1. 11. Reactions of Alkyl Halides: Nucleophilic Substitutions and Eliminations

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 Brønsted bases produce elimination d+
Acts as
Nucleophile d+
Acts as
Base

3. Why this Chapter?
Nucleophilic substitution, base induced elimination are among most widely occurring and versatile reaction types in organic chemistry
Reactions will be examined closely to see:
How they occur
What their characteristics are
How they can be used

4. 11.1 The Discovery of Nucleophilic Substitution Reactions: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

5. Reactions of the Walden Inversion
The reactions alter the array 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. Another Example: (+)-1-phenyl-2-propanol (-)-1-phenyl-2-propanol
Used Tosylate as an excellent leaving group

7. Kinetics of Nucleophilic Substitution
Rate (V) = change in concentration with time
Depends on concentration(s), temperature, inherent nature of reaction (barrier on energy surface)
A rate law describes relationship between the concentration of reactants and conversion to products
The rate law is a result of the mechanism
A rate constant (k) is the proportionality factor between concentration and rate
Kinetics = The study of rates of reactions
Rates ↓ as concentrations ↓ but k stays same
Rate units: [concentration]/time such as L/(mol x s)
The order of a reaction is sum of the exponents of the concentrations in the rate law

8. Rate is dependant on both Nucleophile & Substrate
11.2 The SN2 Reaction
Reaction is with inversion at reacting center
Follows second order reaction kinetics
Ingold nomenclature to describe characteristic step:
S=substitution; N (subscript) = nucleophilic; 2 = both nucleophile and substrate in characteristic step (bimolecular)
Rate is dependant on both Nucleophile & Substrate
Rate = k [CH3-Br] [HO-]

9. SN2 Process
The reaction involves a transition state in which both reactants are together

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

11. Reactant and Transition State Energy Levels Affect Rate
11.3 Characteristics of the SN2 Rxn
Reactant and Transition State Energy Levels Affect Rate
Higher reactant energy level (red curve) = faster reaction (smaller G‡).
Higher transition state energy level (red curve) = slower reaction (larger G‡).

12. The Substrate: Steric Effects on SN2 Reactions
SN2 Sensitive to steric effects
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.

13. The Substrate: Steric Effects : Order of Reactivity in SN2
SN2 Sensitive to steric effects
No reaction at C=C (vinyl or Aryl halides)

14. The Nucleophile: in SN2 Neutral or negatively charged Lewis base
Reaction increases coordination at nucleophile
Neutral nucleophile acquires positive charge
Anionic nucleophile becomes neutral d+ d+

15. The Nucleophile: Relative Reactivity in SN2
Nucleophiles
Depends on reaction and conditions
More basic nucleophiles react faster
Better nucleophiles are lower in a column of the periodic table
Anions(-) are usually more reactive than neutrals

16. The Nucleophile: Examples

17. The Leaving Group: in SN2
Stable anions that are weak bases are usually excellent leaving groups and can delocalize charge
very basic or very small grps are poor leaving groups .
Alkyl fluorides, alcohols, ethers, and amines do not typically undergo SN2 reactions.

18. The Leaving Group: in SN2
-OH needs to be turned into a good leaving group.
So can convert to a Cl Br
Tos
Which are excellent leaving groups.
(p-toluenesufonylchloride
p-TosCl)

19. The Leaving Group: in SN2
O of the epoxide can be turned into a good leaving group so epoxide can be opened with a weak nucleophile.
Addition of an acid (H+) will make epoxide C’s more electrophilic.
Cl- attacks less hindered site.
(If choice of epoxide C’s is 1o or 2o then major product is from attack at less hindered 1o
If choice of epoxide C’s is 1o vs 3o then major product is from attack at more + 3o) d+ d+

20. Caged nucleophiles can’t attack so well
The Solvent: in SN2
Solvents that can donate hydrogen bonds (protic) (-OH or –NH) slow SN2 reactions by associating with reactants
Energy is required to break interactions between reactant and solvent
Caged nucleophiles can’t attack so well

21. The Solvent: in SN2 Poor for SN2 Good for SN2
Protic solvents (with -OH or –NH) slow SN2 reactions by complexing with reactants
Polar aprotic solvents (no NH, OH, SH) form weaker interactions with substrate and permit fast SN2 reactions

22. 11.4 The SN1 Reaction
Tertiary alkyl halides react rapidly in protic solvents by a mechanism that involves departure of the leaving group prior to addition of the nucleophile

23. The reaction involves a planar carbocation intermediate
SN1 Reaction
The reaction involves a planar carbocation intermediate

24. SN1 Energy Diagram Rate = k [RX]
Called an SN1 reaction since rate is dependant only on substrate
SN1 occurs in two distinct steps while SN2 occurs with both events in same step
Rate = k [RX]
The slowest step (Rate-determining step) is formation of the carbocation intermediate

25. Stereochemistry of SN1 Reaction
The planar intermediate leads to loss of chirality since a free carbocation is achiral
Nucleophile can attack either face of planar carbocation
Product is racemic or has some inversion

26. Stereochemistry of SN1 Reaction
Carbocation is biased to react on side opposite leaving group
Suggests reaction occurs with carbocation loosely associated with leaving group (in an ion pair) during nucleophilic addition

27. Stereochemistry of SN1 Reaction: 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

28. Stereochemistry of SN1 Reaction: Example:

29. Learning Check:
The optically pure tosylate shown was heated in acetic acid to yield a product mixture. If complete inversion had occurred the optically pure acetate product would have [a]D=+53.6o However the product mix has [a]D =+5.3o. What percentage racemization and what percentage inversion has occurred?

30. Solution:
The optically pure tosylate shown was heated in acetic acid to yield a product mixture. If complete inversion had occurred the optically pure acetate product would have [a]D=+53.6o However the product mix has [a]D =+5.3o. What percentage racemization and what percentage inversion has occurred?
x 100 = 9.9 % inverted
+53.6
So: 90.1 % racemic

31. 11.5 Characteristics of the SN1 Rxn
Substrate: in SN1
Ability to form stable carbocation intermediate best
Tertiary alkyl halide is most reactive by this mechanism
Remember Hammond postulate,”Any factor that stabilizes a high-energy intermediate stabilizes transition state leading to that intermediate”

32. Substrate: in SN1 Allylic and Benzylic Halides
Allylic and benzylic intermediates stabilized by delocalization of charge

33. Learning Check:
Rank the following substances in order of their expected SN1 reactivity:

34. Solution:
Rank the following substances in order of their expected SN1 reactivity: 1 4 2 3

35. Leaving Group: in SN1 Critically dependent on leaving group
the larger halides ions are better leaving groups
H2O, formed when OH of an alcohol is protonated in acid
p-Toluensulfonate (TosO-) is excellent leaving group
A leaving group won’t leave unless it’s stable on its own.
(Weak conjugate bases of strong acids make great leaving groups).

36. Leaving Group: in SN1
H2O leaving group formed when OH of alcohol is protonated in acid
rds
Nucleophile attacks after rds

37. Nucleophiles: in SN1
SN1 Reaction rate is not normally affected by nature or concentration of nucleophile since nucleophilic addition occurs after formation of carbocation.
Once the carbocation is formed the rest is quick and easy regardless of nature of nucleophile.

38. The Solvent: in SN1
Solvents that stabilize the carbocation intermediate and also transition state and speeds rate
SN1 reactions go faster with polar protic solvents that cage the carbocation intermediate.

39. The Solvent: in SN1 Polar Solvents Promote Ionization
Polar, protic and unreactive Lewis base solvents facilitate R+ formation

40. Learning Check:
Predict whether the following reactions is more likely to be SN1 or SN2.

41. Solution:
Predict whether the following reactions is more likely to be SN1 or SN2.
2o benzylic; forms stable carbocations or can be attacked from behind
Good leaving group
SN1
Good nucleophile
Polar protic solvent
1o; easily attacked from behind; wouldn’t give stable carbocation
Good leaving group
SN2
Good nucleophile
Polar aprotic solvent

42. Learning Check:
Predict whether the following reactions is more likely to be SN1 or SN2.

43. Solution:
Predict whether the following reactions is more likely to be SN1 or SN2.
SN2
SN1
1o allylic; forms stable carbocations or can be attacked from behind
2o allylic; forms stable carbocations or can be attacked from behind
Good leaving group
Good leaving group after protonation with H+
Strong nucleophile
Weak nucleophile
Polar aprotic solvent
Would not stabilize a carbocation intermediate
Polar protic solvent
Stabilizes carbocation intermediate

44. 11.6 Biological Substitution Rxns
SN1 and SN2 reactions are common in biochemistry
Unlike in the laboratory, substrate in biological substitutions is often organodiphosphate rather than an alkyl halide

45. Biological Substitution: Examples
SN1
SN1 E1
Biosynthesis of Geraniol in Roses

46. Biological Substitution: Examples
SN2
Biosynthesis of Adrenaline

47. 11.7 Elimination Reactions: of Alkyl Halides
Opposite of addition
Generates an alkene
Can compete with substitution and decrease yield, especially for SN1 processes

48. Elimination Reactions: E1
Competes with SN1
Favored over SN1 when have poor Nu- that can still be a base

49. Elimination Reactions: E1 Example
Competes with SN1
Favored over SN1 when have poor Nu- that can still be a base
SN1 E1

50. Elimination Rxns: Zaitsev’s Rule
In the elimination of HX from an alkyl halide, the more highly substituted alkene product predominates

51. Elimination Reactions: E2
Competes with SN2
Favored over SN2 when have strong base and steric hinderance

52. 11.8 The E2 Reaction: Mechanism
Base grabs H that is anti-periplanar to leaving group
Transition state combines
leaving of X and transfer of H
Product alkene forms stereospecifically

53. The E2 Rxn: Deuterium Isotope Effect
In RDS Breaking of C-H bond is slower than breaking of C-D bond.

54. Elimination Rxns: E2 Stereochemistry
Overlap of the developing  orbital in the transition state requires anti-periplanar geometry so electrons can give back-side SN2 type attack.

55. Elimination Rxns: Predicting E2 Products
E2 is stereospecific
Meso-1,2-dibromo-1,2-diphenylethane with base gives cis 1,2-diphenyl
cis 1,2-diphenyl product

56. Elimination Rxns: Predicting E2 Products
E2 is stereospecific
RR or SS 1,2-dibromo-1,2-diphenylethane gives trans 1,2-diphenyl S S
Trans 1,2 diphenyl product

57. 11.9 The E2 Rxn: Cyclohexene Formation
Abstracted proton and leaving group should align trans-diaxial to be anti periplanar in approaching transition state
Equatorial groups are not in proper alignment

58. The E2 Rxn: Cyclohexene Formation Example
Fast
200 x’s slower since
Ring must flip to less stable ring conformation in order to get anti-periplanar E2

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

60. 11.10 The E1cB Reactions

61. E1cB Reaction
Takes place through a carbanion intermediate

62. 11.11 Biological Elimination Rxns
All three elimination reactions occur in biological pathways
E1cB very common
Typical example occurs during biosynthesis of fats when 3-hydroxybutyryl thioester is dehydrated to corresponding thioester
E1cB

63. 11.12 Summary of Reactivity: SN1, SN1, E1,E1cB, E2

64. Summary of Reactivity: SN1, SN1, E1,E1cB, E2
Strongly basic nucleophiles give more elimination as steric bulk increases.
Primary halides with strongly basic nucleophiles give mostly SN2 products.
Branched halides with strongly basic nucleophiles give about 50/50 SN2 and E2 products.
Tertiary halides with strongly basic nucleophiles give exclusive E2 products. With neutral or weakly basic nucleophiles SN1 and E1 pathways compete.

65. Summary of Reactivity: SN1, SN1, E1,E1cB, E2

66. Unimolecular Substitution in Polar Media -
Important Concepts
Unimolecular Substitution in Polar Media -
Secondary haloalkanes: slow
Tertiary haloalkanes: fast
When the solvent is the nucleophile, the process is called solvolysis.
Rate Determining Step in Unimolecular Substitution -
Dissociation of the C-X bond to form a carbocation intermediate.
Added strong nucleophile changes the product but not the reaction rate.
Carbocation Stabilization by Hyperconjugation: Tertiary > Secondary. Primary and methyl unstable.

67. Important Concepts
Racemization - Often occurs upon unimolecular substitution at a chiral carbon.
Unimolecular Elimination – Alkene formation accompanies substitution in secondary and tertiary system.
Bimolecular Elimination - May result from high concentrations of strong base. The elimination involves the anti conformational arrangement of the leaving group and the extracted hydrogen.
Substitution Favored - by unhindered substrates and small, less basic nucleophiles
Elimination Favored - by hindered substrates and bulky, more basic nucleophiles.

68. Which of the following is the product of the SN2 reaction between the hydroxide ion (HO–) and (R)-CH3–CHDI? D = 2H (deuterium) 1. 2. 3. 4. 5. 1 2 3 4 5

69. Consider the reaction of (S)-(–)-1-iodo-2-methylbutane to produce (+)-2-methyl-1-butanol. What is the absolute configuration of the product? R S
R and S (racemic mixture)
R and S (unequal amounts)
There is no chiral center in the product

70. Which of the following SN2 reactions is expected to have the highest rate?
methyl bromide with water in DMSO
ethyl bromide with chloride in methanol
ethyl bromide with hydroxide in HMPA
ethyl chloride with ammonia in acetonitrile
methyl bromide with hydrosulfide (HS–) in HMPA

71. It cannot be determined.
When A and B react in t-BuOH, the above rate expression is observed. What is the most likely mechanism of this reaction? E2
SN2 E1
SN1
It cannot be determined.

72. What is the main reason that polar aprotic solvents are favored over polar protic solvents for SN2 reactions?
Polar aprotic solvents dissolve nucleophiles more readily than polar protic solvents.
Polar aprotic solvents destabilize anions.
Polar aprotic solvents stabilize cations, including carbocations.
Polar aprotic solvents form stabilizing hydrogen bonds.
Polar aprotic solvents prevent rearrangements from occurring.

73. What statement about the SN2 reaction of methyl bromide with hydroxide is incorrect?
The reaction kinetics is first-order in hydroxide.
In the transition state the carbon is sp2 hybridized.
Absolute configuration is inverted from R to S.
The reaction is faster in HMPA than in water.
The reaction can be catalyzed by I–.

74. Select the substrate which would react fastest in the substitution reaction.1. 2. 3. 4. 5. 1 2 3 4 5

75. Which electrophile will react the fastest by the SN2 mechanism with cyanide (NC–) in DMF?
phenyl iodide (Ph–I)
vinyl tosylate (H2C=CH–OTos)
ethyl bromide
cyclohexyl bromide
benzyl tosylate (Ph-CH2-OTos)

76. Which of the following reagents is the best nucleophile for an SN2 reaction?
methanol
methoxide
acetate
hydroxide
water

77. Which set of reaction conditions represents the best way to carry out the following transformation?
AcOH
NaOAc in AcOH
NaOAc in H2O
NaOAc in DMSO
AcOH in HMPA

78. Which of the following will give the fastest SN1 reaction?1. 2. 3. 5. 4. 1 2 3 4 5

79. In a reaction between an alkyl halide and methoxide, doubling the alkyl halide concentration doubles the rate of the reaction. Which of the following is a reasonable conclusion?
The reaction is an SN2 process.
The reaction proceeds by the SN1 mechanism.
The observation indicates an E2 process.
This is a reaction with E1 mechanism.
None of these

80. Which compound would serve as the best starting material for the transformation shown below?1. 2. 3. 4. 5. 1 2 3 4 5

81. Including stereoisomers, how many products are possible from the following reaction?1 2 3 4 5

82. What mechanism is most likely to operate for the following reaction?
SN1
SN2 E1 E2
E1cB

83. Select the reagent and solvent combination which would result in the fastest rate of substitution (R = CH3 in all cases).
ROH, HMPA
RS–, H2O
RO–, H2O
RS–, DMSO
RSH, H2O

84. Which of the following is the best nucleophile?
(CH3)3N
(CH3)2P–
(CH3)2O
CH3O–

85. What is the major product of the following reaction?1. 2. 3. 4. 5. 1 2 3 4 5

86. What is the most likely product of the following reaction?2. 1. 3. 4. 5. 1 2 3 4 5

87. Which of the two stereoisomers of 4-t-butylcyclohexyl iodide (127I) will undergo SN2 substitution with 128I– faster, and why?
A will react faster because it is more stable
B will react faster because it gives a more stable product.
A will react faster because nucleophile’s approach from the bottom face of the molecule is easier for steric reasons.
A and B will react with the same rate because the transition states for both reactions are the same.
B will react faster because it is less stable than A, and the transition state for both reactions is of the same energy.