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Racemisation and method of resolution

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Racemisation is the process where a pure enantiomer is converted into a 50/50 mixture of both enantiomers, called a racemate. This can occur through various chemical reactions or physical changes that allow for inversion or interchange of chiral centres. Resolution is the separation of the enantiomers in a racemate. Several methods can be used to induce and monitor racemisation, such as changes in pH, temperature, catalysts, or conformational changes. Resolution techniques include forming diastereomeric salts, molecular complexes, or exploiting kinetic or thermodynamic differences in reactions.

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Racemisation and method of resolution

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•Racemisation is the process when the enantiomer is converted into racemic modification (i.e. chemical reactions) or when one pure form of an enantiomer is converted into equal proportion of both enantiomers, forming a racemate. •Resolution is the process when a racemic modification is separated into its constituent enantiomers. •Racemisation is a thermodynamically favorable process and it proceed spontaneously if a convenient pathway is available for the interconversion of the enantiomers. •It is reversible process because any mechanism of racemisation must operate from either of the enantiomers.

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•If a molecule contains more than one chiral centre and configurational inversion takes place at one centre, the product formed is a diasteriomer i.e epimer, the process is called as epimerization. •Due to the free energy difference, the two epimers exists in unequal amounts in equilibrium. •Racemisation is usually monitored by observing the gradual zeroing of optical rotation. 13C-NMR also gives a good probe for monitoring epimerization of both optically active and inactive stereoisomers.

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•If a ligand at a tetrahedral chiral centre is removed by heterolytic cleavage leaving behind on anionic species, the latter undergoes rapid inversion so that when the ligand recombines. •An acidic proton is removed using mild to strong bases such as Sodium Hydroxide and Sodium Alkoxides.

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Example- OH Ph-C -C H (M e)C H 2 M e Ph-C -C (M e)C H 2 M e Ph-C -C (M e)C H 2 M e O H 2O O O ------- (1) Phenyl S-butyl ketone OH O P h -C H -C O 2 H P h -C -C O 2 P h -C = C OH H 2O OH OH O ------- (2) Mandelic acid

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•When the concerned proton is very acidic as in the disulphone, the carbanion may form in appropriate solvents without any base and racemisation takes place spontaneously. ------- (3) • Mineral acid also effect racemisation of a ketone containing an α-H. ------- (4)

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•Electron withdrawing group may be detached from a chiral centre with an electron pair leaving behind a cationic species. •Racemisation occurs when the substrate is capable of giving rise to a stable carbocation. ------- (5) ------- (6)

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•Free radical having a near planar structure and if a chiral centre is converted into a free radical pair by homolytic cleavage of a bond the recombination of pair leads to racemic product. •Example- Benzylic allylic, tertiary stable radicals undergo racemisation under the influence of heat or light.

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•Enantiomers are interconverted through stable achiral intermediates and get racemised. •Example- Secondary alcohol in the form of its aluminium derivative heated with ketone (acetone), reversible oxidation- reduction done and an equilibrium is established between enantiomers or diastereomers.

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------- (7) M= dialkoxyaluminium •Acid chloride of an optically active carboxylic acid, in presence of tertiary amine undergoes racemisation through a ketone. ------- (8)

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•Racemisation takes place through rotation around a single bond or bonds and the interconversion usually takes place readily via an achiral conformation. •Most of these enantiomeric atropisomers racemise by application of heat leads to bond stretching or bond behind and helps the non-polar enantiomers to cross the planar transition state. •Cyclic compounds which exist in enantiomeric conformations undergo racemisation through ring inversion. •Example- cis-1,2-dimethylcyclohexane and cis-decalin

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Fig: Racemisation through rotation around single bond In above structural features i.e. a biphenyl derivative [(+)-methyl (-)- methyl 2,6,2l,6l-tetranitrobiphenyl-4,4l-dicarboxylate] prepared by Mislow and Bolstad.

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•In SN2 reaction, the reaction of optically active 2-iodooctane with Sodium iodide, the reaction becomes reversible and an equilibrium between the two enantiomers leading to racemisation. Fig: Conformational inversion in SN 2 reaction

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•In SN 1 reaction, a rate determining step leaving behind a carbonium ion and has a planar structure and so extensive racemisation occurs. Fig: Retension of configuration: SN 1 mechanism

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•A compound with a labile chiral centre can undergo configurational change in solution at equilibrium. If there exists a chiral element in the environment one or other of the enantiomers would predominate in equilibrium and shows complete racemisation known as asymmetric transformation. •The change in the optical rotation is known as Mutarotaion. Mutarotation is an experimental observation-phenomenological in nature and does not have any mechanical implication.

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•Conformational changes which occur in solution (involving a single phase) is known as first order asymmetric transformation. •Example- All reducing sugars (excepting a few ketoses) and many of their undergo first order asymmetric transformation and exhibit mutarotation. •In glucose, equilibrium (in water) corresponds to 38% of the α- and 62% of the β-form.

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Fig: First order asymmetric transformation in glucose •Mechanism involves protonation of the oxide ring, depolarisation of 1-OH by base followed by ring opening to the aldehyde form. •Its subsequent ring close to the original hemiacital or its epimer by acid catalysts.

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•Mutarotation due a structural change given with gluconolactone a solution of which in water establishes between δ-glucono and γ-gloconolactone through the intermediate gluconic acid. Fig: Mutarotation due to saturated change

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•In an asymmetric transformation one of the enantiomer or diasteriomers crosses the phase boundry i.e. comes out of the solution as crystals or immisible liquids known as second order asymmetric transformation. •100% conversion of a racemic mixture into a pure enatiomer. •Example- A solution of glucose in ethanol is concentrated, the less soluble α-form crystallises first and after equilibrium only α-form of glucose is obtained. Crystallisation of glucose from pyridine gives the β-form only.

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Racemisation and method of resolution

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•Three types of crystalline forms, i. Conglomerate with homochiral assemblies of enantiomers in a single crystal. ii. Racemic compounds containing equal number of (+) and (-) isomers in the unit cell of crystal. iii. Pseudoracemates with no preference for enantiomers in the crystal structure. •In the case of conglomerate, the two enantiomorphous crystals are distinguishable visually and can be separated by hand-sorting with the help of a magnifying glass and a pair of tweezers. •The preferential crystallisation depends on the principle that the solubility of the enantiomer is less than that of the racemic form.

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• Pasteur developed method for the formation of diastereomeric salts and their fractional crystallisation is the best method for resolution. • Example- Resolution of a racemic acid (±)-A with an optically pure base (+)-B which combines with racemic acid gives two diastereomeric salts respectively. (±)-A + (+)-B (+)-A. (+)-B + (-)-A. (+)-B •Two salts differ in properties such as solubility, boiling point and adsorption coefficient. •Diposition of the salt with mineral acid would furnish (+)-A in enantiomerically pure form.

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•Instead of forming stable salts or covalent compound with the substrates and the resolving agents, have molecular complexes which form easily and decompose easily which are suitable for resolution. •Example- Digitonin a steroidal saponin forms addition complexes with various alcohols ex. Α-terpineol, isocarvomenthal and phenolic compounds gives (+) 2- Naphthylcamphylamine.

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Digitonin (+)-2-Nphthylcamphylamine Fig: Some chiral complexing reagent

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•Gas chromatography use for analysis as well as separation of enantiomers. •Trifluroacetyl derivatives of optically active amino acid have been used for gas chromatographic resolution of racemic alcohols with esters. •Paper chromatography effects partial resolution of camphorsulphonic acid.

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•Rsolution based on two steps, i. Epimerisation of a diatereomeric species. Example- Treatment 2-(p-carboxybenzyl)-1-hydrindanone with brucine in acetone solution, diastereomers precipitates in over 90% yield. O OH O 2-(p-carb ox y b en zy l)-1 -hy d rin d an o n e

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ii. Precipitation of the predominant epimer . Example- (-)-menthyl ester of racemic phenylchloroacetic acid treated with base, it epimerises and gives equilibrium mixture of esters with 57% (-)- acid and 43%(+)- acid. HO O Cl p hen y lch lo ro acetic acid

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i. Kinetic method of resolution: .........thermodynamically controlled condition .........kinetically controlled condition

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•Racemic substrate i.e. (±)-A is react with an optically active reagent i.e. (+)-B, shows two diastereomeric transition states , p* leading to the p-diastereomer, (+)-A.(+)-B and n*leading to the n-diastereomer, (-)-A.(+)-B. ii. Kinetic method using diastereomeric substrate: •A mixture of diastereomers used in a reaction with an achiral reagent. •The two diastereomers are react at different rates and a partial separation of diastereomers may be effected. •Example- Hydrolysis of mandelic acid and menthol shows partial resolution and partial separation of diastereomeic esters.

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•Biochemical method having important application in the resolution of (±)-amino acids. •Acetylated (±)-amino acid is treated with an enzyme ‘acylase I’ till the half of the acetyl groups hydrolysed i.e. L-amino acid and unhydrolysed group i.e. D-amino acid.

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Racemisation and method of resolution

  • 2. •Racemisation is the process when the enantiomer is converted into racemic modification (i.e. chemical reactions) or when one pure form of an enantiomer is converted into equal proportion of both enantiomers, forming a racemate. •Resolution is the process when a racemic modification is separated into its constituent enantiomers. •Racemisation is a thermodynamically favorable process and it proceed spontaneously if a convenient pathway is available for the interconversion of the enantiomers. •It is reversible process because any mechanism of racemisation must operate from either of the enantiomers.
  • 3. •If a molecule contains more than one chiral centre and configurational inversion takes place at one centre, the product formed is a diasteriomer i.e epimer, the process is called as epimerization. •Due to the free energy difference, the two epimers exists in unequal amounts in equilibrium. •Racemisation is usually monitored by observing the gradual zeroing of optical rotation. 13C-NMR also gives a good probe for monitoring epimerization of both optically active and inactive stereoisomers.
  • 4. •If a ligand at a tetrahedral chiral centre is removed by heterolytic cleavage leaving behind on anionic species, the latter undergoes rapid inversion so that when the ligand recombines. •An acidic proton is removed using mild to strong bases such as Sodium Hydroxide and Sodium Alkoxides.
  • 5. Example- OH Ph-C -C H (M e)C H 2 M e Ph-C -C (M e)C H 2 M e Ph-C -C (M e)C H 2 M e O H 2O O O ------- (1) Phenyl S-butyl ketone OH O P h -C H -C O 2 H P h -C -C O 2 P h -C = C OH H 2O OH OH O ------- (2) Mandelic acid
  • 6. •When the concerned proton is very acidic as in the disulphone, the carbanion may form in appropriate solvents without any base and racemisation takes place spontaneously. ------- (3) • Mineral acid also effect racemisation of a ketone containing an α-H. ------- (4)
  • 7. •Electron withdrawing group may be detached from a chiral centre with an electron pair leaving behind a cationic species. •Racemisation occurs when the substrate is capable of giving rise to a stable carbocation. ------- (5) ------- (6)
  • 8. •Free radical having a near planar structure and if a chiral centre is converted into a free radical pair by homolytic cleavage of a bond the recombination of pair leads to racemic product. •Example- Benzylic allylic, tertiary stable radicals undergo racemisation under the influence of heat or light.
  • 9. •Enantiomers are interconverted through stable achiral intermediates and get racemised. •Example- Secondary alcohol in the form of its aluminium derivative heated with ketone (acetone), reversible oxidation- reduction done and an equilibrium is established between enantiomers or diastereomers.
  • 10. ------- (7) M= dialkoxyaluminium •Acid chloride of an optically active carboxylic acid, in presence of tertiary amine undergoes racemisation through a ketone. ------- (8)
  • 11. •Racemisation takes place through rotation around a single bond or bonds and the interconversion usually takes place readily via an achiral conformation. •Most of these enantiomeric atropisomers racemise by application of heat leads to bond stretching or bond behind and helps the non-polar enantiomers to cross the planar transition state. •Cyclic compounds which exist in enantiomeric conformations undergo racemisation through ring inversion. •Example- cis-1,2-dimethylcyclohexane and cis-decalin
  • 12. Fig: Racemisation through rotation around single bond In above structural features i.e. a biphenyl derivative [(+)-methyl (-)- methyl 2,6,2l,6l-tetranitrobiphenyl-4,4l-dicarboxylate] prepared by Mislow and Bolstad.
  • 13. •In SN2 reaction, the reaction of optically active 2-iodooctane with Sodium iodide, the reaction becomes reversible and an equilibrium between the two enantiomers leading to racemisation. Fig: Conformational inversion in SN 2 reaction
  • 14. •In SN 1 reaction, a rate determining step leaving behind a carbonium ion and has a planar structure and so extensive racemisation occurs. Fig: Retension of configuration: SN 1 mechanism
  • 15. •A compound with a labile chiral centre can undergo configurational change in solution at equilibrium. If there exists a chiral element in the environment one or other of the enantiomers would predominate in equilibrium and shows complete racemisation known as asymmetric transformation. •The change in the optical rotation is known as Mutarotaion. Mutarotation is an experimental observation-phenomenological in nature and does not have any mechanical implication.
  • 16. •Conformational changes which occur in solution (involving a single phase) is known as first order asymmetric transformation. •Example- All reducing sugars (excepting a few ketoses) and many of their undergo first order asymmetric transformation and exhibit mutarotation. •In glucose, equilibrium (in water) corresponds to 38% of the α- and 62% of the β-form.
  • 17. Fig: First order asymmetric transformation in glucose •Mechanism involves protonation of the oxide ring, depolarisation of 1-OH by base followed by ring opening to the aldehyde form. •Its subsequent ring close to the original hemiacital or its epimer by acid catalysts.
  • 18. •Mutarotation due a structural change given with gluconolactone a solution of which in water establishes between δ-glucono and γ-gloconolactone through the intermediate gluconic acid. Fig: Mutarotation due to saturated change
  • 19. •In an asymmetric transformation one of the enantiomer or diasteriomers crosses the phase boundry i.e. comes out of the solution as crystals or immisible liquids known as second order asymmetric transformation. •100% conversion of a racemic mixture into a pure enatiomer. •Example- A solution of glucose in ethanol is concentrated, the less soluble α-form crystallises first and after equilibrium only α-form of glucose is obtained. Crystallisation of glucose from pyridine gives the β-form only.
  • 21. •Three types of crystalline forms, i. Conglomerate with homochiral assemblies of enantiomers in a single crystal. ii. Racemic compounds containing equal number of (+) and (-) isomers in the unit cell of crystal. iii. Pseudoracemates with no preference for enantiomers in the crystal structure. •In the case of conglomerate, the two enantiomorphous crystals are distinguishable visually and can be separated by hand-sorting with the help of a magnifying glass and a pair of tweezers. •The preferential crystallisation depends on the principle that the solubility of the enantiomer is less than that of the racemic form.
  • 22. • Pasteur developed method for the formation of diastereomeric salts and their fractional crystallisation is the best method for resolution. • Example- Resolution of a racemic acid (±)-A with an optically pure base (+)-B which combines with racemic acid gives two diastereomeric salts respectively. (±)-A + (+)-B (+)-A. (+)-B + (-)-A. (+)-B •Two salts differ in properties such as solubility, boiling point and adsorption coefficient. •Diposition of the salt with mineral acid would furnish (+)-A in enantiomerically pure form.
  • 23. •Instead of forming stable salts or covalent compound with the substrates and the resolving agents, have molecular complexes which form easily and decompose easily which are suitable for resolution. •Example- Digitonin a steroidal saponin forms addition complexes with various alcohols ex. Α-terpineol, isocarvomenthal and phenolic compounds gives (+) 2- Naphthylcamphylamine.
  • 24. Digitonin (+)-2-Nphthylcamphylamine Fig: Some chiral complexing reagent
  • 25. •Gas chromatography use for analysis as well as separation of enantiomers. •Trifluroacetyl derivatives of optically active amino acid have been used for gas chromatographic resolution of racemic alcohols with esters. •Paper chromatography effects partial resolution of camphorsulphonic acid.
  • 26. •Rsolution based on two steps, i. Epimerisation of a diatereomeric species. Example- Treatment 2-(p-carboxybenzyl)-1-hydrindanone with brucine in acetone solution, diastereomers precipitates in over 90% yield. O OH O 2-(p-carb ox y b en zy l)-1 -hy d rin d an o n e
  • 27. ii. Precipitation of the predominant epimer . Example- (-)-menthyl ester of racemic phenylchloroacetic acid treated with base, it epimerises and gives equilibrium mixture of esters with 57% (-)- acid and 43%(+)- acid. HO O Cl p hen y lch lo ro acetic acid
  • 28. i. Kinetic method of resolution: .........thermodynamically controlled condition .........kinetically controlled condition
  • 29. •Racemic substrate i.e. (±)-A is react with an optically active reagent i.e. (+)-B, shows two diastereomeric transition states , p* leading to the p-diastereomer, (+)-A.(+)-B and n*leading to the n-diastereomer, (-)-A.(+)-B. ii. Kinetic method using diastereomeric substrate: •A mixture of diastereomers used in a reaction with an achiral reagent. •The two diastereomers are react at different rates and a partial separation of diastereomers may be effected. •Example- Hydrolysis of mandelic acid and menthol shows partial resolution and partial separation of diastereomeic esters.
  • 30. •Biochemical method having important application in the resolution of (±)-amino acids. •Acetylated (±)-amino acid is treated with an enzyme ‘acylase I’ till the half of the acetyl groups hydrolysed i.e. L-amino acid and unhydrolysed group i.e. D-amino acid.