1. Based on McMurry’s Organic Chemistry, 6th edition
11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations
Based on McMurry’s Organic Chemistry, 6th edition

2. Alkyl Halides React with Nucleophiles and Bases
Alkyl halides are polarized at the carbon-halide bond, making the carbon electrophilic
Nucleophiles will replace the halide in C-X bonds of many alkyl halides (reaction as Lewis base)

3. Alkyl Halides React with Nucleophiles and Bases
Nucleophiles that are Brønsted bases produce elimination

4. Substitution vs. Elimination

5. The Nature of Substitution
Substitution requires that a "leaving group", which is also a Lewis base, departs from the reacting molecule.
A nucleophile is a reactant that can be expected to participate as a Lewis base in a substitution reaction.

6. Substitution Mechanisms
SN1
Two steps with carbocation intermediate
Occurs in 3°, allyl, benzyl
SN2
Concerted mechanism - without intermediate
Occurs in primary, secondary

7. The SN2 Reaction
Reaction occurs with inversion of configuration at electrophilic C
Follows second order reaction kinetics
Ingold nomenclature to describe rate-determining step:
S=substitution
N (subscript) = nucleophilic
2 = both nucleophile and electrophile in rate-determining step (bimolecular)

8. SN2 Process
The transition state for the rate-determining (and only) step contains both reactants (substrate alkyl halide and nucleophile).

9. SN2 Transition State
The transition state of an SN2 reaction has a planar arrangement of the carbon atom and the remaining three groups
Hybridization is sp2

12. 11.5 Characteristics of the SN2 Reaction
Sensitive to steric effects
Methyl halides are most reactive
Primary are next most reactive
Unhindered secondary halides react under some conditions
Tertiary are unreactive by this path
No reaction at C=C (vinyl or aryl halides)

13. Order of Reactivity in SN2
The more alkyl groups connected to the reacting carbon, the slower the reaction

14. Vinyl and Aryl Halides:

15. Order of Reactivity in SN2

16. The Nucleophile Neutral or negatively charged Lewis base
Reaction increases coordination (adds a new bond) at the nucleophile
Neutral nucleophile acquires positive charge
Anionic nucleophile becomes neutral
See Table 11-1 for an illustrative list

17. For example:

19. Relative Reactivity of Nucleophiles
Depends on reaction and conditions
More basic nucleophiles react faster (for similar structures. See Table 11-2)
Better nucleophiles are lower in a column of the periodic table
Anions are usually more reactive than neutrals

21. The Leaving Group
A good leaving group reduces the energy of activation of a reaction
Stable anions that are weak bases (conjugate bases of strong acids) are usually excellent leaving groups
Stronger bases (conjugate bases of weaker acids) are usually poorer leaving groups

22. The Leaving Group

23. Poor Leaving Groups
If a group is very basic or very small, it does not undergo nucleophilic substitution.

24. The Solvent
Protic solvents (which can donate hydrogen bonds; -OH or –NH) slow SN2 reactions by associating with reactants (anions).
Energy is required to break interactions between reactant and solvent
Polar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit faster reaction

25. Some Polar Aprotic Solvents

26. Summary of SN2 Characteristics:
Substrate: CH3->1o>2o>>3o (Steric effect)
Nucleophile: Strong, basic nucleophiles favor the reaction
Leaving Groups: Good leaving groups (weak bases) favor the reaction
Solvent: Aprotic solvents favor the reaction; protic reactions slow it down by solvating the nucleophile
Stereochemistry: 100% inversion

27. Prob. 11.36 Arrange in order of SN2 reactivity

28. 11.6 The SN1 Reaction
Tertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to the addition of the nucleophile.
Reaction occurs in two distinct steps, while SN2 occurs in one step (concerted).
Rate-determining step is formation of carbocation:

29. SN1 Reactivity:

30. SN1 Energy Diagram k1
k-1 k2

31. Rate-Limiting Step
The overall rate of a reaction is controlled by the rate of the slowest step
The rate depends on the concentration of the species and the rate constant of the step
The step with the largest energy of activation is the rate-limiting or rate-determining step.
See Figure 11.9 – the same step is rate-determining in both directions)

32. SN1 Energy Diagram k1
k-1 k2

34. Stereochemistry of SN1 Reaction
The planar carbocation intermediate leads to loss of chirality
Product is racemic or has some inversion

36. Stereochemistry of SN1 Reaction
Carbocation is usually biased to react on side opposite leaving group because it is unsymmetrically solvated
The second step may occur with the carbocation loosely associated with leaving group.
The result is racemization with some inversion:

37. Effects of Ion Pair Formation

38. Prob. 11.9: What is the % inversion & racemization?

39. 11.9 Characteristics of the SN1 Reaction
Tertiary alkyl halide is most reactive by this mechanism
Controlled by stability of carbocation

40. Relative Reactivity of Halides:

41. Delocalized Carbocations
Delocalization of cationic charge enhances stability
Primary allyl is more stable than primary alkyl
Primary benzyl is more stable than allyl

43. Allylic and Benzylic Halides
Allylic and benzylic intermediates stabilized by delocalization of charge (See Figure 11-13)
Primary allylic and benzylic are also more reactive in the SN2 mechanism

45. Relative SN1 rates (formolysis): RCl + HCOO-1

46. Formation of the allylic cation:

47. Effect of Leaving Group on SN1
Critically dependent on leaving group
Reactivity: the larger halides ions are better leaving groups
In acid, OH of an alcohol is protonated and leaving group is H2O, which is still less reactive than halide
p-Toluensulfonate (TosO-) is an excellent leaving group

48. Nucleophiles in SN1
Since nucleophilic addition occurs after formation of carbocation, reaction rate is not normally affected by nature or concentration of nucleophile
The nucleophile must be preferably neutral (not basic; example: CH3OH rather than CH3O-) to prevent competition with elimination reactions.

50. Solvent Is Critical in SN1
The solvent stabilizes the carbocation, and also stabilizes the associated transition state. This controls the rate of the reaction.
Solvation of a carbocation by water

51. Polar Solvents Promote Ionization
Polar, protic and unreactive Lewis base solvents facilitate formation of R+
Solvent polarity is measured as dielectric polarization (P) (Table 11-3)

52. Effect of Solvent

53. Solvent Polarity

54. Summary of SN1 Characteristics:
Substrate: Benzylic~allylic>3o >2o
Nucleophile: Does not affect reaction (although strong bases promote elimination)
Leaving Groups: Good leaving groups (weak bases) favor the reaction
Solvent: Polar solvents favor the reaction by stabilizing the carbocation.
Stereochemistry: racemization (with some inversion)

55. Prob. 11.35 Arrange in order of SN1 reactivity

56. Practice Problem 11.2: SN1 or SN2?

57. Problem 11.14: SN1 or SN2?

58. 11.10 Alkyl Halides: Elimination
Elimination is an alternative pathway to substitution
Elimination is formally the opposite of addition, and generates an alkene
It can compete with substitution and decrease yield, especially for SN1 processes

59. Zaitsev’s Rule for Elimination Reactions (1875)
In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates

60. Mechanisms of Elimination Reactions
Ingold nomenclature: E – “elimination”
E1 (1st order): X- leaves first to generate a carbocation
a base abstracts a proton from the carbocation
E2 (2nd order): Concerted transfer of a proton to a base and departure of leaving group

61. 11.11 The E2 Reaction Mechanism
A proton is transferred to base as leaving group begins to depart
Transition state combines leaving of X and transfer of H
Product alkene forms stereospecifically

63. E2 Reaction Kinetics
One step (concerted): rate law dependent on base and alkyl halide
Rate = k[R-X][B]
Reaction goes faster with stronger base, better leaving group

64. Geometry of Elimination – E2
Antiperiplanar allows orbital overlap and minimizes steric interactions

66. E2 Stereochemistry
Overlap of the developing  orbital in the transition state requires periplanar geometry, anti arrangement

67. Comparison of SN2 and E2:

68. Predicting Product E2 is stereospecific
Meso-1,2-dibromo-1,2-diphenylethane with base gives cis 1,2-diphenyl-1-bromoethene
RR or SS 1,2-dibromo-1,2-diphenylethane gives trans 1,2-diphenyl-1-bromoethene

69. Anti periplanar geometry

70. 11.12 Elimination From Cyclohexanes
Abstracted proton and leaving group should align trans-diaxial to be anti periplanar (app) in approaching transition state (see Figures and 11-20)
Equatorial groups are not in proper alignment

71. 11.12 Elimination From Cyclohexanes

72. Axial vs. Equatorial Leaving Groups

74. 11.14 The E1 Reaction Competes with SN1 and E2 at 3° centers
Rate = k [RX]

75. Stereochemistry of E1 Reactions
E1 is not stereospecific and there is no requirement for alignment
Product has Zaitsev orientation because the step that controls product formation is loss of proton after formation of carbocation

76. Comparing E1 and E2 Strong base is needed for E2 but not for E1
E2 is stereospecifc, E1 is not
E1 gives Zaitsev orientation; E2 may not due to stereospecificity
E1 is favored in protic solvents; competes with SN1

77. Comparing E1 and E2

78. Reactivity Summary: SN1, SN2, E1, E2

79. General Pattern by Substrate

80. Primary alkyl halides (SN2 vs E2)

81. Secondary alkyl halides (SN2 vs E2)

82. Tertiary alkyl halides (SN1/E1 vs E2)

83. Practice Problem 11.5

84. Answers

85. Problem 11.20