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)
Nucleophiles that are also Brønsted bases can produce elimination

3. 11.1 The Discovery of the Walden Inversion
In 1896, Walden showed that (-)-malic acid could be converted to (+)-malic acid by a series of chemical steps with achiral reagents
This established that optical rotation was directly related to chirality and that it changes with chemical alteration
Reaction of (-)-malic acid with PCl5 gives (+)-chlorosuccinic acid
Further reaction with wet silver oxide gives (+)-malic acid
The reaction series starting with (+) malic acid gives (-) acid

4. Reactions of the Walden Inversion

5. Significance of the Walden Inversion
The reactions alter the configuration at the chirality center
The reactions involve substitution at that center
Therefore, nucleophilic substitution can invert the configuration at a chirality center
The presence of carboxyl groups in malic acid led to some dispute as to the nature of the reactions in Walden’s cycle

6. 11.2 Stereochemistry of Nucleophilic Substitution
In the 1920’s and 1930’s Kenyon and Phillips carried out a series of experiments to find out how inversion occurs and determine the precise mechanism of nucleophilic substitution reactions.
Instead of halides they used tosylates (OTos) which are better “leaving groups” than halides.
(alkyl toluene sulfonates)

7. Only the second and fifth steps are reactions at carbon So inversion certainly occurs in these substitution steps

8. Problem 11.1
Write a stereochemical equation for this
nucleophilic substitution reaction:
(S)-2-bromohexane + CH3COO- 

9. 11.3 Kinetics of Nucleophilic Substitution
Rate is change in concentration with time
Depends on concentration(s), temperature, inherent nature of reaction (activation energy)
A rate law describes relationship between the concentration of reactants and rate of conversion to products – determined by experiment.
A rate constant (k) is the proportionality factor between concentration and rate
Example: for S  P
an experiment might find
Rate = k [S] (first order)

10. Reaction Kinetics Experiments show that for the reaction
The study of rates of reactions is called kinetics
Rates decrease as concentrations decrease but the rate constant does not
The rate law depends on the mechanism
The order of a reaction is sum of the exponents of the concentrations in the rate law – the example below is second order
Experiments show that for the reaction
OH- + CH3Br  CH3OH + Br-
Rate = k[OH-][CH3Br]

11. 11.4 The SN2 Reaction
One type of nucleophilic substitution reaction has the following characteristics:
Reaction occurs with inversion at reacting center
Follows second order reaction kinetics
rate = k [Nu:-][RX]
Nomenclature suggested by Hughes and Ingold in 1937:
S=substitution
N (subscript) = nucleophilic
2 = bimolecular - both nucleophile and substrate in rate determining step

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

15. 11.5 Characteristics of the SN2 Reaction
Sensitive to steric effects
Methyl halides are most reactive
Primary are next most reactive
Secondary might react
Tertiary are unreactive by this path
No reaction at C=C (vinyl halides)

16. Reactant and Transition-state Energy Levels
Higher reactant energy level (red curve) = faster reaction (smaller G‡).
Higher transition-state energy level (red curve) = slower reaction (larger G‡).

17. Steric Effects on SN2 Reactions
The carbon atom in (a) bromomethane is readily accessible
resulting in a fast SN2 reaction. The carbon atoms in (b) bromoethane (primary), (c) 2-bromopropane (secondary), and (d) 2-bromo-2-methylpropane (tertiary) are successively more hindered, resulting in successively slower SN2 reactions.

18. Steric Hindrance Raises Transition State Energy
Very hindered
Steric effects destabilize transition states
Severe steric effects can also destabilize ground state

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

20. The Nucleophile Neutral or negatively charged Lewis base
Reaction increases coordination at nucleophile
Neutral nucleophile acquires positive charge
Anionic nucleophile becomes neutral
See Table 11-1 for an illustrative list

22. 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

24. The Leaving Group
A good leaving group reduces the barrier to a reaction
Stable anions that are weak bases are usually excellent leaving groups and can delocalize charge

25. Poor Leaving Groups Problem 11.6 Rank in order of SN2 reactivity
If a group is very basic or very small, it is prevents reaction
Problem Rank in order of SN2 reactivity
CH3Br, CH3OTs, (CH3)3Cl, (CH3)2CHCl

26. The Solvent
Solvents that can donate hydrogen bonds (-OH or –NH) slow SN2 reactions by associating with reactants
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

27. Problem 11.7
Benzene, ether, chloroform are not protic
or very polar. How would they affect SN2
reactions?

31. 11.6 The SN1 Reaction
Previously we learned that tertiary alkyl halides
react extremely slowly in SN2 reactions. But tert-butyl bromide reacts with water 1,000,000 times faster than methyl bromide.
Tertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to addition of the nucleophile
Called an SN1 reaction – occurs in two distinct steps while SN2 occurs with both events in same step
If nucleophile is present in reasonable concentration (or it is the solvent), then ionization is the slowest step

33. SN1 Energy Diagram Step through highest energy point is rate-limiting
rate = k[RX]

34. 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 highest energy transition state point on the diagram is that for the rate determining step (which is not always the highest barrier)
This is the not the greatest difference but the absolute highest point (Figures – the same step is rate-determining in both directions)

35. Stereochemistry of SN1 Reaction
The planar intermediate should lead to loss of chirality
A free carbocation is achiral
Product should be racemic

36. SN1 in Reality
Carbocation is biased to react on side opposite leaving group
Suggests reaction occurs with carbocation loosely associated with leaving group during nucleophilic addition
Alternative that SN2 is also occurring is unlikely

37. Effects of Ion Pair Formation
If leaving group remains associated, then product has more inversion than retention
Product is only partially racemic with more inversion than retention
Associated carbocation and leaving group is an ion pair

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

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

41. 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

43. 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 excellent leaving group

45. Nucleophiles in SN1
Since nucleophilic addition occurs after formation of carbocation, reaction rate is not affected normally affected by nature or concentration of nucleophile

46. Solvent Is Critical in SN1
Stabilizing carbocation also stabilizes associated transition state and controls rate
Solvation of a carbocation by water

47. 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)
Nonpolar solvents have low P
Polar SOLVENT have high P values

49. Effects of Solvent on Energies
Polar solvent stabilizes transition state and intermediate more than reactant and product

52. 11.10 Alkyl Halides: Elimination
Elimination is an alternative pathway to substitution
Opposite of addition
Generates an alkene
Can compete with substitution and decrease yield, especially for SN1 processes

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

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

57. 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

58. E2 Reaction Kinetics One step – rate law has base and alkyl halide
Transition state bears no resemblance to reactant or product
Rate = k[R-X][B]
Reaction goes faster with stronger base, better leaving group

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

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

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

62. Practice problem 11.4 E2 rxn of
(1S,2S)-1,2-dibromo-1,2-diphenylethane

63. 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

64. Kinetic Isotope Effect
Substitute deuterium for hydrogen at  position
Effect on rate is kinetic isotope effect (kH/kD = deuterium isotope effect)
Rate is reduced in E2 reaction
Heavier isotope bond is slower to break
Shows C-H bond is broken in or before rate-limiting step

65. 11.14 The E1 Reaction Competes with SN1 and E2 at 3° centers
V = k [RX]

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

67. Comparing E1 and E2 Strong base is needed for E2 but not for E1
E2 is stereospecifc, E1 is not
E1 gives Zaitsev orientation

68. Homework problems for Chapter 11
21 – 23, 25 (SN2 only), 26, 27,
29 – 32, 36, 37, 39 – 41
OWL for Chapter 11 due Jan 22
Problems 24, 25, 28, 34, 35, 38, 39,
46, 47, 49, 50, 55, 59, 62, 65

69. 11.15 Summary of Reactivity: SN1, SN2, E1, E2
Alkyl halides undergo different reactions in competition, depending on the reacting molecule and the conditions
Based on patterns, we can predict likely outcomes (See Table 11.4)