90  Examples: NaOEt, DMSO NaSMe, DMSO © 2014 by John Wiley & Sons, Inc. All rights reserved.

91  Examples: ●Need S N 2 reactions to control stereochemistry ●But S N 2 reactions give the inversion of configurations, so how do you get the “retention” of configuration here?? ●Solution: “double inversion”  “retention” © 2014 by John Wiley & Sons, Inc. All rights reserved.

92 (Note: Br ⊖ is a stronger Nu than I ⊖ in polar aprotic solvent.) NaBr DMSO NaCN DMSO (S N 2 with inversion) (S N 2 with inversion) © 2014 by John Wiley & Sons, Inc. All rights reserved.

93  Vinylic and phenyl halides are generally unreactive in S N 1 or S N 2 reactions 14A.The Nonreactivity of Vinylic and Phenyl Halides © 2014 by John Wiley & Sons, Inc. All rights reserved.

94  Examples © 2014 by John Wiley & Sons, Inc. All rights reserved.

95  Substitution 15.Elimination Reactions of Alkyl Halides  Elimination © 2014 by John Wiley & Sons, Inc. All rights reserved.

96  Substitution reaction (S N ) and elimination reaction (E) are processes in competition with each other © 2014 by John Wiley & Sons, Inc. All rights reserved.

97 15A.Dehydrohalogenation halide as LG β carbon β hydrogen  carbon  β LG β hydrogen ⊖ O t Bu © 2014 by John Wiley & Sons, Inc. All rights reserved.

98  Conjugate base of alcohols is often used as the base in dehydrohalogenations 15B.Bases Used in Dehydro- halogenation R−O ⊖ + Na ⊕ + H 2 R−O−H R−O ⊖ + Na ⊕ + H 2 Na NaH © 2014 by John Wiley & Sons, Inc. All rights reserved.

99  Rate = k[CH 3 CHBrCH 3 ][EtO ⊖ ]  Rate determining step involves both the alkyl halide and the alkoxide anion  A bimolecular reaction 16.The E2 Reaction © 2014 by John Wiley & Sons, Inc. All rights reserved.

100 Mechanism for an E2 Reaction β α EtO ⊖ removes a  proton; C − H breaks; new  bond forms and Br begins to depart Partial bonds in the transition state: C − H and C−Br bonds break, new  C−C bond forms C=C is fully formed and the other products are EtOH and Br ⊖ © 2014 by John Wiley & Sons, Inc. All rights reserved.

101 Free Energy Diagram of E2 Reaction G‡G‡ E2 reaction has ONE transition state  Second-order overall  bimolecular Rate = k[CH 3 CHBrCH 3 ][EtO ⊖ ] © 2014 by John Wiley & Sons, Inc. All rights reserved.

102  E1: Unimolecular elimination 17.The E1 Reaction © 2014 by John Wiley & Sons, Inc. All rights reserved.

103 Mechanism of an E1 Reaction slow r.d.s.  carbon β hydrogen fast © 2014 by John Wiley & Sons, Inc. All rights reserved.

104 Free Energy Diagram of E1 Reaction © 2014 by John Wiley & Sons, Inc. All rights reserved.

105 slow r.d. step Aided by the polar solvent, a chlorine departs with the e⊖ pair that bonded it to the carbon Produces relatively stable 3 o carbocation and a Cl⊖. The ions are solvated (and stabilized) by surrounding H 2 O molecules © 2014 by John Wiley & Sons, Inc. All rights reserved.

106 Free Energy Diagram of E1 Reaction © 2014 by John Wiley & Sons, Inc. All rights reserved.

107 fast H 2 O molecule removes one of the  hydrogens which are acidic due to the adjacent positive charge. An e ⊖ pair moves in to form a double bond between the  and  carbon atoms Produces alkene and hydronium ion © 2014 by John Wiley & Sons, Inc. All rights reserved.

108 18.How To Determine Whether Substitution or Elimination Is Favoured  All nucleophiles are potential bases and all bases are potential nucleophiles  Substitution reactions are always in competition with elimination reactions  Different factors can affect which type of reaction is favoured © 2014 by John Wiley & Sons, Inc. All rights reserved.

109 E2 (b) (a) SN2SN2 (b) (a) 18A. S N 2 vs. E2 © 2014 by John Wiley & Sons, Inc. All rights reserved.

110  With a strong base, e.g. EtO ⊖ ●Favor S N 2 Primary Substrate © 2014 by John Wiley & Sons, Inc. All rights reserved.

111  With a strong base, e.g. EtO ⊖ ●Favor E2 Secondary Substrate © 2014 by John Wiley & Sons, Inc. All rights reserved.

112  With a strong base, e.g. EtO ⊖ ●E2 is highly favored Tertiary Substrate © 2014 by John Wiley & Sons, Inc. All rights reserved.

113  Unhindered “small” base/Nu ⊖ Base/Nu ⊖ : Small vs. Bulky  Hindered “bulky” base/Nu ⊖ © 2014 by John Wiley & Sons, Inc. All rights reserved.

114 Basicity vs. Polarizability © 2014 by John Wiley & Sons, Inc. All rights reserved.

115 Tertiary Halides: S N 1 vs. E1 & E2 © 2014 by John Wiley & Sons, Inc. All rights reserved.

116 E2E1SN2SN2SN1SN1 Mostly S N 2 with weak bases; e.g. with CH 3 COO ⊖ Very favorable with weak bases; e.g. with H 2 O; MeOH Hindered bases give mostly alkenes; e.g. with t BuO ⊖ Mostly Very little; Solvolysis possible; e.g. with H 2 O; MeOH Very little Strong bases promote E2; e.g. with RO ⊖, HO ⊖ Strong bases promote E2; e.g. with RO ⊖, HO ⊖ ── ─ Always competes with S N 1 ─ Very fast ── 19.Overall Summary © 2014 by John Wiley & Sons, Inc. All rights reserved.

117 Review Problems H⊖H⊖ Intramolecular S N 2 S N 2 with inversion © 2014 by John Wiley & Sons, Inc. All rights reserved.

118 sp 2 hybridized carbocation Cl ⊖ attacks from top face Cl ⊖ attacks from bottom face S N 1 with racemization © 2014 by John Wiley & Sons, Inc. All rights reserved.

119  END OF CHAPTER 6  © 2014 by John Wiley & Sons, Inc. All rights reserved.


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