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Asymmetric synthesis and

stereochemistry

Ref. Books:

Stereochemistry Conformation & Mechanism

- P. S. Kalsi

Organic Chemistry - L. G. Wade

Organic Chemistry - I. L. Finar Vol. 2

Stereochemistry of Carbon Compounds

- E. L. Eliel

Stereochemistry

The branch of chemistry that deals with spatial

arrangements of atoms in molecules and the

effects of these arrangements on the chemical

and physical properties of substances.

Stereochemistry refers to the 3-dimensional

properties and reactions of molecules.

Deals with:

Determination of the relative positions in

space of atoms, group of atoms.

Effects of position of atoms on the properties.

The different spatial arrangements that a

molecule can adopt due to rotation about σ

bonds are called conformations and hence

conformational isomers or conformers.

The study of the energy changes that occur

during these rotations is called conformational

analysis.

Conformational Analysis Conformational mobility of cyclohexane

Chair conformations readily interconvert, resulting

in the exchange of axial and equatorial positions by

a ring-flip.

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Substituted cyclohexanes

The planar diagram predicts achiral and

optically inactive.

But we know the structure is not planar.

Chirality of conformationally mobile systems

(1S,2R)

Br Br

Cis-1,2-dibromocyclohexane Cis-1,2-dibromocyclohexane

Br Br

Chirality of conformationally mobile systems

This is a chiral structure and would be expected to be

optically active

cis-1,2-dibromocyclohexane

Consider the chair interconversion….

Br

Br

Br

Br

Chirality of conformationally mobile systemsBr

Br

Br

Br

cis-1,2-dibromocyclohexane

The two chair forms are enantiomers but not isolatable

(conformational enantiomers)

Two structures have the same energy. Rapid

interconversion. 50:50 mixture. Racemic mixture.

optically inactive.

Planar structure predicted correctly

SR(ax,eq) SR(eq,ax)

No mirror planes. Predicted to

be chiral, optically active.

Each structure is chiral. Not mirror images! Not the

interconvertible (configurational isomers or

configurational enantiomers). Present in different

amounts. Optically active

R,R (eq.eq) R,R (ax,ax)

Trans 1,2 dibromocyclohexane

(1S,2S)

Br Br

trans-1,2-dibromocyclohexane

Br

Br

Br

Br

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Mobile conformers If equilibrium exists between two chiral

conformers, the molecule is not chiral.

Judge chirality by looking at the most

symmetrical conformer.

Cyclohexane can be considered to be planar, on

average.

1,2-cis isomer exists as a pair of conformational

enantiomers, while the trans-isomer exist as a

pair of configurational enantiomers.

Relative order of stability of 1,2-

dibromidecyclohexane is:

Trans ee cis trans aa

Conformation of 1,3-trans-dibromocyclohexane

Maximum number of equatorial substituents will be the

preferred conformation if other forces (dipole interaction,

hydrogen bonding) are absent.

Trans 1,3-dibromocyclohexane is chiral and exist as two

enantiomers.

Each enantiomer is ae and has only one conformer.

ae

ea ae

ea

(identical)

Conformation of 1,3-cis-dibromocyclohexane

cis-1,3-dibromocyclohexane contains an internal

symmetry plane, meso compound.

Cis ee is more stable

Cis aa is unstable

eeaa

ee ea aa

Conformation of 1,4-cis,trans-dibromocyclohexane

Both cis and trans-isomers are achiral, has a plane

of symmetry.

All the chair conformers of these isomers are achiral

Di-equatorial conformer of the trans isomer is

predominated

ee aa

ae ea

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Substitution Cis Trans

1,2-X2

eq,ax ax,eq

interconverting enantiomers

eq,eq ax,ax

isolable enantiomers

two conformations each

1,2-XY

eq,ax ax,eq

isolable enantiomers

two conformations each

eq,eq ax,ax

isolable enantiomers

two conformations each

1,3-X2

eq,eq ax,ax

meso compound

two conformations

eq,ax ax,eq

isolable enantiomers

two conformations each

1,3-XY

eq,eq ax,ax

isolable enantiomers

two conformations each

eq,ax ax,eq

isolable enantiomers

two conformations each

1,4-X2

No chiralcenter

eq,ax ax,eq

equivalent conformations

eq,eq ax,ax

two conformations

1,4-XY

No chiralcenter

eq,ax ax,eq

two conformations

eq,eq ax,ax

two conformations

Nonmobile conformers

The planar conformation of the biphenyl derivative is too

sterically crowded. The compound has no rotation

around the central C—C bond and thus it is

conformationally locked.

The staggered conformations are chiral: They are

nonsuperimposable mirror images.

Definitions

Gauche(staggered) - A low energy

conformation where the bonds on

adjacent atoms bisect each other

(60o dihedral angle), maximizing the

separation.

Eclipsed - A high energy

conformation where the bonds on

adjacent atoms are aligned with

each other (0o dihedral angle).

Definitions

Anti - Description given to two

substituents attached to adjacent

atoms when their bonds are at

180o with respect to each other.

Syn - Description given to two

substituents attached to adjacent

atoms when their bonds are at 0o

with respect to each other.

Syn

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Types of strain

Torsional strain- The potential energy

arises due to the repulsion between

pairs of bonds caused by the

electrostatic repulsion of the electrons

in the bonds. Groups are eclipsed.

Steric strain- The potential energy

arises due to the repulsion

between the electron clouds of

atoms or groups. Groups try to

occupy some common space.

A molecule experiences strain when its chemical structure

undergoes some stress which raises its internal energy in

comparison to a strain-free reference compound.

Strains

Angle strain – The potential energy arises due to

distortion of a bond angle from it's optimum

value caused by the electrostatic repulsion of

the electrons in the bonds. e.g. cyclopropane

Strain in cyclicalkanes Axial methyl group is gauche to C3 in the ring

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Equatorial methyl group is anti to C3 in the ring

CH3-CH3 gauche 3.8

cis 1,3-dimethylcyclohexane

trans 1,3-dimethylcyclohexane

Two CH3-H diaxial interaction

E=7.6 kJ/mol

E=7.6 kJ/mol

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cis 1,4-dimethylcyclohexane

trans 1,3-dimethylcyclohexane

Four CH3-H diaxial interaction

ax,ax eq,eq

ax,eq eq, axE=7.6 kJ/mol

Two CH3-H diaxial interactionE=7.6 kJ/mol

E=15.2 kJ/mol E=0

cis 1-Chloro-4-t-butylcyclohexane

Methods for determining conformations

A number of methods have been used to

determine configuration;

X-ray and electron diffraction, IR, Raman, UV,

NMR spectra, photoelectron spectroscopy,

Optical Rotatory Dispersion (ORD) and

Circular Dichroism (CD) measurements.

Optical rotation: the rotation of linearly

polarized light by the sample

Optical Rotatory Dispersion (ORD): the

variation of optical rotation as a function of

wavelength. The spectrum of optical rotation.

Circular Dichroism (CD): the difference in

absorption of left and right circularly light.

Chiral structure can be distinguished and

characterized by polarized light

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Dichroism is used to denote direction-

dependent light absorption.

Circular Dichroism (CD): The difference in the

absorption of L-CPL and R-CPL and occurs

when a molecule contains one or more chiral

chromophores.

Birefringence refers to the direction-

dependent refraction index.

Circular birefringence A phenomenon in which

there is a difference between the refractive

indices of the molecules of a substance for right

and left-circularly polarized light

Optical rotation

When a plane polarized light (PPL) is passed

through optically active compound due to it’s

circular birefringence results in unequal rate of

propagation of left and right circularly

polarized rays.

This unequal rate of propagation of both left

and right circularly polarized light deviates the

PPL from it’s original direction and it is called

as optical rotation

Optical rotation caused by compound changed

with wavelength of light was first noted by Biot

in 1817.

Light and Polarization

Light can be represented as a transverse electromagnetic

wave made up of mutually perpendicular, fluctuating

electric and magnetic fields. The left side of the following

diagram shows the electric field in the xy plane, the

magnetic field in the xz plane and the propagation of the

wave in the x direction. The right half shows a line tracing

out the electric field vector as it propagates. Traditionally,

only the electric field vector is dealt with because the

magnetic field component is essentially the same.

To really understand circular dichroism, one

must first understand the basics of

polarization.

Vertically Polarised Light Horizontally Polarised Light

Linearly polarized light is light whose

oscillations are confined to a single plane.

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Polarized Light

Consider two light waves, one polarized in the YZ plane and the

other in the XY plane.

If the waves reach their maximum and minimum points at the same

time (they are in phase), their vector sum leads to one wave,

linearly polarized at 45 degrees.

Similarly, if the two waves are 180 degrees out of phase, the resultant

is linearly polarized at 45 degrees in the opposite sense.

If we take horizontally and vertically polarised light

waves of equal amplitude that are in phase with each

other, the resultant light wave (blue) is linearly polarised

at 45 degrees, as shown in the animation below:

45 Degree Polarised Light

If the two waves are 90 degrees out of phase (one is at an

extremum and the other is at zero), the resulting wave is circularly

polarized.

In effect, the resultant electric field vector from the sum of the

components rotates around the origin as the wave propagates.

The following diagram shows the sum of the electric field vectors for

two such waves.

The most general case is when the phase difference is at an

arbitrary angle (not necessarily 90 or 180 degrees.) This is called

elliptical polarization because the electric field vector traces out an

ellipse (instead of a line or circle as before.)

These concepts can be rather abstract the first time they are

presented. The following simulation allows the user to change the

phase shift to an arbitrary value to observe the resultant polarization

state.

Left-handed/counter-

clockwise circularly

polarized

Right-handed/clockwise

circularly polarized light

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If the two polarization states are out of phase, the resultant

wave ceases to be linearly polarized. For example, if one of

the polarized states is out of phase with the other by a

quarter-wave, the resultant will be a helix and is known as

circularly polarized light (CPL).

The helices can be either right-handed (R-CPL) or left-

handed (L-CPL) and are non-superimposable mirror images.

The optical element that converts between linearly polarized

light and circularly polarized light is termed a quarter-wave

plate. A quarter-wave plate is birefringent, i.e. the refractive

indices seen by horizontally and vertically polarised light are

different.

A suitably oriented plate will convert linearly polarized light

into circularly polarized light by slowing one of the linear

components of the beam with respect to the other so that

they are one quarter-wave out of phase. This will produce a

beam of either left- or right-CPL.

Left Circularly Polarised (LCP) Light

Right Circularly Polarised (RCP) Light

The difference in absorbance of left-hand and right-

hand circularly polarised light is the basis of circular

dichroism. A molecule that absorbs LCP and RCP

differently is optically active, or chiral.

Classification of polarization

Light in the form of a plane wave in space is said to be linearly polarized

Two plane waves of equal amplitude by differing in phase by 90°, then

the light is said to be circularly polarized

Two plane waves of differing amplitude are related in phase by 90°, or

if the relative phase is other than 90° then the light is said to be

elliptically polarized.

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According to Fresnel, a plane polarized light may

be considered as the combination of two circularly

polarized light of which one is right circularly

polarized light (RCPL) & other is left circularly

polarized light (LCPL) which are in equal &

opposite in nature.

A circularly polarized light (CPL) is one whose

plane of polarization rotates continuously & in the

same sense around the axis of the polarization of

the wave & it may be described as right handed

screw or helix twisting around the direction of

propagation, where LCPL wave describe the left

handed screw.

Rotation of plane polarized light

(Fresnel’s explanation) The figure below represents how the electric vector of

RCPL (ER) & that of LCPL (EL) combined to give a

plane polarized wave (E)

E

El ER

RCPL + LCPL = PPL

Plane of polarization

The two circularly polarized light vibrate in

opposite direction with the same angular

velocity if refractive index is same

Zero resultant

The two circularly polarized light vibrate in

opposite direction with same angular velocity if

refractive index is same.

Variation of E as a resultant of two rotating vector EL and ER

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The angle of rotation per unit path length is,

α = (nL – nR ) π / λ

Where,

λ = wavelength of incident light

n = refractive index

If RCPL travels faster α is positive & the

medium is dextrorotatory,

If LCPL travels faster then α is negative & the

medium is levorotatory.

Optical Rotatory Dispersion (ORD)

ORD is defined as the rate of change of

specific rotation or rotatory power with change

in wavelength.

Light is an electromagnetic radiation and

consist of vibrating electric and magnetic

vector perpendicular to each other.

ORD curves in recent years are made use in

structural determination by comparing the

curve obtain from compound believed to have

related structures particularly applied to

carbonyl compounds.

E.g. ORD curves have been used to locate

the position of carbonyl groups in steroid

molecules.

Rotatory dispersion curves (i.e. plot of optical

rotation against wavelength.) can be classified

into two main types.

1. Plain curves

2. Cotton effect curves.

When a ray of monochromatic polarized light

strikes a solution, several phenomenon’s occurs

like:

1. Reflection on the surface

2. Refraction

3. Rotation of plane polarization

4. Absorption

Enantiomers are optically active compounds.

Optically active molecules have different

refractive indices, and different extinction

coefficients for L and R circularly polarized

light.

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Principle of optically rotatory dispersion (ORD)

There are two types of plane polarized light

(PPL)

1. Right circularly plane polarized light (RCPL)

2.Left circularly plane polarized light (LCPL)

They are equal and opposite direction.

When a PPL is passed through an optical active

compound due to it’s circular birefringence

results unequal rate of propagation of left and

right circularly polarized rays.

When the components are recombined, the

PPL will be rotated through an angle

nl, nf are the indices of the refraction for

LCPL and RCPL

is in radians per unit length (from ), =

Usually reported as a specific rotation [],

measured at a particular T, concentration and

(598 nm, Na D line)

nl nr

ORD curve is a plot of molar rotation [] vs .

Clockwise rotation is plotted positively,

counterclockwise rotation is plotted negatively.

ORD is based solely on the refraction index

A plain curve is the ORD for a chiral compound

that lacks a chromophore

Chiral compounds containing a chromophore

can give anomalous, or Cotton effect, curves.

These are the main fundamental evidence for

the structural elucidation, absolute

configuration and conformational studies for

organic compound.

Plain curves (normal smooth curves or single curves)

The curves obtained do not contain any peak or inflections and that

the curve do not cross the zero rotation line and devoid of maxima

and minima within the measurable range.

This type of curve obtained for compound which do not have

absorption in the wavelength region where optical activity being

examined or when compound does not have chromophore in it, i.e.

alcohol, acids, etc.

The plain curve again divided into +ve and –ve curves according to

rotation of the compound.

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The combination of circular dichroism and

circular birefringence is known as cotton

effect. Which may be studied by observing the

change of optical rotation with the wavelength

so called ORD.

It was discovered by a French physicist Aime.

COTTON.

The curves obtained by plotting optical rotation

v/s wavelength down to about 220nm using

photoelectric spectropolarimeters, known as

ORD curves or Cotton effects.

Cotton effect

The absolute magnitude of the optical rotation

at first varies rapidly with , crosses zero at

absorption maxima and then again varies

rapidly with but in opposite direction, this is

known as Cotton effect and the curves

describing such effect is called Cotton effect

curves.

Anomalous curves are of two types:

(a) Single cotton effect curves

(b) Multiple cotton effect curves

These curves on the other hand shows a

number of extreme peaks and troughs

depending on the number of absorbing groups

and therefore known as anomalous dispersion

of optical rotation.

This type of curves is obtained for the

compounds which contain an asymmetric

carbon atom and also contain chromophore,

which absorb near the UV region.

Anomalous curvesSingle cotton effect curves

These are anomalous dispersion curves which shows maximum and

minimum both of them occurring in the region of maximum absorption.

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In this type of ORD curves two or more peaks

and troughs are obtained.

E.g. camphor

Multiple cotton effect curves Circular dichroism (CD)

Chiral substances show differential absorption

of circularly polarized light which is called

Circular dichroism.

Measurement of how an optical active

compound absorbs right and left circularly

polarized light (ER and EL)

For CD the resultant transmitted light is not

plane polarized but elliptically polarized.

Plane polarized light Elliptically polarized light

Circular dichroism

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Phenomena of CD and ORD

A beam of linearly polarized light of wavelength

lamda can be considered as the sum of two

components: beams of right- and left-circularly

polarized light, with electric vectors ER and EL,

respectively.

When such light interacts with an asymmetric

molecule (such as most biological

macromolecules) two phenomena, CD and ORD,

are observed, and the molecule ER and EL

travel at different speeds through the molecule.

This difference in refractive index leads to

ORD.

In the region of light absorption, the dispersion

is anomalous. Rotation first increases sharply

in one direction, falls to zero at the absorption

maximum, and then rises sharply in the

opposite direction. This anomalous dispersion

is called a Cotton effect.

Positive Cotton effect is where the peak is at a

higher wavelength than the trough.

Negative Cotton effect is the opposite.

Optically pure enantiomers always display

opposite Cotton effect ORD curves of identical

magnitude.

Phenomena of CD and ORD

A typical electronic absorption band (A) with its associated

circular dichroism (B) and optical rotatory dispersion (C) curves.

Zero crossover point

between the peak and

the trough closely

corresponds to the

normal UV λmax.

In a region where the

molecule does not

absorb light, the rotation

plotted against

wavelength yields a

plain curve.

Phenomena of CD and ORDCD, ORD and absorbance spectra of R and S

forms of camphor sulphonic acid

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Applications of CD

Determination of secondary structure of proteins that cannot be

crystallized

Investigation of the effect of e.g. drug binding on protein

secondary structure

Dynamic processes, e.g. protein folding

Studies of the effects of environment on protein structure

Secondary structure and super-secondary structure of

membrane proteins

Study of ligand-induced conformational changes

Carbohydrate conformation

Investigations of protein-protein and protein-nucleic acid

interactions

Folding recognition

Difference between ORD & CD

Graphs are obtained by

specific rotation vs

wavelength

Circularly polarized light Plane polarized light

Dispersive phenomena

Plane polarized is used

and is not converted to

elliptical light

Circular polarized is

used and is converted

to elliptical

Absorptive phenomena

Graphs are obtained

molar ellipicity vs

wavelength

ORD CD

Optical Purity : The optical purity is a measure of

enantiomeric purity of a compound and is given in terms

of its enantiomeric excess (ee). Optical purity is

expressed as a percentage.

A pure enantiomer would have an optical purity and

enantiomeric excess of 100%.

A fully racemised compound has 0% optical purity.

If the enantiomeric excess is 90%, means 90% pure

enantiomer, remaining 10% contains equal amounts

of each enantiomer (i.e. 5% + 5%).

Enantiomeric excess of a mixture of enantiomers is

numerically equal to its optical purity.

Optical Purity Optical Purity

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Enantiomeric excess Optical Purity

Optical purity (o.p.) is sometimes called

enantiomeric excess (e.e.).

One enantiomer is present in greater amounts.

X 100o.p. = rotation of pure enantiomer

observed rotation

Problem: The specific rotation of (S)-2-iodobutane is

+15.90. Determine the % composition of a mixture of (R)-

and (S)-2-iodobutane if the specific rotation of the mixture

is -3.18.

= 20%X 100o.p. =3.18

15.90

l = ee + (100-20)/2 = 60%

d = (100-20)/2 = 40%

Expressed mathematically:

enantiomeric excess = % of major enantiomer - % of

minor enantiomer.

Enantiomeric excess (ee): The excess of one

enantiomer over the other in a mixture of enantiomers.

Example: A mixture composed of

86% R enantiomer

14% S enantiomer

ee of the mixture = 86% - 14% = 72%

X 100e.e =d l

d+l

X 100=(excess of one over the other)

(entire mixture)

Enantiomeric Excess (e.e.)

Problem : When optically pure (R)-(-)-2-bromobutane is heated

with water, 2-butanol is the product. (S)-2-butanol forms twice of

(R)-2-butanol. Find the e.e. and the observed rotation of the

product. [α]=13.50° for pure (S)-2-butanol.

Let consider x = amount of (R) enantiomer formed

= 33% 100=2x-x

2x+x 100e.e =

| d-l |

d+l 100=x

3x

100o.p. =rotation of pure enantiomer

observed rotation

We know, e.e. = o.p.

100observed rotaion =

33 13.50= 4.5

2x = amount of (S) enantiomer formed

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Metal hydrides are an alternative

Reduction of carbonyls by hydrogenation

HAl

HH

HLi

HB

HH

HLi

LiAlH4 LiBH4

HB

HH

HNa

ROAl

OROR

HLi

NaBH4

BH3-THF

O

O

BH Al

H

DiBAl-Hcatecholboranediborane or Borane

RLi

RMgX

organolithium Grignard

RCu

RLi

Cuprate

Carbanionic-organometallics

Neutral boranes and aluminanes

Aluminum hydrides and borohydrides

Alternative Reducing Agents

Aluminium isopropoxide

[(CH3)2CHO]3Al

Used as catalysts and an intermediates in a different

reaction.

Widely used as a selective reducing agent for

aldehydes and ketones.

Inexpensive and easy to handle among other aluminum

alkoxides.

Meerwein-Ponndorf-Verley Reduction

In this method carbonyl compounds (aldehydes or

ketones) are reduced to the respective alcohol by

treatment with aluminium alkoxides (isopropoxide) in

isopropanol solution.

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Meerwein-Ponndorf-Verley Reduction

A relatively old method of reducing carbonyl groups

(principally aldehydes and ketones)

Isopropanol behaves as the hydride donor

The by-product is acetone

The reaction is reversible - the reverse oxidation is

known as the Oppenauer Oxidation.

The mechanism is typical of a range of reagents

proceeding through a well-defined chair-like

Zimmerman-traxler T.S. in which the beta-hydride is

transferred intramolecularly to the carbonyl group.

Mechanism of Meerwein-Ponndorf-Verley Reduction

[R/S]

Racemic mixture

Enantioselective Meerwein-Ponndorf-Verley Reduction