1. Chapter 8 I. Nucleophilic Substitution (in depth) II
Chapter 8 I. Nucleophilic Substitution (in depth) II. Competion with Elimination 1

2. 24

3. Nucleophilic Substitution
Substrate is a sp3 hybridized carbon atom
(cannot be an a vinylic halide or an
aryl halide except under special conditions to
be discussed in Chem 227) C X X 3

4. 24

5. Kinetics
Many nucleophilic substitutions follow a second-order rate law CH3Br + HO – CH3OH + Br –
rate = k [CH3Br] [HO – ]
What is the reaction order of each starting material?
What can you infer on a molecular level?
What is the overall order of reaction? 21

6. Bimolecular mechanism
one step concerted
HO –
CH3Br +
HOCH3
Br – + 22

7. Bimolecular mechanism
one step concerted
HO –
CH3Br +
HOCH3
Br – + 22

8. Bimolecular mechanismHO
CH3 Br
d -
transition state
one step concerted
HO –
CH3Br +
HOCH3
Br – + 22

9. Stereochemistry of SN2 Reactions23

10. Generalization
Nucleophilic substitutions that exhibit second-order kinetic behavior are stereospecific and proceed with inversion of configuration. 24

11. Inversion of Configuration
nucleophile attacks carbon from side opposite bond to the leaving group 25

12. Inversion of Configuration
nucleophile attacks carbon from side opposite bond to the leaving group
three-dimensional arrangement of bonds in product is opposite to that of reactant 25

13. Inversion of configuration (Walden inversion) in an SN2
reaction is due to “back side attack”
P.Walden, Berichte, 29(1): (1896)
Riga Polytechnical College
Could there be another mechanism that provides the same results?

14. Roundabout SN2 Mechanism
Traditional SN2 Mechanism
Videos courtesy of William L. Hase, Texas Tech University

15. SN2 Reaction Mechanisms: Gas Phase (2008)
Traditional
Roundabout
Physicist Roland Wester and his team in Matthias Weidemüller's group at the University of Freiburg, in Germany, in collaboration with William L. Hase's group at Texas Tech University, provide direct evidence for this mechanism in the gas phase. However, they also detected an additional, unexpected mechanism. In this new pathway, called the roundabout mechanism, chloride bumps into the methyl group and spins the entire methyl iodide molecule 360° before chloride substitution occurs.
The team imaged SN2 reactions at different collision energies, which depend on the speed at which chloride smashes into methyl iodide. Data at lower collision energies support the traditional SN2 mechanism. However, at higher collision energies, about 10% of the iodide ions fell outside of the expected distribution. "We saw a group of iodide ions with a much slower velocity than the rest," says Wester. "Since energy is conserved, if iodide ions are slow, the energy has to be somewhere else."
On the basis of calculations performed by their colleagues at Texas Tech, the team concluded that the energy missing from the iodide transfers to the methyl chloride product in the form of rotational excitation, supporting the proposed roundabout mechanism.

16. J. Mikosch et al., Science 319, 183 -186 (2008)
Fig. 1. Calculated MP2(fc)/ECP/aug-cc-pVDZ Born-Oppenheimer potential energy along the reaction coordinate g = RC-I - RC-Cl for the SN2 reaction Cl- + CH3I and obtained stationary points
J. Mikosch et al., Science 319, (2008)
Published by AAAS

17. J. Mikosch et al., Science 319, 183 -186 (2008)
Fig. 2. (A to D) Center-of-mass images of the I- reaction product velocity from the reaction of Cl- with CH3I at four different relative collision energies
J. Mikosch et al., Science 319, (2008)
Published by AAAS

18. J. Mikosch et al., Science 319, 183 -186 (2008)
Fig. 3. View of a typical trajectory for the indirect roundabout reaction mechanism at 1.9 eV that proceeds via CH3 rotation
J. Mikosch et al., Science 319, (2008)
Published by AAAS

19. Stereospecific Reaction
A stereospecific reaction is one in which stereoisomeric starting materials give stereoisomeric products.
The reaction of 2-bromooctane with NaOH (in ethanol-water) is stereospecific.
(+)-2-Bromooctane (–)-2-Octanol
(–)-2-Bromooctane (+)-2-Octanol 24

20. Stereospecific ReactionH
CH3 Br
CH3(CH2)5 C H
CH3 HO
(CH2)5CH3
NaOH
(+)-2-Bromooctane
(–)-2-Octanol 25

21. A) R- & R- B) S- and S- C) R- & S- D) S- & R-
Question
(+)-2-Bromooctane
(–)-2-Octanol C H
CH3 Br
CH3(CH2)5 C H
CH3 HO
(CH2)5CH3
NaOH
The absolute configurations of (+)-2-bromooctane and (–)-2-octanol are respectively:
A) R- & R- B) S- and S- C) R- & S- D) S- & R- 25

22. A) R- & R- B) S- and S- C) R- & S- D) S- & R-
Answer
(+)-2-Bromooctane
(–)-2-Octanol C H
CH3 Br
CH3(CH2)5 C H
CH3 HO
(CH2)5CH3
NaOH
The absolute configurations of (+)-2-bromooctane and (–)-2-octanol are respectively:
A) R- & R- B) S- and S- C) R- & S- D) S- & R- 25

23. H Br CH3 CH2(CH2)4CH3 HO H CH3 CH2(CH2)4CH3 R-
1) Draw the Fischer projection formula for (+)-S-2-bromooctane.
2) Write the Fischer projection of the (–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration. H Br
CH3
CH2(CH2)4CH3 HO H
CH3
CH2(CH2)4CH3 R- 29

24. Question
True (A) / False (B)
A racemic mixture of (R- ) and (S- )-2-bromobutane produces an optically active product.

25. Answer
True (A) / False (B)
A racemic mixture of (R- ) and (S- )-2-bromobutane produces an optically active product.
Optically inactive starting materials produce optically inactive products. The products in this case are also racemic. Inversion occurs with both enantiomers.

26. A conceptual view of SN2 reactions30

27. Why does the nucleophile attack from the back side?

28. Steric Effects in SN2 Reactions32

29. Crowding at the Reaction Site
The rate of nucleophilic substitution by the SN2 mechanism is governed by steric effects.
Crowding at the carbon that bears the leaving group slows the rate of bimolecular nucleophilic substitution. 33

30. Reactivity toward substitution by the SN2 mechanism
RBr LiI RI LiBr
Alkyl Class Relative bromide rate
CH3Br Methyl 221,000
CH3CH2Br Primary 1,350
(CH3)2CHBr Secondary 1
(CH3)3CBr Tertiary too small to measure 33

31. A bulky substituent in the alkyl halide reduces the
reactivity of the alkyl halide: steric hindrance

32. Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr 34

33. Decreasing SN2 Reactivity
CH3Br
CH3CH2Br
(CH3)2CHBr
(CH3)3CBr 34

34. Reaction coordinate diagrams for (a) the SN2 reaction of
methyl bromide and (b) an SN2 reaction of a sterically
hindered alkyl bromide

35. Question
Which chloride will react faster with NaI in acetone?
A) B)
C) D)

36. Answer
Which chloride will react faster with NaI in acetone?
A) B)
C) D)

37. Crowding Adjacent to the Reaction Site
The rate of nucleophilic substitution by the SN2 mechanism is governed by steric effects.
Crowding at the carbon adjacent to the one that bears the leaving group also slows the rate of bimolecular nucleophilic substitution, but the effect is smaller. 33

38. Effect of chain branching on rate of SN2 substitution
RBr LiI RI LiBr
Alkyl Structure Relative bromide rate
Ethyl CH3CH2Br 1.0
Propyl CH3CH2CH2Br 0.8
Isobutyl (CH3)2CHCH2Br 0.036
Neopentyl (CH3)3CCH2Br 35

39. Question
Which alkyl chloride will react faster with NaI in acetone?
A) B)
C) D)

40. Answer
Which alkyl chloride will react faster with NaI in acetone?
A) B)
C) D)

41. 8.1 Functional Group Transformation By Nucleophilic Substitution

42. Nucleophilic Substitution
Y : –
: X – + + R X Y R
nucleophile is a Lewis base (electron-pair donor)
often negatively charged and used as Na+ or K+ salt
substrate is usually an alkyl halide, (most often 1o) 2

43. But, all nucleophiles (neutral electron rich molecules)
The nucleophiles described in Sections are anions. .. HO : –
CH3O HS C N N3 –
But, all nucleophiles (neutral electron rich molecules)
are Lewis bases. ..
HOH
CH3OH
NH3 : 6

44. Table 8.1 Examples of Nucleophilic Substitution
Alkoxide ion as the nucleophile .. O: R' – + R X
gives an ether +
: X R .. O R' – 4

45. Table 8.1 Examples of Nucleophilic Substitution
Carboxylate ion as the nucleophile O .. –
R'C O: + R X ..
gives an ester +
: X R .. O
R'C – 4

46. Table 8.1 Examples of Nucleophilic Substitution
Hydrogen sulfide ion as the nucleophile .. S: H – + R X
gives a thiol +
: X R .. S H – 4

47. Question
Select the major organic product when (S)-2-propanol is reacted with SOCl2 in pyridine
followed by the addition of NaSH in ethanol.
A) B)
C) D)

48. Answer
Select the major organic product when (S)-2-propanol is reacted with SOCl2 in pyridine
followed by the addition of NaSH in ethanol.
A) B)
C) D)

49. Question
The best combination of reactants for preparing (CH3)3CSCH3 is:
A) (CH3)3CCl + CH3SK
B) (CH3)3CBr + CH3SNa
C) (CH3)3CSK + CH3OH
D) (CH3)3CSNa + CH3Br

50. Answer
The best combination of reactants for preparing (CH3)3CSCH3 is:
A) (CH3)3CCl + CH3SK
B) (CH3)3CBr + CH3SNa
C) (CH3)3CSK + CH3OH
D) (CH3)3CSNa + CH3Br

51. Table 8.1 Examples of Nucleophilic Substitution
Cyanide ion as the nucleophile – C N : + R X
gives a nitrile +
: X R – C N : 4

52. Table 8.1 Examples of Nucleophilic Substitution
Azide ion as the nucleophile .. – N : + R X ..
gives an alkyl azide +
: X R – N : 4

53. 8.2 Relative Reactivity of Halide Leaving Groups17

54. RI most reactive RBr RCl RF least reactive Generalization
Reactivity of halide leaving groups in nucleophilic substitution is the same as for elimination. RI
RBr
RCl RF
most reactive
least reactive 18

55. Br is a better leaving group than Cl
Problem 8.2
A single organic product was obtained when 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product?
BrCH2CH2CH2Cl + NaCN
Br is a better leaving group than Cl 19

56. Problem 8.2
A single organic product was obtained when 1-bromo-3-chloropropane was allowed to react with one molar equivalent of sodium cyanide in aqueous ethanol. What was this product?
BrCH2CH2CH2Cl + NaCN
CH2CH2CH2Cl + NaBr C N : 19

57. Question
What is the major product of the reaction of the dihalide at the right with 1 equivalent of
NaSH in dimethyl sulfoxide?
A) B)
C) D)

58. Question 8
What is the major product of the reaction of the dihalide at the right with 1 equivalent of
NaSH in dimethyl sulfoxide?
A) B)
C) D)

59. 8.12 Improved Leaving Groups Alkyl Sulfonates

60. Leaving Groups
We have seen numerous examples of nucleophilic substitution in which X in RX is a halogen.
Halogen is not the only possible leaving group, though.

61. Alkyl methanesulfonate (mesylate)
Other RX Compounds
ROSCH3 O
ROS O
CH3
Alkyl methanesulfonate (mesylate)
(triflate = -CF3 )
Alkyl p-toluenesulfonate (tosylate)
Behave in the same way as alkyl halides

62. Preparation
Tosylates are prepared by the reaction of alcohols with p-toluenesulfonyl chloride (usually in the presence of pyridine).
ROH +
CH3
SO2Cl
pyridine
ROS O
CH3
(abbreviated as ROTs)

63. Tosylates Undergo Typical Nucleophilic Substitution Reactions
KCN H
CH2OTs H
CH2CN
(86%)
ethanol- water

64. The best leaving groups are weakly basic.

65. Table 8.8 Approximate Relative Reactivity of Leaving Groups
Leaving Relative Conjugate acid pKa of Group Rate of leaving group conj. acid
F– HF 3.5
Cl– 1 HCl -7
Br– 10 HBr -9
I– HI -10
H2O H3O
TsO– TsOH CF3SO2O– CF3SO2OH -6

66. Table 8.8 Approximate Relative Reactivity of Leaving Groups
Leaving Relative Conjugate acid pKa of Group Rate of leaving group conj. acid
F– HF 3.5
Cl– 1 HCl -7
Br– 10 HBr -9
I– HI -10
H2O H3O
TsO– TsOH CF3SO2O– CF3SO2OH -6
Sulfonate esters are extremely good leaving groups; sulfonate ions are very weak bases.

67. Tosylates can be Converted to Alkyl Halides
NaBr
OTs
CH3CHCH2CH3 Br
CH3CHCH2CH3
DMSO
(82%)
Tosylate is a better leaving group than bromide.

68. Tosylates Allow Control of Stereochemistry
Preparation of tosylate does not affect any of the bonds to the chirality center, so configuration and optical purity of tosylate is the same as the alcohol from which it was formed. C H
H3C OH
CH3(CH2)5 C H
H3C
OTs
CH3(CH2)5
TsCl
pyridine

69. Tosylates Allow Control of Stereochemistry
Having a tosylate of known optical purity and absolute configuration then allows the preparation of other compounds of known configuration by SN2 processes. C H
CH3
(CH2)5CH3 Nu
Nu–
SN2 C H
H3C
OTs
CH3(CH2)5

70. Nucleophiles and Nucleophilicity1

71. Table 8.4 Nucleophilicity
Rank Nucleophile Relative rate
strong I-, HS-, RS- >105
good Br-, HO-, 104
RO-, CN-, N3-
fair NH3, Cl-, F-, RCO2- 103
weak H2O, ROH 1
very weak RCO2H 10-2 5

72. Table 8.4 Nucleophilicity
Rank Nucleophile Relative rate
good HO–, RO– 104
fair RCO2– 103
weak H2O, ROH 1
When the attacking atom is the same (oxygen in this case), nucleophilicity increases with increasing basicity. 7

73. Nucleophiles and Nucleophilicity SN1 vs. SN2

74. Nucleophiles
Many of the protic solvents in which nucleophilic substitutions can be carried out are themselves nucleophiles. ..
CH3OH and EtOH .. ..
HOH
for example 6

75. The term solvolysis refers to a nucleophilic
substitution in which the nucleophile is the solvent.
SN2 Reactions are favored in Polar Aprotic Non-nucleophilic Solvents
An aprotic solvent is one that does not have an —OH group.
SN1 Reactions are favored in Polar Protic Solvents 2

76. Substitution by an anionic nucleophile: SN2 kinetics
Solvolysis
Substitution by an anionic nucleophile: SN2 kinetics
R—X + :Nu—
R—Nu + :X— +
Solvolysis: SN1 kinetics
R—X + :Nu—H
R—Nu—H + :X—
Carbocation intemediate
2nd intermediate 2

77. Solvolysis (protic solvents) : SN1 kinetics
Substitution by an anionic nucleophile in an aprotic non-nucleophilic solvent SN2 kinetics
R—X + :Nu—
R—Nu + :X—
Solvolysis (protic solvents) : SN1 kinetics +
R—X + :Nu—H
R—Nu—H + :X—
products of overall reaction
R—Nu + HX 2

78. Example: Methanolysis
Methanolysis is a nucleophilic substitution in which methanol acts as both the solvent and the nucleophile. H O
CH3 : H O
CH3 : R +
–H+
The product is a methyl ether. O :
CH3 R ..
R—X + 3

79. Some typical solvents in solvolysis
solvent product from RX
water (HOH) ROH
methanol (CH3OH) ROCH3
ethanol (CH3CH2OH) ROCH2CH3
formic acid (HCOH)
acetic acid (CH3COH) O O
ROCH O O
ROCCH3 4

80. Question
Which of the following is not a good nucleophile in an SN1 solvolysis reaction?
A) NaOCH3
B) CH3OH
C) CH3CH2OH
D) H2O

81. Answer
Which of the following is not a good nucleophile in an SN1 solvolysis reaction?
A) NaOCH3
B) CH3OH
C) CH3CH2OH
D) H2O