Chapter 5
Nucleophilic Substitution
1
2
1
3
5.1 Substitution by the Ionization (SN1) Mechanism
4
Advanced Organic Chemistry (Chapter 5)
2
Fig. 4.2. Solid line: polar solvent; dashed line: nonpolar solvent. (a) Solvent
effects on R–X → R+ + X−. Polar solvents increase the rate by stabilization of
the Rδ+ - - -Xδ− transition state.
(b)Solvent effect on R–X+→R+ + X. Polar solvents decrease the rate because
stabilization of R--δ+ --X transition state is less than for the more polar
reactant.
5
5.2 Substitution by the Direct (SN2) Mechanism
RX
+
rate  
Y
-
k
RY
+
X
-
d [ RX ]
d [Y  ]

 k[ RX ][Y  ]
dt
dt
6
Advanced Organic Chemistry (Chapter 5)
3
7
MO Description
Y
C
X
LUMO
C
Y
Y
C
X
HOMO
X
Y
p- orbitals which interact
in SN2 T.S.
C
X
MO resulting at SN2 T.S.
Fig. 5.3: MO description of the T.S. for an SN2 displacement at carbon.
8
Advanced Organic Chemistry (Chapter 5)
4
5.3 Detailed Mechanistic Description and Borderline
Mechanisms
Winstein: Concept of ion pairs
R
X
ionization
R+X
intimate
ion pair
R+
X
dissociation
solvent separated
ion pair
R+
+
X
-
dissociated
ions
The process of ionization initially generates a carbocation and counterion in
immediate proximity to one another. This species, called a contact ion pair (or
intimate ion pair), can proceed to a solvent-separated ion pair in which one or more
solvent molecules are inserted between the carbocation and leaving group, but in
which the ions are kept together by the electrostatic attraction. The “free
carbocation,” characterized by symmetrical solvation, is formed by diffusion from the
anion, a process known as dissociation.
9
Advanced Organic Chemistry (Chapter 5)
Attacking the Nuclephile or Solvent:
Intimate Ion Pair
Solvent Separated Ion Pairs
Dissociated Ions
Inversion of Configuration
Partial Racemization
Racemization
10
5
Intimated and Solvent Ion Pairs:
80% acetone and water
18
O
Cl
O
CHOCC6H4NO2
keq
Cl
CHO18CC6H4NO2
Dissociated Ions:
O
Cl
O
CHOCC6H4NO2
optically active
krac
Cl
CHOCC6H4NO2
racemic
At 100 0C, kex/krac = 2.3
Slide 9
11
Advanced Organic Chemistry (Chapter 5)
Addition of nuclephile to the system (0.14 M NaN3):
keq: Unchanged
krac: No Racemization
When a better nucleophile is added to the system (014M NaN3), kex is found to be
unchanged, but no racemization of reactant is observed. Instead, the intermediate that
can racemize is captured by azide ion and converted to substitution product with
inversion of configuration.
Slide 8
12
Advanced Organic Chemistry (Chapter 5)
6
Isotope Labeling: Bond breaking without net substitution
O*
(CH3)2CH O S Ph
CF3COOH
k = 36 x 10-4
(CH3)2CHO2CCF3
O*
k = 8 x 10-4
O
O* = O18
(CH3)2CH O* S Ph
O*
Ion pair formation and recombination is occurring
competitively with ion pair formation and substitution.
13
Advanced Organic Chemistry (Chapter 5)
A study of the exchange reaction of benzyl tosylates during solvolysis in several
solvents showed that with electron-releasing group (ERG) substituents, e.g.,
p-methylbenzyl tosylate, the degree of exchange is quite high, implying reversible
formation of a primary benzyl carbocation. For an electron-withdrawing group
(EWG), such as m-Cl, the amount of exchange was negligible, indicating that
reaction occurred only by displacement involving the solvent. When an EWG is
present, the carbocation is too unstable to be formed by ionization. This study also
demonstrated that there was no exchange with added “external” tosylate anion,
proving that isotopic exchange occurred only at the ion pair stage.
14
7
Demonstrating the ion pair return
The ion pair return phenomenon can also be demonstrated by comparing the
rate of racemization of reactant with the rate of product formation. For a
number of systems, including l-arylethyl tosylates, the rate of decrease of
optical rotation is greater than the rate of product formation, which indicates
the existence of an intermediate that can re-form racemic reactant. The
solvent-separated ion pair is the most likely intermediate to play this role.
15
Advanced Organic Chemistry (Chapter 5)
Racemization, however, does not always accompany isotopic scrambling.
16
8
The energy barriers separating the contact, solvent-separated, and dissociated ions are
thought to be quite small. The reaction energy profile in Figure 4.4 depicts the three
ion pair species as being roughly equivalent in energy and separated by small barriers.
17
The gradation from SN1 to SN2 mechanisms can be summarized in terms of the shape
of the potential energy diagrams for the reactions, as illustrated in Figure 4.5. Curves
A and C represent the SN1 and SN2 limiting mechanisms. The gradation from the SN1
to the SN 2 mechanism involves greater and greater nucleophilic participation by the
solvent or nucleophile at the transition state. An ion pair with strong nucleophilic
participation represents a mechanistic variation between the SN 1 and SN 2 processes.
This mechanism is represented by curve B and designated SN2(intermediate). It
pictures a carbocation-like TS, but one that nevertheless requires back-side
nucleophilic participation and therefore exhibits second-order kinetics.
18
9
Fig. 4.5. Reaction energy profiles for substitution mechanisms. A is the SN 1
mechanism. B is the SN 2 mechanism with an intermediate ion pair or
19
pentacoordinate species. C is the classical SN 2 mechanism.
20
10
The reaction of azide ion with substituted 1-phenylethyl chlorides is an
example of a coupled displacement. Although it exhibits second-order
kinetics, the reaction has a substantially positive ρ value, indicative of an
electron deficiency at the TS. The physical description of this type of
activated complex is called the “exploded” SN 2 TS.
Reactant structure also influences the degree of nucleophilic solvent participation.
Solvation is minimized by steric hindrance and the 2-adamantyl system is
regarded as being a secondary reactant that cannot accommodate significant backside nucleophilic participation.
21
Robbins: Ion pairs might not only be involved in SN1
and borderline processes but also in
displacement exhibiting the stereochemical
and kinetic characteristic of the SN2 process.
R
R +X -
X
SOR
R+
NuR
ROS + SOR
X-
R+
NuR
X-
+
ROS + SOR
RNu + NuR
Nu Attack
Solvent Attack
R+X-
Inversion
Inversion
R+ ║ X-
Inversion
Retention or Inversion
Racemization
Racemization
R+ + X-
22
Advanced Organic Chemistry (Chapter 5)
11
Structure and Reactions of Carbocation Intermediates
Structure and Stability of Carbocations
(CH3)3CCl
(CH3)3C + Cl
G°gas phase=153 kcal/mol
Ionization in solvent is feasible because of solvation.
Evidences: 1) Liquid SO2 solution of Ph3CCl is conducting.
2) Ph3CClO4 has ionic behavior.
HH
C
H
H
H
H
23
Advanced Organic Chemistry (Chapter 5)
Relative Stability
R+
+
ROH + H+
H2O
pK R 
[R  ]
 log
 HR
[ ROH]
HR: Acidity function of the medium
For dilute solutions:
HR = pH
24
Advanced Organic Chemistry (Chapter 5)
12
25
Hydride Affinity
R+
+
H-
R-H
o
H = Hydride Affinity
26
Advanced Organic Chemistry (Chapter 5)
13
Stability Order of Carbocations Based on Solvolysis Rate:
3° > 2° > 1° > CH3+
Stabilization of Carbocations:
27
28
14
CH3 O CH2
CH3 O CH2
(H3C)2N CH2
(H3C)2N CH2
H3C
CH3
O
H
O
H
H
H
(A)
G# = 14 kcal/mol (NMR)
29
Advanced Organic Chemistry (Chapter 5)
The destabilizing effects of CYANO and FORMYL groups are
less than MO methods predicted values.
C
C N
C
C N
C
C O
H
C
C O
30
H
15
Cyclopropyl Cation:
tri-Cyclopropyl methyl Cation > tri-phenyl methyl cation
H
CH3
CH3
H
CH3
CH3
H
CH3
CH3
H
CH3
CH3
perpendicular
conformation
bisect conformation
31
Advanced Organic Chemistry (Chapter 5)
CH3
CH3
OTs
Relative Rate for Solvolysis:
OTs
1
300
H
H
OTs
Relative Rate for Solvolysis:
Rearrangement:
OTs
105
1
→ t-Bu
C → t-pentyl
C → t-hexyl
C4
+
+
5
6
+
32
Advanced Organic Chemistry (Chapter 5)
16
Study of Carbocations Rearrangement
NMR spectroscopy in supper acid media (magic acid):
FSO3H - SbF5 - SO2
Powerful protonating ability
Non-Nucleophilic
Carbocations have Sp2 hybridization
Br
Br
1
10-3
Br
10-10
33
Advanced Organic Chemistry (Chapter 5)
5.5 Nucleophilicity and Solvent Effect
Factors the Effect on Nucleophilicity:
1) A high Solvation Energy of The Nuclephile lowers the G.S.
and increase the activation energy.
2) Stronger bond between nucleophilic atom and carbon cause
the stabilization of the T.S. and will reduce the activation
energy.
3) A bulky nuclephile will be less reactive than smaller one
because of non-bonded repulsions that develop in the T.S.
4) High electronegativity is unfavorable.
5) Polarizibility: The more easily distorted the atom, the better
its nucleophilicity. Polarizibility increase with atomic number
going down in the periodic table.
34
Advanced Organic Chemistry (Chapter 5)
17
Nucleophilicity Constant (n):
Reference Reaction: Methanolysis of Me-I
nMeI  log(k Nucleophile / k MeOH )
in MeOH, 25 C
35
Advanced Organic Chemistry (Chapter 5)
36
18
Nucleophilicity and Basicity Relationship
The correlation is better if the attacking atom is the same
CH3O- > PhO- > CH3COO- > NO3Nucleophilicity increase going down the periodic table.
I- > Br- > Cl- > FPhSe- > PhS- > PhO37
Advanced Organic Chemistry (Chapter 5)
Hard-Soft-Acid-Base Concept
Hard nucleophiles prefer hard electrophiles while soft
nucleophiles prefer soft electrophiles.
Therefore, a soft anion should act as a nucleophile, giving the
substitution product, while a hard anion is more likely to
abstract a proton, giving the elimination product.
38
Advanced Organic Chemistry (Chapter 5)
19
a- Effect
Atoms which are directly bonded to an atom with one or more
unshared pairs of electrons tend to be stronger nucleophiles than
would otherwise be expected.
HOO- > HO-
H2NNH2, NH2OH > NH3
1) G.S. Destabilization of the nucleophile by lone pair-lone pair
repulsion
2) Stabilization of charge deficiency at the T.S. by lone pair.
39
Advanced Organic Chemistry (Chapter 5)
Nucleophilicity order In protic solvents, e.g. MeOH:
-
-
-
I > Br > Cl
Nucleophilicity order In polar aprotic solvents, e.g., DMSO:
-
-
-
I < Br < Cl
Aprotic Solvents
O
HCN(CH3)2
O
CH3SCH3
O=P[N(CH3)2]3
N
CH3
DMF
DMSO
HMPA
NMP
O
O
S
O
O
Sulfolane
40
Advanced Organic Chemistry (Chapter 5)
20
5.6 Leaving Group Effects
The reactivity of the leaving groups generally parallel their
electron-attracting capacity.
-
-
CF3COO >> CH3COO
The order of reactivity of the halide leaving group (C-X bond):
-
-
-
-
I > Br > Cl >> F
Increasing the reactivity by coordination to electrophilic species:
CH3OH + Br -
CH3Br + OH -
The reaction is greatly accelerated in acidic media.
41
Advanced Organic Chemistry (Chapter 5)
42
21
5.7 Steric and Strain Effects on Substitution
In primary alkyl substrates the reaction rate decrease with
increasing substrate size (direct displacement).
43
Advanced Organic Chemistry (Chapter 5)
In the case ionization and stabilization of cationic T.S.,
the reaction rate increase with increasing steric factor.
Acetolysis:
R
H
H
Br
CH3
R C Br
CH3
krel =
R = CH3
= 103.7
R=H
krel =
R = CH3
= 1011.1
R=H
44
Advanced Organic Chemistry (Chapter 5)
22
B-Strain (Back-Strain) in Highly Branched Systems
Facilate The Ionization:
Hydrolysis in 80 % aqueous acetone:
R
H3C C OPNB
krel =
CH3
R =t-Bu
R = CH3
= 4.4
45
Advanced Organic Chemistry (Chapter 5)
t-Bu
H
H
H
H
OPNB
H2 O
acetone
46
23
5.8 Substituent Effect on Reactivity
a-Substituent effect: Direct SN2 reaction proceeds more easier
than SN1 reaction in a-halo derivatives of ketones, aldehydes,
acids, esters, nitriles and related compounds.
47
Advanced Organic Chemistry (Chapter 5)
- X
- X

O
O
-
Nu
-

Nu
resonance representation of electronic
interaction with carbonyl group at the
T.S. for substitution which delocalizes
negative charge
MO representation of stabilization by
interaction with * orbital
48
24
5.9 Stereo Chemistry of Nucleophilic Substitution
Reaction of alcohols with SOCl2:
O
O
ROH + Cl-S-Cl
Cl
R O S Cl
Cl-R + SO2 + HCl
O
O
O
O
+ RO-S-Cl
O
O R O-S-Cl
- SO2
RCl +
O
Cl
O
R O
O
49
Advanced Organic Chemistry (Chapter 5)
Diazonium Ion Decomposition
RNH2
H+
R-N-N=O
R-N=N-OH
R-N
R+ + N2
N + H2O
H
AcOH
AcOH
AcOH
R+ + N
R-N=N-OH
AcOH
AcOH
AcOH
AcOH
AcOH
ROH
N OH2
AcOH
AcOH
AcOH
AcOH
Alcohol Formation: Net-retention of Configuration
Ester Formation: Retention and inversion is more similar.
50
Advanced Organic Chemistry (Chapter 5)
25
5.10 Neighboring-Group Participation
Solvolysis of 2-acetoxycyclohexyl p-toluenesulfonate:
OTs
OTs
OCOCH3
OCOCH3
k = 1.9 x 10-4 (100 °C)
cis-Isomer
AcO-
k = 2.9 x 10-7 (100 °C)
OCOCH3
trans
AcOH
OCOCH3
OCOCH3
-
trans-Isomer
AcO
trans
AcOH
OCOCH3
51
Advanced Organic Chemistry (Chapter 5)
H
OTs
H
O
O
OCOCH3
H
H
O
O
O
O
H
H
Achiral
H
OTs
C2H5OH
OCOCH3
O
CH3
O
OEt
51 %
H
52
Advanced Organic Chemistry (Chapter 5)
26
Solvolysis of 4-chloroalkanol
Cl(CH2)4OH
H2O
+ HCl
O
CH3OCH2CH2CH2CHCH3
ArSO3CH2OCH2CH2CH2CHCH3
OSO2Ar
OCH3
(A)
(B)
CH3
O
CH3
RO
H
H
RO
ROCH2CH2CH2CHCH3
CH3OCH2CH2CH2CHCH3
OR
OCH3
53
Advanced Organic Chemistry (Chapter 5)
Transanular participation of ether oxygen
X
O
X
X
X
O
O
relative rate
1.0
O
0.014
O
4.85 x 104
0.14
O
54
Advanced Organic Chemistry (Chapter 5)
27
p Electron of C=C Participation
Acetolysis of Norbornenes
 OTs
OTs
OAc
+
AcOH
anti
TsO
AcONa
syn
AcO
rearrangement
product
kanti
 107
k sys
55
Advanced Organic Chemistry (Chapter 5)
Extent of p Electron of C=C Participation
X
Substitution at C-7 position of Norbornenes
X
OCOAr
OH
O
, H2O
O
X = OCH3
H
CF3
Realtive Rate
3
40
3.5 x 104
56
Advanced Organic Chemistry (Chapter 5)
28
p Electron of C=C Participation
Formolysis of cyclopent-3-enyl tosylates
D
D
D
OTs
D
H
D
O2CH
HCOOH
D
H
D
D
Retention of configuration
-
-
O2CH
OTs
HCOOH
57
Advanced Organic Chemistry (Chapter 5)
Synthetic Use of p Electron of C=C Participation
Acetolysis of 2-cyclopent-3-enylethyl tosylate:
TsO
CH2CH2OTs
AcO
AcOH
AcO
58
Advanced Organic Chemistry (Chapter 5)
29
Aromatic p Electron Participation (Phenium Ion)
b-phenyl group participation
+
C C
C C
X
Phenium Ion
H3C
+
H
C
AcOH
H
H
OTs
C
CH3
H3C
C C
H3C
H
C
CH3
OAc
C
H
H
+
H
H3C
C
CH3
C
CH3 H
OAc
erythro
H
C
AcOH
H
C
H
+
CH3
OTs
CH3
H
C C
H3C
threo
C
H
H
OAc
C
CH3
CH3
achiral intermediate
CH3
+
H
H
C
C
CH3 CH3
OAc
racemic mixture
59
Advanced Organic Chemistry (Chapter 5)
Isotope labeling:
ks
Ph*CH2CH2OS + TsOH
SOH
Ph*CH2CH2OTs
+
k
SOH
Ph*CH2CH2OS + PhCH2*CH2OS + TsOH
The extent of label scrambling increases as solvent
nucleophilicity decreases.
r = -0.7
Positively charged T.S.
Weak substituent effect
60
Advanced Organic Chemistry (Chapter 5)
30
5.11 Rearrangement of Carbocations
1,2-H-Shift or 1,2-alkyl-Shift :
Driving Force : Formation of more stable carbocation
R
R
R
R
R
R
R
R
R
R
R
R
H
H
H
61
Advanced Organic Chemistry (Chapter 5)
Effect of Solvent Nucleophilicity on Extent of
Rearrangement
OAc
OTs
OAc
AcOH
+
+
AcO
64 %
NH2
30 %
OH
trace
OH
HONO
+
+
H2O
HO
21 %
68 %
11 %
62
Advanced Organic Chemistry (Chapter 5)
31
CH3CH2*CHCH3
AcOH
CH3CH2*CHCH3
OAc
OAc
91 %
9%
OTs
CH3CH2CDCD3
CF3COOH
+ CH3CH*CH2CH3
CH3CH2CDCD3 + CH3CHCHDCD3
OTs
OTf
OTf
49 %
+
45 %
CH3CHDCHCD3 + CH3CDCH2CD3
OTf
OTf
4%
2%
63
Advanced Organic Chemistry (Chapter 5)
D
H
CH3CH2CDCD3
OTs
CH3 C C CD3
H
CH3 C
H
D
H
C CD3
H
CH3 C C CD3
D
H
CH3CDCH2CD3 + CH3CHDCHCD3
OTf
OTf
OH
FSO3H
SbF5, SO2ClF
-78 °C
64
Advanced Organic Chemistry (Chapter 5)
32
Conclusion:
1) In acetolysis, a large part of the reaction must be
occurring via direct nucleophilic participation by the
solvent or rapid ion pair capture so that only a relatively
small amount of hydride shift occurs.
2) In non-nucleophilic super acid media, the cations
are
relatively
long-lived
and
undergo
several
rearrangements, eventually leading to the most stable
accessible ion.
65
Advanced Organic Chemistry (Chapter 5)
H-Shifts between carbon atoms separated by several
atoms
1,5-H- Shifts: Cyclononyl-1-14C tosylate
5
*
*
OTs
*
4
H
* * *
3
H
1
2
H
or H
* = 14C label
66
Advanced Organic Chemistry (Chapter 5)
33
Reaction of cyclooctene with CF3COOD
5
D
4
D
3
CF3COOD
H
D
F3CCOO
H
D
+
2
1
OOCCF3
HOOCCF3
H
D+
H
H
H
D
Hydride Bridge
(observed at -150 °C)
CF3COOH
H
F3CCOO
H
H
H
+
OOCCF3
D
D
67
Advanced Organic Chemistry (Chapter 5)
Hydride-bridge ion in which the bridging hydride is
located in a bicyclic cage.
H
Stable in CF3COOH
Ring Contraction
CH2
CH3
thermodynamically
favored
68
Advanced Organic Chemistry (Chapter 5)
34
H
H
H
H
H
H
H
H
H
H
H
C
H
H
H
H
H
CH3
H
CH3
69
Advanced Organic Chemistry (Chapter 5)
Carbocation Rearrangement Facilitation via The
Product Stabilization by a Functional Group
Pinacol rearrangements
R
R
C CR2
- H+
RC CR3
OH
OH
RC CR3
O
H
OH
Ph2C C(CH3)2
H+
OH
O
Ph2C C(CH3)2
OH
Ph2C C CH3
CH3
OH2
OH
O
Ph2C CCH3
CH3
-H+
Ph2C CCH3
CH3
70
Advanced Organic Chemistry (Chapter 5)
35
Study of Carbocation Rearrangements by NMR at low
Temperature in Super Acid Media
SbF5
Cl
H
FSO3H, SO2ClF
-65 °C
H
0 °C
, -9
ing
nch
que
E
F
H 3O
G
C
H
-
C
H
H
H
H
H
MeO
multi
step
H3C
J
H3C
I
H
stable
below -30 °C
71
Advanced Organic Chemistry (Chapter 5)
5.12 The Norbornyl Cation and Non-Classical Carbocations
HOAc
KOAc
OAc
kexo / kendo = 350
OBs
exo
exo and endo
Optically Active Exo Brosylate → Exo Product
(100% racemization)
Optically Active Endo Brosylate → Exo Product
(98% racemization)
Back
72
Advanced Organic Chemistry (Chapter 5)
36
7
5
4
5
OBs
5
4
6
4
3
1
6
3
2
3
7
1
2
non-classical ion
chiral
6
7
2
1
Achiral
achiral
(plane of symmtry)
73
Advanced Organic Chemistry (Chapter 5)
OBs
OAc
H
+
OAc
H
82 ±15 %
retention of configuration
H
H
Classical ion
achiral
(plane of symmtry)
H
Non-clssical ion
chiral
74
Advanced Organic Chemistry (Chapter 5)
37
H.C.Brown: Rapidly equilibrating classical ion and nonclassical ion as T.S.
75
Advanced Organic Chemistry (Chapter 5)
76
38
High
exo/endo
rate
ratio:
Comparing
of
exo-norbornyl brosylate with cyclopentyl brosylate and
not with cyclohexyl brosylate (Preference for exo
attack).
HOBs
OBs
krel
14
OBs
H
1
eclipsed
Slide 64
77
Advanced Organic Chemistry (Chapter 5)
Solvolysis exo and endo 2-phenyl-norbornyl-pnitrobenzoate in aqueous Dioxane
OPNB
Ph
Ph
kexo / kendo = 140
OPNB
OH
Ph
78
Advanced Organic Chemistry (Chapter 5)
39
Evidences for Non-Classical Ions:
1) NMR Spectroscopy in non-nucleophilic media
(supper acids).
2) X-Ray crystallography
79
Advanced Organic Chemistry (Chapter 5)
END OF CHAPTER 5
80
40