Topic 5F

Stereochemistry

Stereochemistry• Study of three-dimensional shape of molecules and how this affects their chemical and physical properties• Very important in biology• Isomers that have the same formula and connectivity but differ only in the way the atoms are arranged in space are STEREOISOMERS• Constitutional isomers having different connectivity and are joined up in a different way are NOT stereoisomers

71

CH3CH2

CH2CH2

CH3 CH3C

CH2CH3 CH3

CCH3

CH3 CH3H CH3

2,2-dimethylpropanen-pentane 2-methylbutane

Optical isomerism• Optical isomers: differ in the way they rotate plane polarised light.

– Enantiomers: isomers that are nonsuperimposable mirror images of each other. – Diastereomers: stereoisomers that are not enantiomers. Isomers with more than one chiral carbon that

are not enantiomers but differ only in configurations about chiral carbons.

72

Optical Isomerism

• Carvone and the essence of spearmint are optical isomers or ENANTIOMERS• They possess CHIRAL carbon and they are chiral molecules• They interact with plane-polarised light differently

72

OCH3

H

O

CH3HCH2CH3

CH3CH2

Spearmint essenceCarvone(caraway)

Mirror images• Mirror images that can be superimosed are ACHIRAL

73

The mirror image of this fork can be stacked on top of the real thing since the fork is symmetrical.It is achiral.

Mirror image

Real fork

Chirality or handedness• From the Greek word “cheir” — hand

• Hands are non-superimposable — they are chiral

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• Any molecule that cannot be superimposed on its mirror image is said to be chiral

Chiral carbons

• Have four different substituents attached to them

• Chiral carbons have no symmetry they are asymmetric

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A

CD

B

B

CD

B

A

CC

B

A

CA

B

Chiral Achiral

Achiral molecules

• Carbons bearing two identical substituents are ACHIRAL• They can be superimposed upon their mirror image

74

Real molecule Mirror image

Mirror

B

A

D

DD

DB

AA

B D

D

A

B D

D

Mirror image

Examples of achiral molecules

• Each have two identical substituents

75

OH

CH2OH

CH2OH

H

H

CO2H

NH2

H

OH

CH3

CH2CH3

CH3

2-hydroxy-2-methylbutane

Glycine1,2,3-propanetriol (glycerol)

Chiral molecules• A chiral molecule is unique and can not be

superimposed upon its mirror image

75

B D

C C

D

A

B

Mirror

Mirror imageReal molecule

Mirror image

C

DB

A

C

BD

A Mirror image

C

DB

A

A

DB

C

A

Examples of chiral molecules 76

OH

C CH2OH

Br

H

CH3

CH3

C CO2H

NH2

H

CH(CH3)2

C

C CO2H

Cl

H

NH2

C CH3

CH2CH2CH3

H

O

CH3

H

CH2CH3

CO2H

NH2

H

ValineAlanine

**

2-aminopentane2-Chloro-propanoic acid

2-Bromo-2-hydroxyethanol

*

***

Carvone(caraway)

Amino acids

Ranking groups(1) Higher atomic number of atom bonded to the chiral carbon

means higher priority.

H C N O F S Cl Br I, Increasing priority

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(2) If two atoms are the same, proceed to the second atom or even farther along the chain to the first point of difference.(3) Groups with pi bonds are given single-bond equivalents by duplication or triplication of multiply bonded atoms. You will learn to use this rule in second year.

(4) E/Z isomers use the same priority rule

(R) and (S) nomenclature Cahn-Ingold-Prelog system

• Align smallest group away from you

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Steps:

QuickTime™ and aAnimation decompressor

are needed to see this picture.

• Assign priorities to all groups attached to the chiral centre

• Determine in what direction priorities decrease, clockwise or anticlockwise

(S) (R)

Assigning (R) or (S)

• If groups descend in priority clockwise then (R)“R” from Latin word “rectus”

78

• If groups descend in priority anticlockwise then (S)“S” from Latin word “sinister”

F

C H

Cl

Br

(S) configuration

3

21

4

3

1

*

2

F

C H

Br

Cl

(R) configuration

1

*

2

3

4

2 1

3

Examples 78I

C H

CH2CH3

HO*

OH

C H

CH2CH3

CH3

*

I

C H

CH2CH3

HO*

1

2

3

4

OH

C H

CH2CH3

CH3

*

2

3

4

1

C

OH

CH3 CH2CH3

1

23 R

(R)-2-butanol

C

I

HO CH2CH3

1

2 3S

(S)-1-iodopropanol

Enantiomeric pairs

• Enantiomers (from Greek enantio, “opposite” and merso , “part”) have opposite configuration

78

Enantiomers

ClClI

BrBr

I

HH

Mirror

Examples of enantiomers• Enantiomers come in pairs:

79

CH3CH2CH2

NH2

H

CH2CH2CH3

CH3

NH2

HCH3

Mirror

Enantiomers of 2-aminopentane

* *

CO2H

H

NH2

CH3

CO2H

H

NH2

CH3

Mirror

Enantiomers of alanine

**

Fischer projections

• Configurations at carbon can be represented on paper by Fischer projections

79

A

C

C

DBQuickTime™ and a

Animation decompressorare needed to see this picture.

A

C

C

DB

Fischer projection

Example• Enantiomers of glyceraldeyde as Fischer projections:

80

C

C H

OH

HOCH2

C

CH

HO

CH2OH

O H O H

CH OH

CHO

CH2OH

C HHO

CHO

CH2OH

**

Enantiomers of glyceraldehydeMirror

H OH

CHO

CH2OH

HHO

CHO

CH2OHFischer projections

More than one chiral carbon• Each chiral carbon treated separately

81

CHO

CH2OH

OHH

OHH

CHO

CH2OH

OHH

OHH

2,3,4-trihydroxybutanal Fischer projection

2

3

4

CHO

CH2OH

OHH

OHH

CHO

CH2OH

OHH

OHH4

3

1R

3R

2

4

3

2

1R

2R

(2R,3R)-2,3,4-Trihydroxybutanal

Numbers of isomers

• 2n Isomers, n = number of chiral centres

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CHO

CH2OH

OHH

OHH

CHO

CH2OH

HO H

HO H

CHO

CH2OH

OHH

HHO

CHO

CH2OH

HO H

H OH

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

2

3

Numbers of isomers• 2n Isomers, n = number of chiral centres• Isomers NOT mirror images are DIASTEREOMERS

82

2

3

CHO

CH2OH

OHH

OHH

CHO

CH2OH

HO H

HO H

CHO

CH2OH

OHH

HHO

CHO

CH2OH

HO H

H OH

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

Numbers of isomers• 2n Isomers, n = number of chiral centres• Isomers NOT mirror images are DIASTEREOMERS

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2

3

CHO

CH2OH

OHH

OHH

CHO

CH2OH

HO H

HO H

CHO

CH2OH

OHH

HHO

CHO

CH2OH

HO H

H OH

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

Meso compounds

• Two centres but possess a plane of symmetry

• Tartaric acid has only three streoisomers

83

CO2H

CO2H

OHH

OHH

CO2H

CO2H

HO H

HO H

CO2H

CO2H

OHH

HHO

CO2H

CO2H

HO H

H OH3

2

3

2

3

2

3

2

Enantiomersof tartaric acid

Not enantiomersmeso-tartaric acid

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

Properties of enantiomers• They behave differently in chiral environments

– Chiral reactants– Chiral catalysts– Biological environments

• Interaction with plane-polarised light– The name optical isomerism stems from this

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• 1815 Jean-Baptiste Biot discovered that some substances rotate the plane of polarised light.• Sugar cane rotates light through 60°• Such compounds are OPTICALLY ACTIVE• All such compounds contain chirality.

84Interaction with polarised light

Side view of planepolarised light

Polarizingfilter

Cross section of light wave

Plane polarisedlight

Plane Polarised light:

Interaction with polarised light 85

Dextro- and levorotation

• Compounds that rotate the plane of polarised light to the LEFT are LEVOROTATORY or the (–) form

85

• Compounds that rotate the plane of polarised light to the RIGHT are DEXTROROTATORY or the (+) form

polarisingfilter

Plane polarisedlight

Sample solutioncell

Rotated lightUnpolarisedlight

=-20°CounterclockwiseLevorotatory

=+35°ClockwiseDextrorotatory

Specific rotation

• Magnitude of rotation depends upon– Nature of substance– Concentration of the solution– Temperature– Wavelength of light– Solvent

• Enables comparison of measurements under different conditions

85

[]D T

Specific rotation

• is the observed rotation in degrees• T is the temperature at measurement• D is the sodium D line (589.3 nm)• l is the cell length in decimeters (dm)• c is the concentration in g/mL

85

[]D = T

l x c (solvent)

Solution: = -14.4° l = 5/10 = 0.5 dm c = 1.8/10 =0.18 g/mL

[]TD = -14.4/0.5 x 0.18

 = -160.0° (chloroform)

Example 85

Specific rotation of cocaine:1.80g dissolved in 10.0 mL of chloroform in a 5.0 cm cell gave an observed rotation at 20° with (sodium D line) of -14.4°

N CO2CH3

H

OCOPh

H

CH3

Cocaine

Configuration• There is no relationship between the actual configuration at a carbon and the direction of rotation of plane

polarised light

For instance:

86

Same configuration

C

CH

HO

CH2OH

O OH

H OH

CO2H

CH2OH

(-) Glyceric acid

*

oxidationC

CH

HO

CH2OH

O H

H OH

CHO

CH2OH

(+) Glyceraldehyde

*

Racemic mixtures• Enantiomers rotate the plane of polarised light by equal amounts but in opposite directions.• A 50:50 mixture of enantiomers does not rotate the plane of polarised light. No net rotation• RACEMIC MIXTURE

87

OCH3

H

O

CH3HCH2CH3

CH3 CH2

Spearmint essenceCarvone(caraway)

(+) (–)

50 : 50 No net rotation

Chirality in the biological world

• Example:Only one form of the amino acid alanine (S) is incorporated into protein molecules.The enantiomer (R) is oxidised and metabolised

88

Enantiomers of alanine

CO2H

H

R-doesn't fit protein shape

Chiral protein

too big

too small

*

RCH3

NH2

CO2H

NH2

S-fits protein shape

Chiral protein

S

*

CH3

H

Chiral drugs• Radically different roles of enantiomers.

89

Thalidomide

NH

O

O

H

N

O

O

(S) form is an analgesic(R) form inactive

(S) form is a Teratogen (auses foetal deformities)(R) form is anAnti-depressant

CH3 CO2H

CH3

CH3

H

H

Ibuprofen

(S) (S)