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 G?
R+R

RR

S+S

SS

R+S

RS

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)].
increases with enantiomer ratio (reflecting increased proportion
of heterochiral aggregates vs. homochiral).
The anisochrony occurs under conditions of fast exchange.
R+R

RR

S+S

SS

R+S

RS

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

Cl
O

CH3

P
O

CH3

O
O

O
Cl

COOCH3

COOH

O
F3C

COOH
H

CN

NCO
F3C

OCH3

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

F3C

NH2

NH2
H

H3C

H3C

COOH
H

NO2

HN

OH
H3C

OH

OH
NO2

quinine"
cinchonine, "
other alkaloids

NMR methods for determination of enantiomer ratios

based on diastereotopicity
CH3
O
COOH
H

OH

H3C

CH3

CH3

98.5%
CH3
O
H3C

CH3

CH3

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.)

dip

3cos 2 1
=K
r3

O
H

NMR methods for determination of enantiomer ratios

based on diastereotopicity

Chiral shift reagent

Enhance anisochrony (LIS); externally enantiotopic groups become
diastereotopic.
Much larger (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

H3C

CH3

CF3
O

H3C

Yb/3

NMR methods for determination of enantiomer ratios

based on diastereotopicity

Determination of ratios between nicotine enantiomers using CSR

3'
2'

N
CH3

H3C

CH3

CF3
O

H3C

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

(R)-MTPA ester

MeO
O

L1
H

Ph
CF3

OMTPA
< 0

C
H

(S)-MTPA ester

L1 and L2 are ligands connected to the chiral

carbon of the secondary alcohol
MTPA plane

= S R

> 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.
defined differently for different reagents [e.g., S R 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 behavior (1H 2D NMR better than 19F
NMR) = advanced Moshers method.
Computational results show that the Moshers 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

OCH3