Stereochemistry.Prof. Attilio Citterio

Dipartimento CMIC “Giulio Natta”

https://iscamapweb.chem.polimi.it/citterio/it/education/course-topics/

Scuola di Ingegneria Industriale e dell’Informazione

Insegnamento di Chimica Generale

083424 - CCS CHI e MAT

Attilio Citterio

Classification of Isomers.2

Isomers(different compounds with same molecular formula)

Constitutional Isomers(isomers whose atoms

have a different connectivity)

Stereoisomers(isomers that have the same

connectivity but differ in spatial arrangement of their atoms)

Enantiomers(stereoisomers that are

nonsuperimposable mirrorimages of each other)

Diastereomers(stereoisomers that areNOT mirror images of

each other)

Attilio Citterio

Configurational Isomers.3

H

H

H

Cl

H

H

H

H

Cl

H

Different conformations of stereoisomer A

stereoisomer B

C2H5

H

H

H

Cl

H

120°120°

C2H5H5C2

H

H

H

H5C2Cl

H

120°120°

H

H

H

Cl

H

120°

H5C2

No one conformation of A corresponds to B

The two compounds are Configurational Isomers

The two compounds are not two different conformations

stereoisomer A

Attilio Citterio

Two Enantiomers.4

HC2H5

ClH

C2H5Cl

AB

CH3CH3

The two compounds are Specular Images

NOT superimposable

They are defined

ENANTIOMERS

d

ba c

C

d

bac

C

Attilio Citterio

Asymmetric (Chiral) Carbon Atom5

The Carbon atom is hybridized sp3 and is bound to four different substituents

Ca

b

d

c

Attilio Citterio

R,S Cahn-Ingold-Prelog Convention6

The group with lower priority

must be placed

far from the observer

HC

CH3

H5C2

12

3

C3H7

4

CC2H5

CH3

HH7C3

3

21

4

Rectus

“clockwise”

R

Attilio Citterio

Cahn-Ingold-Prelog Convention.

R,S Nomenclature System7

4

1

2

4

31

2

3

RectusR SinisterS

Attilio Citterio

Specific Rotation and R,S –Configuration.

No necessary correlation exists between the (R) and (S) designation and

the direction of rotation of plane-polarized light.

8

Relative vs. Absolute

Configuration (5.15A)(R)-(+)-2-Methyl-1-butanol

25

5.756D

(S)-(−)-2-Methyl-1-butanol

25

5.756D

Same

Configuration

(R)-(+)-3-Methyl-1-butanol (R)-(−)-1-Chloro-3-methylbutane

(R)-(−)-1-Chloro-3-methylbutane (S)-(+)-1-Chloro-3-methylbutane

25

1.64D

25

1.64D

Attilio Citterio

Racemic Forms (Racemate).9

Racemate

CH2CH3

CH3

CH3CH2

H3C

Attilio Citterio

Racemic Forms (Racemate).10

(R)-2-butanol (S)-2-butanol+

.

50:50

Optically inactive

.

.

0 rotation

Racemate = Equimolar mixture of (R) and (S) enantiomer

Attilio Citterio

Physical Properties of Stereoisomers.

Enantiomers also:

• Have the same chemical properties (except

reaction/interactions with chiral substances)

• Show different behavior only when they interact with

other chiral substances (enzymes)

• Rotate plane-polarized light in equally in opposite

directions - this property of enantiomers is called

optical activity

11

Attilio Citterio

Optical Activity.

• The property possessed by chiral substances of rotating

the plane of polarization of plane-polarized light

• The electric field (like the magnetic field) of light is

oscillating in all possible planes

• When this light passes through a polarizer (Polaroid lens),

we get plane-polarized light (oscillating in only one plane)

12

Polaroid

lens

Attilio Citterio

Optical Activity and Polarimeter (2).

Polarimeter – instrument to measure optical activity

13

= observed optical

rotation

Attilio Citterio

Optical Activity – Measuring on Polarimeter.14

Attilio Citterio

Optical Activity – Measuring on Polarimeter (2).15

Attilio Citterio

Optical Activity – Measuring on Polarimeter (3).16

(c) Two circularly-polarized beams

counter-rotating at the same velocity

(in phase), and their vector sum.

The net result is like (a).

(d) Two circularly-polarized beams

counter-rotating at the different

velocities, such as after interaction

with a chiral molecule, and their

vector sum. The net result is like (b).

(From Adamson, A Textbook of Physical Chemistry, 3° ed. © 1986 Brooks/Cole, a part of Cengage Learning, Inc.

Attilio Citterio

Optical Activity – Calculating Specific Rotation.17

temperature

wavelength of light

(e.g. D-line of Na

lamp, l = 589.6 nm)concentration of

sample solution

in g/mL

length of cell

in dm (1 dm = 10 cm)

observed

rotation

Attilio Citterio

Enantiomeric Excess (ee).18

Non-equimolar mixture of (R) and (S) enantiomer

Enantiomerically enriched – Optically active

The enantiomeric excess can be calculated from optical rotations:

E.g. a mixture of the 2-butanol enantiomers showed a specific rotation of +6.76°

Pure

..

.

.

.

.

Racemate (50:50)

.

.

(R)

(R)-2-butanol

(+13.52°)

(R

(+6.72°)

(S)

(-6.72°)(R

(+6.72°)(R)

(+3.36°)

(S)

(+3.36°)

% Enantiomeric excess =moles of one enantiomer - moles of other enantiomer

total moles of both enantiomers 100

% Enantiomeric excess * =specific rotation of the pure enantiomer

observed specific rotation 100

6.76Enantiomeric excess 100 50%

13.52

Attilio Citterio

Stereo-selective Synthesis (Kinetic Resolution).19

>99% ee >99% ee

Attilio Citterio

Stereo-selective Synthesis (Kinetic Resolution) (2).20

Attilio Citterio

Chiral Drugs (for Chiral Receptor).21

OH

O

OH

O

H Me H Me

Ibuprofen (Isobutyl phenyl pripionic

acid)

(S)

Active anti-inflamatory agent

(R)

No anti-inflamatory activity

H

N

OHO

Acetaminophen (Tylenol)

OH

O

NH2HO

HO

Me

OH

O

Me NH2

(R)

No activity

HO

HO

(S)

Methyldopa (Aldomet)

Anti-hypertensivedrug

OH

O

NH2

HO

HO

H

L-DOPA

H3CO

OH

O

(S)-Naproxene

H Me

(S)-BINAP-Ru(Ac)2

H3CO

OH

OH H

OH

O

SH H NH2

(R)

Penicillamine

N

S

Penicillin G

CH3

H CO2H

CH3

H H H N

O

Therapeutic agent

for primary chronic arthritisHighly toxic

O

Me

MeOH

OMe

Me

SH H NH2

(S)

Attilio Citterio

Molecules with Multi-Stereogenic Centers.22

.

.

enantiomers

enantiomers

diastereomers

.

.

diastereomers

.

.

diastereomers

Diastereomers have different physical properties: different

m.p. and b.p., different solubilities, and so forth.

Total number of stereoisomers will not exceed 2n, where n

is equal to the number of tetrahedral stereogenic centers.

Attilio Citterio

Naming Molecules with Multi-Stereogenic Centers.23

.

.

enantiomers

enantiomers

diastereomers

.

.

diastereomers

.

.

diastereomers

Diastereomers have different physical properties: different m.p.

and b.p., different solubilities, and so forth.

Total number of stereoisomers will not exceed 2n, where n

is equal to the number of tetrahedral stereogenic centers.

(2R,3R)-2,3-dibromobutane

Attilio Citterio

Molecules with Multi-Stereogenic Centers

Meso Compounds.24

enantiomers

enantiomers

..

.

(superimposable)

Attilio Citterio

Molecules with Multi-Stereogenic Centers

Meso Compounds (2).25

enantiomers

Meso Compound

.

Total number of stereoisomers will not exceed 2n, where n is equal

to the number of tetrahedral stereogenic centers.

diastereomers

Attilio Citterio

Molecules with Multi-Stereogenic Centers

Fisher Projection Formula.26

.

Vertical lines represent bonds that project behind the plane of the paper (or that lie

in it). Horizontal lines represent bonds that project out of the plane of the paper.

Attilio Citterio

Molecules with Multi-Stereogenic Centers

Fisher Projection Formula (2).27

.

Vertical lines represent bonds that project behind the plane of the paper (or that lie

in it). Horizontal lines represent bonds that project out of the plane of the paper.

Attilio Citterio

Stereoisomerism of Cyclic Compounds.28

.

.

.

.

.

.

Mirror plane

trans-1,3-dimethylcyclohexane

cis-1,3-dimethylcyclohexane

Attilio Citterio

1,2-Dimethylcyclohexane.29

trans-1,2-dimethylcyclohexane

.

.

.

.

H

Me

H

Me

H

Me

H

Me

Enantiomers

H

Me

Me

H

H

Me

Me

H

Enantiomers

1,2-dimethylcyclohexane

cis-1,2-dimethylcyclohexane

Attilio Citterio

1,2-Dimethylcyclohexane.30

trans-1,2-dimethylcyclohexane

.

.

.

H

Me

H

Me

.

H

Me

H

Me

Enantiomers

H

Me

Me

H

H

Me

Me

H

Enantiomers

1,2-dimethylcyclohexane

cis-1,2-dimethylcyclohexane

.

.

diastereomers

.

Attilio Citterio

1,2-Dimethylcyclohexane.31

1,2-dimethylcyclohexane

trans-1,2-dimethylcyclohexane

.

.

.

.

H

Me

H

Me

H

Me

H

Me

Enantiomers

H

Me

Me

H

H

Me

Me

H

Enantiomers

.

.

diastereomers

.

Identical

HH

HH

Me Enantiomers MeMeMe

cis-1,2-dimethylcyclohexane

Attilio Citterio

1,2-Dimethylcyclohexane.32

1,2-dimethylcyclohexane

trans-1,2-dimethylcyclohexane

.

.

.

.

H

Me

H

Me

H

Me

H

Me

Enantiomers

H

Me

Me

H

H

Me

Me

H

Enantiomers

.

.

diastereomers

.

Enantiomers

Identical

HH

HH

MeMeMe

Me

cis-1,2-dimethylcyclohexane

Attilio Citterio

Compounds with Stereogenic Centers Other

than Carbon or No Stereogenic Centers.33

H

Me

H

Me

Mirror

(S)-Naproxene

Attilio Citterio

Other Chirality in Organic Chemistry.34

Attilio Citterio

Other Chirality in Organic Chemistry.35

enantiomers

Attilio Citterio

Other Chirality in Organic Chemistry.36

mirror

enantiomers

allene