1. Chapter 8: Nucleophilic Substitution
Chem 331, Chapter 8
Chapter 8: Nucleophilic Substitution
The SN2 Reaction

2. Nucleophilic Substitution Functional group transformation
Leaving groups
Two mechanisms
SN2 Mechanism
Kinetics
Stereochemistry
Mechanism
Steric effects
Nucleophiles and nucleophilicity
SN1 Mechanism
Carbocation stability
Solvent effects
Substitution vs Elimination
Substitutions of Alcohols
Sulfonate esters
Reaction with HX
Chem 331, Chapter 8

3. I. Nucleophilic Substitution
Chem 331, Chapter 8
I. Nucleophilic Substitution
substitution
reaction

4. I. Nucleophilic Substitution
Chem 331, Chapter 8
I. Nucleophilic Substitution
A. Functional group transformation

5. I. Nucleophilic Substitution
Chem 331, Chapter 8
I. Nucleophilic Substitution
B. Leaving groups
weaker base = better leaving group
reactivity: R-I > R-Br > R-Cl >> R-F
best L.G.
most reactive
worst L.G.
least reactive
precipitate
drives rxn
(Le Châtelier)

6. I. Nucleophilic Substitution
Chem 331, Chapter 8
I. Nucleophilic Substitution
C. Two mechanisms
general: Rate = k1[RX] + k2[RX][Y–]
k1 increases
RX = CH3X 1º 2º 3º
k2 increases
k1 ~ 0
Rate = k2[RX][Y–]
(bimolecular)
SN2
k2 ~ 0
Rate = k1[RX]
(unimolecular)
SN1

7. II. SN2 Mechanism A. Kinetics e.g., CH3I + OH–  CH3OH + I–
Chem 331, Chapter 8
II. SN2 Mechanism
A. Kinetics
e.g., CH3I + OH–  CH3OH + I–
find: Rate = k[CH3I][OH–], i.e., bimolecular
 both CH3I and OH– involved in RLS
and recall, reactivity: R-I > R-Br > R-Cl >> R-F
 C-X bond breaking involved in RLS
 concerted, single-step mechanism:
[HO---CH3---I]–
CH3I + OH–
CH3OH + I–

8. II. SN2 Mechanism B. Stereochemistry: inversion of configuration
Chem 331, Chapter 8
II. SN2 Mechanism
B. Stereochemistry: inversion of configuration
Stereospecific reaction:
(R)-(–)-2-bromooctane
(S)-(+)-2-octanol
Reaction proceeds with
inversion of configuration.

9. II. SN2 Mechanism C. Mechanism Back-side attack:
Chem 331, Chapter 8
II. SN2 Mechanism
C. Mechanism
Back-side attack:
inversion of configuration
sp3
sp2
high energy TS
sp3

10. II. SN2 Mechanism D. Steric effects e.g., R–Br + I–  R–I + Br–
Chem 331, Chapter 8
II. SN2 Mechanism
D. Steric effects
e.g., R–Br + I–  R–I + Br–
1. branching at the a carbon ( X–C–C–C.... )
a b g
Compound Rel. Rate
methyl CH3Br 150
1º RX CH3CH2Br 1
2º RX (CH3)2CHBr 0.008
3º RX (CH3)3CBr ~0
increasing
steric hindrance

11. II. SN2 Mechanism D. Steric effects 1. branching at the a carbon
Chem 331, Chapter 8
II. SN2 Mechanism
D. Steric effects
1. branching at the a carbon
minimal steric hindrance -
methyl bromide
maximum steric hindrance –
tert-butyl bromide

12. II. SN2 Mechanism D. Steric effects 1. branching at the a carbon
Chem 331, Chapter 8
II. SN2 Mechanism
D. Steric effects
1. branching at the a carbon
Reactivity toward SN2:
CH3X > 1º RX > 2º RX >> 3º RX
react
readily
by SN2
(k2 large)
more
difficult
does not
react by
SN2
(k2 ~ 0)

13. II. SN2 Mechanism D. Steric effects 2. branching at the b carbon
Chem 331, Chapter 8
II. SN2 Mechanism
D. Steric effects
2. branching at the b carbon
Rel. Rate 1
0.003
increasing
steric
hindrance
~ no SN2 with neopentyl substrates

14. II. SN2 Mechanism E. Nucleophiles and nucleophilicity anions
Chem 331, Chapter 8
II. SN2 Mechanism
E. Nucleophiles and nucleophilicity
anions
neutral species
solvolysis
reactions
hydrolysis
alcoholysis

15. II. SN2 Mechanism E. Nucleophiles and nucleophilicity nucleophilicity
Chem 331, Chapter 8
II. SN2 Mechanism
E. Nucleophiles and nucleophilicity
nucleophilicity
charged species are more nucleophilic than neutral species
when nucleophilic atoms are in the same row, nucleophilicity follows basicity
when nucleophilic atoms are in the same column, nucleophilicity follows ionic radius (polarizability)
HO– > H2O
RO– > ROH
HS– > H2S
H2N– > HO– > F–
H3N > H2O
RO– > RCO2–
I– > Br– > Cl– > F–
HS– > HO–
PH3 > NH3

16. II. SN2 Mechanism E. Nucleophiles and nucleophilicity Summary:
Chem 331, Chapter 8
II. SN2 Mechanism
E. Nucleophiles and nucleophilicity
Summary:
very good Nu: I–, HS–, RS–, H2N–
good Nu: Br–, HO–, RO–, CN–, N3–
fair Nu: NH3, Cl–, F–, RCO2–
poor Nu: H2O, ROH
very poor Nu: RCO2H

17. Chem 331, Chapter 8
II. SN2 Mechanism
Which reaction will proceed faster in each of the following pairs?
What will be the product?

18. III. SN1 Mechanism A. Kinetics e.g., 3º, no SN2
Chem 331, Chapter 8
III. SN1 Mechanism
A. Kinetics
e.g.,
3º, no SN2
Find: Rate = k[(CH3)3CBr] unimolecular
 RLS depends only on (CH3)3CBr

19. Chem 331, Chapter 8
III. SN1 Mechanism
A. Kinetics

20. III. SN1 Mechanism A. Kinetics Two-step mechanism: R+ RBr + CH3OH
Chem 331, Chapter 8
III. SN1 Mechanism
A. Kinetics
Two-step mechanism: R+
RBr + CH3OH
ROCH3 + HBr

21. III. SN1 Mechanism B. Stereochemistry: stereorandom
Chem 331, Chapter 8
III. SN1 Mechanism
B. Stereochemistry: stereorandom

22. III. SN1 Mechanism C. Carbocation stability
Chem 331, Chapter 8
III. SN1 Mechanism
C. Carbocation stability
R+ stability: 3º > 2º >> 1º > CH3+
R-X reactivity toward SN1: 3º > 2º >> 1º > CH3X
CH3+
1º R+
2º R+
3º R+

23. III. SN1 Mechanism C. Carbocation stability Rearrangements possible:
Chem 331, Chapter 8
III. SN1 Mechanism
C. Carbocation stability
Rearrangements possible:

24. Chem 331, Chapter 8
III. SN1 Mechanism
Which of the following compounds will react fastest by SN1? Which by SN2?

25. IV. SN1 vs SN2 A. Solvent effects nonpolar: hexane, benzene
Chem 331, Chapter 8
IV. SN1 vs SN2
A. Solvent effects
nonpolar: hexane, benzene
moderately polar: ether, acetone, ethyl acetate
polar protic: H2O, ROH, RCO2H
polar aprotic: DMSO DMF acetonitrile
SN1 mechanism promoted by polar protic solvents
stabilize R+, X– relative to RX
in less polar solvents
in more polar solvents
R+X– RX

26. them more nucleophilic
Chem 331, Chapter 8
IV. SN1 vs SN2
A. Solvent effects
SN2 mechanism promoted by moderately polar & polar aprotic solvents
destabilize Nu–, make
them more nucleophilic
e.g., OH– in H2O: strong H-bonding to water makes OH– less reactive
OH– in DMSO: weaker solvation makes OH– more reactive (nucleophilic)
in DMSO
in H2O
RX + OH–
ROH + X–

27. IV. SN1 vs SN2 RX = CH3X 1º 2º 3º B. Summary
Chem 331, Chapter 8
IV. SN1 vs SN2
Rate = k1[RX] + k2[RX][Nu]
B. Summary
rate of SN1 increases (carbocation stability)
RX = CH3X 1º 2º 3º
rate of SN2 increases (steric hindrance)
react
primarily
by SN2
(k1 ~ 0, k2 large)
may go
by either
mechanism
reacts
primarily
by SN1
(k2 ~ 0, k1 large)
SN2 promoted good nucleophile (Rate = k2[RX][Nu])
-usually in polar aprotic solvent
SN1 occurs in absence of good nucleophile (Rate = k1[RX])
-usually in polar protic solvent (solvolysis)

28. Chem 331, Chapter 8
IV. SN1 vs SN2
What would be the predominant mechanism in each of the following reactions?
What would be the product?

29. V. Substitution vs Elimination
Chem 331, Chapter 8
V. Substitution vs Elimination
A. Unimolecular or bimolecular reaction?
(SN1, E1)
(SN2, E2)
Rate = k1[RX] + k2[RX][Nu or B]
this term gets larger as [Nu or B] increases
 bimolecular reaction (SN2, E2) favored by high concentration of good Nu or strong B
this term is zero when [Nu or B] is zero
 unimolecular reaction (SN1, E1) occurs in absence of good Nu or strong B

30. V. Substitution vs Elimination
Chem 331, Chapter 8
V. Substitution vs Elimination
B. Bimolecular: SN2 or E2?
Rate = kSN2[RX][Nu] + kE2[RX][B]
1. substrate structure: steric hindrance
decreases rate of SN2, has no effect on rate of E2
 E2 predominates
steric
hindrance
increases
sterically hindered nucleophile

31. V. Substitution vs Elimination
Chem 331, Chapter 8
V. Substitution vs Elimination
B. Bimolecular: SN2 or E2?
2. base vs nucleophile
stronger base favors E2
better nucleophile favors SN2
good Nu
weak B
good Nu
strong B
poor Nu
strong B

32. V. Substitution vs Elimination
Chem 331, Chapter 8
V. Substitution vs Elimination
C. Unimolecular: SN1 or E1?
for both, Rate = k[R+][H2O]
 no control over ratio of SN1 and E1

33. V. Substitution vs Elimination
Chem 331, Chapter 8
V. Substitution vs Elimination
D. Summary
1. bimolecular: SN2 & E2
Favored by high concentration of good Nu or strong B
good Nu, weak B: I–, Br–, HS–, RS–, NH3, PH3 favor SN2
good Nu, strong B: HO–, RO–, H2N– SN2 & E2
poor Nu, strong B: tBuO– (sterically hindered) favors E2
Substrate:
1º RX mostly SN2 (except with tBuO–)
2º RX both SN2 and E2
3º RX E2 only
b-branching
hinders SN2

34. V. Substitution vs Elimination
Chem 331, Chapter 8
V. Substitution vs Elimination
D. Summary
2. unimolecular: SN1 & E1
Occurs in absence of good Nu or strong B
poor Nu, weak B: H2O, ROH, RCO2H
Substrate:
1º RX SN1 and E1 (only with rearrangement)
2º RX
3º RX
can’t control
ratio of
SN1 to E1
SN1 and E1 (may rearrange)

35. V. Substitution vs Elimination
Chem 331, Chapter 8
V. Substitution vs Elimination

36. VI. Substitution of Alcohols
Chem 331, Chapter 8
VI. Substitution of Alcohols
Can’t substitute directly:
R–OH + Y–  R–Y + OH–
strong base,
very poor leaving group
when Y– is a
stronger base
than OH–
R–O– + HY

37. VI. Substitution of Alcohols
Chem 331, Chapter 8
VI. Substitution of Alcohols
A. Review: reactions of ROH with HX
R–OH + HX  R–X + H2O
1º ROH: SN2
3º ROH: SN1

38. VI. Substitution of Alcohols
Chem 331, Chapter 8
VI. Substitution of Alcohols
A. Review: reactions of ROH with HX
2º ROH: mixture of SN1 and SN2
26% racemization (SN1) 74% inversion (SN2)
Rearrangements possible:

39. VI. Substitution of Alcohols
Chem 331, Chapter 8
VI. Substitution of Alcohols
B. Substitution via sulfonate esters
Scheme:

40. VI. Substitution of Alcohols
Chem 331, Chapter 8
VI. Substitution of Alcohols
B. Substitution via sulfonate esters

41. VI. Substitution of Alcohols
Chem 331, Chapter 8
VI. Substitution of Alcohols
B. Substitution via sulfonate esters
e.g.,
Formation of sulfonate esters occurs with retention of configuration:

42. VI. Substitution of Alcohols
Chem 331, Chapter 8
VI. Substitution of Alcohols
C. Other inorganic esters

43. VI. Substitution of Alcohols
Chem 331, Chapter 8
VI. Substitution of Alcohols
C. Other inorganic esters