NMR and chirality
Lecture outline
1.  Classification of compounds and ligands
2. NMR properties of stereoisomers
3. Methods of determination of enatiomeric
ratios based on diastereotopicity
NMR of diastereomers
Chiral derivatizing agents (CDAs)
Chiral solvating agents (CSAs)
Chiral shift and relaxation reagents (CSRs, CRRs)
4. Methods for determination of absolute
stereochemistry
Classification of compounds
Compounds with identical molecular formula
Isomeric
Identical
Stereoisomers
Constitutional isomers
Diastereoisomers
Enantiomers
Classification of homomorphic nuclei
Homomorphic nuclei
Heterotopic
Homotopic
Constitutionally heterotopic
Diastereotopic
Stereoheterotopic
Enantiotopic
Isochrony (chemical shift equivalence) and anisochrony
in enantiomers and racemates
Do enantiomers have identical NMR spectra (all respective pairs of nuclei
are isochronous)?
Do NMR spectra of racemates show one set of signals?
Are NMR spectra of racemates identical with those of the individual
enantiomers?
Do homochiral and heterochiral nonbonded interactions have
the same ΔG?
R+R
R……R
S+S
S……S
R+S
R……S
NMR spectra of enantiomers and racemates
pure (–)
OCH3
N
OH
H
N
racemate
Dihydroquinine
1:1 mixture
of (–) and racemate
Isochrony (chemical shift equivalence) and anisochrony
in enantiomers and racemates
Enantiomer discrimination: measurable differences between physical
properties of enantiomers vs. racemates due to energetic differences
between homochiral and heterochioral nonbonded intramolecular
interactions.
Solid state:
Solid state 13C NMR spectra of enantiomers and racemates are
normally different.
Solid state 13C NMR can be used to determine enantiomer purity
of a sample.
Isochrony (chemical shift equivalence) and anisochrony
in enantiomers and racemates
Solutions (in achiral media):
Enantiopure and racemic compounds generally give identical but
sometimes different NMR spectra.
Chemical shifts reflect time averaged and concentration-weighed
environments of nuclei in (R ⇔ RR ⇔ RS) compared to (S ⇔ SS ⇔ RS)].
Δδ increases with enantiomer ratio (reflecting increased proportion
of heterochiral aggregates vs. homochiral).
The anisochrony occurs under conditions of fast exchange.
R+R
R……R
S+S
S……S
R+S
R……S
R ⋅ ⋅ ⋅ R ] [S ⋅ ⋅ ⋅ S]
[
K=
=
2
2
[R ]
[S]
R ⋅ ⋅ ⋅ S]
[
K=
[R ][ S ]
Self-induced anisochrony
pure (–)
OCH3
N
OH
H
N
racemate
Dihydroquinine
1:1 mixture
of (–) and racemate
Isochrony (chemical shift equivalence) and anisochrony
in enantiomers and racemates
Lessons:
Do not try to compare NMR spectra of samples with different or unknown
enantiomeric composition.
….These extra peaks may not be impurities….
Direct determination of enantiomeric excess!
NMR methods for determination of enantiomer ratios
based on diastereotopicity
Chiral derivatization agents
COOH
H
COOH
COOH
OCH3
F3C
H3C
OCH3
OCH3
F
F
Cl
O
F
F
O
CH3
P
O
CH3
O
O
P
O
Cl
F
COOCH3
COOH
O
F3C
COOH
H
F
CN
F
F
F
F
NCO
F3C
OCH3
F
R + R → RR
S + R → SR
H
O
Si Cl
COOH
Si CH3
NMR methods for determination of enantiomer ratios
based on diastereotopicity
Chiral derivatization agents
Sharp, well resolved resonances should be present
COOH
F3C
OCH3 H
The CDA must be enantiomerically pure and stable
R + R → RR
S + R → SR
R + R → RR
R + S → RS
Reagent should be added in large excess and the reaction
forced to completion to avoid kinetic resolution (control with
racemate).
COOH
OCH3
NMR methods for determination of enantiomer ratios
based on diastereotopicity
Chiral solvating agents
OH
F3C
OH
OH
H
F3C
H
F3C
NH2
NH2
H
H3C
H
H3C
H
O
COOH
H
NO2
HN
OH
H3C
OH
H
OH
NO2
quinine"
cinchonine, "
other alkaloids
NMR methods for determination of enantiomer ratios
based on diastereotopicity
CH3
O
COOH
H
OH
H3C
N
N
CH3
O
CH3
98.5%
CH3
O
H3C
N
CH3
N
CH3
O
1.5%
–OCH2– group, 400 MHz, CDCl3
NMR methods for determination of enantiomer ratios
based on diastereotopicity
Chiral solvating agents
Sharp, well resolved resonances should be present.
The CSA do not need to be enantiomerically pure and stable
(as always when transient, dynamic species are involved; absence
of enantiomeric purity diminishes anisochrony).
Anisochrony strongly CSA-concentration dependent
Apolar solvents preferred.
NMR methods for determination of enantiomer ratios
based on diastereotopicity
Chiral shift reagent
Pseudocontacs shift
(positive or neg.)
Δ dip
3cos 2 ϑ −1
=K
r3
L
€
r
ϑ
O
H
R
NMR methods for determination of enantiomer ratios
based on diastereotopicity
Chiral shift reagent
Enhance anisochrony (LIS); externally enantiotopic groups become
diastereotopic.
Much larger Δδ (10-50 times larger) compared to CSAs.
The CSR do not need to be enantiomerically pure and stable
(as always when transient, dynamic species are involved; absence
of enantiomeric purity diminishes anisochrony).
Resonance broadening by chemical exchange (especially at
higher fields!).
Apolar solvents required.
CSRs are decomposed by strongly coordinating compounds.
NMR methods for determination of enantiomer ratios
based on diastereotopicity
Determination of ratios between nicotine enantiomers using CSR
3'
2'
N
CH3
N
H3C
CH3
CF3
O
H3C
O
Yb/3
NMR methods for determination of enantiomer ratios
based on diastereotopicity
Determination of ratios between nicotine enantiomers using CSR
3'
2'
N
CH3
N
H3C
CH3
CF3
O
H3C
O
Yb/3
Methods for determination of absolute configuration
Methods based on chiral derivatization agents (CDAs).
Transformation of a chiral compound with two enantiomeric CDAs to TWO
diastereomeric species followed by comparison of spectra of the latter.
MOSHER METHOD
COCl
F3C
COCl
OCH3
H3CO
CF3
1-Methoxy-1trifluoromethylphenylacetic
acid
MTPA
Methods for determination of absolute configuration
Methods based on chiral derivatization agents (CDAs).
Transformation of a chiral compound with two enantiomeric CDAs to TWO
diastereomeric species followed by comparison of spectra of the latter.
L2
Ph
O
L1
H
L2
OMe
CF3
O
(R)-MTPA ester
MeO
O
L1
H
Ph
CF3
O
OMTPA
Δδ < 0
C
H
(S)-MTPA ester
L1 and L2 are ligands connected to the chiral
carbon of the secondary alcohol
MTPA plane
Δδ = δS – δR
Δδ > 0
Methods for determination of absolute configuration
Methods based on chiral derivatization agents (CDAs).
Transformation of a chiral compound with two enantiomeric CDAs to TWO
diastereomeric species followed by comparison of spectra of the latter.
(R)-MTPA acid gives
(S)-MTPA chloride –
avoid confusion!!!!
Methods for determination of absolute configuration
MOSHER METHOD (AND RELATED METHODS)
1.
2.
3.
4.
5.
6.
7.
8.
9.
CDA must have a bulky polar group to fix a well-defined conformation.
Carboxylic acid generally used for covalent derivatization
Aromatic group to induce anisotropic effect.
Δδ defined differently for different reagents [e.g., δS – δR for MPA,
(methoxyphenylacetic esters)].
Originally described as an empirical rule, but is founded on conformational
preferences (similarly as, e.g., asymmetric induction rules).
Success depends on the presence of the expected, well-defined
conformation.
One should use as many resonances as possible, not just one resonance,
and they should exhibit consistent Δδ behavior (1H 2D NMR better than 19F
NMR) = “advanced Mosher’s method”.
Computational results show that the Mosher’s model is simplified and the
conformational behavior is complex (explains some anomalies)
MPA and analogs better than MTPA.
Methods for determination of absolute configuration
Alternatives to MTPA
COOH
H
OCH3
MPA
COOH
COOH
H
OCH3
H
OCH3