Hugo Meekes

Hugo.Meekes@science.ru.nl

Solid State Chemistry / IMM

Chirality and Stereochemistry

Chiral molecules: Left and Right

Chiral objects: Left and Right

Chiral molecules: Left and Right

Two stereoisomers called enantiomers

Chiral molecules: other stereoisomers

-bi-2-naphthol

Axial chirality

Other stereoisomers: Non-chiral

Cis-trans isomers

Diastereoisomers

Conformational isomers (rotamers)

Not mirror images

Chiral molecules: Nomenclature

Natural amino acid Alanine

Enantiomers: left- and right handed individuals

Chiral molecules: Nomenclature

Alanine: projection along C*-H

7N < 6C < 1H

R(ectus) Alanine S(inister) Alanine

Cahn-Ingold-Prelog priority rules

Chiral molecules: Nomenclature

D,L used for amino acids and sugars

D(extro) Alanine L(aevo) Alanine

Chiral molecules: Nomenclature

+ (dextro) / - (laevo): optical rotation (optical activity)

+ Alanine - Alanine

Chiral molecules: physical properties

Physical property D/L

Melting point equal

Boiling point equal

Solubility equal

equal

Optical activity (polarimetry) +/-

Circular dichroism +/-

Physisorption (chiral chromatography) +/-

Chiral molecules: chemical properties

Chemical property D/L

Reactivity for achiral reagents equal

Reactivity for chiral reagents +/-

Chiral molecules: bioactivity

limonene

m

aspartame

m

Smell

Taste

L D

LL DD

R.H. Mazur, J. Med. Chem. 13 (1970) 1217

Chiral molecules: bioactivity

morning sickness birth defects

(S)-thalidomide (R)-thalidomide

Chiral molecules: physical properties

Physical property D/L

Melting point equal

Boiling point equal

Solubility equal

equal

Optical activity (polarimetry) +/-

Circular dichroism +/-

Physisorption (chiral chromatography) +/-

Chiral molecules: chemical properties

Chemical property D/L

Reactivity for achiral reagents equal

Reactivity for chiral reagents +/-

Chiral characterization

Optical activity

(polarimetry)

Physisorption: (chiral) HPLC

(High-Performance Liquid Chromatography)

Chiral characterization : optical activity

(g/mL)ion concentrat x (dm) elength tub

)(rotation

lc

TSpecific rotation

Polarimeter measures rotation of linearly polarized light

Chiral characterization : chiral HPLC

HPLC measures the flow time of molecules through the column

In chiral HPLC the column is filled with a chiral adsorbent

different retention times for R and S enantiomers

Chiral molecules: Separation

Separation

Synthesis

Crystallization

Hugo Meekes

Hugo.Meekes@science.ru.nl

Solid State Chemistry / IMM

Abrasive Grinding as a Route

to Chiral Purity

Classical resolution using crystallization

Racemic conglomerate

D-tartaric acid

L-tartaric acid

Louis Pasteur

1822-1895

21

Crystal structure

Molecule

aspartame

Unit cell

aspartame

Crystal Forms of Enantiomers

Right handed (R) molecule

Left handed (S) molecule

Racemic compound Solid solution Racemic conglomerate 88 % 10 % 2 %

Crystal Forms of Enantiomers

Racemic compound Racemic conglomerate

DL-valine L-valine

Crystal Forms of Enantiomers

DL-valine L-valine

Only racemic conglomerates are fit for chiral separation

Chiral Separation: nucleation and attrition

Crystal Nucleation combined with Secondary Nucleation

Havinga, Egbert. Chem. Weekblad 38 (1941) 642; Kondepudi et al. Science 250 (1990) 975

Achiral solution but racemic conglomerate

NaClO3 solution

crystals

The new players in the grinding approach

Cristobal Viedma and Wim Noorduin

Chiral Separation using intense stirring (grinding)

Cristobal Viedma Phys. Rev. Lett. 94 (2005) 065504

Time (hours)

Intense stirring NaClO3

NaClO3 without grinding

Ostwald ripening: Large crystals grow at the cost of smaller ones

Ostwald Ripening

-END STATE: ONE SINGLE CRYSTAL, L or D

-Ostwald ripening takes a long time

-Small crystals are effective Ostwald ripeners!!

-Attrition helps but gives many L and D crystals !?!

-NEAR EQUILIBRIUM PROCESS: NO NUCLEATION

NaClO3

W. Noorduin et al., Crystal Growth & Design, 8 (2008) 1675

Monte Carlo Simulation Monte Carlo Simulation

Computer Simulation