ADDITION REACTIONS

•Key words: Addition to alkenes and

alkynes, markovnikov’s rule,
electrophilic and nucleophilic
additions
Introduction
Conversion of multiple bonds, such as a double or a triple bond, into
other functional groups are usually achieved using addition reactions.
The reaction of multiple bonds will convert an unsaturated compound to
more saturated and functionalized species. In this module, a number of
examples of electrophilic addition to electron rich double bonds are
presented. When a double bond is activated by attaching it with electron
withdrawing groups, conjugated addition is observed. Regioselectivity as
well as stereochemical considerations are presented in this chapter.
 ELECTROPHILIC
ADDITION REACTIONS

Markovnikov’ additions
Markovnikov’s rule
 Addition of hydrogen to an unsymmetrical olefin occurs at
those carbon atoms with maximum number of hydrogen
atoms. (i.e., the carbon with least substitution).
 Electronegative group goes to more substituted carbon
atom.
 Such an addition leads to a stabler carbocation.
 Such a reaction may lead to constitutional isomers but
actually one of the products is formed as major product.
X

X
Formed
H
HX
X=F, Cl.
X
Olefin
Not formed
 Origin …
X

HX X

X=F, Cl .
carbocation is more stablised in T.S.

Stereo specific product

H X X

carbocation is not enough stablilised in transition state

Olefin

 Consider two possible sites for hydrogen addition (i) terminal or (ii)
internal (substituted carbon).
 The addition of hydrogen at the terminal carbon leads to better
stabilization of carbocation, the chances of stabilization increases with
increase in conjugation with olefin.
 The terminal carbocation require higher activation energy which is not
a favorable condition, leading to slower reaction rate. However, the
generation of non terminal carbocation is assisted by hyperconjugative
stabilization leading to a lower activation energy.
Alkenes-some facts
 Due to trigonal planar geometry of olefin carbon
atoms the addition can occur on the same side (syn
periplanar) or on opposite sides (anti periplanar).
 Alkenes are generally nucleophilic. The C=C double
bond provides a higher energy HOMO (highest
occupied molecular orbitals).
 Electron donating groups increase the rate for
electrophilic attack as they assist in carbocation and
positive charge stabilization in the TS.
 REACTIONS of ALKENES
H
OH
OH

X
Hydrohalogenation X

1.OsO 4 HX
X
2.NaHSO 3 (X=halogen)
CH
Carbene addition I
2
2 ,Z Halogenation
Et n(
Cu
2O ) X2 (X=Cl,Br)
RO
DR. SUNOJ (IIT MUMBAI)
H X
1. Cl2 or Br 2
2. H2 O
1.Hg(OAc) 2 OH
2.R-OH olefins
1. acid
2. H2 O Halohydrin formation
1.Oxymercuration
2.Demercuration 1.BH 3 R-COOH Peroxy Pt ,H 2
2.H2 O2 ,OH H 2O 2 acids H
HO
H
OH

O
Hydration
Hydroboration Epoxidation
 1.HALOGENATION REACTION

 In this reaction the pi bond of alkene and σ bond of

halo acid is broken to form two new σ bonds.
 The reaction generally follows Markovnikov’s addition.
 In the first step, the alkene pi bond acts as a Lewis base
to add to an electrophile.
 In the second step, the halogen act as a Lewis base to
attack the Lewis acid, i.e. the carbocation.
 Reaction is exothermic as reactant posseses higher
energy bonds than the products .
Example of bromination reaction
 In this reaction alkene interacts with LUMO of
bromine (i.e. empty σ* orbital) to form a three
membered cyclic bromonium ion intermediate.
 The bromide anion attacks the cyclic bromonium ion
resulting in generation of product 1,2-dibromide
Br
Br
slow SN2 attack
Br Br Br

Br
cyclic bromonium ion
 stereochemistry
stereoselectivity
 Achiral olefin in halogenation reaction results in the formation
of racemic mixture as shown below. H
H
H 3C S H
H3C
Br Br S Br
Br
S R
C2 H 5
C2H5
H
H H
Br
Br
H C2 H 5 H H
H3 C C 2H 5 H 3C H
Br Br

H3 C C 2 H5 C2 H 5
BromoniumHion H H3 C
Bromonium ion
Trans-2-pentene Cis-2-pentene
Br
H 3C
H R H

H3 C
R H Br
Br R
Br
S C 2H 5 C2 H 5
H
Both cis and trans-2-pentenes (±)Enantiomers
produce racemic mixture (in the
(±)Enantiomers
absence of any chiral source)
 The reaction of olefins with halo acids in the presence of
Halohydrin formation reaction
aqueous solvents is termed as halohydrin reaction.
 Reaction generally follows Markovnikov’s rule.
 The reaction takes place with anti addition.
 Bromine water & N-Bromo succinimide are commonly used
reagents in bromohydrin formation.
 Chlorine water can be used for chlorohydrin formation.

Br

1.Br2
2.H2 O OH
Mechanism (halohydrin formation)

 The reaction starts with attack of π bond of alkene on σ* bond of

Br2 to form a three membered cyclic bromonium ion.
 Water can attack the bromonium ion as shown through a SN2
transition state . Markovnikov’s rule is generally obeyed. Anti
addition take place.

Br
R R' R Br R' Br

- Br
..
R'' R''' O OH
R'' R''' H H
O
Br Br
 Why don’t the halide ion attack
HH
as in conventional halogenation….?
stereochemistry
 Regioselectivity :-In case of alpha methyl styrene the addition of
hydroxyl occur at the more substituted carbon to give the major
product. Br HO

OH Br

N-Bromo succinimide
95% aq. acetone.

Major product Minor product

 Stereoselectivity :- the addition of hydroxyl group occur anti to

the halonium ion giving major product. In the bromohydrin
formation reaction of cyclohexene we get trans bromohydrin as
major product.
H H
O OH 2

OH
Br

Br Tr ans - Bromohydrin
Br
Br Br
Addition of water or solvent to alkene
(oxymercuration , demercuration ,solvomercuration )
 Most of the alkenes do not favor hydration when subjected to aqueous acid.
Here is a better approach to overcome this situation.
 Oxomercuration :-Convert alkene to organomercurial alcohol in aqueous solvent.
 Demercuration :- Transforms organomercurial alcohol to corresponding alcohol.
 Solvomercuration :-Transfer organomercurial ether to product ether as per the
solvent used.
 General reaction :-

HOR NaBH4
Hg(OAc)2 demercuration
oxymercuration
HgOAc H
OR
Alkene Mercuric acetate OR
organomercurial ether or alcohol

 Generation of reagent :-

O O O O

Hg Hg
O O aq. medium O O
+vely charged mercury species Acetate anion
acting as electrophile
MECHANISM ….
Mercuration /solvomercuration :-
 The reaction starts with nucleophilic attack by double bond on +vely
charged mercuric acetate species resulting in the formation of three
membered cyclic mercurinium ion.
OAc

O Hg
Hg
O

Alkene
 In this step SN2 attack by the solvent leads to the formation of
organomercurial species.
HgOAc HgOAc
OAc

Hg
SN2 attack

O OR
H R organomercurial alcohol or ether
OH
R
H2O
 Demercuration :- In this step there is substitution of hydrogen
in place of mercuric group to give the final alcohol or ether.
HgOAc

NaBH 4,NaOH,H 2O
H
OR
OR Alcohol or ether
(R = Alkyl, H)

 The reaction take place following Markovnikov’s rule i.e.

addition of hydrogen occurs at the least substituted end.
H 2O
H H
H OH
Hg(OAc) 2 H

H 2O
H H H H Hg(OAc)
Hg
(OAc) H
3,3-dimethyl-1-butene Markovnikov product

NaBH4
reduction

OH H
H

H
H

3,3-dimethyl-2-butanol (major)
 Substituted Theophylline Mercurials and Their Demercurating
O COCF
Reactions. H C O Ac H3 C
3

3
N N
N
N Hg(OCOCF3)2 in CF3COOH HgOCOCF3
Mercuration N
N O N
O N
CH3
CH3

H2 O

O H H
H3 C O
H3 C
N N
N Halo- demercuration
N
X HgOCOCF3
O N N N
O N

CH3 CH3

X = Halogen

 Bergstrom, D. E.; Ruth, J. L. J. Am. Chem. Soc. 1976, 98, 1587.

 Korn, A. P.; Ottensmeyer, F. P.; Jack, T. R. Inorg. Biochem. 1979, 10, 235.
Solvomercuration examples...

 Solvomercuration in the presence of trifluoroacetate mercury (II) salt

{Hg(OCOCF3)2}. The reason for using trifluoro acetate salt instead of
acetate salt is to enhance electrophilicity .
 Examples :-1. conversion of 1-ethyl ethene to corresponding ether.
Hg(OCOCF3) H

Hg(OCOCF3)2 NaBH4
Ethyl alcohol
OC2H5 OC2H5

 Ether synthesis from cyclopentene.

OCH2CH(CH 3) 2 OCH2CH(CH3) 2

Hg(OCOCF3)2 NaBH4
1,1-dimethyl ethanol

Hg(OCOCF3 ) H
DIOL FORMATION REACTIONS
 Diol formation in alkenes can be achieved from
various reactions :-
Hydroxylation with Potassium permangnate.
Osmium tetroxide catalysed dihydroxylation.
Upjohn dihydroxylation.
Woodward reaction.
Prevost reaction.
Epoxide ring opening reaction.
Hydroxylation with Potassium permangnate.
 Hydroxylation is carried out in cold media preferably in basic
conditions.
 Hot conditions may lead to oxidation forming carboxylic acid
 The hydroxylation occur with syn addition & formation of cyclic
intermediate.
OH
O O

Mn

O O OH

OH
COOH
MnO 4, base
cold aq solution COOH
OH
 Disadvantages :-
 The product yield obtained is very low.
 The product can be a mixture of diol & carboxylic acid.
 A better stereoselective epoxidation can be achieved with Osmium
tetraoxide.
 Osmium tetroxide catalyzed asymmetric dihydroxylation
(sharpless dihydroxylation)

 In 1980, Sharpless reported the first asymmetric dihydroxylation of olefins by

replacing pyridine with a chiral tertiary amine ligand derivatives dihydroquinine
acetate with improved yield.
 The addition of diol takes place without affecting the other functional groups in
the molecule.
 Reagents are commercially available as preformulated mixtures: (Asymmetric
Dehyroxylation) AD-mix α and AD-mix β containing the necessary bidentate
chiral ligand, stoichiometric oxidant, and the osmium tetroxide in the form of
dipotassium osmate dihydrate (K2OsO4(OH)4).

R R' OsO in catalytic amount

4 OH
chiral ligand in catalytic amount HO

AD-mix alpha or AD-mix beta

oxidant in stoichiometric amount
R'' R''' organic /aqueous solvent HO OH
R,R',R'',R''' =H ,alkyl or aryl group Entantiomeric cis vicinal diol
Recent Developments in the Osmium-
catalyzed Dihydroxylation of Olefins :

The two catalytic cycles in the asymmetric dihydroxylation

Selectivity of addition
 The addition of both hydroxyl groups occur on the syn face.
 The selectivity of the face is decided as per the reagent used.
AD-mixα :- (DHQ)2PHAL + K2OsO2(OH)4 + K3Fe(CN)6
AD-mix β:- (DHQD)2PHAL + K2OsO2(OH)4 + K3Fe(CN)6
HO OH
AD mix beta (top face or beta face)
R
R'

R'' R'''

AD mix alpha (bottom face or alpha face)

R= small group , R'= Medium group HO OH

R''= Large group , R'''= Smallest group or H

Enantiomeric cis or
vicinal diol
Epoxide ring opening reaction.
 Epoxide ring opening results in the formation of trans diol.
 Epoxide ring opening can be achieved by using an electrophilic or a
nucleophilic reagent.
 The ring opening occur by SN2 mechanism, hence the diol formed will
be exhibit a trans geometry.

Electrophilic ring opening

H
HO HO
O O
acid in aq. medium

OH2 OH
H2O
Nucleophilic ring opening

O H2 O HO
O O
nucleophile in aq. medium

OH OH OH
 Ring opening in the presence of organometallic reagents (RMgX,
RLi, RCºCM, LiAlH4, NaBH4,transition metal catalyst ):-
 Organometallic reagents can act as nucleophile in epoxide ring
cleavage reaction
 The reaction takes place by SN2 attack resulting in the
formation of trans product.
 Organometallic reagent react with epoxide in basic media as
they are strong nucleophlies.
 When these nucleophilic reagent attack, it results in breaking of
the epoxide ring with formation of alcohol after acidic workup.
 In the case of Grignard reaction the C-C bond formation occur
at the β position from the newly formed hydroxyl group.

O
R R
acid
OMgx hydrolysis OH
RMgX
(X=Halogen) MgX2
Cyclopropane ring formation
reactions
Simmon-Smith reaction.
Howard Ensign Simmons, Jr. and R. D. Smith

 A Organo chelotropic , stereospecific reaction of

alkene with di-iodo methane (used for synthesis of
non halogenated cyclopropane) in the presence of
copper-zinc couple is called Simmon-Smith reaction.
 The methylene group is added to a less sterically
hindered face of alkene making the reaction stereo
specific.
 General reaction :-
CH 2I2 Zn/Cu ICH 2z nI

R' R''' R' R'''

ICH2 znI ZnI2

R R'' R R''
MECHANISM
 The mechanism is concerted which involves carbene transfer
assisted by Zinc catalyst. The stereoselectivity depends on the face
on which the addition takes place & presence of different groups
on the substrate.
I
H
ZnI
Zn(Cu) C
CH 2I2 Zn H2
diethyl ether I
as solvent. I
H

ZnI2

 In substrates like allylic alcohols, the cyclopropane ring formation

occurs on the same side of the –OH group. (this is due to a weak
bonding in the corresponding TS).
weak bond with hydroxyl oxygen
in T.S. OH
OH OH HO
I ZnI
H

Zn(Cu) C
CH 2I2 Zn H2
diethyl ether I
as solvent. I
H

ZnI2
More examples on cyclopropanation
H OH H OH H OH
Z n(C 2H 5)2 , CH 2I 2 (5 eq)
CH 2I 2 , -10 C to R.T.
H3 C CH 3 H 3C CH3 H 3C CH3

H H H

75% yield sy n : anti (6:1)

H OH H OH
H OH
Zn(C2 H5 )2 , CH 2I 2 (5 eq)
CH2 I2 , -10 C to R.T . Ph CH3 Ph CH3
Ph CH 3
H H
H
86% yield sy n : anti (7:1)

H OH H OH H OH
Z n(C 2H 5)2 , CH 2I 2 (5 eq)
CH 2I 2 , -10 C to R.T.
Ph Ph C2 H5 Ph C2 H5
C2 H5

H H H
97% yield syn : an ti (130:1)

H OH H OH H OH
Zn(C2 H5 )2 , CH 2I 2 (5 eq)
CH2 I2 , -10 C to R.T.
Ph Ph C 2H 5 Ph C 2H 5
C 2H 5

H H H
87% yield syn : ant i (110:1)
Johnson-COREY-CHAYKOVSKY reaction
[A. William Johnson , E.J. Corey , Michael Chaykovsky ]
 The reaction involves the synthesis of epoxide from aldehyde & ketone,
aziridines from imines , cycloprapanes from enones.
 The reaction is diastereoselective favoring trans substitution in the
product regardless of the initial stereochemistry.
 The ylides are generated in situ by the deprotonation of sulfonium
halides with strong bases.
 General reaction :-
Sulfur ylides u sed O O
Sulfu r ylid e
O O Dimethyl sulfoxide R R'
R R'
Epoxide
S S Aldehyde or ketone

NH HN
Dimethyl sulfoxonium methylide
Sulfu r ylid e
Dimethyl sulfoxide R R'
R R' Aziridine
Imine
O O
S
S
Sulfu r ylid e
Dimethyl sulfo xide R
R
Dimethyl sulfonium methide
Enone Cyclopropanes R'
R'
mechanism
 In the reaction the nucleophilic sulfur ylide attacks the
carbonyl or imide substrate.
 The negative charge is transferred from anionic carbon of ylide
to electronegative group of substrate as a result sulfonium
cation is expelled & formation of cyclopropane or epoxide ring
take place.

Generation of sulfonium halide (In situ ,presence of strong bases)

R'
X base
S S
S
DMSO
R CH 3

R
R'
Base
S S
O CH 3 DMSO
X O

When R , R' are one or both elctron withdrawing group the ylide formed is stable.
 Contd…..
Reaction with aldehyde or ketone.
R' R''
O O
O S
1
S S
H 3C R''
R 2 R''

R' NH NH R''
HN S
S 1
S
H 3C R''
R 2 R''

O
O O
R' R' O
3 1 R''
R'' S S
S R''
2
R R 4
 Reaction with Michael acceptors:-
Unstabilised ylides(kinetically controlled product):-the epoxide formed is irreversible
,unstable undergoes ring closure to form 1,2 addition product i.e. epoxide.
Stabilised ylides (thermodynamic product):- ylides stabilized with electron
withdrawing group give 1,4 addition product. Although 1,2 addition product is
formed but it is reversible kinetic product. 1,4 addition product formation result
due to strong sigma bond formation at the expense of pi bond forming stable
product.
STEREOCHEMISTRY
In cyclopropanation, the reaction occurs with anti betaine formation
resulting in trans product formation.
 This is due to rotation around the central bond in a molecule to attain a
more stable conformation , a back side attack result in trans product
formation.
 In the case of the synbetaine the barrier to bond-rotation was higher
than reversal to starting materials whereas for the anti-betaine, the
barrier to returning to starting materials was higher than bond rotation
to the transoid conformation.
HYDRO BORATION REACTION
Herbert C. Brown

 The addition of water to alkene in the presence of boron reagent are

known as hydroboration- oxidation reaction.
 The addition follows syn addition with cis stereoselectivity.
 Unlike other addition reactions, here the hydroxyl group get added
to the least substituted carbon.
 In this reaction peroxide also play a equal role in deciding the site of
addition.
 In such reaction the reagent BH3 is used which consist of
electrophilic boron and electron donation is done by hydrogen
atom.
 No carbocation intermediate is involved in this reactions
suggesting that a concerted addition take place.
 If BH3 is used as reagent it can hydroborate three alkene units. The
number of alkenes undergoing hydroboration are equal to no. of
hydrogens attached directly to boron in the borane reagent.
 The product obtained in such reactions are a racemic mixture, the
stereoselectivity can be improved by using chiral borane reagents.
REACTION :-
 Concerted addition of boron to sterically least hindered carbon.
 The oxidation occur in the presence of peroxide to give the syn addition
product.

MECHANISM Of HydroBoration:-
 In the first step alkene acts as a nucleophile and attack on electrophilic
Boron.
 In the Second step ,Peroxide act as nucleophile & attack the electrophilic
boron followed by migration of C-B bond to form C-O bond. Hydrolysis
result in formation of alcohol.
 First Step:

Second Step:
stereoselectivity
 Some of the commonly used boron reagents for regioselective
hydroboration reactions.
9-Borabicyclo(3.3.1)nonane (9-BBN)
Disiamylborane. (Sia2BH)

 EXAMPLES:-
 Hydroboration of cis-4-methyl-2-pentene
H OH HO H
(H3C) 2HC CH3
(H3C) 2HC CH 3 (H 3C) 2HC CH3
1. 9-BBN , THF
2.oxidation
H H H
H
H H 2-Methyl-3-pentanol
4-Methyl-2-pentanol,
With 9-BBN 99.8% 0.2%
With Sia2BH 97% 3%
 Hydroboration of 1-methyl cyclopentene.

OH

OH
1.Hydroboration
2.Oxidation

2-methyl cyclopentenol
With 9-BBN 99.9%

BH3 98.5%

HBCl 2 99.8%
Epoxidation reactions
Epoxide formation reaction
Some General Feature of Electrophilic Epoxidation
Epoxidation using peroxy acids is described here
Epoxidation is favored by electron donating substituent.
More the electron donating ability of the substituent on
the double bond, higher is the energy of alkene HOMO
resulting in increase in nucleophilicity.
More nucleophilic the pi bond is, greater is interaction
with the σ* orbital of the electrophilic O-O bond
increasing the rate of oxirane formation.
A peroxy acid or peracid is an acid
in which an acidic -OH group has been replaced by
an -OOH group. They are less acidic compared to carboxylic acids.
All peroxy acids are very powerful oxidizing agents with electrophilic properties.

Peracids that are not commercially available are prepared

by the reaction of the acid
chloride or anhydride with high strength hydrogen peroxide or urea and hydrogen
peroxide.
The major attribute ofperoxy acids is the presence of electrophilic oxygen between
the carbonyl carbon and the -OH group, which is attacked by pi (π) bond containing
compound with high electron density.
Peroxy carboxylic acid have electron deficient low energy LUMO which is the sigma*
O-O bond.
 Mechanism of epoxidation

Step I :- Attack of nucleophilic alkene on electrophilic oxygen of peroxy acid.

Step II :- Transfer of electron density from O-O bond to electrophilic carbonyl
Oxygen.
Step III :- Attack of carbonyl oxygen on –OH Hydrogen leading to it’s abstraction.
Step IV :- Release of Carboxylic acid.
 Stereochemistry of epoxidation
 Formation of epoxide occurs on the same face of pi (π)
bond being attacked, hence geometry of alkene is
preserved in the product.
 e.g., epoxidation of cholesterol to 5α,6α- epoxy
cholestan-3β-ol using m-chloro perbenzoic acid.

Cl
H
H
O
OH

H H O
,heat H H

HO
HO Cl Cl O

Cholesterol 5α,6α- epoxy cholestan-3β-ol

 Epoxidation occurs from (alpha attack) lower side of

cholesterol molecule selectively .
 Influence of –OH and -NH group on
epoxidation.(The concept of hydrogen bonding).
 When an allylic alcohol or allylic amine is epoxidized the peroxy acid prefer to
attack from the same side of –OH or -NH .
 The TS stabilization through hydrogen bonding leads to a syn product in
excess.

NHR
NHR Hydrogen Bonding.
O
O H

N H
R O
O
O O
HO
cis-product
 When the nitrogen or hydrogen group is masked then the epoxidation
formation occur below the ring & the previous
Transition trend is followed.
State.
Epoxidation in the absence of hydrogen
bonding.
 In the example below when the amino group was masked, major
product was obtained with epoxide below the plane i.e., anti
addition.
NHCOCl NHCOCl
NHR
O
epoxidation
heat O

Cl

HO Me3 SiO Me3 SiO

SiMe3 Cl R-COOOH
Epoxidation
O

 Hence, distereotopic addition to double bond in compound with

hydrogen bond donors can be controlled.
Vanadium catalyzed epoxidation
 Syn epoxidation of allylic alcohol in presence of VO(acac) & tert-
butyl hydro peroxide .
 General reaction :-
VO(acac)2
O
t-BuOOH

OH OH

Formation of vanadyl complex :-

O
O
O
vanadyl V V
V O O
O O O O

O O
enolate ion of 'acac'
acetyl acetone. VO(acac)2 complex
reactions
 Vanadium catalyst works best for epoxidation of homoallylic alcohol
Ph Ph

VO(O-iPr)3 ,(1 mol%)

O
cumene hydro peroxide , toluene
rt, 24hours

OH OH
J. AM. CHEM. SOC. 2007, 129, 286-287 90%yield,96% ee
 Homogenous catalysis showed higher yield but relatively same enantiomeric excess as in case
of heterogeneous catalyst.[ACS 0002-7863/79/15OI]
OH HO HO
O O

Vanadium catalyst
t-BuOOH

cis-epimer trans-epimer

Ligand% valency % yield Cis epimer Trans epimer system

VO(acac)2 +4 83 97 3 Homogenous
VCI4 +4 86 96 4 Homogenous
VO(SO4) +4 65 97 3 Homogenous
V(acac)3 +3 79 97 3 Homogenous
V2O5 +5 29 95 5 Heterogenous
CsH5V(CO)4 +1 75 94 6 Homogenous
Sharpless epoxidation
Barry K. Sharpless

 The Sharpless Epoxidation is used for enantioselective epoxidation of

prochiral allylic alcohols (primary and secondary allylic alcohols)
 The asymmetric induction is achieved by adding an enantiomerically
enriched tartrate derivative.
 oxidant :- hydroperoxide(tert-butylhydroperoxide in a stoichiometric
amount).
 The catalyst is cheap, easily available, and the requirement is only 5-
10% mol of the substrate when used in molecular sieves.
 Yield of Sharpless epoxidation reaction are good with more than 90%
of enantiomeric excess and is determined by the isomer of diethyl
tartrate or di-isopropyl tartrate used.
 3Å Molecular sieves are used to remove water from reaction as water
destroy epoxide ring and catalyst. Catalyst consumption can be
reduced to 5% to 10% by use of molecular sieves.
 COOEt
i-Pr

Sharpless epoxidation
i-Pr
catalyst
O

O
O O
O
HO
COOEt i-Pr Ti Ti
Ti(O-iPr) 4
EtOOC Oi-Pr
Titanium isopropoxide O O
OH COOEt
L-(+)-Diethyl tartarate O OEt

 Each Titanium isopropoxide is O

co-ordinated to one carbonyl group C t-BU-OOH

ter-Butyl Hydroperoxide
of tartarate ligand. OEt

 When tert-butyl hydro peroxide is COOEt

i-Pr
added it displaces one isopropoxide O

ligand and carbonyl group from

i-Pr
EtOOC
O
tartrate to form the final catalyst O O

for epoxidation i.e. dimeric titanium

O
i-Pr Ti Ti
species. O
O O
Visual Representation :- COOEt
Isopropoxide ligand:- violet O

Diethyl tartrate:- red O

t-Bu
t-butyl hydroperoxide :- green
C
Allylic alcohol :- black
OEt
Dimeric Titanium Species.
Mechanism of epoxidation :-
COOEt
i-Pr COOEt

O O
i-Pr i-Pr
EtOOC EtOOC
O O
O O O O
O O
Ti Ti i-Pr Ti Ti
i-Pr HO R

O O O O O O
COOEt Allylic alcohol COOEt
O
O
O
O t-Bu
t-Bu R
C
C
COOEt
OEt
OEt
Dimeric Titanium Species. O
i-Pr
EtOOC
O
O O
HO O
i-Pr Ti Ti

O O O
COOEt
O
O
O
t-Bu
R
R C

Epoxide OEt
Alkene complexation
Selectivity offered by diethyl tartarate.

 The enantioselectivity of oxygen addition to the face of allylic

alkene is dependent on which stereoisomer of diethyl tartrate
(DET) used in the reaction.
 If (-)-DET is used, the addition of oxygen occurs above the plane as
shown.
 If (+)- DET is used, the addition of oxygen occurs below the plane.
D-(-)-DET
Addition of oxygen occur at the top face.

HO O
Ti(O-iPr) 4 ,cat. D-(-)DET
R D-(-)DET
t-BuOOH R

R D-(+)DET
OH

Allylic alcohol in Plane O

R
D-(+)-DET
Addition of oxygen occur below the plane.
Application of Sharpless epoxidation

O
OH 5% Ti(OiPr)4 ,7.4% (+)-DET OH
-20 C ,14hours
epoxidation occur selectively 95% yield , 91% ee
on allylic alcohol double bond.

Intermediate for synthesis of leukotriene C1

COOCH 3 COOCH 3
Ti(OiPr )4 ,(+)-DET , TBHP

OH CH 2Cl2 hours ,-20 C ,48hour s. O OH

80% yield, 95% ee
Recent modifications in Sharpless epoxidation (Additional
Information)
Problem Solution Results

Presence of water lead to failure of Use of molecular sieves which can •Increase in yield
epoxidation. absorb water . •Catalyst consumption reduced
•epoxide ring breaking, (10-15% of original value.)
•Destruction of catalyst •Ease of isolation of product

Solubility Use of chiral polymeric support with •Improved enantioselectivity.

•Some reactant may not be active functional group. (e.g. •Improved yield.
completely soluble. polystyrene support)
Heterogeneous catalysis •Use of porous silica support •Improved yield.
•Catalyst and reactant should be in •Ageing of catalyst •Lesser consumption of catalyst
different phases to perform proper •Change of solvent (less polar to •Continuous reaction & product
isolation of product. medium polar) Isolation is possible.
•Use of polymeric support.

Enantioselectivity Can be improved by higher •Improved enantioselectivity.

derivative of tartrate ligand (diethyl
replaced by iso propyl).

Temperature Use of catalyst like titanocene •Enhanced enantioselectivity and

•Some reaction require high tartrate which can work at high higher yield for reaction requiring
temperature temp. & provide better steric high temperature.
hinderance .
JACOBSON EPOXIDATION (EPOXIDATION OF CIS ALKENES) .
 The Sharpless assymetric epoxidation works better with trans alkenes and
allylic alcohols, but produces low yields with cis-alkenes.
 Jacobson Epoxidation can be used to overcome this problem.
 Jacobson epoxidation allows enantioselective epoxidation of
unfunctionalized alkyl- and aryl- substituted olefins.
 The Jacobsen catalyst is a C2 symmetric manganese(III) salen-like complex,
in catalytic amounts to achieve better stereoselectivity.

N N

Mn

R O O R
Cl

R R
R = alkyl ,t-butyl, o-alkyl ,o-trialkyl.
Jacobson catalyst.
 Reaction ,
R R' R'
Mn-salen catalyst, aq. NaOCl R
CH2 Cl2
H H
O
 The addition of Mn(V) species take place from the side with lower
steric interaction.
R1 R2 R1 R2

(I) O O
Mn
cis epoxide

R1 R2
R1
O (II) R1 R2
+
R2 MnV Mn O O
trans epoxide

R1 R1 R2
O
(III)
Mn O
R2
cis epoxide

(I) = concerted mechanism

(II) = radical mechanism
(III) = via manganoxetane intermediate
a: R1 = alkyl, alkenyl, aryl
b: R1=R2=alkyl
Hydration reactions (addition of water)
 General reaction :-
OH

H 2O H

 Mechanism :-
H
O OH
H
H H 2O B
attack of BH
nucleophile
deprotonation
Protonation to generate more stable carbocation.

 The reaction is regiospecific & follow Markovnikov rule of addition i.e.

formation of carbocation at highly substituted end.
 More the substitution with electron donating group more stable is the
carbocation formed.
NUCLEOPHILIC ADDITION REACTIONS of olefins
Condition for nucleophlic addition reactions

 Normally olefins have electron rich HOMO which favor its

reaction with elecrophiles.
 For nucleophilic addition to take place the alkene should be
attached with an electron withdrawing group, which can
withdraw electron density from the pi-bonds of alkenes.
 When electron withdrawing groups are attached to alkenes, the
LUMO gets more stabilized. This will help to improve the
interaction with the incoming nucleophile
 Some examples of this class of reactions are,
Conjugate addition reactions.
Hydroamination reaction.
Amination reactions
 The addition of nucleophilic amino group across double bond
are called hydroamination reactions.

2% Pd(OAc)2
NH
2% PCP ligand
RT, 12H N CN
CN

98% Yield

NH 2 10% Pd(OAc)2
CN 10% PCP 1,100 0C, 36 H NH
Nucleophilic conjugate addition
 The addition reaction of α, β–unsaturated carbonyl compounds and α, β–
unsaturated nitriles with nucleophiles at 1,4- position is called nucleophilic
conjugate addition.
 alkene having carbonyl or nitrile group in conjugation increases reactivity
toward nucleophiles by resonance stabilization.

Nu OH
H+
1,2
1,2
Nu O
1,4

O
+
H
1,4
Nu

1,2-additions* are also known as direct addition

1,4-additions are known as conjugate addition
Example and Key Steps
 a

Me H Me
H
O N O N OH
Me Me
Me N

Me

Me
O N O
Me
(Me)2NH +

Key factors that control conjugate addition are,

(i) Reaction conditions
(ii) Nature of the α,β-unsaturated carbonyl compound
(iii) Type of nucleophile
 Preference for addition at 1,2 or 1,4 position.
 1,2 addition occur with stronger nucleophiles such as Grignard
reagents, organolithium, lithium aluminum hydrides, sodium
borohydrides.
 1,4 addition occur with weaker nucleophiles like thiols ,
enolates, cyanides, organocopper reagents etc.
 More Examples for 1,4-additions
CH 3
O
H 2N CH 3 60-700c
N
methyl amine 1 hour , 92% O
O
OC 2H5
EtO
OEt

 1,4-Addition reaction of ethyl bromodifluoroacetate to Michael

acceptors .

O O

TMEDA as cataly st
Ref lux for 7 hrs

CF2COOEt
73% yield
ALKYENES
 R'

Addition
R H H

Addition H

Reaction
H
reaction Hydrogenation (except Lindlar catalyst)

of of R R' R H

alkynes.
alkynes H H H R'
R'
Hydrogenation Reduction X
X
2H2 , (Ni /Pt /Pd) R
Hydrogenation or
& Reduction Na , liq. NH3 X
R Li X
with active Halogenation
metals R'
2 X2 H
Whe n R or R' (X= Br,Cl)
is hydrogen R X
R R'
with bases H
(Grignard reagent) Alkynes HX (X= I, Br Cl)
X
When R or R' Hydrohalogenation
is hydrogen H 2O , H2SO4
HgSO4
1.BH 3
R MgBr O
2.NaOH , H2O
R'
O R
Hydration
R
R
Hydroboration
& oxidation
Hydration reactions
 Hydration in alkynes is carried out using mercuric salts as catalyst.
 The addition gives more stable carbocation as per the Markovnikov’s
rule.
 General reactions:-
O
HO H

HgSO4
H 3C H
H 2O H 3C CH3
H3C
H
 Mechanism :-
H 3C Hg H 3C Hg
Hg
Hg+2 SO4 -2
H3C H

H 3C H
H 2O H HO H
H 2O
H

H 3C H
O

H 3C CH3

HO H
hydrohalogenations
 Addition reaction of haloacids occur in anti fashion following Markovnikov’s rule
i.e. the more substituted carbon result in carbocation to which halogen get
attached.
 Initial attack result in haloalkene which furthur react to give the geminal dihalide.
H H
R H R X
HX HX
R H trans addition to
H
Halogenation to form Geminal dihalide
form Haloalkene
X H X

 Examples :-
Cl H H
H
 1. Cl
HCl HCl Cl
H
H 1st eq 2nd eq. H
Ph

 2. H

HCl HCl
H CH3
1st eq 2nd eq.

Cl
Cl
H Cl Cl
 3.
Cl
HCl C 2H 5
CH 3 HCl
1st eq 2nd eq. CH 3

Cl
Hydrogenation and reduction
of alkyne is carried out using gaseous hydrogen at
high pressure using transition metal catalyst (Pt, Pd, Ni ).
 Hydrogenation with Lindlar's catalyst, (prepared by deactivating
palladium catalyst by treating it with lead acetate and quinoline) give
alkene with no furthur reaction, however direct use of Pt or Ni will result
in hydrogenation to alkane.
 Reaction in the presence of above catalyst give cis alkene with syn stereo
selectivity.
 General reaction :- H H H H
Pd , Pt , Ni Pt , Ni
H3C C 2H5 H H
H2 , under pressure H2 , under pressure
H3C C2H5 H3C C2H 5

of alkyne in presence of sodium in Liquid NH3 result in

anti addition to give trans alkene.
R H

Na,Liq NH3
R R'
anti addition
H R'
 The mechanism proceed by generation of electronic centre at a cost of a pi
bond followed by transfer of electron by metal in solvent cage (ammonia) ,
this result in formation of anionic centre on the substrate .
 The ammonia molecule now donate proton forming the ionic soda amide
again , this process repeat twice but this time from opposite centre on the
second carbon , giving trans alkene as product.
H
Na,liq.NH3
-2NaNH2
H

.
Na , 1 electron transf er H-NH2 -NH2
-Na

NH2 Na
-Na
H H
H
NH 2

 Similar type of reaction occur in case of reduction of aromatic compounds

especially benzene where the reagent posses the capacity to break the
aromaticity called Birch reduction.
DIENES
Electrophilic addition
 Dienes with electrophilic reagents like halo acids give electrophilic
addition reaction.
 Consider the reaction,
X

HX

R R
R
Electrophilic reagent
Conjugated diene X

R X R

1,2 addition product 1,4 addition product

 Which is the major product formed predominantly?

 The formation of product will depend on ,
 Stability of carbocation :-
• The addition of proton occurs as per the Markovnikov rule,
the stable carbocation will be formed at the more substituted
carbon atom.

+I effect from both methyl substituent +I effect from one methyl substituent

greater STABILITY lower

 Rate of reaction :-
• The energy of activation for the formation of 1,2 product is
lower and hence formed faster. However, equilibrium is less
favored.
• 1,4 product require higher activation energy but favors
equilibrium.
 Reaction temperature:-
• Kinetic product is product which appear first in reaction but the stable
product is the thermodynamic product.
• 1,2 product is formed first at lower temperature but rearranges to 1,4
product at high temperature or on standing for some time even at low
temperature.
 Reagent :-
• Use of milder condition gives mixture of products , use of excess of
reagent result in 1,4 product .

• Examples:-
Cl

0 0C
Cl2 gas

Cl
Major product Minor product

Br

HBr

Br
Reaction temperature 1,2 product 1,4 product
0 0C 70% 30%

400C 15% 85%

DIELS ALDER REACTION (CYCYLOADDITIONS)
 A class of concerted 4+2 addition cycloaddition are known as
Diels –Alder reactions.
 In this reactions two π bond of a conjugated diene interact with
one π bond of dienophile (an electron deficient alkene) forming
two carbon bonds in single step.

 Reaction occur with breaking of three π bonds (2 from diene + 1

from dienophile ) without formation of any ionic intermediate to
give two new σ bonds one π bond .
EWG
EWG
heat

4diene pi electrons
+2 dienophile pi electrons new pi bond
Cyclic Transition state
pi bonds showing breaking of pi bonds new sigma bond
and formation of two sigma
& one new pi bond(s).
Essential characteristics….
 For a Diels- Alder reaction to take place the diene should have
electron rich HOMO and the dienophile with electron deficient
LUMO.
 The reaction is thermally favored and not photo chemically,
hence reactants should be heated at high temperature .
 This can be briefly illustrated,

 Energy :-
 Diene
 Diene should be in cis conformation, dienes in trans conformation should
change to cis conformation which require energy, hence lower the rate.
 Presence of electron donating group [EDG] on the diene increases the
reactivity. EDG raises the energy of diene HOMO, this will cause more
favorable energy interaction with the LUMO of the dienophile.
 Any group present on the diene will have effect on the rate and
stereochemistry of reaction.
 Dienophile :-
 Dienophiles are alkenes having comparatively lower electron density than
diene.
 It should posses electron withdrawing group [EWG] which can withdraw the
electron density making them more electrophilic.
 This will decrease the energy of alkene LUMO favoring better orbital
interaction. The presence of EDG retard the rate of reaction.

DIENES
EWG EDG EDG
EWG :-
Carbonyl , ester,
nitriles , quaternary
EDG
amines, Halides
Reactivity :- Normal Good Excellent
anhydrides, nitro ,
Least
ester, quaternary
DIENOPHILES amines, acids etc.
EWG EWG EDG EDG:-
Amines , -OR,
-NHCOR , alkyl,
phenyls etc.
EWG

Reactivity :- Excellent Good Normal Least

 Orientation or regioselectivity :-
 As per the frontier molecular theory approach pseudo para or ortho
orientation is favored in products, meta orientation is least favored.
 When diene contains an electron donating substituent and dienophile an
withdrawing substituent, the orientation is such that there is maximum
electron flow toward the electrophilic substituent as shown below
EDG EDG

EWG EWG

Pseudo para orientation

EDG EDG

EWG EWG

Imaginary f low of electron Psuedo meta orientation

 Stereoselectivity
 Diels –Alder reaction exhibits excellent stereoselectivity.
 The stereoselectivity of reactant is maintained in the products
both in case of diene and dienophile. The addition is syn addition
as shown below

Heat
COOEt

COOEt

NC
CN
Cis product:-
CH 3 CH 3 CH 3 CH 3
1. 2.

COOEt COOEt COOEt COOEt

CN CN CN CN

C2 H5 C2 H5 C2 H5 C2 H5
Cis product Cis product

Trans product:-
CH 3 CH 3
3. 4.

COOEt COOEt COOEt COOEt

CH3 CH3

CN NC CN
NC

C2 H5 C2 H5 C2 H5 C2 H5
Trans product Trans product
Orientation of dienophile and end/exo product

 Dienophile are electron deficient. They would try to approach the

diene in such a manner that the electron withdrawing group will
remain toward the newly developing π bond, giving endo as the
major product.
COOEt

DAR COOEt
COOEt

CN CN
CN

Major product Minor product

 In general, Diels Alder reaction are thermodynamically

controlled. Exo product is the kinetic product that appear as a
minor product in the reaction.
 Catalysis
 Catalyst increases electron withdrawal capacity of dienophile making it lower in
energy thereby decrease the HOMO-LUMO gap between diene and dienophile.
 This can be achieved by using Lewis acid catalysts (AlCl3, SnCl4, BF3, TiCl4 etc. ).
Lewis acid coordinates with Lewis base of the dienophile making it more
electrophilic by withdrawing the electron density.
 Examples:-
O

Ti (IV)
Aqueous solvent
20 hours
Conc. Yield
O

1,3-cyclohexadiene p-benzoquinone O 0 % mol 61 %

endo-tricyclo-
 Molecules 2007, 12, 1674-1678 [6.2.2.02,7]dodeca-4,9-3,6-dione
5 % mol 83 %
 Enantioselective Diels-Alder Catalysis by Chiral, Cationic
Oxazaborolidines .
 Oxazaborolidines when protonated with trifluoromethanesulfonic
(triflic) acid gave an enantioselective catalyst for reaction of 2-substituted
acroleins. Reaction :-
H Ar CHO CHO

Ar 20% mol of 1 , -950C,

1 hr ,Diels- Alder reaction

O
N
TfO H
B
95 % yield , 94% ee
H with 92% endo product
O
o-toluidene O

1. Ar = phenyl
2. Ar = 3,5-di-methylphenyl
Diels Alder reaction
CATALYST

O O O O

J. AM. CHEM. SOC. % ee

Catalyst Temp. Time % Yield (endo:exo)
2002, 124, 9992-9993 33 (>98:2) 84
20 % mol of 1 -200C 1 hr.
1hr. 80 (.98:2) 92
10 % mol of 1 -780C
1hr. 91 (98:2) 71
20 % mol of 2 -780C
(I. A) Addition of HBr across carbon-carbon double bond
H
HBr
(1)
H

(2) HBr

(3) Ph HBr
Br

HBr
(4)

H
HBr
(5) H

HBr
(6)
CH 3COOH
40°C
(I. B) Addition of HCl and HI across carbon-carbon double bond
HCl
(1)
CH 2Cl2

CH 3
D HCl
(2) D D
25° C

CH3
(3) (CH3 )3 SiCl
H3 CHC CCH 2CH3
H2 O

(4) HI

(I. C) Addition of Br2 across carbon-carbon double bond

(a) Br2
heat
(5)

(b) Br2
low Temp

(6) Br2

Br2
(7)
MeOH
(I. D) Oxymercuration-Reduction

Hg(OAc) 2
(1) (CH 3 )3 CCH CH2
H2 O, NaBH 4

(CH2 )CH CH2

Hg(OAc)2
(2) O
H 2O, NaBH4
O

(3) Hg(OAc) 2

H2 O, NaBH 4
CH 2

Hg(OAc) 2
(4)
CH 2 H2 O, NaBH 4

Hg(OAc)2
(5)
H 2O, NaBH4
(I. D) Epoxide formation

(a) Br 2, H2 O
(1)
(b) NaOH

H O
O Cl
O

(2)
(m-CPBA)

(3) m-CPBA

m-CPBA
(4)
20°C
(I. E) Cycloaddition reactions
O

(1) + benzene
40 °C
O

OAc
CH 3 O2C
85-90°C
(2) +

OAc

OAc O
benzene
(3) + O
100°C

OAc O
Solutions of Addition of HBr across Solutions of Addition of HCl and
carbon-carbon double bond HI across carbon-carbon double
H
(1)
H bond
Br
H
Cl H
(1)

Br
(2)
H 3C
Cl
D
(2) H
D
D

Ph Br CH3
(3) Br CH 3 CH 2CCH2 CH 3
(3)
Cl

I
(4)
Br
(4)

H H
H + H
(5)
Br Br
major minor

Br OOCCH 3
(6) +

85% 15%
Solutions of Addition of HCl and HI across carbon-carbon double bond

Cl H
(1)

H 3C
Cl
D
(2) H
D
D

CH3

(3) CH 3 CH 2CCH2 CH 3

Cl

I
(4)

Solutions of Addition of Br2 across carbon-carbon double bond

(a) Br
Br
(5)

(b) Br
Br

(6) Br

Br

OMe
(7)
Br
Solutions of Oxymercuration-Reduction

(1) (CH3 )3 CCHCH 3 + (CH3 )3 CCH 2CH2 OH

OH
97% 3%

(CH2 )CH CH 3

(2) OH
O

O
80%

(3)
OH
CH 3

OH
(4)
CH3

OH

(5)
Solutions of Epoxide formation

(1)
O

(2) O

(3) O

O
(4)
Solutions of Cycloaddition reactions

H O
(1)

H
O

OAc
CO 2CH3
(2)

OAc

H O

(3) O

H O