By:

Sagar Ravso Mudshinge

M.S.(Pharm.) IIIrd Sem

Dept. of Medicinal Chemistry

NIPER, S.A.S. Nagar. Punjab

DETERMINATION OF ABSOLUTE CONFIGURATION

BY NMR SPECTROSCOPY

Flow of presentation

• Introduction

• Historical background

• Isomers

• Methods of determination of absolute configuration

• Principle and limitations of X-Ray Crystallography

• General approaches to determine the absolute configuration by

NMR

• Conclusions

Introduction

• Stereoisomers with non-superimposible mirror images are

called as Enantiomers

• Diastereomers are non-mirror image stereoisomers

HOOC

COOH

OH

OH

HOOC

COOH

OH

OH

(2R ,3R)-2,3-dihydroxysuccinic acid(2S,3S)-2,3-dihydroxysuccinic acid

HOOC

COOH

OH

OH(2S,3S)-2,3-dihydroxysuccinic acid

HOOC

COOH

OH

OH(2R,3S)-2,3-dihydroxysuccinic acid

HISTORICAL LANDMARKS IN THE FIELD OF

STEREOCHEMISTRY

Pasteur

Le Bel Vant Hoff

Fischer

1848- Pasteur achieves the first optical resolution of the

(+)- and (-)-enantiomers of tartaric acid.

1874 -van’t Hoff and Le Bel independently suggest

that tetravalent carbon is tetrahedral.

1900- Fischer develops the first systematic method for

depicting stereochemistry (Fischer

projections) and a notation for designating

configuration (D/L notation).

Isomers

Are the structures symmetry related?

Can superimposed by translation

and/or rotation

Homomers

Enantiomers

Does structure have same

constitutionDiastereomers

Yes

No

Yes

Yes

No

Different methods for determination of

absolute configuration

• Nuclear Magnetic Resonance(NMR)

• X-Ray Crystallography

• Optical Rotatory Dispersion(ORD)

• Circular Dichroism(CD)

Principle of X- Ray Crystallography

Tetrahedron: Asymmetry .2009, 20,712–717

Limitations of X- Ray Crystallography

• Need of good quality crystal

• Bulk sample should be enantiomerically pure

• Disorder is common problem

• Location of hydrogen can’t be detected

General approaches to determine the

absolute configuration by NMR

Using chiral solvating agents

Derivatization by chiral auxillary reagents

Single

derivatization

Double

derivatization

Chem. Rev. 2004, 104, 17-117

Characteristics of the auxiliary reagents

• A polar or bulky group to fix a particular conformation

• A functional group (e.g. carboxylic acid) that provides a site for

covalent attachment of the substrate

• A group that is able to produce an efficient and space-oriented

anisotropic effect

H3COOH

O

H

(R)-2-methoxy-2-phenylacetic acid

Chem. Rev., 2012, 112 (8), 4603–4641

Conclusion

• NMR is Better alternative for these kind of assignments due to

its availability and easy handling and shorter duration of

experimentation

• Single and double derivatization methods are available for this

purpose but since it is evolving field there is need of lot of

work in this area tio widen its applicability