1. Chapter 8 Nucleophilic Substitution (in depth) & Competing Elimination
8.1 Functional Group Transformation By Nucleophilic Substitution 1

2. 8.1 Functional Group Transformation By Nucleophilic Substitution

3. 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 2

4. Nucleophilic Substitution
Substrate cannot be an a vinylic halide or an
aryl halide, except under certain conditions to
be discussed in Chapter 23. C X X 3

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

6. Ethyl isobutyl ether (66%)
Example
(CH3)2CHCH2ONa CH3CH2Br
Isobutyl alcohol
(CH3)2CHCH2OCH2CH NaBr
Ethyl isobutyl ether (66%) 5

7. 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

8. Ethyl octadecanoate (95%)
Example O
CH3(CH2)16C OK +
CH3CH2I
acetone, water + KI O
CH2CH3
CH3(CH2)16C
Ethyl octadecanoate (95%) 7

9. 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

10. Example KSH + CH3CH(CH2)6CH3 Br ethanol, water CH3CH(CH2)6CH3 + KBr SH
2-Nonanethiol (74%)
CH3CH(CH2)6CH3 SH 9

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

12. Cyclopentyl cyanide (70%) CN + NaBr
Example Br
NaCN +
DMSO
Cyclopentyl cyanide (70%) CN +
NaBr 11

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

14. Example NaN3 + CH3CH2CH2CH2CH2I 2-Propanol-water
CH3CH2CH2CH2CH2N NaI
Pentyl azide (52%) 13

15. Table 8.1 Examples of Nucleophilic Substitution
Iodide ion as the nucleophile – .. : I + R X
gives an alkyl iodide +
: X R – .. : I 4

16. Example + NaI CH3CHCH3 Br acetone 63% + NaBr CH3CHCH3 I
NaI is soluble in acetone; NaCl and NaBr are not soluble in acetone. 16

17. 8.2 Relative Reactivity of Halide Leaving Groups17

18. 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

19. 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

20. 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

21. 8.12 Improved Leaving Groups Alkyl Sulfonates

22. 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.

23. Alkyl methanesulfonate (mesylate) Alkyl p-toluenesulfonate (tosylate)
Other RX Compounds
ROSCH3 O
ROS O
CH3
Alkyl methanesulfonate (mesylate)
Alkyl p-toluenesulfonate (tosylate)
undergo same kinds of reactions as alkyl halides

24. 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)

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

26. The best leaving groups are weakly basic.

27. 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

28. 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.

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

30. 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

31. 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

32. 8.3 The SN2 Mechanism of Nucleophilic Substitution20

33. Kinetics
Many nucleophilic substitutions follow a second-order rate law CH3Br + HO –  CH3OH + Br –
rate = k[CH3Br][HO – ]
inference: rate-determining step is bimolecular 21

34. Bimolecular MechanismHO
CH3 Br

transition state
one step
HO –
CH3Br +
HOCH3
Br – 22

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

36. 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

37. 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

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

39. Problem 8.4
The Fischer projection formula for (+)-2-bromooctane is shown. Write the Fischer projection of the (–)-2-octanol formed from it by nucleophilic substitution with inversion of configuration. 29

40. Problem 8.4 H Br CH3 CH2(CH2)4CH3 HO H CH3 CH2(CH2)4CH3
The Fischer projection formula for (+)-2-bromooctane is shown. 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 29

41. 8.4 Steric Effects and SN2 Reaction Rates32

42. 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

43. Table 8.2 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

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

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

46. 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

47. Table 8.3 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

48. 8.5 Nucleophiles and Nucleophilicity1

49. The nucleophiles described in Sections 8.1-8.6 have been anions... HO : –
CH3O HS C N
etc.
Not all nucleophiles are anions. Many are neutral. ..
HOH
CH3OH
NH3 :
for example
All nucleophiles, however, are Lewis bases. 6

50. Nucleophiles
Many of the solvents in which nucleophilic substitutions are carried out are themselves nucleophiles. ..
CH3OH .. ..
HOH
for example 6

51. The term solvolysis refers to a nucleophilic
substitution in which the nucleophile is the solvent. 2

52. substitution by an anionic nucleophile
Solvolysis
substitution by an anionic nucleophile
R—X + :Nu—
R—Nu + :X— +
solvolysis
R—X + :Nu—H
R—Nu—H + :X—
step in which nucleophilic substitution occurs 2

53. substitution by an anionic nucleophile
Solvolysis
substitution by an anionic nucleophile
R—X + :Nu—
R—Nu + :X—
solvolysis +
R—X + :Nu—H
R—Nu—H + :X—
products of overall reaction
R—Nu + HX 2

54. 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

55. 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

56. Nucleophilicity is a measure of the reactivity of a nucleophile
Table 8.4 compares the relative rates of nucleophilic substitution of a variety of nucleophiles toward methyl iodide as the substrate. The standard of comparison is methanol, which is assigned a relative rate of 1.0. 2

57. 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

58. Major factors that control nucleophilicity
basicity
solvation
small negative ions are highly solvated in protic solvents
large negative ions are less solvated 10

59. 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

60. Major factors that control nucleophilicity
basicity
solvation
small negative ions are highly solvated in protic solvents
large negative ions are less solvated 10

61. Figure 8.3
Solvation of a chloride ion by ion-dipole attractive forces with water. The negatively charged chloride ion interacts with the positively polarized hydrogens of water. 10

62. Table 8.4 Nucleophilicity
Rank Nucleophile Relative rate
strong I- >105
good Br- 104
fair Cl-, F- 103
A tight solvent shell around an ion makes it less reactive. Larger ions are less solvated than smaller ones and are more nucleophilic. 9