CHAPTER 6

Organic Reactions and

Their Mechanisms
6-1 SUBSTITUTION REACTION
In a substitution reaction, a functional group in a particular chemical
compound is replaced by another group.
group

Reagent Substrate Reactive

intermediate Type of organic substitution

Nucleophilic Aliphatic Carbocation Aliphatic nucleophilic substitution

Aromatic electrophilic substitution
Electrophilic Aromatic Carbanion

Free radical Free radical substitution

The electrophilic and nucleophilic substitution reactions are of

prime importance.
Detailed understanding of a reaction type helps to predict the
product outcome in a reaction. It also is helpful for optimizing a
reaction with regard to variables such as temperature and choice of
2
solvent.
l t
I ALIPHATIC NUCLEOPHILIC SUBSTITUTION
I.
A. General description
RL + Nu: RNu + L:
Nucleophilic substitution reactions can carry out at a saturated
aliphatic
li h ti carbon
b or att other
th unsaturated
t t d carbon
b centre.
t
Charge type:

All
necleophiles
are Lewis
bases.

Solvolysis: solvent used as a necleophile.

Alkylattion: nucleophilic substitution at an alkyl carbon.
Acylation: nucleophilic substitution at an acyl carbon.
carbon 3
B. NUCLEOPHILIC SUBSTITUTION MECHANISMS AT SATURATED CARBON
CENTRES
Bimolecular Nucleophilic Substitution (SN2)

Structure of
The kinetic evidence: Rate = k [RX][Nu] the SN2 transition state

Walden inversion:
(+)-chlorosuccinic acid
1 was converted to (+)
malic acid 2 by action
of Ag2O in water with
retention of
configuration, in the
next step the OH was
replaced by Cl to 3 by
reaction with PCl5. 4
Philips (1923)

2 2 2
2 3

o o o

2 2
There is a high probability that
(a), (c), and (d) proceeded
o
with retention, leaving (b) as
the inversion.

5
ESCHENMOSER ET AL.

The negatively charged carbon attacks the methyl group of

another molecule rather than the nearby one in the same molecule,
that is, the reaction is intermolecular and not intramolecular. The
transition state in an SN2 reaction must be linear.

6
 Unimolecular Nucleophilic Substitution (SN1)

CH3 CH3
H3C Br + 2 H2O H3C OH + Br + H3O+ Reaction kinetics:
CH3 CH3
rate = k [RX]
H3C CH3
Ionization of the
H3C Br H3C C + Br
substrate is the rate-
H3C CH3
determinating step.
CH3 H3C H
H
SN1 H3C C + O H3C O t BuCl
t- B Cl t-Bu
B + + Cl-
CH3 H H3C H 630 kJ/mol (in gas phase)
H 84 kJ/mol (in water)
H3C H H3C
H3C O + O H3C OH + H3O+
H3C H H H3C

Salt effect and common-ion effect: An increase in ionic strength of the

solution usually increases the rate of an SN1 reaction. A common ion will
p
depress the SN1 rate. 7
 Steric factor: The reactions run under SN1 conditions fail or
proceed very slowly at the bridgehead position of [2,2,1](norbornyl)
systems.

Stereochemistry: An excess of inversion is usually observed, as

the leaving group can remain in proximity to the carbocation
intermediate for a short time and block nucleophilic attack.

8
 Ion Pairs in the SN1 Mechanism
i. SN2 process: a
complete inversion
ii. Intimate ion pair R+X:
SR SR x SR + (1-x)RS
(1 x)RS
total inversion if (a)
SH SN 2 SH (b) SH does not take place or
to a combination of
RX R+X R+ X SR + RS
SH inversion and
(a)
R+ + X racemization if there is
competition between (a)
RX X R+ X R+
andd (b).
SH SN 2 SH SH iii. Solvent-separated
R+X: more
RS RS x RS + (1-x)SR
(1 )SR racemization (perhaps
total)
A complete picture of the possibilities for
iv. Free R+: complete
p
solvolysis
l l i in i a solvent
l t SH (ignoring
(i i th
the racemization
possibilities of elimination or rearrangement).
v. The difference: SN1
RS and SR represent enantiomers; x = some and SN2 mechanisms is 9in
fraction. the timing of the steps.
 The Neighboring-Group Mechanism

OBSERVATION with certain substrates:

i. The rate of reaction is g
greater than expected,
p ,
ii. The configuration at a chiral carbon is retained and not inverted or
racemerized.
h neighboring-group
The i hb i mechanism
h i consists
i essentially
i ll off two SN2
substitutions, each causing an inversion so that the net result is
retention of configuration.
Et Et Et Et Et Et Et Et
C -
OH C -Cl- C OH -
C
- -
HO C Cl O C Cl O C O C OH
Me Me
Me Me H
H H H

1 2 3
B
Br
H O HO O
C OH-
H
Me C O C C C C
Me H 10
O -
O O-
Me
EVIDENCE:
( ) Configurational
(i) g retention. Note that both p products are optically
p y
inactive and so cannot be told apart by differences in rotation. The
meso and dl dibromides have different boiling points and indexes of
refraction and were identified by these properties.
H CH3 CH3 H H CH3 CH3 H
HBr
B OH
Br + B OH
Br B Br
Br + Br Br
H CH3 CH3 H H CH3 CH3 H
dl
dl

Br
Br
Br H CH3 CH3 H
H CH3 H H
H+ H CH3 -H2O C C Br Br
H CH3 + Br Br
H CH3 CH3
CH3 H
OH Br- CH3 CH3 H
OH2
(2S,3S) (2R,3S) (2R,3R) (2S,3S)
(2S,3S) 11
CH3 H H CH3 H CH3
HBr
Br OH + Br OH Br Br
H CH3 CH3 CH3
H H
dl meso

Br
Br CH3
H CH3 -H2O CH3 H H Br
C C
CH3 H
H CH3 H Br
-
Br
OH2 CH3

(2R,3S) (2S,3S) meso

12
(iii) Acetolysis of both 4-methoxy-pentyl
4 methoxy pentyl brosylate 1 and 5-methoxy-
5 methoxy
2-pentyl brosylate 2: the same mixture of products. In this case the
intermediate 3 is common to both substrates.
CH3
CH3 CH3
H H O H
O H H O H
OBs
CH3 H CH3 H BsO CH3 H
1 3 2

CH3 CH3
H H H
O O
OAc
AcO C 3
CH C 3 H
CH

60% 40%

Important neighboring groups: COO, COOR, COAr, OCOR, OR, OH,

O, NH2, NHR, NR2, NHCOR, SH, SR, S, I, Br, Cl.
The effectiveness: I > Br > Cl.
13
 CH2
OH-
ClCH2CH2 S CH2 Cl ClCH2CH2 S ClCH2CH2S CH2OH
CH2 S N2
CH2 CH2

H OTs H OTs
H OTs H OAc

AcO-
AcOH
k 1011 1

-TsO- H
H ONB H ONB ONB
AcO-

+ H3C H3C

CH3
k
13.2 148
1

O
NB C NO
O2 14
C. NUCLEOPHILIC SUBSTITUTION AT AN ALIPHATIC TRIGONAL CARBON.
THE TETRAHEDRAL MECHANISM
Acyl substitution is basically a two-step nucleophilic addition and
elimination
li i ti reaction.
ti B th reaction
Both ti steps
t are reversible
ibl reactions.
ti

When reactions
e tion Preliminary R C X + H+ R C X R C X
are carried out OH OH OH
in acid solution, Y
there Step 1 R C X + Y R C X
may also be a OH OH
preliminary and Y Y Y
a final step. Step
p2 R C X R C R C + X
OH OR OH
Y
Final R C R C Y + H+ 15
OH O
D. Reactivity
The Effect of Substrate Structure
mechanism branching at either the or the carbon
For the SN2 mechanism,
decreases the rate.
Table 1. Average relative SN2 Primaryy and secondaryy
substrates generally react by
rates for some alkyl substrates the SN2 mechanism and
R Relative R Relative tertiary by the SN1 mechanism.
rate
t rate
t
Methyl 30 Isobutyl 0.03
Ethyl
y 1 y 10-5
Neopentyl
p
Propyl 0.4 Ally 10
Butyl 0.4 Benzyl 120
Isopropy 0.025
l
Elimination is always a possible side reaction of nucleophilic
16
substitutions
b off tertiary substrates
b ( h
(wherever a hydrogen
h d is present).
)
 Substrates
S b t t off the
th type
t RCOX are usually h more reactive
ll much ti than
th
the corresponding RCH2X. The mechanism here is always the
tetrahedral one. Explanation:
i. The carbonyl carbon has a sizable partial positive charge.
ii. In an SN1 reaction a bond must break in the rate-determining
step, which requires more energy than the shift of a pair of
electrons, which is what happens in a tetrahedral mechanism.
iii. A trigonal carbon offers less steric hindrance to a nucleophile than
a tetrahedral carbon.
Unsturation at the -carbon.

Table 2. Relative rates for the SN1 reaction between ROTs and
ethanol at 25C
CH3CH2- 0.26 PhCH2- 100
(CH3)2CH- 0.69 Ph2CH- ~ 105
17
CH2=CHCH2- 8.6 Ph3C- ~ 1010
NOTE
In general, SN1 rates at allylic substrate are increased by any
substituent in the 1 or 3 position that can stabilized the carbocation
b resonance or hyperconjugation.
by h j ti A
Among th
these are alkyl,
lk l aryl,
l and
d
halo groups.
SN2 rates for allylic and benzylic systems are also increased (See
Tab.1), probably owing to resonance possibilities in the transition
state.
-Substitution
Substitution resonance effect, field effect
ZCH2X SN1 relative rate
Z = RO,, RS or R2N- Veryy rapid
p
Z = RCO, HCO, ROCO, NH2CO, NC, F3C Decreased compared to CH3X

18
Table 3.
3 List of groups in approximately descending order of
reactivity toward SN1 and SN2 reactions. (Z = RCO, HCO, ROCO,
NC, or a similar group)
S 1 reactivity
SN1 i i S 2 reactivity
SN2 i i
Ar3CX RCHDX Ar3CX R3CX
A 2CHX
Ar RCHDCH2X A 2CHX
Ar ZCH2CH2X
ROCH2X, RSCH2X, C=CX ArCH2X R3CCH2X
R2NCH2X

R3CX ZCH2X ZCH2X C=CX

C=CCH2X ZCH2CH2X C=CCH2X ArX
R2CHX ArX RCH2X ~ RCHDX ~ Bridgehead-X
RCHDCH2X
RCH2X ~ R3CCH2X [2,2,1]bridgehea R2CHX
d-X
19
 The Effect of the Attacking Nucleophile
SN1 rate: are independent of the identity of the nucleophile, since
it does not appear in the rate-determining step.
For SN2 reactions in solution there are four principles that govern
the effect of the nucleophile on the rate.
i A nucleophile with a negative charge > its conjugate acid
i. acid.
OH > H2O, NH2 > NH3
ii. In comparing nucleophiles whose attacking atom is in the same
row of the periodic table, nucleophilicity is approximately in order
of basicity. NH2 >RO > OH > R2NH > ArO > NH3 > C6H5N > F
> H2O > ClO4; R3C > R2N > RO > F.
iii. Going down the periodic table, nucleophilicity increases, though
basicity decreases. I > Br > Cl > F (solvation, HSAB principle)
iv. The freer the nucleophile, the greater the rate.
Ex.: The rate of nucleophilic attack by (EtOOC)2CBu-Na+ in benzene was
increased byy the addition of 1,2-dimethoxyethane.
, y 20
NOTE:
i. The four rules given above do not always hold. One reason is
that steric influences often p
playy a p
part.
Basicity: Me3CO > OH or OEt
Nucleophilicity: Me3CO < OH or OEt
ii. Nucleophilicity order for SN2 mechanism (in protonic solvents):
RS > Ar > I > CN > OH > N3 > Br > ArO > Cl > C6H5N
> OAc > H2O.
O
iii. For substitution at a carbonyl carbon, the nucleophilicity order is
not the same as it is at a saturated carbon, but follows the
basicity order more closely.
EtO > MeO > OH > ArO > N3 > F > H2O > Br~ I

21
 The Effect of the Leaving Group

At a saturated carbon. The leaving group comes off more easily

the more stable it is as a free entity. This is usually inverse to its
basicity, and the best leaving groups are the weakest bases. Thus
iodide is the best leaving group among the halides and fluoride the
poorest.
poorest

R OSO2 CH3
ROTs
ROT
p-Toluenesulfonates, Tosylates
R OSO2 Br ROBs
p Bromobenzenesulfonates Brosylates
p-Bromobenzenesulfonates,
R OH

R OSO2 NO2 RONs

p-Nitrobenzenesulfonates,
Ni b lf N
Nosylates
l
ROMs
R OSO2CH3 Methanesulfonates, Mesylates
22
 At a carbonyl carbon. In the tetrahedral mechanism at a carbonyl
carbon, the bond between the substrate and leaving group is still
intact during the slow step. Nevertheless, the nature of the
leaving group still affects the reactivity in two ways:
i. The greater the electron-withdrawing character of X, the greater
the partial positive charge on carbonyl carbon and the more rapid
the attack by a nucleophile.
ii. The nature
Th t off the
th leaving
l i group affects
ff t the
th position
iti off
equilibrium. There is competition between X and Y as to which
group
g p leave:

RCOCl > RCOOCOR

RCOOCOR > RCOOAr > RCOOR
RCOOR > RCONH2 > RCOO-. 23
 The Effect of the Reaction Medium
Table 3. Transition states for SN1 and for SN2 reactions of the four charge
types
Reactants and transition Charge in the transition How an increase in solvent
state
t t relative
l ti tot starting
t ti p l rit affects
polarity ff t ththe rrate
t
states materials

Type a RX + Y YRX Dispersed Small decrease

Type b RX + Y Y+RX Increased Large increase

Type c RX+ + YYRX+ Decreased Large decrease

Type d RX+ + Y Y+RX+ Dispersed Small decrease

RX R+X+ Increased Large increase

RX+ R+X+ Dispersed Small decrease

When there is a greater charge in the transition state than in the

starting compound,
compound the more polar the solvent,
solvent the faster the reaction.
reaction
Even for solvents with about the same polarity, there is a difference
between protonic and aprotonic solvents. In type a and b, TS solvation:
polar aprotonic solvents > prontonic solvents.
It isi quite
it possible
ibl for
f th same reaction
the ti t go by
to b the
th SN1 ini 24
one
solvent and the SN2 in another. (see: J. Am. Chem. Soc. 1961,83,618)
 Phase Transfer Catalysis
A difficulty that occasionally arises when carrying out nucleophilic
substitution reactions is that the reactants do not mix.

organic + 4 +
phase
2
1
aqueous + +
3 + +
phase
+ + +
4 4

25
 Ambident
A bid t Nucleophiles
N l hil / S
Substrates.
b t t R i
Regioselectivity
l ti it

Ambident nucleophiles: Some nucleophiles have a pair of electrons

on eachh off two or more atoms, or canonicall forms
f can be
b drawn
d in
which two or more atoms bear an unshared pair.
Ambident substrates: Some substrates (e.g.,
(e g 1,3-dichlrorbutane)
1 3 dichlrorbutane)
can be attacked at two or more positions.
R
C C C C C C C C C
O OR O O O O
O-alkylation
O alkylation C-alkylation
C alkylation

C C C
O O

H Y O
Y H
R C CH2O R C CH2Y 26

Y R O
 E. Reactions

RX + R
R'2NH RR 2N
RR'
RX + R'3N RR'3N+X
RX + OH ROH RX + R'CONH RNHCOR'
RX + OR' ROR'
C C + RNH2 C C
C C C C O OH NHR
Cl OH O
R OSO2OR
OSO2OR'' + OR
OR' ROR'
ROR
2 ROH ROR
RCOX + H2O RCO2H
RCOOCOR' + H2O RCO2H + R'CO2H
C C + ROH C C RCO2R' + H2O RCO2H + R'OH
OH OR RCONR' + H2O RCO2H + R'2NH (R = H,
H alkyl,
lk l aryl)
l)
O RCOX + R'OH RCO2R'
R3O+ + R'OH ROR' RCOOCOR + R'OH RCO2R'
RX + R'COO R'COOR RCOOH + R''OH RCO2R'' + R'OH
RX + OOH ROOH RCOX + RR'COO
COO RCOOCOR'
RCOOCOR
RCOX + H2O2 RCO3H

27
II Aromatic
II. A ti Electrophilic
El t hili Substitution
S b tit ti

Most substitution at an aliphatic carbon are nucleophilic. In

aromatic systems the situation is reversed, because the high
electron density at the aromatic ring attracts positive species
and not negative ones. In electrophilic substitutions the
attacking
ki species
i i a positive
is i i i
ion or the
h positive
i i endd off a
dipole or induced dipole. The leaving group must necessarily
depart without its electron pair.
In nucleophilic substitutions, the chief leaving groups are
those best able to carry the unshared pair: Br, H2O, OTs,
etc., that is, the weakest bases. In electrophilic
substitutions
b i i the
h most important
i l
leaving
i groups are those
h that
h
can best exist without the pair of electrons necessary to fill
the outer shell, that is, the weakest Lewis acids. The most
common leaving group in electrophilic aromatic substitutions is
the proton (H+).

28
A. The Arenium Ion Mechanism
In the arenium ion mechanism the attacking species may be
produced in various ways, but what happens to the aromatic ring
is basically the same in all cases. For this reason most
attention in the study of this mechanism centers around the
identity of the attacking entity and how it is produced.
produced

X Y Y Y Y
+
Y
X X X X
slow

complexes
Y Y arenium ions
X fast
- X+

X X
+ Y Z Y
The attacking species
is not an ion but a dipole.
X Y
Z Y + Z
29
 Evidence:
i. No isotope effects
If the hydrogen ion departs before the arrival of the
electrophile or if the arrival and departure are simultaneous,
there should be a substantial isotope effect (i.e., deuterated
substrates should undergo substitution more slowly than
nondeuterated compounds) because,
because in each case,
case the CH
C H bond is
broken in the rate-determining step.
However, in the arenium ion mechanism, the CH bond is not
broken in the rate
rate-determining
determining step, so no isotope effect should
be found.
ii. Isolation of arenium ion intermediates

Me
Me Me
EtF-BF3 H Et
Et BF
80C 4
Me Me
Me Me Me Me
mesitylene o
(Mp -15 C)
30
 B. Orientation and Reactivity
Monosubstituted
b d Benzene Rings
Z Z Z
H H H
Ortho Y Y Y

(A)

Z Z Z

Meta H H H
Y Y Y

Z Z Z

Para

H Y H Y H Y
(B)
Any group Z that has an electron donating field effect should stabilize
all three ions.
Electron-withdrawing groups will increase the positive charge on the
ring, and destabilize the arenium ion.
31
Field effects should taper off with distance and are strongest at the
carbon connected to the group Z. +I groups should stabilize all three ions
but mostly the ortho and para
Some substituents have a pair of electrons (usually unshared) that
may be contributed toward the ring. Not only to direct ortho and
para, but
b t also
l tot activate
ti t these
th positions
iti for
f electrophilic
l t tt 32
hili attack
k
Three Types of Groups:
i. Groups that contain an unshared pair of electrons on the atom
connected to the ring.
O, NR2, NHR,
NHR NH2, OH, OH OR,
OR NHCOR,
NHCOR OCOR,
OCOR SR,
SR the four
halogens, and SH (except for the case of thiophenols
electrophiles usually attack the sulfur rather than the ring).
Cl,Cl Br,
Br and I deactivate the ring,ring but they direct ortho
ortho-
para.
ii. Groups that lack an unshared pair on the atom connected to the
ring and that are I.
Approximate deactivating ability: NR3+> NO2 > CF3 > CN > SO3H >
CHO > COR > COOH > COOR > CONH2 > CCl3 > NH3+.
anomaly, since this group directs para
The NH3+ group is an anomaly
about as much as or a little more than it directs meta.
iii. Groups that lack an unshared pair on H
the atom connected to the ring and that H C H
are ortho-para-directing. H H
R, Ar, COO groups, which active the ring. Y Y
33
(E) (F)
 Orientation in Benzene Rings with More than One Substituent
Generalization
ii. If a strong activating group competes with a weaker one or with a
deactivating group, the former controls.
Directing order: NH2, OH, NR2, O > OR, OCOR, NHCOR >, R, Ar >
halogen > meta-directing groups.

iiii. All other things being equal,

equal a third group is least likely to enter
between two groups in the meta relationship (steric hindrance).
iii. When a meta-directing group is
meta to an ortho-para-directing
group, the incoming group primarily
goes ortho to the meta-directing
g g 34
group rather than para.
Reactions
Nitration
OH OH OH NH2 NH3HSO4-
NO2
20%HNO3 HNO3

H2SO4
NO2
NO2

Sulfonation
Halogenation
H
O

SO3 -
+ -
- H+
X X FeX3
+ S O + SO3- X2 FeX
F X3
O
H X
H SO3H + - FeX4- H+
- H+ + X X FeX3
SO3H X
SO3H

Fridel-Crafts Reactions
+ -
R ClAlCl3 R Cl AlCl3 R+AlCl4-

AlCl3 - AlCl 4
CH3CH2CH2Cl PhCHMe2PhCH2CH2CH3 CH3CH2CH2Cl AlCl3 CH3CH2CH2 CH3CHCH3
70% 30%

CH3CH2CH2C O
H2SO4 H+ AlCl3
+ CH3CH2CH2COCl
HO
35
Zn-Hg
CH3CH2CH2CH2
HCl
III Aliphatic Electrophilic Substitution
III.
MECHANISMS
Aliphatic electrophilic substitution can be distinguish
unimolecular (SE1) and bimolecular (SE2). The bimolecular
mechanisms are analogous to the SN2 mechanism in that the new
bond forms as the old one breaks.

Halogenation of Aldehydes and Ketones:

Step 1 H
R2HC C R' R2C C R' Step 1:
slow OH-
O OH R2HC C R' R2C C R'
Step 2 R2C C R' + Br Br R2C C R' + Br O O

OH Step 2:
Br OH
C R' R2C C R' + H R2C C R' + Br Br R2C C R' + Br
Step 3 R2C
Br OH Br O O Br O

36
IV Aromatic
IV. A ti Nucleophilic
N l hili Substitution
S b tit ti

i. Reactions activated by electron-withdrawing groups ortho

and para to the leaving group;
ii. Reactions catalyzed by very strong bases and proceeding
through aryne intermediates;
iii Reactions initiated by electron donor;
iii.
iv. Reactions in which the nitrogen of a diazonium salt is
replaced by a nucleophile.
37
 the SNAr (addition
(addition-elimination)
elimination) mechanism

L L Nu OCH3H7-n
n NHPh
+ Nu

NO2 NO2
-
Nu L- 180
+ PhNH2

NO2 NO2 NO2 NO2 NO2

the aromatic SN1 mechanism

38
 The Benzyne Mechanism

Two factors affect the positions

of the incoming group:
ii. The
Th direction
di ti i which
in hi h the
th
aryne forms.
ii.The
ii The aryne,
aryne once formed,
formed
can be attacked by two
positions. The favored
position for nucleophilic
attack is the one that leads
to the more stable carbanion
39
i t
intermediate,
di t and
d this
thi i
in
turn also depends on the
field effect of Z.
VI Free-Radical
VI. F R di l SSubstitution
b tit ti
Some general characteristics:
1. Reactions are fairly similar whether they are occurring
in the vapor or liquid phase, though solvation of free
radicals in solution does cause some differences.
differences
2. They are largely unaffected by the presence of acids or
bases or by changes in the polarity of solvents, except
that nonpolar solvents may suppress competing ionic
reactions.
3
3. Th
They are
r initiated
initi t d orr accelerated
l r t d byb typical
t pi l free-
fr
radical sources, such as the peroxides referred to, or
by light.
4. Their rates are decreased or the reactions are
suppressed entirely by substrates that scavenge free
40
radicals,
di l e.g., nitric
i i oxide,
id molecular
l l oxygen, or
benzoquinone. These substances are called inhibitors.
 Mechanisms
M h i att an Aromatic
A ti Substrate
S b t t
In the first step, the radical attracts the ring in much the
same way as would an electrophile or a nucleophile:

H Ar H Ar H Ar H Ar
A +
Ar

1
H Ar H Ar H Ar
C
Coupling
li
2

1 2
H Ar Ar H Ar
Disproportionation
2 +

H H
1 3
H Ar Ar
R'
+ R'H
41
1
 REACTIVITY IN ALIPHATIC SUBSTRATES
In a chain reaction, the step that determines what the
product will be is most often an abstraction step. What is
abstracted by a radical is nearly always univalent,
univalent it is
hydrogen or halogen for organic compounds.

i. A univalent atom is much more exposed to attack by the

i
incoming
i radical;
di l
ii. In many cases abstraction of a univalent atom is
energetically more favored.
Table 5. Relative susceptibility to attack by Cl of promary,
secondary, and tertiary hydrogen in the gas phase
p / C
Temp./ Primaryy Secondaryy Tertiaryy
100 1 4.3 7.0
600 1 2.1 2.6
42
Temperature selectivity
Table 6. Relative substitution rates
CH3H CH3CH2-H (CH3) 2CHH (CH3) 3CH PhCH2H Ph2CHH Ph3CH

Br 0.0007 1 220 19400 64000 1.1106 6.4106

Cl 0.004 1 4.3 6.0 1.3 2.6 9.5

Compounds containing electron-withdrawing substituents

CH3 CH2 COOH
CH3 1 7.8
Cl 1 0.03
Electrophilic radical: halogen atoms
Nucleophilic radical: Me, t-butyl, benzyl, cyclopropyl

When the substrate molecule contains a double bond,

treatment with chlorine or bromine leads to addition rather
than substitution.
Vinylic hydrogens are practically never abstracted, allylic
43
hydrogens are greatly preferred to other position of the
molecule.
 REACTIVITY IN AROMATIC SUBSTRATES

Generalizations:
ii. All substituents
b increase reactivity at ortho
h andd para
positions over that of benzene. There is no great difference
between electron-donating
g and electron-withdrawing
g g
groups.
p
ii. Reactivity at meta positions is usually similar to that
of benzene, perhaps slightly higher or lower. This fact,
coupled with the preceding one, means that all substituents
are activating and ortho-para-directing; none are
deactivating or (chiefly) meta-directing.
meta directing
iii. Reactivity at ortho position is usually somewhat
greater than at para positions,
positions except where a large group
decreases ortho reactivity for steric reasons.

44
REACTIONS
Allylic Halogenation
Olefins can be halogenated in the allylic position by a number
of reagents, of which N-bromosuccinimide (NBS) is by far the
most common.
O
peroxides
CH C C + N Br C C C
CCl4
Br
O
NBS (Wohl-Ziegler bromination)

Coupling of Alkynes

The mechanism of the reaction probably begins with loss

of a proton, then carbanion becomes oxidized to the radical.
45
6-2 Addition to Multiple Bonds

There are basically four ways in which addition to a double

or triple bond can take place.
A two-step process,
process with initial attack by a nucleophile,
nucleophile an
electrophile, or a radical, and then second step consists of
combination of the resulting intermediate with, respectively, a
positive species, a negative species, or a neutral entity.
A one
one-step
step mechanism, attack at the two carbon atoms of the
double or triple bond is simultaneous.
Which of the four mechanisms is operating in any given case
is determined by the nature of the substrate, the reagent,
and the reaction conditions. 46
I Stereochemistry
I.
W
Y A W
Y
Syn addition C B A
A C A B
Syn addition B
B
the erythro dl Y erythro dl pair

pair or
W A
W
Y
C B A
A C A B
B
B

Y A
A
Y
C B
Anti addition B
A C
Anti addition W A B W
threo dl pair
B
W A A
the threo dl W B
C B
pair or
A C A Y
Y B 47
B
II.. Electrophilic
p Addition
There is much evidence that when the attack is by Br+ (or a
carrier of it), the bromonium ion is often an intermediate
and the addition is anti.
anti

The atom is A bromide ion attacks the

electrophilic at this CBr * antibonding
ti
time andd attacks
tt k the th molecular
l l orbital
bit l off a
negatively charged, bromonium ion.
high energy -bond The two halogens add in an
portion of the anti addition
dd fashion,
h andd
alkene's C=C bond. It when the alkene is part of
forms for an instant a a cycle the dibromide
single -bond
bond to both adopts
d t th
the t 48
trans
of the carbon atoms configuration.
involved.
 Brominations of maleic acid and fumaric acid: stereospecific
trans-addition:
Br
H CO2H H CO2H
Br2 H CO2H Br
H CO2H + Br
H CO2H H CO2H
Br
(S,S) (R,R)
Br
H CO2H
Br2 H CO2H
(R,S)
HO2C H
HO2C H
Br

49
 When the electrophile is a proton:
ii. The
Th reaction
i i
is general-acid,
l id i l i
implying rate-determining
d i i proton
transfer from the acid to the double bond.
ii. The existence of alkyl substituent effects.
iii Open
iii. O carbocations
b ti are prone to
t rearrange.

H H
H A H
+ +
+ HA C C + A C C + A C C + C C
C C
A

The Reactivity Toward Electrophilic Addition:

CCl3CH=CH2 < CHCl2CH=CH2< CH2ClCH=CH2< CH3CH=CH2

(CH3)2C=C(CH
C C(CH3)2 > (CH3)2C=CHCH
C CHCH3>(CH3)2C=CH
C CH2 > CH3CH=CH
CH CH2 > CH2=CH
CH2

50
 Orientation Markovnikovs rule: For electrophilic attack, the positive
pportion of the reagent
g goes to the side of the double or triple
g p bond that has more
hydrogens.

O
CH3-CH=CH
CH CH2 CH3-CH-CH
CH CH3 H2O
+ H OSOH CH3-CH-CH3
OSO3H OH
O

CH3-CH-CH3
CH3-CH=CH2 BrH
+
Br H3PO4
CH3-CH=CH2 H CH3-CH-CH3
+ OH
OH

CH 3 -CH=CH 2 + H O C C H3 C H 3 -C H-CH 3
O
OC CH 3

O
Br
CH3CH2CH2 C CH2 HBr 51
CH3CH2CH2 C CH HBr CH3CH2CH2 C CH3
Br Br
 Rearrangement

CH3 CH - CH3
HCl 3+ Cl
H3C C CH CH2 - HC C CH CH H3C C CH CH2
Cl 3 3
H H H Cl
1,2-H
CH3 - CH3
Cl
H3C C CH CH2
+
H3C C CH CH2
H Cl H

HgSO
g 4
CH3(CH2)5C CH + HOH H SO CH3(CH2)5C CH2 CH3(CH2)5C CH3
2 4
OH O

52
 Markovnikovs rule also applies for halogen substituents or
the case where bromonium ions or other three-membered
three membered rings are
intermediates.
Y Y Y
Cl C C H + Y+ Cl C C H Cl C C H or Cl C C H

H H H H H H H H
More stable

Y Y W
W
H2C CHR H2C CHR

Stereochemical Orientation Many electrophilic additions to

norbornene and similar strained bicycloalkenes
y are syn
y
addition, in these cases attack is always from the exo side.
unless the exo side is blocked by substituents in the 7
position, in which case endo attack may predominate.

53
 III NUCLEOPHILIC ADDITION
III.
A. Addition to Carbon-Hetero Multiple bonds

With a carbonyl compound electrophiles, the Nu can be:

an alcohol in Acetalisation
an amine in Mannich reaction
a ylides in Wittig reaction
an enolate ion an Aldol reaction
a hydride in reduction
an organometallic nucleophile (RMgX) in the Grignard reaction
54
Acetalisation
R1 R3OH R1 OH 3
R OH R1
OR3
O + H2O
+ +
R2 H H
R2 OR 3
R2 OR3
ketone hemiacetal acetal

55
Mannich reaction
H R R
NH + C O + CH C N CH2 C C
H O O

56
 Schiff base

R2C=O + R'NH2 R'NH-(R2)C-O-H R2C=NR' + H2O

57
Wittig reaction

Aldol reaction

58
Grignard reaction

59
B. Addition to Carbon
Carbon-Carbon
Carbon Double Bonds

Ordinary alkenes are not susceptible to a nucleophilic attack (apolar

bond).

O H
Nu O
Nucleophilic
Nu
conjugate addition: O O H+

Nu Nu O
H
Nu

60
 Michael reaction (1,4-addition)

61
IV FREE-RADICAL ADDITION
IV.

The main effect seems to be steric. 62

V CYCLOADDITION:
V. CLICK CHEMISTRY

The Huisgen 1,3-dipolar cycloaddition using a Cu(I) catalyst at

room temperature the cream
cream of the crop
crop of click reactions.
reactions
R1
N N N Cat. R1 1 N R1 1 N
+ N N + N N 1,2,3-triazole
2 4 5
R 2
R2 R
Cat.: CuI, CuOTf C6H6 1,4- 1,5-

63
6 3
6-3 Eli i ti
Elimination Reactions
R ti

I. E2 and E1 Mechanism

X
C C C C + X- + BH
H
B E2 Mechanism

ii. The proper second-order

second order kinetics;
ii. An isotope effect: kD/kH = 3~8;
iii. Stereochemistry the E2 mechanism is stereospecific: the five atoms
involved (including the base) in the transition state must be in one plane.
64
 Anti
A ti elimination
li i ti i usually
is ll greatly d over syn elimination,
tl favored
f li i ti
probably because a is a staggered conformation and the molecule
requires less energy to reach this transition state than it does to
reach the eclipsed transition state b.

- B-
B

R4 H
R4 R3 R1 R4
H R3 R4 R3 L-
C C
BH R2
R1 R2 R1 R2 R3
R1
L L 65
R2
For a six-membered ring, anti-periplanarity of the leaving groups
requires that they be diaxial even if this is the conformation of higher
energy.

Relative Product
rate
cis-HOOCCH=CClCOOH
i HOOCCH CClCOOH 1
HOOC-CC-COOH
trans-HOOCCH=CClCOOH 50
66
 syn-Elimination

Br
The deuterated - HBr
DH H 94%
norbornyl bromide
H H
cis-isomer: HCl elimination is much
slower than from corresponding
nonbridged compounds.
trans-isomer: Syn elimination can
H Cl Cl H take place (dihedral angle about 0);
H Cl H Cl
reached about eight times faster than
cis-isomer trans-isomer cis-isomer.

a) Anti elimination requires a dihedral angle of 180 180. When this

angle cannot be achieved, anti elimination is greatly slowed or
prevented entirely.
b) Anti elimination is generally
gene all favored
fa o ed in the E2 mechanism,
me hanism butb t
that steric (inability to form the anti-periplanar transition state),
conformational, ion-pairing, and other factors cause syn
67
elimination to intervene (and even predominate) in some cases.
The E1 Mechanism
The E1 mechanism is a two-step process, ionization of the substrate
to give a carbocation that rapidly loses a proton to a base, usually
the solvent:
i. Tertiary and some secondary
substituted alkyl
y halides.
ii. First order kinetics
iii. Reaction mostly occurs in
complete absence of base or
presence of only a weak base
iv. E1 are in competition with SN1
v. No deuterium isotope effect
vi. No antiperiplanar requirement:

Example 1:

pyrolysis

68
sulfonate ester of menthol
II E1CB MECHANISM (CARBANION MECHANISM)
II.
B- H

O2N CH CHR O2N C CHR O2NCH=CHR L-
H
L
L

The E1cB reaction mechanism. Dehydration

y of 1-methyl-2-(2-
y ( 69
fluoroethyl)pyridinium iodide).
Example 2.

If this reaction had taken place by a second-order mechanism, the

nucleophile would not be excepted to have the same ratio of preference for
attack at the hydrogen compared to attack at a neutral chloride as for
h hydrogen
attackk at the h d d to attackk at a positive
compared i i SMe
SM 2 group.

Example 3.
3

70
III Orientation of the Double Bond
III.
i. No matter what the mechanism, a double bond does not go to a
bridgehead carbon unless the ring sizes are large enough (Bredts
rule).
l )

ii. Zaitsevs rule: the double bond goes mainly toward the most
highly substituted carbon.

71
iii. Elimination
iii Eli i ti from
f compoundsd with
ith charged
h d nucleofuges,
l f e.g., NR3+,
SR2+ (those that come off as neutral mlecules), follow Hofmanns rule
if the substrate is acyclic: the double bond goes mainly toward the
least highly substituted carbon, but Zaitsevs rule if the leaving group
is attached to a six-membered ring.

iv. No matter what the mechanism, if there is a double bond (C=C or

C=O) or an aromatic ring already in the molecule that can be in
conjugation with the new double bond,
bond the conjugated product
usually predominates, sometimes even when the stereochemistry is
unfavorable.
72
IV REACTIVITY
IV.
Factors influencing the elimination reactivity:
Substrate structure
The attacking base
The leaving group
The medium
Elimination Reaction vs Nucleophilic Substitution:
Substitution generally predominates and elimination occurs only
during precise circumstances. Generally, elimination is favored over
substitution when
steric hindrance increases
basicity increases
temperature
p increases
the steric bulk of the base increases (KOBut)
the nucleophile is poor.
73
Competition between E and Sn
C C
Steric hindrance
SN1 H E1
RO-, ROH
CH3(CH2)15CH2CH2Br CH3(CH2)15CH=CH2CH3(CH2)15CH2CH2OR
Z

CH3O-, CH3OH ~1%

1% (E2) 99%(SN2)
X
Me3CO-, Me3COH ~85%(E2) ~15%(SN2)
C C
SN2 E2
H

Basicity Z

1RX 2 RX 3 RX
CH3COO-(CH3)2CHBr CH3COOCH(CH3)2Br-
E2S
N2

C2H5O-(CH3)2CHBr CH3CH2O CH(CH3)2CH2=CHCH3

C2H5O->CH3COO- 21% 79%

Temperature
C2H5OH
(CH3)C BrC2H5ONa M 3C OEtCH2=CMe
Me CM 2

25 9SN1 91E1+E2
55 0% 100%(E1+E2)
74
6 4 Rearrangement Reaction
6-4
In a rearrangement reaction a group moves from one atom to
another in the same molecule.
molecule Most are migrations from an atom to
an adjacent one (called 1,2 shift), but some are over longer
distances.

A rearrangementt is i nott wellll represented

t d by
b simple
i l and
d discrete
di t
electron transfers. The actual mechanism of alkyl groups moving
probably involves transfer of the moving alkyl group fluidly along a
bond, not ionic bond-breaking and forming.
Some key rearrangement reactions:
1,2-rearrangements
, g
pericyclic reactions
olefin metathesis
75
 Wagner-Meerwein rearrangement
A Wagner-Meerwein rearrangement is a class of carbocation 1,2-
rearrangement
g reactions in which a hydrogen,
y g , alkyl y or aryl
y ggroup
p
migrates from one carbon to a neighboring carbon.
The rearrangement was first discovered in bicyclic terpenes:

76
 Beckmann rearrangement
This is an acid-catalyzed rearrangement of an oxime to an amide.
Cyclic oximes yield lactams.
The mechanism is generally believed to consist of an alkyl migration
with expulsion of the hydroxyl group to form a nitrilium ion followed
by hydrolysis:
OH O
O N
H
H2SO4 N
NH2OH

cyclohexanone cyclohexanoxime caprolactam

77
 Claisen rearrangement
The Claisen rearrangement is a powerful carbon-carbon bond-
forming g chemical reaction. The heating g of an allyl
y vinyl
y ether will
initiate a [3,3] rearrangement to give a , -unsaturated carbonyl.

78
 Pinacol Rearrangement

79
 Hofmann rearrangement

80
6-55 Organic Redox Reaction
6
In organic chemistry oxidations and reductions are different from
ordinary redox reactions because many reactions carry the name but
d nott actually
do t ll involve
i l electron
l t t
transfer
f ini the
th electrochemical
l t h i l sense
of the word.
Categories or simple functional groups arranged according to
oxidation state

81
I Organic
I. O i reductions
d ti
Several reaction mechanisms exist for organic reductions:
Direct electron transfer in Birch reduction
Hydride transfer in reductions, LiAlH4
Hydrogen reduction with a catalyst such as Lindlar catalyst
Disproportionation reaction such as the Cannizzaro reaction

H H
Birch reduction: Na
NH3 (l), ROH
H H
H
R O H H H H R O H H
C
H H

C C C
H H
e H e H H
82
83
II. ORGANIC OXIDATIONS
Several reaction mechanisms exist for organic oxidations:
Single electron transfer;
Oxidations through ester intermediates with chromic acid;
Hydrogen
y g atom transfer as in Free radical halogenation;
g ;
Oxidation with oxygen (combustion);
Oxidation involving ozone (O3) in ozonolysis;
Oxidations
O id ti involving
i l i an elimination
li i ti reactionti mechanism
h i such
h as
the Swern oxidation;
oxidation by nitroso radicals, fremys salt or TEMPO.

Na2Cr2O7, H2SO4
94%
OH H2O, Et2O
O

84
Ozonolysis

85
Oxidation by TEMPO

86