Chapter 3

Mechanisms of Organic Reactions

3.1
Reaction Thermodynamics and Kinetics

net reaction describes the starting materials and the products of a reaction

reaction mechanisms describes the individual elementary steps of the reaction

catalyst takes part in the reaction mechanism but is retained unchanged

Organic Reaction Mechanisms
Net Reaction and Mechanism
91
acid alcohol water
net reaction
reaction mechanism
starting materials products
elementary steps
catalyst
R
O
OH
+
HO R' R
O
O
+
R'
H
2
O
H
R
OH
OH
H
HO R'
R
OH
OH
O
H
R'
R
O
OH
O
R'
H
H
R
O
OH
R'
+ H
H ~ + H
2
O
ester

Gibbs free reaction energy G

R
determines whether and in which direction the reaction runs

standard Gibbs free reaction energy G

R
at standard conditions (1 bar, 25C, reactants 1 mol/L)

thermodyamics are concerned with the energy balance of chemical reactions

Thermodynamics of Chemical Reactions (1)
92
R
O
OH
+
HO R' R
O
O
+
R'
H
2
O
G
R
=G

R
+RT ln
[RCOOR][H
2
O]
[RCOOH][ROH]
G
R
>0
G
R
<0
G
R
=0
exergonic reaction, runs from left to right
endergonic reaction, runs from right to left
reaction is in equilibrium
Organic Reaction Mechanisms

equilibrium constant K
R
is the ratio of reactant concentrations in equilibrium

standard free reaction enthalpy G

R
determines the position of the equilibrium (at given temp.)

thermodyamics are concerned with the energy balance of chemical reactions

Thermodynamics of Chemical Reactions (2)
93
R
O
OH
+
HO R' R
O
O
+
R'
H
2
O
G
R
=G

R
+RT ln
[RCOOR]
eq
[H
2
O]
eq
[RCOOH]
eq
[ROH]
eq
=0
K
R
=
[RCOOR]
eq
[H
2
O]
eq
[RCOOH]
eq
[ROH]
eq
pK
R
=logK
R
G

R
=RT lnK
R
pK
R

G

R
RT
Organic Reaction Mechanisms

standard reaction enthalpy H

R
is negative (advantageous) if bonds in products are stronger

standard reaction entropy S

R
is positive (advantageous) if the disorder increases

thermodyamics are concerned with the energy balance of chemical reactions

Thermodynamics of Chemical Reactions (3)
94
R
O
OH
+
HO R' R
O
O
+
R'
H
2
O
G

R
=H

R
TS

R
Gibbs-Helmholtz Equation
exothermic reactions, sum of all bond energy changes negative
endothermic reactions, sum of all bond energy changes positive
exotropic reactions, disorder, degrees of freedom decrease
endotropic reactions, disorder, degrees of freedom increase S

R
>0
S

R
<0
H

R
>0
H

R
<0
Organic Reaction Mechanisms

reaction rates r are proportional to the product of the concentrations of all reactants

rate constants k are the proportionality factors

reaction order is the sum of all exponents of the concentrations of all reactants in the rate law

molecularity is the number of molecules actually involved in an elementary reaction

for simple, single-step reactions, the molecularity determines the reaction order

reaction kinetics refers to how fast reactions proceed, i.e., the reaction rates

rate laws describe the relation between substrate concentrations and reaction rates
Kinetics of Chemical Reactions
95
A B
A + B C + D
A + B + C D
r
1r
=k
1r
[B] r
1f
=k
1f
[A]
r
2r
=k
2r
[C][D] r
2f
=k
2f
[A][B]
r
3f
=k
3f
[A][B][C]
r
4f
=k
4f
[A]
2
[C]
r
3r
=k
3r
[D]
frst order monomolecular monomolecular frst order
second order bimolecular bimolecular second order
third order trimolecular monomolecular frst order
third order trimolecular bimolecular second order
r
4r
=k
4r
[C]
2
2 A + B 2 C
Organic Reaction Mechanisms

the ratio of rate constants of forward and reverse reactions determines equilbrium constant K

the faster the forward reaction (relative to reverse), the larger is K

the faster the forward (relative to reverse) reaction, the more the equilibrium is on product side

in thermodyamic equilibrium, concentrations of reactants do not change anymore

forward and reverse reaction are equally fast

Relation of Theromdynamics and Kinetics
96
A + B C + D r
2r
=k
2r
[C][D] r
2f
=k
2f
[A][B]
r
2f
=r
2r
k
2f
[A][B] =k
2r
[C][D]
k
2f
k
2r
=
[C][D]
[A][B]
=K
Organic Reaction Mechanisms

starting materials (S) and products (P) are stable compounds, i.e., energetic minima

transition states () are saddle points in the energy hypersurface, maxima in the reaction prole

reaction proles are simplied energy diagrams of chemical reactions, following the lowest
energy path from the starting materials to the products in the energy hypersurface
Reaction Proles (1)
97
P

S
E
d
HBr
d
HH
Br + H H H + Br H
S

E
Rkt
P
Organic Reaction Mechanisms

starting materials (S) and products (P) are stable compounds, i.e., energetic minima

transition states () are saddle points in the energy hypersurface, maxima in the reaction prole

reaction proles are simplied energy diagrams of chemical reactions, following the lowest
energy path from the starting materials to the products in the energy hypersurface
Reaction Proles (2)
98
P

S
E
d
HBr
d
HH
Br + H H H + Br H

S
E
Rkt
P
Organic Reaction Mechanisms

Boltzmann distribution of molecular thermal energies

Relation of Reaction Proles, Thermodynamics, and Kinetics
99

S
E
Rkt
P
G
f
= G
r
< 0
G
f

< G
r

S
E
Rkt
P
G
f
= G
r
> 0
G
f

> G
r

K
R
=
k
f
k
r
exergonic reaction endergonic reaction
E
A,r
G

r
=RT lnk
r
E
A, f
G

f
=RT lnk
f
fast
slow
slow
fast
G

R
=G

f
G

r
r
f
=r
r
k
f
[S]
eq
= k
r
[P]
eq
k
f
k
r
=
[P]
eq
[S]
eq
=K
R
Organic Reaction Mechanisms

Polanyi Principle: Dierence in activation energies proportional to dierence in free enthalpies

Hammond Postulate: Energetically more similar states are also geometrically more similar

Polanyi Principle and Hammond Postulate for mechanistically similar, single-step reactions
Hammond Postulate and Polanyi Principle
100

3
S
E
Rkt
P
1
P
2
P
3
G
3f
> G
2f
= 0 > G
3f

G
3f

> G
2f

= G
2r

> G
3f

exergonic
endergonic
late transition state
higher activation energy
early transition state
lower activation energy
Organic Reaction Mechanisms

overall reaction rate and molecularity are controlled by slowest, rate-determining step

typically, the generation of the reactive intermediate is the rate-determining step

intermediate is a good approximation for the transition state of the rate-determining step

elementary reactions are steps between the minima in the reaction prole, i.e., between
starting materials (S), intermediates (I), and products (P), seprated by transition states ().
Multistep Reactions
101

1
I
E
Rkt
S

2
P
G
f
= G
r
< 0
G
2f

< G
2r

elementary step 1 elementary step 2
slow fast
G
1f

> G
1r

Organic Reaction Mechanisms

change in standard Gibbs free reaction energy G

R
leads to change of equilibrium
concentrations

in reality, even more drastic because ln K ~ G

R
Reaction Proles: Thermodynamics and Kinetics
102
S
E
Rkt
P
G
f
= G
r
< 0

less exergonic reaction more exergonic reaction

equilibrium less on product side equilibrium more on product side
G

R
=RT lnK
R
Rkt
S
E
P
G
f
= G
r
< 0

Organic Reaction Mechanisms

change in Gibbs free energy of transition state G

leads to change in reaction rates

in reality, even more drastic because ln k ~ G

Reaction Proles: Thermodynamics and Kinetics

103
higher energy transition state lower energy transition state
forward/reverse reactions slower forward/reverse reactions faster
S
E
Rkt
P
G
f
= G
r
< 0

G
f

G
r

S
E
Rkt
P
G
f
= G
r
< 0

G
f

G
r

f
=RT lnk
f
G

r
=RT lnk
r
and
Organic Reaction Mechanisms

Reaction Proles: Thermodynamics and Kinetics
104
higher energy transition state very high energy transition state
forward/reverse reactions slower
S
E
Rkt
P
G
f
= G
r
< 0

G
f

G
r

equilibrium cannot be established
metastable
S
E
Rkt
P
G
f
= G
r
< 0
G
f

G
r

Organic Reaction Mechanisms

change in temperature changes equilbrium (due to Gibbs-Helmholtz equation G = H T S)

change in temperature also causes reaction rates because of thermal energy of molecules
Reaction Proles: Thermodynamics and Kinetics
105
lower temperature higher temperature
forward/reverse reactions slower forward/reverse reactions faster
S
E
Rkt
P
G
f
= G
r
< 0

G
f

G
r

Rkt
S
E
P
G
f
= G
r
< 0

for endotropic reaction (S>0):

equilbrium less on the product side
for endotropic reaction (S>0):
equilbrium more on the product side
Organic Reaction Mechanisms
3.2
Classifcation of Organic Reactions

classication according to reaction type, i.e., the type of changes to molecular topology
Classication of Organic Reactions (1)
107
R
1
X
R
2
R
3
+ Y
R
1
Y
R
2
R
3
+
X
Substitution
Substitution
R
3
R
1
R
2
R
4
Y
X
R
2
R
3
R
4
R
1
+ X + Y
Addition
Elimination
R
3
R
1
R
2
R
4
+ Y
Y
R
2
R
3
R
4
R
1
Addition
Elimination
R
1
X
Y
R
3
R
2
X
Y
R
3
R
2
R
1
Rearrangement
Rearrangement
Organic Reaction Mechanisms

classication according to reactive intermediate

Classication of Organic Reactions (2)
108
R
R
R
H
H
R
1
C
R
2
R
3

R
R
R
X
X
R
R
R
Y
Y
R
1
C
R
2
R
3

C R
1
R
2
R
3
carbanion
sp
3
pyramidal
carbocation
sp
2
planar
carbon radical
sp
2
or sp
2
or in between
planar or pyramidal
bond heterolysis bond homolysis
polar mechanisms
nucleophiles or electrophiles
radical mechanisms
radical starters
Organic Reaction Mechanisms
3.3
Nucleophilic Substitutions (S
N
Reactions)

a nucleophile is an electron pair donor, an electrophile is an electron pair acceptor

Nucleophilic Substitutions (S
N
Reactions)
110
R
1
C LG
R
2
R
3
+ Nu
R
1
C Nu
R
2
R
3
+
LG
R
1
R
2
R
3
R
1
R
2
R
3
Nu LG
Nu LG
+
nucleophilic substitution
nucleophile leaving group
electrophilic center
S
N
1 Mechanism: leaving group leaves frst (and allows nucleophile to come in subsequently
S
N
2 Mechanism: nucleophile attacks (and forces leaving group to leave simultaneously)
transition state
intermediate
Organic Reaction Mechanisms

the departure of the leaving group generates a carbocation as a true intermediate

the formation of the intermediate is energetically disfavorable, rate-determining

good leaving group, stabilized carbocation will decrease energy of the intermediate (favorable)
S
N
1 Mechanism: Rate-Determining Step is Unimolecular
111
R
1
C LG
R
2
R
3
R
1
C Nu
R
2
R
3
+
R
1
R
2
R
3
sp
3
sp
3
sp
2
LG

Nu
+
R
1
C Nu
R
2
R
3
sp
3
or

1
I
E
Rkt
S

2
P
G
f
= G
r
< 0
G
2f

< G
2r

slow fast
G
1f

> G
1r

racemic mixture pure enantiomer planar, achiral
Organic Reaction Mechanisms

Examples of S
N
1 Reactions
112
Cl
+ MeOH
Cl
+ MeOH
O
Me
H
H
OMe
trityl chloride methanol
good leaving group
excellently stabilized cation
moderate nucleophile
OTf
+
O
O
CH
3
NaOAc
TfO
CH
2
Br Br
+
Na
OAc
Br
Na
benzylbromotrifate sodium acetate
excellent leaving group
well-stabilized cation
moderate nucleophile
Organic Reaction Mechanisms

pK
A
values are a measure of the strength of a Brnsted acid

the lower the pKA value, the more is the equilibrium on the side of the dissociated ions

pK
A
values of the corresponding acids are a measure for leaving group quality (lower is better)

S
N
1 reactions are cation-anion dissociation reactions like acid-base reactions
Analogy of S
N
1 Reactions and Acid-Base Reactions
113
pK
A
=logK
A
=log
[H
+
][LG

]
HLG
Organic Reaction Mechanisms
R

LG
R

+
LG
R

H LG +
LG H
S
N
1 reaction
acid-base reaction
Brsted acid
Brsted acid leaving group
conjugate base

residues that correspond to acids with pK

A
< 0 are good leaving groups

residues that correspond to acids with pK

A
< 10 are moderate leaving groups

residues that correspond to acids with pK

A
< 20 are poor leaving groups

residues that correspond to acids with pK

A
> 20 are not leaving groups at all

leaving group quality is approximately inverse to the basicity of the obtained anion

scale by pK
A
values of the corresponding acids
Leaving Group Quality
114
O H
5
O
Me >
O H
1
O
CF
3
>
O H
10
S
O
Me >
15
O
O H
S
O
CF
3
O
>
O H
7
S
O O
F H Cl H Br H I H
> > >
10 9 7 3
F H OH H NH
2
H CH
3
H
> > >
3 16 38 48
Organic Reaction Mechanisms

Trivial Names and Abbreviations of Important Leaving Groups
115
O R
O
Me >
O R
O
CF
3
>
O R
S
O
Me >
O
O R
S
O
CF
3
O
>
O R
S
O O
OAc R OTFA R OMs R OTf R OTs R
trifuoromethanesulfonate
trifate
methanesulfonate
mesylate
4-toluenesulfonate
tosylate
trifuoroacetate acetate
Organic Reaction Mechanisms

S
N
1 reactions very favorable in benzyl or allyl position (in particular with donor atoms)

S
N
1 reactions also observed on highly substituted sp
3
carbons

S
N
1 reactions never observed in phenyl position (or other sp
2
or sp hybridized carbons)

carbocations are electron-decient, must be stabilized by electron-donating groups

Stabilization of the Carbocation Intermediate (1)
116
triphenylmethyl
trityl
diphenylmethyl
phenylmethyl
benzyl
ethenylmethyl
allyl
tertiary
carbon
secondary
carbon
primary
carbon
phenyl
(sp
2
)
Organic Reaction Mechanisms
H
H
H
R R
R
R R
H
R H
H
> > > > >
R
Si
R
R
> >> C
H
H
>> >
>
>
R
Sn
R
R
>
>
>
H
H
D
H
H
>
A

the more delocalization (donor groups, larger aromatic systems), the better stabilization

stabilization by resonance (+M eect)

Stabilization of the Carbocation Intermediate (2)
117
H
H
H
C
H
H
HC
H
H
CH
H
H
H
H
compare to phenyl cation
H
H
H
C
H
H
C
H
H
H
H
RO RO RO RO
CH
H
H
RO
Organic Reaction Mechanisms

the more alkyl groups (the higher substituted), the better stabilized is carbocation

stabilization by inductive eects (+I eect); conceptual explanation by hyperconjugation

Stabilization of the Carbocation Intermediate (3)
118
R
Sn
R
R
R
Si
R
R
R
C
R
R
> >
C C
H
H
H
!

!
+
<
<
<
!
+
R
R
<
C C
H
H
H
R
R
C C
H
H
H
R
R
C C
H
H
H
R
R
C C
H
H
H
R
R
EN 1.9 EN 1.9 EN 2.5

stabilization by decreasing electronegativity (and size) of cationic center

Organic Reaction Mechanisms

nucleophile interacts with antibonding * orbital of the CLG bond

back-side attack and concerted departure of leaving group under stereoinversion

good nucleophile (and good leaving group) will favor S

N
2 reaction
S
N
2 Mechanism
119

E
Nu LG
R
1
C
R
2
R
3
LG Nu
R
1
C
R
2
R
3
LG Nu
R
1
C
R
2
R
3
Nu LG
R
1
C
R
2
R
3
E
(S)
(P)
pure enantiomer pure enantiomer
stereoinversion
R
1
C LG
R
2
R
3
sp
3
R
1
R
2
R
3
Nu LG
LG
R
1
C Nu
R
2
R
3
sp
3
Nu
Organic Reaction Mechanisms

there is no simple, rational nucleophilicity scale! No relation to basicity!

nucleophilicity is a kinetic parameter, basicity is a thermodynamic parameter

determination of nucleophilicity n according to Pearson:

Nucleophilicity
120
Nu +
H
3
C I CH
3
Nu + I
MeOH +
H
3
C I CH
3
MeO
+
H I
n =log
k
Nu
k
MeOH
k
Nu
k
MeOH
R
2
P
> R
2
N
RS
> RO
R
3
P
> R
3
N
R
2
S
> R
2
O
>
>
R
3
C
> R
2
N RO
> F > > > >
I
> Br Cl
> F >
C O
R
R
R
> C O
H
R
R
> C O
H
R
H
> C O
H
H
H
Pearson et al., J. Am. Chem. Soc. 1968, 90, 3319.

Examples for Nucleophilic Substitutions
121
Br
Br
EtO
OEt
Br
+
OMe
Br
EtO
OMe
EtO
+
Br
Br
EtO
Br
EtO
+
OTf
Cl
EtO +
OEt
Cl
Br
Br
Br
TfO
Si
Cl
Cl
EtO +
Si
OEt
Cl
Cl
Organic Reaction Mechanisms

aldehydes (H) and ketones (R) have no leaving groups

amides (NR
2
), acids (OH), and carboxylates have very poor leaving groups

acid halides, anhydrides (and some esters) have good (or at least moderate) leaving groups

reminder: leaving group quality strictly controlled by basicity of the leaving group anion!

carbonyl carbon atoms are inherently very reactive electrophilic centers

Nucleophilic Reactions on Carbonyl Compounds
122
R
C
R
O
R
C
R
O
R
R
O
R
R
O
(HOMO) * (LUMO)
R H
O
R OR'
O
> > >
R R'
O
R OH
O
R O
O
> >
R' NR'
2
O
R O
O
> >
R Hal
O O
R
acid halides acid anhydrides ketones aldehydes esters amides acids carboxylates

electrophilicity controlled by M eect and I eect

Organic Reaction Mechanisms

addition of the nucleophile prior to cleavage of the leaving group is possible, advantageous!

carbonyl carbons are very reactive electrophilic centers

carbonyl carbons are sp

2
hybridized, coordinatively unsaturated
Nucleophilic Substitution on Carbonyl Compounds: AdditionElimination Mechanism (S
AE
)
123
O
C
Nu LG
R
+
sp
2
sp
3
C
O
LG
R
Nu
+
or
O
C
Nu LG
R
sp
3
LG

sp
2
C
O
LG
R
Nu +

1
I
E
Rkt
S

2
P
G
f
= G
r
< 0
G
2f

< G
2r

slow fast
G
1f

> G
1r

Organic Reaction Mechanisms

Active Acid Derivatives
124
Cl
O
O
O
H
3
C
O
CH
3
S
O
S
O
F
3
C
O
CF
3
O O
Cl
S
O O
H
3
C
acid chlorides
acid anhydrides
perfuorophenyl esters
N-succinyl esters
Cl
O
R
O
O
R
F
F
F
F
F
N
O
O
R
O
O
O
O
R
O
R R
O
O R O
O
Cl
O
F
F
F
F
F
C
O
F
F
F
F
F
N
O
O
O
N
O
O
O
etc.
etc.
pK
A
(HCl) = 7
pK
A
(RCOOH) 4
pK
A
(PfpOH) 6
pK
A
(SuOH) 10
benzoyl chloride
(BzCl)
tosyl chloride
(TsCl)
acetic anhydride
(AcOAc, Ac
2
O)
mesyl chloride
(MsCl)
Trific anhydride
(TfOTf, Tf
2
O)
Cl
S
O
H
3
C
O
active ester
active ester
Cl
O
H
3
C
acetyl chloride
(AcCl)
Organic Reaction Mechanisms

Examples for Nucleophilic Substitutions on Carbonyl Carbons
125
OH
Cl
S
O O
CH
3
NEt
3
HNEt
3
Cl
O
TsCl
S
O
O
CH
3
OTs
NH
2
NEt
3
HNEt
3
AcO
HN
Ac
2
O
NHAc
O
O
H
3
C
O
CH
3
CH
3
O OH HO OH
tosylation
acetylation
Organic Reaction Mechanisms

solution: peptide coupling reagents

no amide (peptide) formation between carboxylic acid and amine:

Example: Peptide Coupling Reactions
126
dicyclohexylcarbodiimide (DCC)
R
O
OH
+ H
2
N R'
R
O
O
+ H
3
N R'
R
O
OH
N
C
N
NEt
3
HNEt
3
R
O
O
NH
C
N
O
O
R
+ HNEt
3
NEt
3

H
2
N R'
N
H
O
R
R' +
N
H
C
N
H
O
peptide
Organic Reaction Mechanisms
3.4
Electrophilic Additions to Olefns (A
E
Reactions)

Reactions of Olens with Electrophiles
128
R R
El
El
H
H
H
H
H
H
Nu +
R
El
H
H
H
Nu
R
R COOH Cl
> > >
R
Ph R
R
R
R
R
R
OR
> > > >

olens are (weak) nucleophiles and react with electrophiles to form carbocations

reactivity order
decreasing electron density (M or I efect)
Organic Reaction Mechanisms

Examples
129

hydrohalogenation of olens

hydration of olens
H
OH
H HSO
4
H
2
O
H
Br
H Br
Br
Br
Br Br

halogen addition to olens

Organic Reaction Mechanisms

Mechanism of Electrophilic Additions to Olens
130

1
I
E
Rkt
S

2
P
G
f
= G
r
< 0
G
2f

< G
2r

slow fast
G
1f

> G
1r

(HOMO)
* (LUMO)
backside attack

electrophile adds to double bond so that more stable cation is formed

nucleophile attacks from the other side

C
R
3
H
C
R
1
R
2
C
R
3
H
C
R
1
R
2
El
El Nu +
C
R
4
H
C
R
1
R
2
C
R
4
H
C
R
1
R
2
C
R
4
H
C
R
1
R
2
El
C C
R
1
El
R
2
H
R
3
Nu
C
R
3
H
C
R
1
R
2
C
R
3
H
C
R
1
R
2
El
El Nu +
C
R
3
H
C
R
1
R
2
C
R
3
H
C
R
1
R
2
C
R
3
H
C
R
1
R
2
El
C C
R
1
El
R
2
H
R
3
Nu
Organic Reaction Mechanisms

Regioselectivity of Electrophilic Additions: Markovnikov-Rule
131

1
I
E
Rkt
S

2
P
G
f
< G
r

G
2f

< G
2r

slow
fast
G
1

> G
1

1
I
P

2
G
2f

< G
2r

slower fast
H
H
H
H
H
H
Ph
Br
Br
H
Ph
H
H
H
Ph
H
H Br
H
H
Ph
H
H
Br
Br
H
H
H
Ph
H

electrophile adds to double bond so that more stable cation is formed

IMarkovnikov rule: in HX addition, X is added to the higher substituted carbon (the more you
have, the more you get)
Organic Reaction Mechanisms

Stereoselectivity of Electrophilic Additions
132
Me
H
H
Ph
Br
Me
H
H
Ph
Br
+
Br Br
(R) (R)
(S) (S)
Me
H
Br
Br
Ph
H
C
H
Me
C
H
Ph
Br
(S) (S)
(R) (R)
H
Me
Br
Br
H
Ph
+
Me
Ph
H
H
Br
Me
Ph
H
H
Br
+
Br Br
(R) (R)
(R) (R)
Me
H
Br
Br
H
Ph
C
H
Me
C
Ph
H
Br
(S) (S)
(S) (S)
H
Me
Br
Br
Ph
H
+
(E)
(Z)

electrophilic additions are diastereospecic, i.e., an olen with a given conguration (E or Z) will
specically be transformed into one diastereomer of possible adducts (a pair of enantiomers)

electrophilic additions are trans-additions

Organic Reaction Mechanisms
3.5
Electrophilic Substitutions on Aromatic Compounds

Multiple Bonds Aromatic Compounds Do Not React Like Olens
134
El
El
H
H
H
Nu +
H
H
El
El
H
H
Nu
H
Elelctrophilic Addition
Elelctrophilic Substitution

electrophilic addition leads to loss of aromaticity, energetically disfavorable

electrophilic Substitution re-establishes aromatic system

Organic Reaction Mechanisms

Examples
135

bromination

Friedl-Crafts alkylation and acylation

sulfonation and nitration

H
Br
+ AlBrCl
3
R
R
H
Cl R
R
O
O
Br AlCl
3
!

!
+
R
Cl AlCl
3
!

!
+
R
O
+ AlCl
3
+ AlCl
3
+ AlCl
4
H Br
Br Br
+ FeCl
3
Br Br FeCl
3
!

!
+
+ FeBrCl
3
H SO
3
H
H
2
SO
4
H
2
O
H NO
2
HNO
3
/ H
2
SO
4
H
2
O
NO
2
H
3
O 2 HSO
4
HSO
3
HSO
4
Organic Reaction Mechanisms

Mechanism of Electrophilic Aromatic Substitutions
136
complex
addition product
substitution product

in electrophilic aromatic substituions, the most acidic hydrogen is replaced with an electrophile

1
E
Rkt

2
P
P
G
f
= G
r
< 0
G
2f

< G
2r

slow fast
G
1f

> G
1r

El
H
H
El H
El
H
H
H
El
complex
Organic Reaction Mechanisms

Regioselectivity in Electrophilic Aromatic Substitutions
137

substituents with +M eect direct the electrophile into ortho or para-positions

substituents with +M eect increase electron density, nucleophilicity, reactivity

RO
HC
RO
CH
H
C RO RO
RO
RHN
>
RO
>
I
>
Br
>
Cl
>
F
>
para
major
meta
none
ortho
minor
Br
Br Br
+ FeCl
3 RO RO
+
RO
+
RO Br
Br
Organic Reaction Mechanisms

Regioselectivity in Electrophilic Aromatic Substitutions
138

substituents with M eect direct the electrophile into meta-positions

substituents with M eect decrease electron density, nucleophilicity, reactivity

HC CH
H
C
O
RO
O
RO
O
RO
O
RO
O
RO
para
traces
meta
major
ortho
traces
Br
Br Br
+ FeCl
3 O
2
N O
2
N
+
O
2
N
+
O
2
N Br
Br
S
>
N
> > > >>
O
RO
O
O
O
O
RO
O
RN
O
HO
O
O
H
sulfonate nitro carboxylic esters carboxylic amides carboxylic acids carboxylates
Organic Reaction Mechanisms
3.6
Elimination Reactions

-Hydrogen Eliminations
140

most common are eliminations of hydrogen (H) and leaving group (LG) on adjacent carbons
E1 mechanism: leaving group leaves frst, hydrogen leaves subsequently
E1
cb
mechanism: base frst removes hydrogen and generates conjugate base, then leaving group leaves
E2 mechanism: concerted reaction

-hydrogen eliminations are reverse reactions of electrophilic additions to olens

olefn
LG

C
R
4
R
3
C
R
1
R
2
C
R
3
H
C
H
R
1
R
2
H
H
C C
R
1
H
R
2
H
R
3
LG
+ Base
H Base

C C
R
1
R
2
H
R
3
LG
C C
R
1
H R
2
H
R
3
LG
Base
!

!
+
!
+
!

" #
LG

Organic Reaction Mechanisms

Competition of S
N
1 and E1 Reactions
141

E1 eliminations are inevitable side reactions of S

N
1-type substitution reactions! Factors:

both: good leaving group, stabilized carbocation (identical intermediate!)

E1: absence of a nucleophile, non-nucleophilic base (if any), many or acidic -hydrogens

S
N
1: presence of a (good, not too basic) nucleophile, few or non-acidic -hydrogens
LG

C
R
3
H
C
H
R
1
R
2
H
C C
R
1
H
R
2
H
R
3
LG
H
Nu
+
C
R
4
R
3
C
R
1
R
2
C C
R
2
H
R
1
H
R
3
Nu
C C
R
1
H
R
2
H
R
3
Nu
+
(base)
E1 Elimination
S
N
1 Substitution
Organic Reaction Mechanisms

Competition of S
N
2 and E1
cb
/E2 Reactions
142
Organic Reaction Mechanisms

eliminations are often-observed side reactions of S

N
2-type substitution reactions!

however, they do not share the same intermediate

E1
cb
/E2: moderate/poor leaving group, strong non-nucleophilic base, acidic -hydrogens

S
N
2: good, non-basic nucleophile (e.g., I

, RS

, PR
3
, H
2
O), few or non-acidic -hydrogens
E1
cb
Elimination
S
N
2 Substitution
C C
R
1
H
R
2
H
R
3
LG
+ Base
H Base

C C
R
1
R
2
H
R
3
LG
C
R
4
R
3
C
R
1
R
2
Nu
+
C C
R
1
H
R
2
H
R
3
LG
Nu
C C
R
2
H
R
1
H
R
3
Nu
LG

Non-Nucleophilic Bases
143
Organic Reaction Mechanisms

non-nucleophilic bases have a high pK

A
(of BH) but are strongly sterically hindered!
lithium diisopropylamide
LDA, pK
A
40
lithium hexamethyldisilazide
LHMDS, pK
A
40
diisopropylethylamine
DIEA, pK
A
10
triisopropylamine
TIPA, pK
A
10
1,8-bis(dimethylamino)naphthalene
proton sponge, pK
A
12
1,4-diazabicyclo[2.2.2]octane
DABCO, pK
A
12
1,5-diazabicyclo[4.3.0]non-5-ene
DBN, pK
A
12
1,8-Diazabicyclo[5.4.0]undec-7-ene
DBU, pK
A
12
N
Li
Si
N
Si
Li
N
N
N
N
N
N
N N
N N
3.7
Radical Substitutions and Additions

Radical Substitution Reactions (S
R
)
145
initiation
CH
3
Cl Cl 2 Cl
+ Cl
CH
2
+ H Cl
CH
2
+ Cl Cl
CH
2
Cl
+ Cl
2 Cl Cl Cl
CH
2
+ Cl
CH
2
Cl
CH
2
2
CH
2
CH
2
propagation
termination reactions
product
side product
product
Organic Reaction Mechanisms

Radical Addition Reactions (A
R
)
146
initiation
propagation
termination reactions
product
side product
product
Br Br 2 Br
+ Br
H
C
+ Br Br
2 Br Br Br
+ Br
2
CH CH
Br
H
C Br
+ Br
Br
Br
Br
Br
H
C Br
H
C Br
BrH
2
C CH
2
Br
Organic Reaction Mechanisms