NMR and chirality - ku · PDF fileNMR and chirality. 3. Methods of determination of enatiomeric ratios based on diastereotopicity NMR of diastereomers Chiral derivatizing agents (CDAs)

NMR and chirality

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)

Lecture outline

1.  Classification of compounds and ligands

4. Methods for determination of absolute stereochemistry

2. NMR properties of stereoisomers

Classification of compounds

Compounds with identical molecular formula

Identical Isomeric

Constitutional isomers Stereoisomers

Diastereoisomers Enantiomers

Classification of homomorphic nuclei

Homomorphic nuclei

Homotopic Heterotopic

Constitutionally heterotopic Stereoheterotopic

Diastereotopic 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?

Do homochiral and heterochiral nonbonded interactions have the same ΔG?

Are NMR spectra of racemates identical with those of the individual enantiomers?

R + R R……R

S + S S……S

R + S R……S

Dihydroquinine

N

N

OH

H

OCH3pure (–)

racemate

1:1 mixture of (–) and racemate

NMR spectra of enantiomers and racemates

Solid state 13C NMR spectra of enantiomers and racemates are normally different.

Enantiomer discrimination: measurable differences between physical properties of enantiomers vs. racemates due to energetic differences between homochiral and heterochioral nonbonded intramolecular interactions.

Solid state 13C NMR can be used to determine enantiomer purity of a sample.

Solid state:


Solutions (in achiral media):


Enantiopure and racemic compounds generally give identical but sometimes different NMR spectra.

The anisochrony occurs under conditions of fast exchange.

Δδ increases with enantiomer ratio (reflecting increased proportion of heterochiral aggregates vs. homochiral).

€

K =R ⋅ ⋅ ⋅S[ ]R[ ] S[ ]

€

K =R ⋅ ⋅ ⋅R[ ]R[ ]2

=S ⋅ ⋅ ⋅S[ ]S[ ]2

R + R R……R

S + S S……S

R + S R……S

Chemical shifts reflect time averaged and concentration-weighed environments of nuclei in (R ⇔ RR ⇔ RS) compared to (S ⇔ SS ⇔ RS)].

Self-induced anisochrony

Dihydroquinine

N

N

OH

H

OCH3pure (–)

racemate

1:1 mixture of (–) and racemate

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!

Chiral derivatization agents

NMR methods for determination of enantiomer ratios based on diastereotopicity

COOHOCH3H

COOHOCH3F3C

COOHOCH3H3C

F

FF

F

FCH3

CH3

OPOO

Cl OOPCl

O

OHF3CCOOH

COOHCNF

F

FF

F

F

NCOOCH3F3C O

Si Cl

COOCH3H

Si CH3

COOH

R + R → RR

S + R → SR

Chiral derivatization agents


COOHOCH3H

COOHOCH3F3C

R + R → RR S + R → SR

R + R → RR R + S → RS

Sharp, well resolved resonances should be present

The CDA must be enantiomerically pure and stable

Reagent should be added in large excess and the reaction forced to completion to avoid kinetic resolution (control with racemate).

Chiral solvating agents


OHHF3C

OHHF3C

OHHF3C

NH2HH3C

NH2HH3C

HNHH3C

ONO2

NO2

COOHOHH OH

OH

quinine"cinchonine, "other alkaloids


N

O

H3C CH3O

NCH3

CH3

N

O

H3C CH3O

NCH3

CH3COOH

OHH

–OCH2– group, 400 MHz, CDCl3

1.5%

98.5%

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.


Chiral shift reagent

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Δ dip = K 3cos2ϑ −1r3

Pseudocontacs shift (positive or neg.)

OR

H

L r ϑ


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

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.

Chiral shift reagent

Much larger Δδ (10-50 times larger) compared to CSAs.

CSRs are decomposed by strongly coordinating compounds.


Determination of ratios between nicotine enantiomers using CSR

N

NCH3

2'3'

O

CF3

OYb/3

CH3H3C

H3C


Determination of ratios between nicotine enantiomers using CSR

N

NCH3

2'3'

O

CF3

OYb/3

CH3H3C

H3C

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.

COClOCH3F3C

COClCF3H3CO

1-Methoxy-1-trifluoromethylphenylacetic

acid MTPA

MOSHER METHOD




CH

OMTPAΔδ > 0Δδ < 0

Δδ = δS – δR MTPA plane

(R)-MTPA ester (S)-MTPA ester

OCF3

H O

MeO Ph

L1

L2O

CF3H O

Ph OMe

L1

L2

L1 and L2 are ligands connected to the chiral carbon of the secondary alcohol




(R)-MTPA acid gives (S)-MTPA chloride – avoid confusion!!!!


MOSHER METHOD (AND RELATED METHODS)

1.  CDA must have a bulky polar group to fix a well-defined conformation. 2.  Carboxylic acid generally used for covalent derivatization 3.  Aromatic group to induce anisotropic effect. 4.  Δδ defined differently for different reagents [e.g., δS – δR for MPA,

(methoxyphenylacetic esters)]. 5.  Originally described as an empirical rule, but is founded on conformational

preferences (similarly as, e.g., asymmetric induction rules). 6.  Success depends on the presence of the expected, well-defined

conformation. 7.  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”.

8.  Computational results show that the Mosher’s model is simplified and the conformational behavior is complex (explains some anomalies)

9. MPA and analogs better than MTPA.


Alternatives to MTPA

COOHOCH3H

COOHOCH3H

COOHOCH3H

MPA

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NMR and chirality - ku · PDF fileNMR and chirality. 3. Methods of determination of enatiomeric ratios based on diastereotopicity NMR of diastereomers Chiral derivatizing agents (CDAs)