WELCOME

RACEMIC MODIFICATION, METHOD, RESOLUTION AND PROPERTIES.

Mr. DILIP R. DAVHAREM.Pharm. IInd Sem. (Pharmaceutical Chemistry)

UNIVERSITY DEPARTMENT OF PHARMACEUTICAL SCIENCES, RASHTRASANT TUKADOJI MAHARAJ

NAGPUR UNIVERSITY, NAGPUR

Contents.DefinationHistoryMethod of racemic modificationProperties of racemic modificationResolution of racemic modification

DefinationRACEMIC MODIFICATIONA mixture of enantiomers is called a racemic

modification.Racemic modification is optically inactive if the

mixture is 50:50. When enantiomers are mixed together, the

rotation caused by a molecule of one isomer is exactly cancelled by an equal and opposite rotation caused by a molecule of its enantiomer.

(dl) or (±) – lactic acid.

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OPTICAL ISOMERS

The two forms are called optical isomers. Mirror image non superimposable. Optical isomers also called enantiomers.

C

C

CH3

OH

H OH

OC

C

CH3

O

OH H

OH

(d) or (+) Lactic acid (l) or (-) Lactic acid The phenomenon is called optical isomerism.

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ENANTIOMERSEnantiomers Greek word enantio =

oppositeIsomers that are mirror image of

each other are called enantiomers.Two stereoisomers that are not

superimposable mirror image of each other.

2,3-Dichloropentane

CH3C

C

C2H5

H Cl

Cl H

CH3C

C

C2H5

Cl H

H Cl

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NomenclatureA racemic mixture is denoted by the

prefix (±)- or dl- , indicating an equal (1:1) mixture of dextro and levo isomers. Also the prefix rac- (or racem-) or the symbols RS and SR (all in italic letters) are used.

If the ratio is not 1:1 (or is not known), the prefix (+)/(−), D/L- or d/l- (with a slash) is used instead.

The usage of d and l is strongly discouraged by IUPAC.

Racemic Mixtures

Equal quantities of d- and l-enantiomers.Notation: (d,l) or ()No optical activity.The mixture may have different boiling point (b. p.) and

melting point (m. p.) from the enantiomers!

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Racemic Products If optically inactive reagents combine to

form a chiral molecule, a racemic mixture is formed.

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Racemic Mixture

o

(g/mL) 1.7598 1.7598 1.7723

m.p. C 168-170 168-170 210-212

[] (degrees) - 12 + 12 0

(R,R) Tartaric acid (S,S) Tartaric Acid (+/-) Tartaric acid

Racemic Mixture (Racemate): 50/50 mixture of enantiomers

CO2H

CO2H

H OH

HO H H OH

HO H

CO2H

CO2H

R,R S,S

11Figure 1.  Classification of racemic modifications

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1. Conglomerate If the molecules of the substance have a greater

affinity for the same enantiomer than for the opposite one, a mechanical mixture of enantiomerically pure crystals will result.

The melting point of the racemic conglomerate is always lower than that of the pure enantiomer. Addition of a small amount of one enantiomer to the conglomerate increases the melting point.

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2. Pseudoracemate (sometimes racemic solid solution)

When there is no big difference in affinity between the same and opposite enantiomers, then in contrast to the racemic compound and the conglomerate, the two enantiomers will coexist in an unordered manner in the crystal lattice. Addition of a small amount of one enantiomer changes the melting point just little bit or not at all.

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Formation of Racemic ModificationI. By Mixing:-

Racemic modification is by intimate mixing of exactly equal amounts of dextorotatory (+) and levorotatory (-) isomers. This process is associated with an entropy mixing, since the racemic modification represents a more random state of affairs than the separate enantiomers.

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2. By synthesis

Any synthesis of dissymmetric molecules, starting from either symmetric molecules or a racemic modification and using active reagent or catalysts and no asymmetric physical influence always produces a racemic modification.

The first method is exemplified by the bromination of propionic acid to alpha bromopropionic ace by the Hell-Volhard-Zelinsky (H-V-Z) Method.

two alpha hydrogen bears the same relationship to the other and to the rest of the molecule each is replaced at the

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Rate as the other and equal numbers of (+) and (-) molecule of alpha bromopropionic acid result.

Bromination of propionic acid

H C

COOH

CH3

HH-V-Z H-V-ZBr C

COOH

H

CH3

H C

COOH

CH3

Br

Propionic Acid 2 Bromo Propionic Acid2 Bromo Propionic Acid(-) (+)

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3. Epimerization, Mutarotation and Asymmetric Transformation.

a) Epimerization :- Change in configuration (arrangement of the group) at one asymmetric atom in a compound having more than one such atom. Epimerization of an optically active compound does not involve racemization.

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b) Mutarotation and first-order asymmetric Transformation. :-

In 1846 Dubrunfaut discovered that, When glucose is dissolved in water and the optical activity of the solution observed, there is a gradual change in roatation from an initial value corresponding to [a]20

D of +1110 to an equilibrium value of [a]20 D +52.50

In the case of (+) glucose mutarotation involves a change of configuration at the No. 1 carbon ( called anomeric center) owing to an opeining and reclosing of the hemiacetal ring.

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The intermediate open-chain aldegyde form is present in negligbly small concentration. Equilibrium corresponds to 38% of the alpha and 62% of the beta form.

H C OH

C

C

OHH

C

C

CH2OH

HHO

OHH

OH

H C

C

C

OHH

C

C

CH2OH

HHO

OHH

OHH

O HO C

C

C

C

C

CH2OH

H

OHH

HHO

OHH

OH

D GlucoseD GlucoseFructose

+1110

+19.20Equilibrium mixture +52.50

Properties of Racemic Modification1. Physical propertiesRacemate may have different physical properties from

either of the pure enantiomers because of the differential intermolecular interactions . The change from a pure enantiomer to a racemate can change its density, melting point, solubility, heat of fusion, refractive index, and its various spectra. Crystallization of a racemate can result in separate (+) and (−) forms, or a single racemic compound.

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a) Racemic Mixture :- In a crystal each enatatiomers has a greater affinity for molecule of the same kind than for molecule of the other enantiomer. In that case once molecule of the (+) form is laid down in the crystal, only (+) molecule will grow on it. And similarly (-).

eg. Solubility and Melting Point of racemic mixture.

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Resolution The separation of a racemate into its

components, the pure enantiomers, is called resolution.

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used for resolution of racemic mixtures1. Mechanical Separation or Spontaneous Resolution:-

It was the first method used by Pasteur (1884) for the

resolution of sodium ammonium tartarate which

crystallizes out in the form of racemic mixtures below

270C.

In this method crystals of the two forms have

different shapes, being mirror image of each other.

They can be separated with the help of magnifying

lens and small forceps. This method is laborious and

is applicable to onlu those isomers having different

crystal.

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2. Preferential crystallization by inoculation (Gernez-1866)This method involves the seeding of a saturated solution of the racemic mixture with a pure crystal of one of the two enantiomers. The solution now becomes supersaturated with respect to the added enantiomers and after sometimes cooling it begins to crystallize out.

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Example:-

1.Harda (1865) obtained total optical resolution of free alpha- amino acids with the aid of ‘/” or d-isomers of the ccorresponding amino acid.

Sometimes seeds with a a crystal of optically active form of another molecule re also possible.

Crystal of (-) asparagines crystallizes out (±) sodium ammonium tartarate from solution of racemic modification.

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3. Biochemical separation:This method is based on the fact that when certain

micro-organisms (e.g. bacteria yeast, mould, fungi) are grown in dilute solution of racemic modification they assimilate on one enantiomers rapidly than the others.

e.g. The mould penicillin glaucum preferentially destroys the (+) isomers of racemic ammonium tartarate and thus leaves the (-) ammonium tartarate in solution.

Thia method has certain disadvantage viz.

One isomer is always destroyed and sometimes some of the other isomer is also destroyed.

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Sometimes it is impracticable to find a microorganism ( Enzyme) applicable to given racemic form.

Sometimes the racemic modification may be toxic for the micro-organism and may destroy the enzyme or may not be attacked by either ot them.

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4. By diastereomerism ( Pasteur-1858)

This method converting the eanantiomers of a racemic modification to diastereomers with the aid of a pure enantiomers of other compound. Diastereomers are non-identical, they have different physical properties and hence easily be separated its two compounds by fractional crystallization. After complete separation of the two diastereomers.

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Hence success depend upon:-

Diastereomers- easily formed in crystalline form.

Easy to convert back into parent compound.

Resolving agent should be cheaper or readily prepared and recoverable.

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Biological significance Additionally, many psychotropic drugs show

differing activity or efficacy between isomers, e.g. amphetamine is often dispensed as racemic salts while the more active dextro amphetamine is reserved for refractory cases or more severe indications.

Biological Discrimination

Chapter 5 31

References:-E.L.Eliel and S.H. Wilen, Stereochemistry of

organic compounds, A Wiley-Interscience Publication , John Wiley & Sons, New York.

E.L. Eliel Stereochemistry of carbon compounds, Tata McGraw-Hill Publishing Company Ltd, New Delhi.

R.T. Morrison, R.N. Boyd, Textbook of Organic Chemistry, Sixth Edition, Prentice Hall Of India Pvt. Ltd. , New Delhi.

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Thank You.