Advanced Stereochemistry

Presented By
Dr. Sujata Deo
Associate Professor
Department of Chemistry
Govt. Institute of science,
Nagpur
 Syllabus
ORGANIC CHEMISTRY SPECIALIZATION
CH-401: Paper XIII (Special I-Organic Chemistry)
Unit III: 15 h
A] Advanced Stereochemistry:
Conformation of sugars, monosaccharides, disaccharides,
mutorotation,
Recapitulation of Stereochemical concepts- enantiomers,
diastereomers, homotopic and heterotopic ligands, Chemo-,
regio-, diastereo-and enantio-controlled approaches;
Chirality transfer,
 Stereoselective addition of nucleophiles to carbonyl group:
Re-Si face concepts,
Models:Cram’s rule, Felkin Anh rule, Houk model, Cram’s
chelate model.
Asymmetric synthesis use of chiral auxiliaries,
asymmetric hydrogenation,
asymmetric epoxidation
asymmetric dihydroxylation,
Unit 3 – Stereochemistry

 Stereoisomers
 Chirality
 (R) and (S) Nomenclature
 Depicting Asymmetric Carbons
 Diastereomers
 Fischer Projections
 Stereochemical Relationships
 Optical Activity
 Resolution of Enantiomers
Stereochemistry

 Stereochemistry:
 The study of the three-dimensional
structure of molecules

 Structural (constitutional) isomers:

 same molecular formula but different
bonding sequence

 Stereoisomers:
 same molecular formula, same bonding
sequence, different spatial orientation
Stereochemistry CH3
O
 Stereochemistry plays an important role in
determining the properties and reactions of
organic compounds: H
H 3C CH2

CH3 CH3
O O

H H
H 3C CH2 H 2C CH3

Caraway seed spearmint

Stereochemistry

 The properties of many drugs depends on their

stereochemistry:
HN HN

O O O O
N HC H 3 CNHH3N
CHH3 C H 3N H

Cl Cl Cl Cl

(S)-ketamine (R)-ketamine
anesthetic hallucinogen
Stereochemistry

 Enzymes are
capable of
distinguishing
between
stereoisomers:
Types of Stereoisomers

 Two types of stereoisomers:

 enantiomers
 two compounds that are nonsuperimposable
mirror images of each other

 diastereomers
 Two stereoisomers that are not mirror
images of each other

 Geometric isomers (cis-trans isomers) are

one type of diastereomer.
Chiral

 Enantiomers are chiral:

 Chiral:
 Not superimposable on its mirror image

 Many natural and man-made objects are chiral:

 hands
 scissors
 screws (left-handed vs. right-handed threads)

Right hand threads

slope up to the right.
Chiral

 Some molecules are chiral:

Asymmetric
(chiral) carbon
Asymmetric Carbons

 The most common feature that leads to

chirality in organic compounds is the presence
of an asymmetric (or chiral) carbon atom.
 A carbon atom that is bonded to four
different groups

 In general:
 no asymmetric C usually achiral
 1 asymmetric C always chiral
 > 2 asymmetric C may or may not be
chiral
Asymmetric Carbons

Example: Identify all asymmetric carbons

present in the following compounds.
C H 2C H 3
H OH H H CH3
H H H
H C C C C H H 3C

H H H H

Br
Br Br
Br H CH3
Achiral

 Many molecules and objects are achiral:

 identical to its mirror image
 not chiral

H H H H

Cl Cl Cl Cl
Internal Plane of Symmetry

 Cis-1,2-dichlorocyclopentane contains two

asymmetric carbons but is achiral.
 contains an internal mirror plane of
symmetry s
H H

Cl Cl

 Any molecule that has an internal mirror plane

of symmetry is achiral even if it contains
asymmetric carbon atoms.
Internal Plane of Symmetry

 Cis-1,2-dichlorocyclopentane is a meso
compound:
 an achiral compound that contains chiral
centers
 often contains an internal mirror plane of
symmetry
Internal Plane of Symmetry

Example: Which of the following compounds contain

an internal mirror plane of symmetry?

H O 2C CO 2H Br C H 2C H 3
H H CH 3
C C C C
HO OH H H 3C H
H 3C H 2C
H H Br

H
H O 2C CO 2H O
C C F C O HF C
HO H Cl
H OH HO C H F
H
Chiral vs. Achiral
 To determine if a compound is chiral:
 0 asymmetric carbons: Usually achiral
 1 asymmetric carbon: Always chiral
 2 asymmetric carbons: Chiral or achiral
 Does the compound have an internal plane
of symmetry?
– Yes: achiral
– No:
– If mirror image is non-
superimposable, then it’s chiral.
– If mirror image is superimposable,
then it’s achiral.
Conformationally Mobile Systems

 Alkanes and cycloalkanes are conformationally

mobile.
 rapidly converting from one conformation to
another

 In order to determine whether a cycloalkane is

chiral, draw its most symmetrical conformation
(a flat ring).
 H Br

Chiral vs. Achiral Br H

Example: Identify C Hthe

3 following molecules as
chiral or achiral.
C H 3 C C H 2C H 3
Cl CH 3 CH 3CH 2 H
Cl Br
CH 3CCH 2CH 3 C C
CH 3CH CH 2CH 2CH 3 H
Br CH 2CH 3
Cl

H Br Br Br

Br H H H

H3
trans-1,3-dibromocyclohexane
C H 2 C Hethylcyclohexane
3

l
(R) And (S) Nomenclature

 Stereoisomers are different compounds and

often have different properties.

 Each stereoisomer must have a unique name.

 The Cahn-Ingold-Prelog convention is used to

identify the configuration of each asymmetric
carbon atom present in a stereoisomer.
 (R) and (S) configuration
(R) and (S) Nomenclature

 The two enantiomers of alanine are:

C O 2H C O 2H

C
C
H H
CH3
H 3C NH2 H 2N

Natural alanine Unnatural alanine

(S)-alanine (R)-alanine
(R) and (S) Nomenclature

 Assign a numerical priority to each group

bonded to the asymmetric carbon:
 group 1 = highest priority
 group 4 = lowest priority

 Rules for assigning priorities:

 Compare the first atom in each group (i.e.
the atom directly bonded to the asymmetric
carbon)
 Atoms with higher atomic numbers have
higher priority
 (R) and (S) Nomenclature

1 3
Cl CH3
3 C 2 C
H 3C H4
O C H 2C H 3 NH2
H 1 F 2
4

Example priorities:

I > Br > Cl > S > F > O > N > 13C > 12C > 3H > 2 H >
1H
(R) and (S) Nomenclature

 In case of ties, use the next atoms along the

chain as tiebreakers.

2 CH CH Br
2 2

C H4
3 CH CH
3 2
C H (C H 3 ) 2
1

CH(CH3)2 > CH2CH2Br > CH3CH2

 Y

(R) and (S)

C Y
Nomenclature
C Y C

Y C
 Treat double and
Y triple bonds as if both atoms
C
C
O inY the bondC were
Y
C Yduplicated
C or triplicated:
O C H Y C
Y
C Y Y
OH C
H C Y C Y C Y C Y C
C H 2O H C Y C
Y C Y C
Y C
C O
O 2 H C Y
C Y C C Y2
O C H

Y C C 1 C
1
OH OH
H
4 C H 2O H C 4 HY C H 2O H
3 C Y3
Y C
(R) and (S) Nomenclature

 Using a 3-D drawing or model, put the 4th

priority group in back.

 Look at the molecule along the bond between

the asymmetric carbon and the 4th priority
group.

 Draw an arrow from the 1st priority group to

the 2nd group to the 3rd group.
 Clockwise arrow (R) configuration
 Counterclockwise arrow (S) configuration
 (R) and (S) Nomenclature
C H 3)2
Example: Identify the asymmetric carbon(s) in
each of the following compounds and determine
whether it has the (R) or (S)Oconfiguration.
CH3
CH3 H
C H
C H 2CC H 3 C
C H 2C H 3 C H (C H 3 ) 2
O HH CH3
OH Br

Br Br
O CH3
COH
C
CH3 C O 2H C H 2C
H3 H
H H
OH
(R) and (S) Nomenclature

Example: Name the following compounds.

C H 2C H 3
C
Br CH3
H

Br CH3

H CH3
(R) and (S) Nomenclature

 When naming compounds containing multiple

chiral atoms, you must give the configuration
around each chiral atom:
 position number and configuration of each
chiral atom in numerical order, separated by
commas, all in ( ) at the start of the
compound name

H
H Br
Cl
(2S, 3S)-2-bromo-3-chlorobutane
H 3C CH 3
Depicting Structures with Asymmetric
Carbons
Example: Draw a 3-dimensional formula for (R)-
2-chloropentane.
Step 1: Identify the asymmetric carbon.
Cl

C H 3 C* C H 2C H 2C H 3

H
Step 2: Assign priorities to each group attached to
the asymmetric carbon.
1
C Cl
2
3 CH C C H 2C H 2C H 3
3

H 4
Depicting Structures
Cl with Asymmetric
Carbons
CH3 C C H 2C H 2C H 3
Step 3: Draw a “skeleton” with the asymmetric carbon
in the center and H
the lowest priority group attached to
the “dashed” wedge (i.e. pointing away from you).

Cl
C
CH3 C CH
H 2C H 2C H 3

H
Step 4: Place the highest priority group at the top.
Cl

C
H
Depicting Structures with Asymmetric
Carbons
Cl

Step
C H 5:
3
CForC(R)
H 2 Cconfiguration,
H 2C H 3 place the 2nd and
3rd priority groups around the asymmetric
H
carbon in a clockwise direction.
Cl

C
H
C H 3 C H 2C H 2C H 3

Step 6: Double-check your structure to make

sure that it has the right groups and the right
configuration.
Depicting Structures with Asymmetric
Carbons
Example: The R-enantiomer of ibuprofen is not
biologically active but is rapidly converted to the
active (S) enantiomer by the body. Draw the
structure of the R-enantiomer.

H O 2 CCH CH 2 CH (CH 3 ) 2

CH 3
Depicting Structures with Asymmetric
Carbons
Example: Captopril, used to treat high blood
pressure, has two asymmetric carbons, both with
the S configuration. Draw its structure.

N C CH CH 2 SH

CH 3
CO 2 H