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Hugo Meekes
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
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