SCHOOL OF SCIENCE & HUMANITIES

DEPARTMENT OF CHEMISTRY

UNIT – I -Mechanisms and Determination Methods– SCYA7302

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 UNIT 1

MECHANISMS AND DETERMINATION METHODS

1.0. Introduction

Organic reactions involves the conversion of one functional group into another by
the attack of the reagent.

Substrate + Reagent Intermediates + Products

1.1Types of organic Reactions:

 Substitution Reaction

 Addition Reaction

 Elimination Reaction

 Rearrangements

a) Substitution Reaction

Reactions in which atom or group linked to carbon atom is replaced by another atom or
group.

Category:

• Substitution at saturated carbon atom

• Substitution at unsaturated carbon atom

Mediated by nucleophile, electrophile and Free radicals.

b)Addition Reaction

Compounds with unsaturation in the molecule have a tendency to add with a reagent without
eliminating a group or atom.

The reactions are Mediated by nucleophile and electrophile.

c)Elimination Reaction

The number of groups or atoms attached to the carbon decrease and the degree of
unsaturation increases.

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These reactions are categorized based on the molecularity of the equation

D)REARRANGEMENTS

The reactions in which the carbon skeleton is changed to give structural isomer of the
original molecule. Atoms or groups shift from one position to another within the molecule
resulting in a new molecular structure.

1.2 MECHANISMS FOR SUBSTITUTION REACTIONS

1.2.a. Nucleophilic Substitution Reactions: (SN): Nucleophiles reacts at electron deficient

centers.

Eg: Conversion of alkyl halide to alcohols is of two types

1) SN1- Substitution Nucleophilic Unimolecular.

In this reaction, the rate is dependent on the concentration of alkyl halide only.

2) SN2- Substitution Nucleophilic Bimolecular.

The rate is dependent on concentration of alkyl halide and OH- ions.

i) SN1- Substitution Nucleophilic Unimolecular.

Step wise Mechanism:

Rate α [R-X] independent of OH-

The reaction follows First order Kinetics.

Stereochemistry: Racemic compounds.

ii) SN2- Substitution Nucleophilic Bimolecular.

Concerted Mechanism

Rate α [alkyl halide] [OH-]

The reaction follows Second order Kinetics.

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Stereochemistry: Complete inversion of configuration.

Factors Governing SN1 and SN2

1) Structure of the Substrate:

Primary alkyl halide undergoes SN2 while tertiary alkyl halide undergoes SN1
mechanism. Secondary alkyl halide undergoes both SN1 and SN2 .Tertiary alkyl halides
the 3 alkyl groups increases the electron density around the central carbon atom for the
formation of carbocation

2) Steric effect:

SN2 mechanism involves attack of nucleophile from the opposite side of the leaving group.
Hence, in tertiary alkyl halide the 3 alkyl groups prevents the attack of nucleophile thereby it
follows SN1 mechanism.SN2 mechanism operates in primary alkyl halide and the rate of the
reaction decreases with the increase in the alkyl group.

CH3X > CH3CH2X > n-C4H9X

3) Rearrangement of carbocations

SN1 mechanism favours- stable carbocation hence it may undergo either 1,2 alkyl
shift or hydride shift.

1,2 alkyl shift:

4) Solvent Effect

Protic solvents like water, alcohol favours SN1 mechanism but slows down SN2 mechanism.
Aprotic solvents like DMSO, DMF favours SN2 mechanism. Solvent molecules orient with

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their negative end towards the carbocation and positive end towards the anion favouring
carbocation formation with lowering in activation energy which compensates for bond
breaking.

iii) Substitution Nucleophilic Internal (Sni)

Substitution reaction takes place by intra molecular process.

iv) Aromatic Nucleophilic substitution (SNAr)

It occurs in the substrate with sufficient π-electron deficient systems due to the presence of
electron withdrawing groups (nitro) at ortho or para positions.It is a two step process-
addition and elimination sequence with the first step being the rate determining step.

It differs from SN1 and SN2, the Ar-X bond is not broken until after the rate determining
step. The nature of the leaving group affects the rate at which nucleophile attacks.

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1.2.b Electrophilic Substitution

Electrophiles attack the substrate rich in electrons.

Types:

Electrophilic substitution at saturated carbon atom or unsaturated carbon atom or at aromatic

systems.

Designated:

SE1: Electrophilic substitution Unimolecular.

SE2: Electrophilic substitution Bimolecular

i) SE1- Substitution Electrophilic Unimolecular

It occurs in Two steps:

1. Slow ionization to form Carbanion

2. Fast combination of the anion with the electrophile to form Products.

Rate α [substrate] independent of electrophile.

kinetics-First order

Stereochemistry: Racemic Mixture

Chlorination of acetone to α-chloroacetone.

CH3COCH3 + Cl2 ClCH2COCH3 + Cl-

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ii) SE2- Substitution Electrophilic Bimolecular

It takes place by concerted Mechanism.

Incoming group approaches the reactive site from the front side as the leaving group.

Rate α [Substrate] [Electrophile]

Kinetics: Bimolecular

Stereochemistry: Retention of configuration.

iii) Electrophilic substitution at aromatic system.

Chlorination of Benzene

Carbocation is stabilised by resonance.

Eg: Friedel-Crafts Reaction

Alkylation: Electrophilic substitution Reaction.Primary and secondary alkyl halide follows

SE2 mechanism while tertiary alkyl halide follows SE1 mechanism

Primary alkyl halide- SE2 Mechanism

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Tertiary alkyl halides –SE1 Mechanism.

Benzene on reaction with n-propyl chloride undergoes 1,2 hydride shift to form isopropyl
cation.

Friedel-Crafts acylation:

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1.3 Elimination Reaction
Two substituent from a pair of adjacent atoms in a molecule are removed resulting in an
unsaturation. The two groups removed from the substrate are
1. Electrophile usually a proton, and
2. Nucleophile may be X-, OH-, RCOO-.
Elimination can be
α- Elimination: Two groups are removed from the same carbon atom
β-Elimination: Two groups are removed from adjacent carbon atom.

1.3.1E1 Mechanism:

Dehydrohalogenation of alkyl halide.

E1 Mechanism:

1.3.2E2 Mechanism:(Trans elimination):

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1.3.3 Rules For Elimination Reaction:
Saytzeff Rule: Olefin with large number of alkyl groups around C=C bond (More
substituted alkene).

Hofmann Rule: Olefins with least number of alkyl groups around C=C bond (least
substituted Olefin)

1.4 Addition Reactions

Reactions of double or triple bonds.
In alkenes and alkynes, the molecules are attacked by electrophiles.
In carbonyl group, the molecules are attacked by nucleophiles..
Two Types
1. Addition at carbon to carbon multiple bonds.

Addition of halogen acids to olefins.

Markownikoff’s Rule: the negative part of the reagent adds to the carbon constituting the
double bond poor in hydrogen.

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Addition at carbon to oxygen multiple bonds

Hydride Transfer Reaction

Reduction of ketone to secondary alcohol

Mechanism:

1.5 EQUILIBRIA AND FREE ENERGY

Equilibria: concentration of reactants and products don’t change.

The free energy change of the reaction is related to equilibrium constant by,
∆Go =-RTlnK
=-2.303 RT log K (Kcal/mol, R=1.986cal/deg-mol)
∆Go= -1.36 log K (Kcal/mol) at 298K
∆Go = (Free energy of products)-(Free energy of reactants)
∆Go= - 1.36 log K (Kcal/mol) at 298K.

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K=10, ∆Go= -1.36 Kcal/mol.
K=0.1, ∆Go= +1.36 Kcal/mol.
K=1, ∆Go= 0 Kcal/mol.
The Gibbs standard Free energy is related to enthalpy and entropy
∆Go= ∆Ho - T∆So
∆Ho = (enthalpy of products) –(enthalpy of reactants)
∆So = (entropy of products) –(entropy of reactants)
∆Ho = ∆Ho for bonds being broken- ∆Ho for bonds being formed

Eg 1: Chlorination of Methane:

Exothermic nature –change in the order or freedom of motion of a system.

Greater the entropy of the system, favourable negative value of ∆Go

Eg 2 : Chlorination of ethane to give chloroethane and HCl

∆Ho =-28kCal/mol
∆So = +0.5e.u
At room temp, T ∆So = -0.15Kcal/mol
∆Go= ∆Ho –for chemical reactions involving bond breaking and bond formation.

1.6 Exergonic and Endergonic Reactions

Exergonic Reactions-Products are more stable;Reaction release more energy.
Endergonic Reactions-reactants are more stable and reaction consume more energy.
Transition state Theory

Ea= ∆H# + RT; ∆G# = ∆H# -T∆S# ; k=Ae-Ea/RT

Reaction Profile -SN2

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Transition state has definite geometry, charge distribution and no finite existence

Reaction Profile -SN1

Intermediates have fully formed bonds; species which is a product and reactant.

1.7 Thermodynamic and kinetic controlled Reactions:

Consider the addition of HBr to 1,3 butadiene where the products are
Rapidly formed -Kinetic product.
Stable product- Thermodynamic product.

The addition of HBr to 1,3-buta diene can lead to either 1,2 addition or 1,4 addition product.
The formation of 1,4 addition product requires higher energy transition state which is a
thermodynamic product, while 1,2 addition product has a less energy transition state and is
formed rapidly even at low temperatures.

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Mechanism:

Addition of DCl to 1,3 –Pentadiene

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1.8 Hammond Postulate
1. Structure of Transition state is used to predict the products.
2. Structure of Transition state lies between the structure of reactants and products.

Transition state 1-Exergonic reaction- Resembles the reactants than the products.

Transition state 2-Endergonic reactions- Resembles the products than the reactants

 The structure of transition state is more similar to the structure close in its energy

Endergonic reactions Exergonic reactions

Free energy

Products
Free Energy

Reactants Reactants
Products

Reaction Progress Reaction progress

Fig 1.1 Free energy profile for endergonic and exergonic reactions.
In endergonic reactions, the free energy of the products is larger than the free energy of the
reactants while in the exergonic reactions, the free energy of the products is less than the
free energy of the reactants.

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Consider a Regioselective Reaction:of 1-propene

1.9 Curtin –Hammett Principle

Chemical reactions involving conformers in which the two conformers are rapidly
interconverting with each other relative to the rate of product formation. The product
formation depends only on the relative energies of the representative transition state
involved and not on the relative populations of the ground state conformers.
Consider a stereoselective elimination of 2-bromo butane

1.10 Macroscopic Reversibility.

At equilibrium, the individual molecular processes and the exact reverse processes must
have an equal probability of occurring.
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Consider a free radical reaction of chlorination of methane

1.11Methods of Determining Mechanisms

i) Identification of products.
Epoxidation of alkene: Formation of carbocation suggests a possibility of a mixture
of cis-trans epoxide.

Reaction in which two new bonds are formed at the same time doesn’t change the
stereochemistry of the olefin

ii) Detection of intermediates

a) Direct isolation: Hoffmann rearrangement:

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b) Spectroscopic Determination

Reactions involving benzyne as an intermediate is detected by IR spectroscopy –stretching

frequency of 1846 cm-1 which is intermediate between double and triple bond.

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C NMR- δ=182.7 ppm are also not of pure triple bonds.
c) Indirect Evidence:
Formation of one alkyl halide from another. Reaction follows SN2-Concerted mechanism

d) Trapping:
Benzynes are identified by reacting with dienes to form Diels-Alder adduct.

iii) Stereochemical Evidence

Chiral alkyl halide is used as the starting material, for an SN2 the inversion can be
detected due to change in the configuration while for an SN1 reaction, racemization
occurs.

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SN1 Reaction: Racemic Mixture

iv) Kinetic Isotope Effects

C-D bond is 1.2 kcal/mol more stronger than C-H bond. kH/kD values are greater
than 1.5 –Primary kinetic isotope effect, C-H(D) bond breaks in the rate determining step.
kH/kD is 1-1.5, Secondary kinetic isotope effect- C-H(D) bond cleavage is not involved in
the rate determining step.
Eg 1: Bromination of acetone

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kH/kD = 7 primary kinetic isotope effect indicates that the proton removal is involved in the
rate determining step.

v) Kinetic Evidence
Rate is dependent on the concentration of both reactants in the rate determining step and
hence it is bimolecular in nature.

Rate= k[CH3Br][I-]

vi) Isotopic Labelling: 18O, isotropic tracer has been used in base promoted ester hydrolysis
reaction, proceeds by acyl oxygen cleavage and the reaction is independent on the structure
of R and R’. The alcohol is enriched with 18O.

vii) Crossover Experiments: Hoffmann Reaction: Reaction proceeds by intra molecular

rearrangement. Migrating group doesn’t separate from the substrate. Mixture of 3-
deuteriobenzamide and 15N benzamide gives deuteriobenzamine and benzamine. Not mixed
anilines are not formed.

References:
1. Clayden, Greeves, Warren and Wothers., Organic chemistry, 2nd Edition, Oxford
University, 2012.

2. J. March’s Advanced Organic Chemistry Reaction, Mechanisms and Structure, Wiley

2007.

3. Guo-Qiang Lin, Yue-Ming Li, Albert S.C. Chan., Principles and applications of
Asymmetric synthesis,John Wiley 2001.
4. Finar I. L., Organic Chemistry, 6th Edition, Pearson Education Asia, 2004.

5. Carey F. A., and Sundberg R. J., Advanced Organic Chemistry Part-A and B, 5th edn,
Springer Publishers 2007.

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 SCHOOL OF SCIENCE & HUMANITIES
DEPARTMENT OF CHEMISTRY

UNIT – II STEREO, ENANTIO, REGIO, CHEMO SELECTIVE REACTIONS –

SCYA7302

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 UNIT 2

STEREO, ENANTIO, REGIO, CHEMO SELECTIVE REACTIONS

2.0. Introduction

Enantiomers- Chiral molecules with one or more stereocenters which are non superimposable
mirror images. Diastereoisomers- Stereoisomers which are non-superimposable and non-
mirror images.

2.1 Optical Rotation

Optically active compound rotates the plane polarized light either to Right-
dextrorotatory ,d (+) or Left- levorotatory, l(-).Optical rotation is measured using a
polarimeter and it is a function of Concentration, Sample thickness, Temperature and
wavelength.

Optical rotation or specific rotation or denoted by [α]λt

[α]λt = α x 100/(l x C)

[α]λt = α /(l x d t)

t= temperature in °C

λ= wavelength of polarized light D= 5893 Å

c= concentration of sample in g/100mL.

l= sample thickness in dm.; α= observed angle of rotation in degrees

d= density of pure liquid in g/mL.

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Molecular rotation of the optical compound is denoted by [M]

[M] = [α]λt Mol. weight/(100).

Optical yield or Enantiomeric excess (ee) or diastereomeric excess (de) in %

ee or de (%) = [α]λt product x100/ [α]λt of E

For a racemic mixture, the optical purity is zero.

2.2 Optical Isomers

The possible optical isomers for a molecule with a chiral centre is given in the Table.2.1

Table 2.1 Optical isomers with a compound with chiral centre

Compound Optical active forms Optical inactive

forms
Chiral carbons, molecule can’t be divided 2n 0
into two equal and similar halves

Even number of chiral carbons, molecule 2(n-1) 2(n-2/2)

can be divided into two equal and similar
halves
Odd number of chiral carbons, molecule 2(n-1)-2(n-1)/2 2(n-1/2)
can be divided into two equal and similar
halves

Ex:1 Calculate the specific rotation of an optically pure compound (A) in ° with a conc. of
5g/10mL and sample thickness of 100mm measured at a wavelength of 589 nm and at 25°c,
gives a rotation of +40°.

[α]λt = α x 100/(l x C)

= +40 / 1x 5/10 =+80°

2.3 Stereoselective Reactions

Predominantly one stereoisomer. One stereoisomer is formed more rapidly. Two

equally pathway are available for the same mechanism. Due to difference in free energy of
the transition state only one isomer is formed in preference over the other. Both addition and
elimination reaction exhibit stereoselctive reactions.

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a) Stereoselective dehydrohalogenation of 2-bromo pentane

• Saytzeff ‘s rule, 2-pentene will predominate in the reaction .

• To know whether the product exists in E or Z isomer-Curtin-Hammett principle.

b) Consider a elimination of HBr from 1,2 dibromo 1,2 diphenyl ethane to form alkene

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c) Consider a elimination of HBr from 1,2 dibromo butane

2.4 Regioselective Reactions

A chiral molecule can predominantly forms only one stereoisomer is known as

Regioselective reactions. Consider a reaction of 1-propene which forms 2-bromopropane as
the major product.

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a) Addition of halogens to Cis-2-Butene: Cis alkenes on bromination gives a racemic 2,3
dibromo alkane. Bromine ion attacks the bromonium ion equally from a and b from opposite
face by SN2 reactivity

b) Addition of halogens to trans-2-Butene: Trans alkenes on bromination gives a meso 2,3

dibromo alkane. Bromine ion attacks the bromonium ion equally from a and b from opposite
face by SN2 reactivity

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2.5 Hydroboration Reactions

Addition of B-H bond to carbon containing multiple bonds.

Alkylborane can be oxidised in which boron is replaced by –OH.

Stereochemistry is the syn-addition.

Mechanism:

The π-bond in alkene is electron rich while the boron is electron poor. The reaction is initated
via the co-ordination of BH3 with the π electrons of the double bond followed by the
formation of carbon-hydrogen bond via four centre transition state. The addition is dominated
by steric considerations. It is a regioselective reactions with the boron becomes attached to
the less substituted and less sterically congested carbon. The hydrogen being bonded to the
more crowded carbon. The alkylborane producta sre not primarily isolated but are converted
by subsequent reactions directly to desired products. The most important reactionof the
alkylborane is the oxidation with alkaline hydrogen peroxide to give an primary alcohol.

Alkene gets converted to primary alcohol in alkaline hydroboration reation. The

addition of water to the intermediate follows Anti-Markownikov rule.

The oxidation of trialkyl borane with alkaline hydrogen peroxide replaces the boron atom
with a hydroxyl group in the same stereochemical position. The net result of hydroboration
and the oxidation-hydrolysis is the addition of water across a double bond with a Anti-
Markownikov orientation.

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Mechanism;

2.6 Enantioselective Reactions

One Enantiomer is formed in preference over the other.Optically active compound is

formed from achiral starting material.Chiral catalyst or a reagent.

Eg: Epoxidation of allylic alcohol; Hydrogenation of alkene; Dihydroxylation of

alkenes; Reduction of ketones

a) Hydrogenation of alkene:

Alkene undergoes hydrogenation using Wilkinson's catalyst to form alkane. The

reaction proceeds by exchanging one phosphine ligand for a solvent molecule to afford a
complex which then bind to two hydrogen atom of the metal. displacement of the solvent
molecule by the alkene follows a stepwise syn-transfer and the saturated molecule leaves the
metal centre.

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1-acetamidopropenoic acid is treated with Wilkinson’s catalyst – Racemic Mixture

8
In the presence of optically active catalyst, a stereoisomer is obtained.

b) Reduction of aldehydes and ketones

Meerwein-Poondorf-Verley reaction [MPV] :

Reduction of carbonyl to alcohols in aluminium isopropoxide in isopropanol medium.

Transfer of hydride ion from the isopropoxide to the carbonyl compound takes place by a six-
membered cyclic transition state.

Aluminium alkoxide is derived from optically active (S)-butane-2-ol reacts with 6-methyl
heptan2-one results in enantiomeric S-6 methylheptan2-ol.

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 Two diastereomeric transition state differing in energy

c) Sharpless asymmetric Epoxidation:

Oxidation of allylic alcohol to epoxides. The epoxidation is carried out with t-

Butylhydroperoxide and the catalyst Titanium tetraisopropoxde/Diethyl tartrate. The
procedure is highly enantioselective with enantiomeric pure tartrate esters are included

Table 2.2 The reaction conditions for Sharpless epoxidation reaction.

Substrate Allyl alcohol

Oxidant t-Butylhydroperoxide

Catalyst Titanium tetraisopropoxde/Diethyl tartrate

Solvent Dichloromethane at 20oC.

Stereochemistry: Right [Alcohol] (+)DET Wedge; (-)DET) Dash

Left [Alcohol] (+)DET Dash; (-)DET) Wedge

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The structure of the oxidant , DET which determines the stereochemistry of the product is
given below

Mechanism:

The reaction proceeds with an alkoxy -exchange between the two alkoxide residues in
the titanium complex and the two hydroxyl groups in the tartrate ester to give an complex.
The remaining isopropoxide residue undergoes further exchange with the hydroxyl group of
the allylic alcohol and the hydroxyl group of the peroxide. The co-ordination activates the
peroxide and the topography of the complex determines the favourable enantioselective
transfer of oxygen to the olefinic centre to form the product either a cis or trans epoxide.

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Mechanism:

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d) Oxidation of alkenes to epoxides:

It is an Enantioselective oxidation using peracids. Syn addition of oxygen atom to the double
bond. Ring formation occurs in a single step.

Trans alkene gives trans-epoxide.Usually, the syn addition occurs from the less hindered side.

Substituted epoxides exhibits optical and geometrical isomerism. Trans alkene results in
chiral molecule. Cis alkene results in achiral molecule.

Mechanism:

S-isomer trans R-isomer

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e) Dihydroxylation Reactions

With OsO4: Reactions proceed with a cyclic intermediate to form cis-diols.

Reaction is stereospecific with syn addition of oxygen to π bond of the alkene to form cis
diols

Syn-addition is preferred as the bonds formed in the cyclic intermediate is decomposed by the
fission of the bonds between oxygen atom and the metal.

Fumaric acid gives Racemic mixture

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2.7 Cram’s Rule:

In a Kinetically controlled addition to a carbonyl carbon atom which has a chiral

centre in the α position, anion attacks from the side containing the small group and the chiral
is so oriented that the medium group is in eclipsing to the carbonyl group.

2-Phenyl propanaldehyde on reduction form alcohols with erthyo as the major product.

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2.8 Felkin-Anh Model

The C-L bond is perpendicular to the carbonyl group with L, M and S substituents are
arranged in clockwise direction. The nucleophile attack from the less hindered side with an
obtuse angle to the carbonyl group.

Felkin-Anh Model is applied to compound with alkoxy, hydroxyl or other complexing group
as substituents.

2.9 Chemoselective Reactions

Preferential reaction of one functionalgroup by a reagent is known as chemoselective

reactions. several oxidation and reducing agents acts as chemoselective reagent to bringabout
organic synthesis.

Eg: Metal in liquid ammonia, acetylides, Wilkinson's catalyst, OsO4, KMnO4 bring
selectivereduction or oxidation of the functional group to form the product.

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a) Metal in liquid ammonia: Birch Reduction

Reaction in which aromatic system can be reduced to form dienes.

• Presence of electron releasing groups:

• Presence of electron withdrawing groups:

b) Acetylenes:

It form trans-alkenes. Series of electron and proton-transfer steps.Radical anion

formed is a strong base and therefore removes a proton from NH3 Vinylic anion favours the
more stable trans configuration with bulky groups as far apart as possible. Alkynes gives
trans-alkenes

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c) Chemoselective nature of Wilkinson’s catalyst: -CO, CN, -NO2 are not attacked and
selective reductions are carried.

d) Chemo-Enantioselective reaction

OsO4 with chiral ligand results in optical active reagent to form an enantiomeric product.

18
References:

1. Clayden, Greeves, Warren and Wothers., Organic chemistry, 2nd Edition, Oxford
University, 2012.

2. J. March’s Advanced Organic Chemistry Reaction, Mechanisms and Structure, Wiley

2007.

3. Guo-Qiang Lin, Yue-Ming Li, Albert S.C. Chan., Principles and applications of
Asymmetric synthesis,John Wiley 2001.

4. Finar I. L., Organic Chemistry, 6th Edition, Pearson Education Asia, 2004.

5. Carey F. A., and Sundberg R. J., Advanced Organic Chemistry Part-A and B, 5th edn,
Springer Publishers 2007.

19
 SCHOOL OF SCIENCE & HUMANITIES
DEPARTMENT OF CHEMISTRY

UNIT – III - ASYMMETRIC SYNTHESIS – I – SCYA7302

1
 UNIT 3

ASYMMETRIC SYNTHESIS – I

3.0. Introduction

• Conversion of achiral starting material iinto chiral product in a chiral environment.

• Substrate and reagent combine to form diastereomeric transition states One of the two
reactants must have a chiral element to induce asymmetry at the reaction site.
• Asymmetry is created by conversion of trigonal carbons to tetrahedral ones at the site
of the functionality.
• Enantiomeric Transition state yields a racemic product.

TS1 TS2 TS1

A
Free energy (G)

Free energy (G)

B TS2
A
B

Reactant A Reactants
Products Products
Products

Reaction progress Reaction Progress

Fig.3.1 Enantiomeric and Diastereomeric Transition state

• Diastereomeric Transition state yields a enantiomeric excess compound. The

asymmetric synthesis takes place by following methods;

i. Chiron approaches
ii. Acyclic Diastereoselective approaches
iii. Double asymmetric synthesis

1
3.1 Chiron approaches

Naturally occurring chiral compounds provide an enormous range and diversity of possible
starting materials, enantiomeric purity

Table 3.1 Examples of Chiral pool

Amino Acids Hydroxy Acids Carbohydrates

l-alanine l-lactic acid d-arabinose
l-arginine d-lactic acid l-arabinose
d-asparagine (S)-malic acid l-ascorbic acid
l-asparagine (Poly)-3(R)-hydroxybutyrate

Chiral pool synthesis follows SN2 mechanism

Eg; 1

Male bark beetles producesa pheromone which is a diene alchol, (s)-ipsenol, produced from
(s)-leucine.

2
Eg 2: Another insect pheromone is called sulcatol, secondary alcohol. It is a mixture of 65:35
enantiomers.

3.2 Acyclic Diastereoselective Approaches

Asymmetric synthesis involves the formation of a new stereogenic unit in the substrate by a
chiral group derived from a naturally occurring chiral compound.

It can be divided into four major classes,

(1) substrate controlled methods;

(2) auxiliary-controlled methods;

(3) reagent-controlled methods, and

(4) catalyst-controlled methods.

1) Substrate-controlled reaction

First generation of asymmetric synthesis

It is based on intramolecular contact with a stereogenic unit that already exists in the chiral
substrate. Formation of the new stereogenic unit most often occurs by reaction of the

3
substrate with an achiral reagent at a diastereotopic site controlled by a nearby stereogenic
unit.

S* + R P*

Chiral boron enolates reacts with aldehydes with high stereoselective syn-aldol.

2) Auxiliary-controlled reaction

Second generation of asymmetric synthesis.

Asymmetric control is achieved intramolecularly by a chiral group in the substrate. The

directing group, the ``chiral auxiliary'', is deliberately attached to the original achiral substrate
in order to direct the enantioselective reaction. The chiral auxiliary will be removed once the
enantioselective transformation is completed.

S + A* R P-A* P*

Diel-Alder’s reaction: Reaction of achiral dienophile with auxillary reagent is reacted with
diene to form stereoselective product.

4
3) Reagent-controlled methods

Achiral substrate is directly converted to the chiral product using a chiral reagent. The
stereocontrol is now achieved intermolecularly.

S + R* P*

The reaction of a chiral substrate with a chiral reagent in which two new stereogenic units are
formed stereoselectively in one step.

S* + R* P*

Eg: Addition of chiral metal allyls to achiral aldehydes where the metal is B,Ti, Sn and Si.
The chirality is induced by the ligands attached to the metal.

4) Catalyst-controlled methods

Application of chiral catalysts to induce the conversion of achiral substrates to chiral product

cat*/L*

S P*

The addition of a ligand increases the reaction rate of an existing catalytic transformation

Eg: Alkylation of aldehydes

5
The catalyst used is Binaphthol, which is a atropisomers arises from restricted rotation about
single bonds.

Eg: Alkylation of aliphatic aldehyde

3.3 Double Asymmetric Synthesis:

Reaction of an enantiomerically pure substrate and an enantiomerically pure reagent.

Chiral substrate *A-C(x) is converted to A*-(*Cn)-C(z) by process I, where both C(x) and
C(z) denote appropriate functional groups for the chemical operation. a chiral reagent *B-
C(y) is allowed to react with *A-C(x) to provide a mixture of stereoisomers Ð*A-*C-*C-*B
(process II).

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The reagent *B-C(y) is chosen in such a manner that high stereoselectivity at *C is achieved
in the reaction

1. When the desired *A-*C-*C-*B is the major product in the matched pair reaction, the
resultant stereoselectivity should be higher than the diastereo facialselectivity of *A-C(x).

2. If the product *A-*C-*C-*B occurs as the minor product, this presents a mismatched pair
reaction, The diastereofacial selectivity of the reagent must be large enough to outweigh that
of *A-C(x) in order to create the desired *C-*C stereochemistry with high selectivity.

I
*A *CX *A *Cn-Cz

CY *B II
III

*A *C-*C *B

Fig. 3.2 Chiral centres in Double asymmetric Reactions

3.4 Asymmetric Oxidations:

a) Sharpless asymmetric epoxidation:

Oxidation of allylic alcohol to epoxides. The epoxidation is carried out with t-

Butylhydroperoxide and the catalyst Titanium tetraisopropoxde/Diethyl tartrate.

7
Mechanism:

The reaction proceeds with an alkoxy -exchange between the two alkoxide residues in
the titanium complex and the two hydroxyl groups in the tartrate ester to give an complex.
The remaining isopropoxide residue undergoes further exchange with the hydroxyl group of
the allylic alcohol and the hydroxyl group of the peroxide. The co-ordination activates the
peroxide and the topography of the complex determines the favourable enantioselective
transfer of oxygen to the olefinic centre to form the product either a cis or trans epoxide.

b) Selective opening of 2,3 epoxide alcohols

i) Red-Al: sodium bis(2-methoxyethoxy)aluminum hydride:

Ring opening results in the formation of 1,3 diols with the transfer of hydride occurs
at the least substituted side.

8
 Mechanism:

Red-Al

ii) LiBH4/Ti(OiPr)4

Ring opening results in the formation of 1,3 diols with the transfer of hydride occurs
at the least substituted side.

9
Mechanism:

iii) Organometallic reagents-Gilman Reagents: Ring opening takes place at the least
substituted side with the alkyl group act as nucleophile.

10
Mechanism:

iv) Payne Rearrangement:

Nucleophilic ring opening takes place at c1 in the presence of a base to form 2,3 diols.

Nu: PhS-, BH4-, CN-, TsNH-

11
3.5 Intra molecular Diels-Alder Reaction

Dienophile bearing chiral auxillary can be used in this reaction to produce natural products.

3.6 Retro Diels Alder reaction

On heating, adduct produces a diene and a olefin containing double bond. During this
reaction two single bond breaks to form two pi bonds with a total 3 pi bonds in both diene
and dienophile.

12
 The diene and dienophile is used for various organic synthesis. Usually, the retro-diels
alder reaction takes place in flash vaccum pyrolysis at 500- 6000 c to form diene, with the
dienophile in this cases mostly is a cyclopentadiene. this reaction is highly useful in the
preparation of 4,5-dialkyl cyclopentenone product which are usually thermodynamically less
stable. The alkene , cyclopentadiene is protected by this cyclopenteneone group and can be
prepared by flash vacuum pyrolysis. The alkenes which are difficult to synthesize by
conventional methods can be obtained by retro diels-alder reaction.

The following examples where the alkene,cyclopentadiene can be obtained by this

method.

13
Case 1: CO2 is eliminated

14
Case 2 : Acetylene is eliminated.

Case 3 : SO2 is eliminated

15
References:

1. Clayden, Greeves, Warren and Wothers., Organic chemistry, 2nd Edition, Oxford
University, 2012.

2. J. March’s Advanced Organic Chemistry Reaction, Mechanisms and Structure, Wiley

2007.

3. Guo-Qiang Lin, Yue-Ming Li, Albert S.C. Chan., Principles and applications of
Asymmetric synthesis,John Wiley 2001.

4. Finar I. L., Organic Chemistry, 6th Edition, Pearson Education Asia, 2004.

5. Carey F. A., and Sundberg R. J., Advanced Organic Chemistry Part-A and B, 5th edn,
Springer Publishers 2007.

16
 SCHOOL OF SCIENCE & HUMANITIES
DEPARTMENT OF CHEMISTRY

UNIT – IV - ASYMMETRIC SYNTHESIS –II – SCYA7302

1
 UNIT 4

ASYMMETRIC SYNTHESIS –II

4.1 Asymmetric Reformatsky Reaction

It is a crossed condensation reaction leads to aldol type products. It involves the

addition of organozinc reagent to the carbonyl group of an aldehyde or ketone. The raection
extends the carbon skeleton of an aldehyde or ketone with a reaction of α-bromoester with
carbonyl compound to form β-hydroxy ester. The organozinc reagent is less reactive, hence
nucleophilic adddition to the ester goup does not occur.

Mechanism:

The ester enolate anion is first formed which act as a nucleophile to attack a ketone
or an aldehyde. The reaction is not pH dependent since the enolate attacks the ketone more
rapidly compared to its ester precursor.

Eg:1 Asymmetric synthesis of Chiral aldol using SmI2

Samarium Iodide (SmI2) exerts a good chelation with an oxygen moiety in the enolate
and this results in highly stereoselective intra or intermolecular 1,2 or 1,3 asymmetric
induction. SmI2 mediates intermolecular Reformatsky reaction using α-bromoacetyl-2-
oxazolidinone as the chiral auxillary. The reaction is highly diastereomeric excess (de) for
straight high aldehydes. The following reaction gives a stereomeic hydroxy esters with de of
>99%.

1
Mechanism:

The catalyst SmI2 forms chelate moiety with the ketone or the enolate of the ester to
form 5-membered intermediate compound which then attacks the aldehyde to from the
hydroxy ester.

4.2 Double Asymmetric Cycloaddition (Cyclopropanation)

Simmons-Smith Reaction

Conversion olefin to a cyclopropane ring structure using Zn/Cu couple and CH2I2 in
ether. The reaction involves reaction of a double bond compound with diiodo methane and

2
Zn-Cu couple, the attacking species is an organozinc intermediate (ICH2ZnI), a carbene like
species called carbenoid. It behaves like a singlet methylene and reacts with alkene
stereospecifically in a sinle step (concerted step) to form cyclopropane derivatives.

Instead of Zn/Cu couple, diethyl zinc is used the reaction is known as Furukawa
modification.

Reactions:

Eg:1 Cinnamyl alcohol with chiral Bis sulphanoamide in dichloromethane.

The chiral bis sulphanoamide catalyzed cyclopropanation of allylic alcohol. The free
hydroxyl group of allylic alcohol is necessary for producing a chiral environment with the
carbenoid promoting the complexation as alkoxide to form cyclopropane ring structure.

Eg:2 Cinnamyl alcohol with DIBAL and salen ligand

The free hydroxyl group of allylic alcohol complexes with the carbenoid structure and at the
same time with Al from DIBAL and Nitrogen from Salen promoting the formation of
enantiomeric excess cyclopropane ring structure.

3
C) Double asymmetric cyclo propanation:

The curacin, antimitotic drug consists of thiazoline bearing a chiral cyclopropane ring
containing a carboxylic ring is obtained diester tartrate by asymmetric induction processs.

4.3 Aldol Condensation

4.3.1Base Catalyzed: The enolate adds to carbonyl compound to form β-hydroxycarbonyl

compound.

4
Mechanism:

4.3.2 Acid Catalyzed Reactions:

Aldehyde is pronated and adds to the enolate to form β-hydroxycarbonyl compound which
undergoes de hydration to form α,β-unsaturated carbonyl compound

Mecahnism:

4.4 Asymmetric Aldol Reactions

It refers to the condensation of a nucleophile enolate species with an electrophilic

carbon moiety to form C-C bond. The relative syn/anti as well as R/S configuration is
achieved by metal counter ions, ligands binding through these metals.

5
Types:

Substrate controlled; Reagent controlled; Double asymmetric

a) Substrate Controlled reactions:

Addition of chiral enolate (or allyl metal reagent) to a chiral aldehyde (chiral centre at
α position). Diastereoselectivity is determined in the transition state by Cram-Felkh-Ahn
model. Chiral enolates are formed by chiral auxillaries in the form of esters, acyl amides,
imides or boron enolates.

b)Reagent Controlled Reactions:

Addition of chiral or allyl reagent to an achiral aldehyde.

c) Double asymmetric Reactions:

Addition of a chiral enolate or allyl metal reagent to a chiral aldehyde. Enhanced

stereoselectivity can be obtained when both the aldehyde and the reagent exhibit
complementary facile addition.

General Mechanism:

Aldol reaction of an aldehyde with metal enolates creates two new chiral centres in the
product to form 4 possible stereoisomers.

6
Z enolates results in syn aldol

E enolates leads to anti aldol

When the enolate attacks the aldehyde in a re attack it forms 2,3-syn 3,4 syn and 2,3 anti 3,4
syn while with si attack it forms 2,3 syn 3,4 anti and 2,3 anti 3,4 anti.

Stereochemistry is achieved by

 Proper size of the substrate moiety in the enolate

 Proper choice of the reagent
 Conditions for enolization

4.5 Substrate Controlled Aldol Reactions:

Addition of chiral enolate (or allyl metal reagent) to a chiral aldehyde (chiral centre at
α position). Diastereoselectivity is determined in the transition state by Cram-Felkh-Ahn

7
model. Chiral enolates are formed by chiral auxillaries in the form of esters, acyl amides,
imides or boron enolates.

Eg.1:N-acyl oxazolidones:

Z-boron enolates are prepared from N-acyl oxazolidones on reaction with din-butyl
boron trifilate and triethyl amine in CH2Cl2 at -78°c . N-acyl oxazolidones known as Evans
auxiliaries undergoes aldol reaction to form syn aldol.

The structure of the transition state is the bidendate chealtion of the boron with the
oxazolidine carbonyl and the enolate oxygen via chair type transition state.

Reactions:

N-acyl oxazolidines and phenyl substituted acyl oxazolidines on reaction with

aldehyde forms only a syn-aldol. The stereochemistry of the product is dependent on the
enolate structure and boron and steric effect on N-acyl oxazolidines doesn't have any effect.

8
a)

b)

Eg.2: Pyrrolidines Reactions:

Trans-2,5 disubstituted pyrrolidine with zirconium enolate exhibits high

stereoselectivity and it is obtained by reaction of lithium enolate with Zirconium salts by ion-
exchange reactions.

The structure of the transition state is, with MOM is methoxymethyl ether in which
the Zr-bearing bulky ligand is located at the bottom hemisphere with respect to the plane of
Z-enolate. The aldehyde co-ordinates with Zr atom and approaches at the same side adopting
a chair like transition leading to the formation of erythro/syn aldol.

9
Eg.3 Proline Reactions:

Effective chiral reagents of proline amides with zirconium enolate is obtained from the
corresponding lithium enolate with metal exchane reactions of Cp2ZrCl2. Diastereoselectivity
is achieved by zirconium complex to form syn aldol.

'

Eg.4 Silyl Ketene acetals: Mukaiyama aldol reaction

The reaction of silyl enol ether with an aldehyde in the presence of TiCl4 gives a
condensation product, aldol via atransition state with aloss of chlorotrimethyl silane. The
aldehyde approaches the enol silyl ether in the metal centered transition state resulting in the
formation of anti-aldol.

10
The transition state for Mukaiyama aldol reaction is where the ciral enol of silyl ketene
acetals, aldehyde and ephedrine group binds to TiCl4 by two-electron donating to form cis-
ocathedral six-co ordinated complexes. The formation of C-Cbond on the six-co-ordinated
metal is highly stereoselctive in nature. The titanium is co-ordinated with oxygen from both
the aldehyde and the alkene enol ether resulting in the formation of anti- aldol as the major
product.

The asymmetric aldol reaction id performed with the addition of aldehyde to ketene
acetals with high selectivity in the presence of 3,5-di-t-butyl salicyclic acid as the ligand for
TiCl4.

11
4.6 Reagent Controlled Aldol Reactions:

Addition of chiral or allyl reagent to an achiral aldehyde.

Eg.1 Chiral aryl borane –Corey’s reagent

A solution of allyl tributyl tin with borane auxiliaries results in a chiral allyl borane which
reacts with aldehydes to form allyl alcohols with high stereoselectivity. Chiral borane reacts
with aldehyde and ketone to form syn aldol.

The structure of the catalyst borane which act as a chiral auxiliaries.

The structure of the transition state is the phenyl group of the borane forces the vicinal N-
sulfonyl substituent to occupy the face of the five-membered ring opposite to the position
where it is linked. The spatial position of the chair-like transition state favours for the syn-
aldol formation.

a) Reaction with phenyl thioacetate :

The reaction proceeds with the formation of syn aldol with either phenyl thioacetate
or higher substituted thioacetate.

12
The structure of transition state is similar to that for ketone here the presence of phenyl thio
in the chair -like transition state doesn't alter the stereochemistry of the borane resulting in the
formation of syn-aldol.

b) Miscellaneous Reactions:

4.7 Catalyst Controlled Aldol Reactions:

The reaction of achiral aldehyde and enolate takes place in the presence of an chiral
environment, catalyst.

Eg.1 Mukaiyama reactions:

Tributyl tin fluoride, stannous difilate are more effective catalyst for asymmetric aldol
reactions. Tin diflate is treated with chiral diamines as catalyst promoter followed by the

13
 reaction of aldehyde and silyl enol ether in the presence of tributyl tin fluoride to form
syn aldol

The promoters are chiral diamines and the structure of transition state is formed with
rspect to tin. The divalent tin has vacant 'd' orbitals which form complexes with two nitrogen
atoms of the chiral amines leaving one vacant d orbital to be co-ordinated with an aldehyde.
The cationic centre of Sn(II) activates the aldehyde at the sametime the electronegative
fluoride interacts with the silicon atom of the enol ether (not shown) to make it highly
reactive. The dual process results in the formation of entropically favoured intermediate,
ultimately leads to syn-aldol.

Eg.2 Shibasaki’s system –

Bimetallic system (BM) is formed from binaphthol and barium salts to form Shibasaki
system (BaBM) which is a far superior catalyst for direct aldol reaction.

14
The catalyst is BaBM, contains a lewis acid centre to activate and control the orientation of
the aldehyde and lewis base centres favourinf for the addition of ketone to form aldol.

4.8 Double Asymmetric Aldol Reactions

Addition of a chiral enolate or allyl metal reagent to a chiral aldehyde. Enhanced

stereoselectivity can be obtained when both the aldehyde and the reagent exhibit
complementary facile addition. Reaction of a chiral compound with achiral enolate to form a
diastereomeric product.

The interaction of chiral aldehyde with ciral enoalte forms a stereoselective aldol. The
reaction of chiral enolate with 2R and 4S aldehyde results in anti- aldol. On changing the
chirality of the aldehyde to 2S and 4R reverse the results to form syn aldol. High
stereoselectivity is achieved in double asymmetric aldol reactions.

The reaction is further investigated with methyl substituted chiral enolates. the reaction of the
enolates with 2S and 4R forms anti-aldol with the change in the chiralityof the aldehyde in
case of methyl enolates the reuslts are reversed with the formation of syn-aldol.

15
4.9 Asymmetric Transfer Hydrogenation: (Meerwein-Poondorf-Verley Reaction)

Meerwein-Poondorf-Verley reaction-reduction of carbonyl to alcohols in aluminium

isopropoxide in isopropanol medium. Transfer of hydride ion from the isopropoxide to the
carbonyl compound takes place by a six-membered cyclic transition state. Inthis reduction,
the hydride ion is donated by carbon unlike a metal hydride.

The Diastereomeric transition state

16
Eg:1 Using Sm(III) complex:

The asymmetric transfer hydrogenation of ketones using Sm (III) complexe at

ambient temperature in 2-propanol is given with the Sm co-ordinated between Nitrogen and
Oxygen

The Sm(III) complex with oxygen and nitrogen functional groups containing molecules

Eg:2 Using Ruthenium catalyst:

Asymmetric transfer hydrogenation is highly efficient for the preparation of

secondary alcohols in the presence of Ru-based catalyst at room conditions. the reaction can
be completed within 5 minutes. The conversion is achieved using chiral Ru(II) complex as
the catalyst and 2-propanol as the hydrogen donor. Some of the examples of the reaction is
given below.

17
The structure of the catalyst is

Mechanism:

The mechanism takes place in four steps:

18
1) Insertion: The catalyst is Ruthenium(II) complex with the replacement of the chloro ligand
by hydrogen of 2-propanol followed by the addition of ketone in which one of the hydrogen
is realced by the ketone to form a 5-membered co-ordinated complex.

2) Reductive Elimination: In the complex, the hydride ion is transferred to the ketonic group
tofrom secondary alcohol with the reduction of Ru from +2 oxidation state to zero.

3) Oxidative Addition: To recover the catalyst, the Ru is allowed to react with the solvent to
form Hydrogen co ordinated complex where the oxidation state increased to +2.

4) β-Elimination: The alcoholic group is oxidized to ketone with the formation of catalyst
with Ru (II) complex.

4.10 Asymmetric Hydroformylation

Optically active aldehyde play an important precursors for biologically active

compounds and is achieved through hydroformylation reaction. It is a potential route to
prepare enantiomeric pure aldehydes using inexpensive olefins and synthesis gas with Rh and
Co catalyst.

The limitations of Co catalyst is it involves high temperature and pressure which may not be
desirable for industrial purposes. Rh complexes ensures regioselectivity and stereoselectivity
of the reaction Regioselectivity involves the addition of hydride which converts the five co-
ordinated alkene to four co-ordinated primary or secondary alkane. Chiral aldehydes are
unsatble undergoes racemization which is prevented by using triethyl formate as trapping
agent to produce diacetals.

Mechanism:

The mechanism of rhodium-phosphine catalysed hydroformylation reaction is

presented below. The aldehyde regioselectivity is determined in the hydride step which
converts the 5-co ordinated H(alkene)-Rh-(CO)L2 into either a primary or secondary 4-co-
ordinated (alkyl)Rh(CO)L2. The 5-co-ordinated trigonal bipyramidal bisphosphine Rh species
is the most important intermediate with the two phosphine ligands occupy the twoequatorial
or one equatorial and one axial position. Using a chiral diphosphine complex as the catalyst,
branched aldehydes are obatined in ee. Biphosphite ligands with bulky substituents are used
to produce linear aldehydes from 1-alkenes while 1, substituted alkenes forms branched

19
aldehydes in good yield. The presence of electron withdrawing groups affects the formation
of the product with the presence of electron withdrawing groups in the two equatorial
position results in the linear aldehyde while its presence in the axial positions favours the
formation of branched aldehyde.

Eg.1:Styrene to form branched aldehydes in good yield than linear aldehydes.

20
References:

1. Clayden, Greeves, Warren and Wothers., Organic chemistry, 2nd Edition, Oxford
University, 2012.

2. J. March’s Advanced Organic Chemistry Reaction, Mechanisms and Structure, Wiley

2007.

3. Guo-Qiang Lin, Yue-Ming Li, Albert S.C. Chan., Principles and applications of
Asymmetric synthesis,John Wiley 2001.

4. Finar I. L., Organic Chemistry, 6th Edition, Pearson Education Asia, 2004.

5. Carey F. A., and Sundberg R. J., Advanced Organic Chemistry Part-A and B, 5th edn,
Springer Publishers 2007.

21
 SCHOOL OF SCIENCE & HUMANITIES
DEPARTMENT OF CHEMISTRY

UNIT – V -Reagents in Organic synthesis– SCYA7302

1
 UNIT 5

REAGENTS IN ORGANIC SYNTHESIS

5.0. Introduction

Organic compounds with a carbon-metal bond. CH3Li, C2H5MgBr. Excludes compound

where the metal atom is bonded through heteroatom.CH3ONa. Electro negativity of carbon is
2.5 which is much higher than most of the metals which lie between 0.9-1.8.

5.1 Preparation:

(1) Electronegativity difference (∆x≥1), it can be prepared by direct reduction of alkyl halide
with the metal.

(2)Electronegativity difference (∆x<1), it can be prepared by transmetallation method –

covalent nature. Electronegativity of copper is 1.8, Cd is 1.5, Zn is 1.7 and Hg is 1.5.

Step 1- organometallic compound of non-transition metal is prepared by direct reduction of

alkyl halide with metal.

Step 2: The organometallic compound of non transition metal is allowed to react with salt of
higher electronegativity.

a)Preparation of dialkyl mercury

b) Preparation of lithium dialkyl cupurate

5.2 Chemical Reactions:

Rich source of carbanions or nucleophile: Carbon-metal bonds are highly polar due to
electronegativity difference. Magnitude of electronegativity determines the polarity or
ionicity of C-M bond. In Grignard reagent, R-Mg is 1.3, 52% ionic. R-Li is 1.5, 60%
ionic.Highly sensitive to protic solvents, prepared in ether or aprotic solvents.

1
a) Nucleophilic addition:
RMgX and RLi are excellent nucleophile R- and attack the electron deficient carbon
atom of many heteropolar multiple bonds to form FGI.

Nucleophilic addition to form tetrahedral intermediate. Adduct reacts with water to form final
product.

b) Reaction of epoxide and nitrile

c) Reaction of acid derivatives:

d) Regioselectivity to α,β unsaturated carbonyls

Grignard reagent is covalent in nature, act as softer nucleophile attack the electron deficient
β-carbon atom. RLi attacks the hard electron deficient carbonyl carbon atom,

2
5.3 ORGANO COPPER COMPOUNDS
5.3.1 Preparation of Gilman's Reagent:
a) Transmetallating the Grignard’s reagent or organolithium.

The organocopper reagents with the general formula R2CuLi-Lithium organo cuprates or
lithium dialkyl cuprates or Gilman’s reagent.
b) Prepared from alkyl halide:

5.3.2 Chemical Reactions:

a) Reactions with alkyl or aryl halides:
Alkyl halides: Organocuprates are able to displace halide ion from primary and secondary
alkyl halides to form hydrocarbon

Aryl halides:

3
b) Reaction with epoxide:
Epoxide is attacked at the least substituted carbon atom to give corresponding alcohol.

c) Reactions with Acid chloride: Forms Ketones.

d) Reactions with α,β unsaturated carbonyl compound: Conjugated addition compound -

1,4 addition product.

e) Reaction with aldehydes and ketones: It forms anti and syn aldol (30:1).

4
5.3.2 High order cuprates R2Cu(CN)Li2
1) Preparation:
i) Reaction of organolithium with cuprous cyanide.

2) Chemical Reactions:
a) Alkyl halide: Reagents react faster with alkyl halides

b) Active Methylene group: Copper-isonitrile complex is prepared by mixing Cu2O with

alkyl isonitrile and reacting with active methylene group

5.4 ORGANOZINC COMPOUNDS

5.4.1 Preparation
Alkyl iodide on treatment with Zn fillings followed by CO2 distillation gives dialkyl zinc
derivative.

Trialkyl aluminum on reaction with ZnCl2 gives dialkyl zinc derivatives.

5
Physical Properties: Non-polar, soluble inorganic solvents, inflammable in air, less reactive
than Grignard’s reagent.

5.4.2 Chemical Properties:

a)Reactions with water:
Reacts with water forms Hydrocarbon.

b) Reactions with acid chloride: It forms ketones.

c) Reaction with alkyl halides: Reacts with tertiary halide to from hydrocarbon.

d) Simmons-smith reaction:
Reaction of olefinic compound with Zn/Cu couple in di iodomethane-cyclopropane
derivatives. Forms organozinc intermediate [ICH2ZnI]-carbene like species.Stereospecific
reaction with the cis- addition of CH2 group to less hindered side of double bond.

6
e) Reformatsky reaction: Reaction of α-bromoester with carbonyl compound to form β-
hydroxy ester.

5.5 ORGANO CADMIUM COMPOUNDS

5.5.1 Preparation:
a) Action of CdCl2 on Grignard’s reagent or alkyl lithium

Physical Properties: Volatile liquids, Doesn’t react with esters or ketones.

5.5.2 Chemical Properties:

a) Reacts with acid chlorides: Organo cadmium compounds reacts with acid chlorides to
form ketones.

7
b) Synthesis of long chain esters or acids.

5.6 ORGANO LEAD COMPOUNDS- LEAD TETRA ACETATE-LTA [Pb(OCOCH3)4]

5.6.1 Preparation:
Adding red lead oxide (Pb3O4) to a mixture of acetic acid and anhydride at 60-80oC and its is
cooled and separated as LTA.

Physical Properties: Drying agent for solvents, oxidising agent

5.6.2 Chemical Properties:

a) Reactions with monohydric alcohols: Oxidises alcohol to aldehyde without affecting the
double bond.

b)Reactions with 1,2 diols:

8
Mechanism:

c) Reactions with monocarboxylic acids: (Oxidative decarboxylation ): On oxidation with

LTA in the presence of Cu(II) salts, the acids gives alkenes.

d) Dicarboxylic acids: LTA promotes decarboxylation to form unsaturated compound

9
e) With α-substituted acids: They are cleaved to carbonyl compound and CO2.

f) Dehydrogenation and cyclization:

Cyclization of saturated alcohols:Alcohols with δ hydrogen undergoes dehydrogenation
with LTA to form tetrahydro furans as major product.

Cyclization of carboxylic acids:

Dehydrogenation: LTA oxidises primary amine to nitriles

N,N’-disubstituted hydrazines are readily dehydrogenated to azo compound.

g) Acetoxylation: Ketones in enol form can be acetoxylated at α position

10
Acetoxylation in aromatic compounds:

h) Nuclear methylation:

5.7 ORGANOSILICON COMPOUNDS

5.7.1 Preparation- Chlorotrimethyl silanes
Reaction of Grignard’s reagent with silicon chloride.

Allyl trimethyl silane is prepared by reaction of chlorotrialkyl silanes and allyl magnesium
bromide.

5.7.2 Chemical Reactions:

a) Protecting Group: Chlorotrialkylsilanes is used as a protecting group for alcohols,
thioalcohols, amines and terminal alkynes with deprotecting group as HF,KF and aq.NaOH.
As a protecting agent it forms silyl ethers.

11
b) Action of NaOH: silyl ethers can be cleaved by aq.NaOH or acids.

c) Conversion of enolates to silyl enol ethers. Trialkyl chlorosilanes can trap the enolate to
give silyl enol ether.

d) Reaction with Methyl lithium: Silyl enol ether undergoes cleavage with methyl lithium
and fluoride to generate enol.

e) Reaction with aldehydes and Ketone: Silyl enol undergoes aldol condensation and
unsaturated ketones.

f) Dimerization: Silyl ethers dimerizes to from 1,4 diketone.

12
5.7.2 ARYLSILANES AND ALLYLSILANES
Chemical Reaction: Electrophilic substitution at the site of trimethyl silyl group. The
incoming electrophile is directed by silyl group to the carbon atom carrying silyl group.

Alkenyl silanes undergoes electrophilic substitution directed by silyl group.

Allylsilanes undergoes electrophilic attack at the γ-carbon and the double bond is shifted to
α,β position.

5.7.3 SILYL CARBANIONS

Preparation: α-Trimethyl silyl substituted carbanions are readily formed by reaction with Li
or Mg or by reacting with weakly acidic silanes (silanes containing CH group adjacent to
electron withdrawing group) with butyl lithium.

13
Chemical Reaction:
a)Peterson Olefination: Silyl carbanion on reaction with aldehyde or ketone gives β-silyl
alcohol derivative which on treatment with a base forms alkene.

5.7.4 TRIMETHYL SILYLCYANIDES

Preparation: Treating Trimethylsilanes with metallic cyanides

Chemical properties:
a) Reaction with ketones: Trimethyl silylcyanides reacts with ketones in the presence of
lewis acids to from o-trimethylsilyl cyanohydrin which on hydrolysis gives hydroxyacids.

b) Reduction of double bond: Methyl cyclo hexene on reduction with triethylsilane forms
methylcyclohexane

14
c) Reduction of conjugated aldehyde: In the presence of EDG to silanes the carbonyl is
selectively reduced to alcohol.

References:
1. Clayden, Greeves, Warren and Wothers., Organic chemistry, 2nd Edition, Oxford
University, 2012.

2. J. March’s Advanced Organic Chemistry Reaction, Mechanisms and Structure, Wiley

2007.

3. Guo-Qiang Lin, Yue-Ming Li, Albert S.C. Chan., Principles and applications of
Asymmetric synthesis,John Wiley 2001.
4. Finar I. L., Organic Chemistry, 6th Edition, Pearson Education Asia, 2004.

5. Carey F. A., and Sundberg R. J., Advanced Organic Chemistry Part-A and B, 5th edn,
Springer Publishers 2007.

15