Stereochemistry

Stereochemistry:

That part of the science whichdeals with structure in threedimensions

That part of the science whichdeals with structure in threedimensions

StereochemistryIsomers: different compounds having the same molecular formula

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

C lIB r

HIC l

B r

HC H 3 C H 3C H 3CH 3

C H 3

E t

C lC l H

H

C H 3

E t

C lC lHH

C lH

C l H

C lH

H C l

C l H

C lH

C l C l

HH

I s o m e r sD i f f e r e n t c o m p o u n d s t h a t h a v e t h e s a m e m o l e c u l a r f o r m u l a

C o n s t i t u t i o n a l i s o m e r s S t e r e o i s o m e r sA t o m s a r e a t t a c h e d t o o n e a n o t h e r i n d i f f e r e n t w a y s

A t o m s h a v e t h e s a m e c o n s t i t u t i o n b u t d i f f e r e n t a r r a n g e m e n t i n s p a c e

E n a n t i o m e r s D i a s t e r i o m e r s

N o n s u p e r i m p o s a b l e m i r r o r - i m a g e s t e r e o i s o m e r s

N o n m i r r o r - i m a g e s t e r e o i s o m e r s

C o n f o r m a t i o n a l C o n f i g u r a t i o n a l

In t e r c o n v e r t a b l e b y r o t a t i o n

In t e r c o n v e r t a b l eb y b o n d b r e a k i n g

SR

c i s - t r a n s -

c is t r a n s

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

C lIB r

HIC l

B r

HC H 3 C H 3C H 3CH 3

C H 3

E t

C lC l H

H

C H 3

E t

C lC lHH

C lH

C l H

C lH

H C l

C l H

C lH

C l C l

HH

I s o m e r sD i f f e r e n t c o m p o u n d s t h a t h a v e t h e s a m e m o l e c u l a r f o r m u l a

C o n s t i t u t i o n a l i s o m e r s S t e r e o i s o m e r sA t o m s a r e a t t a c h e d t o o n e a n o t h e r i n d i f f e r e n t w a y s

A t o m s h a v e t h e s a m e c o n s t i t u t i o n b u t d i f f e r e n t a r r a n g e m e n t i n s p a c e

E n a n t i o m e r s D i a s t e r i o m e r s

N o n s u p e r i m p o s a b l e m i r r o r - i m a g e s t e r e o i s o m e r s

N o n m i r r o r - i m a g e s t e r e o i s o m e r s

C o n f o r m a t i o n a l C o n f i g u r a t i o n a l

In t e r c o n v e r t a b l e b y r o t a t i o n

In t e r c o n v e r t a b l eb y b o n d b r e a k i n g

SR

c i s - t r a n s -

c is t r a n s

Isomers – different compounds with the same molecularformula.

Structural Isomers – isomers that differ in which atoms arebonded to which atoms.

CH3eg. C4H10 CH3CH2CH2CH3 CH3CHCH3

n-butane isobutane

Isomers – different compounds with the same molecularformula.

Structural Isomers – isomers that differ in which atoms arebonded to which atoms.

CH3eg. C4H10 CH3CH2CH2CH3 CH3CHCH3

n-butane isobutane

Stereoisomers – isomers that differ in the way the atoms areoriented in space, but not in which atoms are bonded to whichatoms.

eg. cis-2-butene trans-2-butene

HC C

H3C CH3

H HC C

H3C H

CH3HC C

H3C CH3

H HC C

H3C H

CH3

Cl H

Cl H

Cl H

H Cl

cis-1,2-Dichloroethene trans-1,2-Dichloroethene

C2H2Cl2

Chirality CenterCarbon has four different groups attached

BrBrClCl

HH HH

ClClBrBr

HH

FF

HH

FF

Chiral Centers

A point in a molecule where four different groups (oratoms) are attached to carbon is called a chiral center

There are two nonsuperimposable ways that 4 differentgroups (or atoms) can be attached to one carbon atom

A chiral molecule usually has at least one chiral center

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A point in a molecule where four different groups (oratoms) are attached to carbon is called a chiral center

There are two nonsuperimposable ways that 4 differentgroups (or atoms) can be attached to one carbon atom

A chiral molecule usually has at least one chiral center

Chiral vs achiral

NOMENCLATURE OFENANTIOMERS: THE (R-S)

SYSTEM• (R) and (S) are from the Latin words

rectus and sinister:• i) R configuration: clockwise (rectus,

“right”)• ii) S configuration: counterclockwise

(sinister, “left”)

• (R) and (S) are from the Latin wordsrectus and sinister:

• i) R configuration: clockwise (rectus,“right”)

• ii) S configuration: counterclockwise(sinister, “left”)

Priority (Cahn-Ingold-Prelog) RulesRule 1: Look at the atoms directly attached to the chiral carbon and

assign priority based on highest atomic number (O > N > C > H)Rule 2: If decision can’t be reached by ranking the first atoms in the

substituents, look at the second, third, or fourth atoms untildifference is found

Rule 3: Multiple-bonded atoms are equivalent to the same number of

single-bonded atoms

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Priority (Cahn-Ingold-Prelog) RulesRule 1: Look at the atoms directly attached to the chiral carbon and

assign priority based on highest atomic number (O > N > C > H)Rule 2: If decision can’t be reached by ranking the first atoms in the

substituents, look at the second, third, or fourth atoms untildifference is found

Rule 3: Multiple-bonded atoms are equivalent to the same number of

single-bonded atoms

Examples

BrI

Cl

H

BrCl

CH3

H

CH3Et

H

FCH3

H

OH

O

CH3

CH2CH3

H

CH3CH2

HI

Cl

Br

BrH

CH3

Et

HEt

CH3

FH

OH

CH3

O

CH3

CH3

CH2OH

CH2CH3CH2

R S R S S

S R R R S

BrI

Cl

H

BrCl

CH3

H

CH3Et

H

FCH3

H

OH

O

CH3

CH2CH3

H

CH3CH2

HI

Cl

Br

BrH

CH3

Et

HEt

CH3

FH

OH

CH3

O

CH3

CH3

CH2OH

CH2CH3CH2

R S R S S

S R R R S

Br

CH3CH2 CH3

H

Br

CH3CH2CH3

H

1

23

4

(S)-2-bromobutane

1

2

34

(R)-2-bromobutane

Br

CH3CH2 CH3

H

Br

CH3CH2CH3

H

1

23

4

(S)-2-bromobutane

1

2

34

(R)-2-bromobutane

Lactic Acid

(S) (R)

4

3 2

1

4

32

1OH

CH3 CO2HH

OH

CH3HO2CH

(S) (R)

4

3 2

1

4

32

1OH

CH3 CO2HH

OH

CH3HO2CH

C.I.P. Priorities

CH2CH2CH3 CH(CH3)2

CH2CH2OH CH2CH

O

CH2CH2CH3 CH=CH2

CO2H CH2Cl

Low High

CH2CH2Br CH(CH3)2

CH2CH2CH3 CH(CH3)2

CH2CH2OH CH2CH

O

CH2CH2CH3 CH=CH2

CO2H CH2Cl

Low High

CH2CH2Br CH(CH3)2

Compounds with more than one stereogeniccenter; (Diasteriomers)

CH3

Et

H

Cl

Cl

H

CH3

Et

Cl

H

H

Cl

CH3

Et

H

H

Cl

Cl

CH3

Et

Cl

Cl

H

H

1

2

3

(2R,3R) (2S,3S) (2R,3S) (2S,3R)

1 2 3 4

1 and 2 are enantiomers, 3 and 4 are also enantiomers

1 and 3 , 1 and 4, 2 and 3, 2 and 4 are diastereomers

Diastereomers are non mirror image stereoisomers

If a molecule has n different stereogenic centers, it may exist in a maximumof 2n stereisomeric forms. There will be a maximum of 2n / 2pairs of enantiomers.in the above case 2 stereogenic centers, 2 pairs of enantiomers, 4 stereoisomers

CH3

Et

H

Cl

Cl

H

CH3

Et

Cl

H

H

Cl

CH3

Et

H

H

Cl

Cl

CH3

Et

Cl

Cl

H

H

1

2

3

(2R,3R) (2S,3S) (2R,3S) (2S,3R)

1 2 3 4

1 and 2 are enantiomers, 3 and 4 are also enantiomers

1 and 3 , 1 and 4, 2 and 3, 2 and 4 are diastereomers

Diastereomers are non mirror image stereoisomers

If a molecule has n different stereogenic centers, it may exist in a maximumof 2n stereisomeric forms. There will be a maximum of 2n / 2pairs of enantiomers.in the above case 2 stereogenic centers, 2 pairs of enantiomers, 4 stereoisomers

CH3

CH3

H

Cl

Cl

H

CH3

CH3

Cl

H

H

Cl

CH3

CH3

H

H

Cl

Cl

CH3

CH3

Cl

Cl

H

H

1

23

(2R,3R) (2S,3S) (2R,3S) (2S,3R)

1 2 3 4

1 and 2 are enantiomers, 3 and 4 are the same compound (Meso structure)

1 and 3 , 2 and 3, are diastereomers

Diastereomers are non mirror image stereoisomers

A meso compound: is an achiral ( optically inactive) diastereomer of a compoundwith stereogenic centers. Its stereogenic centers have opposite configurations.One half of the molecule is the mirror image of the other half

1 pair of enantiomers and a total of 3 isomers

same compound

CH3

CH3

H

Cl

Cl

H

CH3

CH3

Cl

H

H

Cl

CH3

CH3

H

H

Cl

Cl

CH3

CH3

Cl

Cl

H

H

1

23

(2R,3R) (2S,3S) (2R,3S) (2S,3R)

1 2 3 4

1 and 2 are enantiomers, 3 and 4 are the same compound (Meso structure)

1 and 3 , 2 and 3, are diastereomers

Diastereomers are non mirror image stereoisomers

A meso compound: is an achiral ( optically inactive) diastereomer of a compoundwith stereogenic centers. Its stereogenic centers have opposite configurations.One half of the molecule is the mirror image of the other half

1 pair of enantiomers and a total of 3 isomers

same compound

CH3ClBr

H

HClCH3

Br

CH3Cl

H

H

BrCH3

CH3H

Cl

Br

HCH3

CH3Cl

H

H

BrCH3

HCH3

Cl

H

BrCH3

CH3Cl

H

H

BrCH3

HCH3

Cl

Br

HCH3

ExampleWhat is the relation between the following compounds

R Rsame compound

1

2

3 4

(2S,3S) (2R,3S)

Diastereomers

(2S,3S) (2R,3R)

Enantiomers(2S,3S) (2S,3S)

Same compound

CH3ClBr

H

HClCH3

Br

CH3Cl

H

H

BrCH3

CH3H

Cl

Br

HCH3

CH3Cl

H

H

BrCH3

HCH3

Cl

H

BrCH3

CH3Cl

H

H

BrCH3

HCH3

Cl

Br

HCH3

ExampleWhat is the relation between the following compounds

R Rsame compound

1

2

3 4

(2S,3S) (2R,3S)

Diastereomers

(2S,3S) (2R,3R)

Enantiomers(2S,3S) (2S,3S)

Same compound

• Properties of enantiomers and diastereomers• A) Enantiomers• Have the same physical properties except for

direction of rotation of plane polarized light• Have the same chemical properties except for

their reaction with other chiral molecules• (This usually seen in their biological activity)• B) Diastereomers• Have different physical properties• Similar chemical properties

• Properties of enantiomers and diastereomers• A) Enantiomers• Have the same physical properties except for

direction of rotation of plane polarized light• Have the same chemical properties except for

their reaction with other chiral molecules• (This usually seen in their biological activity)• B) Diastereomers• Have different physical properties• Similar chemical properties

• A chiral molecule is one that is optically active

• A racemic mixture (racemic modification) isone with equal ratios of enantiomers (50:50mixture)

• A chiral molecule is one that is optically active

• A racemic mixture (racemic modification) isone with equal ratios of enantiomers (50:50mixture)

• Chemical reactions of stereoisomers• 1) Generation of a chiral center

CH3

CH2Ch3

HH

CH3

H CH2CH3

CH3

CH2Ch3

HClCH3

CH2Ch3

ClHCl2

CH3

Et

BrHCH3

Et

HBrEt

CH3H

heat

.

planar radicalequal ratios

Cl2 2Cl.

Cl.

-HCl

HBr +

planar carbocation equal ratios

Br -

CH3

CH2Ch3

HH

CH3

H CH2CH3

CH3

CH2Ch3

HClCH3

CH2Ch3

ClHCl2

CH3

Et

BrHCH3

Et

HBrEt

CH3H

heat

.

planar radicalequal ratios

Cl2 2Cl.

Cl.

-HCl

HBr +

planar carbocation equal ratios

Br -

Stereochemistry of ElectrophilicAddition Reactions of Alkenes

What is the absolute configuration of the product?

Addition reactions that form one asymmetric carbon

CH3CH2C CH2 HBr CH3CH2CHCH2Br

2-methyl-1-butene

CH3

+ peroxideCH3

*

1-bromo-2-methylbutane

Reaction away from a chiral centerCH3

CH2Ch3

H COOH

EtOH / acid CH3

CH2Ch3

H COOEt

CH2

CH2Ch3

H Cl

OH

CH2Ch3

H Cl

OH

retention of configuration

retention of configuration

KMnO4

CH3

CH2Ch3

H COOH

EtOH / acid CH3

CH2Ch3

H COOEt

CH2

CH2Ch3

H Cl

OH

CH2Ch3

H Cl

OH

retention of configuration

retention of configuration

KMnO4

CH2CH2CH2Cl

CH3CH2 CH3

H

CH2CH2CH2OH

CH3CH2 CH3

HOH-

٣٠

CH

CH3CH2CH2 CH3

H

CH2 CH2CH3

CH3CH2CH2 CH3

HH2

Pd/C

A carbocation reaction intermediate

Addition reactions that form two asymmetric carbons

C C

CH3CH2 CH2CH3

CH3H3C

+ HCl CH3CH2CH

CH3

CCH2CH3

Cl

CH3

C C

CH3CH2

H3CCH2CH3

CH3

H

C C

C C

CH3CH2

H3CCl

CH2CH3

CH3

HCl

CH3CH2

CH2CH3

HCl

H3C

CH3 C C

CH3CH2

CH2CH3

HCH3

H3C

Cl

Two substituents added to the same side of the double bond: synTwo substituents added to opposite sides of the double bond: anti

C C

CH3CH2 CH2CH3

CH3H3C

+ HCl CH3CH2CH

CH3

CCH2CH3

Cl

CH3

C C

CH3CH2

H3CCH2CH3

CH3

H

C C

C C

CH3CH2

H3CCl

CH2CH3

CH3

HCl

CH3CH2

CH2CH3

HCl

H3C

CH3 C C

CH3CH2

CH2CH3

HCH3

H3C

Cl

A radical reaction intermediateAddition reactions that form two asymmetric carbons

Addition reactions that form a bromonium ionintermediate (anti addition)

CH2ClH3C H

CH2CH3

(S)-(-)-1-chloro-2-methylbutane

Cl2, hvC5H10Cl2 + HCl

six fractions:four optically activetwo optically inactive

CH2ClH3C H

CH2CH3

(S)-(-)-1-chloro-2-methylbutane

Cl2, hvC5H10Cl2 + HCl

six fractions:four optically activetwo optically inactive

CH2ClH3C H

CH2CH3

Cl2, hvCHCl2

H3C HCH2CH3

No bonds to the chiral centerare broken, configuration isretained. Product is opticallyactive

A

CH2ClH3C H

CH2CH3

Cl2, hvCHCl2

H3C HCH2CH3

No bonds to the chiral centerare broken, configuration isretained. Product is opticallyactive

A

CH2ClH3C H

CH2CH3

Cl2, hvCH2Cl

H3C ClCH2CH3

A bond is broken to the chiral center.Stereochemistry depends on themechanism. Here, the intermediatefree radical is flat and a racemicmodification is formed. This fractionis optically inactive.

B

CH2ClCl CH3

CH2CH3

+

CH2ClH3C H

CH2CH3

Cl2, hvCH2Cl

H3C ClCH2CH3

A bond is broken to the chiral center.Stereochemistry depends on themechanism. Here, the intermediatefree radical is flat and a racemicmodification is formed. This fractionis optically inactive.

B

CH2ClCl CH3

CH2CH3

+

CH2ClH3C H

CH2CH3

Cl2, hvCH2ClCClH2C HCH2CH3

The product no longer hasa chiral center. It is achiraland optically inactive.

C

CH2ClH3C H

CH2CH3

Cl2, hvCH2ClCClH2C HCH2CH3

The product no longer hasa chiral center. It is achiraland optically inactive.

C

CH2ClH3C H

CH2CH3

Cl2, hvCH2Cl

H3C H

CH3

No bond is broken to the chiral centerand a new chiral center is formed. Theproducts are diastereomers and eachfraction is optically active.

D

CH2ClH3C H

CH3

+ClH HCl

E

CH2ClH3C H

CH2CH3

Cl2, hvCH2Cl

H3C H

CH3

No bond is broken to the chiral centerand a new chiral center is formed. Theproducts are diastereomers and eachfraction is optically active.

D

CH2ClH3C H

CH3

+ClH HCl

E

CH2ClH3C H

CH2CH3

Cl2, hvCH2Cl

H3C HCH2CH2Cl

No bonds to the chiral centerare broken, configuration isretained. Product is opticallyactive

F

CH2ClH3C H

CH2CH3

Cl2, hvCH2Cl

H3C HCH2CH2Cl

No bonds to the chiral centerare broken, configuration isretained. Product is opticallyactive

F

CH2ClH3C H

CH2CH3

(S)-(-)-1-chloro-2-methylbutane

Cl2, hv CHCl2H3C H

CH2CH3

CH2ClH3C Cl

CH2CH3

CH2ClCl CH3

CH2CH3

CH2ClCClH2C HCH2CH3

CH2ClH3C H

CH3

CH2ClH3C H

CH3

CH2ClH3C H

CH2CH2Cl

Cl Cl HH

A B

C D E

F

optically activeoptically inactive

CH2ClH3C H

CH2CH3

(S)-(-)-1-chloro-2-methylbutane

Cl2, hv CHCl2H3C H

CH2CH3

CH2ClH3C Cl

CH2CH3

CH2ClCl CH3

CH2CH3

CH2ClCClH2C HCH2CH3

CH2ClH3C H

CH3

CH2ClH3C H

CH3

CH2ClH3C H

CH2CH2Cl

Cl Cl HH

A B

C D E

F

optically activeoptically inactive

Generation of a second chiral center

CH3

ClH

CH3

CH3

Cl

H

H

Br

CH3

CH3

Cl

Br

H

H

HBr +

Diastereomeric products at different rates and in unequal amounts

CH3

ClH

CH3

CH3

Cl

H

H

Br

CH3

CH3

Cl

Br

H

H

HBr +

Diastereomeric products at different rates and in unequal amounts

Addition reactions that form an additional asymmetriccarbon

importance of stereochemistry inpharmaceutical

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