Chirality and Stereochemistry

Hugo Meekes
Hugo.Meekes@science.ru.nl

Solid State Chemistry / IMM

Chiral molecules: Left and Right

Chiral objects: Left and Right

Chiral molecules: Left and Right

Two stereoisomers called enantiomers

Chiral molecules: other stereoisomers

Axial chirality

1,1-bi-2-naphthol

Other stereoisomers: Non-chiral

Cis-trans isomers

Diastereoisomers

Conformational isomers (rotamers)

Not mirror images

Chiral molecules: Nomenclature

Enantiomers: left- and right handed individuals

Natural amino acid Alanine

Chiral molecules: Nomenclature

7N

R(ectus) Alanine

< 6C < 1H

S(inister) Alanine

Alanine: projection along C*-H

Cahn-Ingold-Prelog priority rules

Chiral molecules: Nomenclature

D(extro) Alanine

L(aevo) Alanine

D,L used for amino acids and sugars

Chiral molecules: Nomenclature

+ Alanine

- Alanine

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

Chiral molecules: physical properties

Physical property
Melting point
Boiling point
Solubility
.
Optical activity (polarimetry)
Circular dichroism
Physisorption (chiral chromatography)

D/L
equal
equal
equal
equal
+/+/+/-

Chiral molecules: chemical properties

Chemical property
Reactivity for achiral reagents
Reactivity for chiral reagents

D/L
equal
+/-

Chiral molecules: bioactivity

D

Smell
limonene
m

DD

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

Chiral molecules: bioactivity

(R)-thalidomide

morning sickness

(S)-thalidomide

birth defects

Chiral molecules: physical properties

Physical property
Melting point
Boiling point
Solubility
.
Optical activity (polarimetry)
Circular dichroism
Physisorption (chiral chromatography)

D/L
equal
equal
equal
equal
+/+/+/-

Chiral molecules: chemical properties

Chemical property
Reactivity for achiral reagents
Reactivity for chiral reagents

D/L
equal
+/-

Chiral characterization

Optical activity
(polarimetry)

Physisorption: (chiral) HPLC

(High-Performance Liquid Chromatography)

Chiral characterization : optical activity

Polarimeter measures rotation of linearly polarized light

Specific rotation

lc

rotation( )
length tube (dm) x concentration (g/mL)

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

Synthesis
Separation

Crystallization

Abrasive Grinding as a Route

to Chiral Purity

Hugo Meekes
Hugo.Meekes@science.ru.nl

Solid State Chemistry / IMM

Classical resolution using crystallization

D-tartaric acid

L-tartaric acid

Louis Pasteur
1822-1895
Racemic conglomerate

Crystal structure

Molecule
aspartame

Unit cell
aspartame
21

Crystal Forms of Enantiomers

Racemic compound
88 %

Solid solution

Racemic conglomerate

2%

Right handed (R) molecule

Left handed (S) molecule

10 %

Crystal Forms of Enantiomers

DL-valine

Racemic compound

L-valine

Racemic conglomerate

Crystal Forms of Enantiomers

DL-valine

L-valine

Only racemic conglomerates are fit for chiral separation

Chiral Separation: nucleation and attrition

NaClO3

solution
crystals

Achiral solution but racemic conglomerate

Crystal Nucleation combined with Secondary Nucleation

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

The new players in the grinding approach

Cristobal Viedma and Wim Noorduin

Chiral Separation using intense stirring (grinding)

NaClO3

Intense stirring

Time (hours)

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

NaClO3 without grinding

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

Ostwald Ripening

NaClO3

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

MonteMonte
Carlo Simulation
Carlo Simulation

Computer Simulation

Ostwald ripening

Free energy of a crystal:

Driving force for Ostwald ripening:

Computer simulation
It always works!!

Attrition Enhanced Ostwald Ripening

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

Should also work for chiral molecules

E. Havinga, Biochem. Biophys. Acta, 13 (1954) 171-174

J. Crusats et al., Chem. Eur. J., 12 (2006) 7776-7781

Back to the roots of chemistry

Amino acid derivative

solution phase ee / %

Solution

100

50

0
0

25

50

75

Solids

time / sec

enantiomeric excess

W.L. Noorduin et al. J. Am. Chem. Soc., 130 (2008) 1158

The Attrition Enhanced Team

Viedma ripening works!!

State of the art in 2013

Problems:
Racemic conglomerate is needed (only 10%)
Racemization in solution is essential
Do we really understand the mechanism?
Outlook:
Make racemic conglomerate
Racemization in solution is a challenge
Mechanism from experiments and modelling