determining stereochemistry by...

©2019 Gregory R. Cook, NDSU

Determining Stereochemistry by

NMR

ORO

CF3

MeO

Ph

©2019 Gregory R. Cook, NDSU

Enantiomers

‣ Enantiomers

‣ (+)-A and (-)-A are identical by NMR

‣ How do we make them different?

‣ change the situation from enantiomeric to diastereomeric

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Diastereomers

‣ Diastereomers

‣ Covalent bonds with other chiral entities

‣ Ionic bonds with other chiral entities

‣ Lewis acid/Lewis base complexation

‣ Chiral solvating agents or additives

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Make it a diastereomer

‣ Covalent Bonds

‣ The most convenient method is to make an ester or amide linkage with a chiral acid

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OHR1R2

R3

O

HOR6

R5R4

enantiopure racemic

+R1R2

R3

O

OR6

R5R4

+R1R2

R3

O

OR6

R5R4

H2NR6

R5R4

racemic

R1R2

R3

O

NH R6

R5R4

+R1R2

R3

O

NH R6

R5R4

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Chiral Acids

‣ Covalent Bonds

‣ Chiral acids first utilized in the 1960’s

Rabin and MislowTetrahedron Lett 1966, 4249

Top. Stereochem. 1967, 2, 199

MosherJ. Org. Chem. 1969, 34, 2543

J. Am. Chem. Soc. 1973, 95, 512

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PhO

OHHHO

mandelic acid

PhO

OHHMeO

O-methylmandelic acid(methyl phenyl acetic acid)

(MPA)

PhO

OHCF3MeO

O-methyltrifluoromethylphenylacetic acid(MTPA)

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R and S

‣ Covalent Bonds

‣ Be careful of naming conventions

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PhO

OHCF3MeO

(R)-MTPA

SOCl2 PhO

ClCF3MeO

(S)-MTPA-Cl

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J. Am. Chem. Soc. 1973, 95, 512

Mandelate and MTPA based Derivatives

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Determining Configuration

‣ Preferred conformation can indicate absolute stereochemistry

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L2L3

O

O

H

F3CL2

L3OMePh

CF3

PhMeO

L3L2

O

O

H

F3CL3

L2OMePh

CF3

PhMeO

Shielded

Shielded

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Fluorine

‣ 19F NMR is an advantage

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L2L3

CF3

PhMeO

L3L2

F3CPh

MeOstericrepulsion

ORO

CF3

MeO

Ph

ORO

CF3MeO

Ph

shielded

©2019 Gregory R. Cook, NDSU

MPA Derivatives

‣ MPA derivatives can also be used

TrostJ. Org. Chem. 1986, 51, 2370

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L2L3

O

O

H

MeO L2L3

HPh

OMe

PhHShielded

O

N

H

MeO

L2L3H

Ph

H

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1° Alcohols

‣ Primary alcohols more difficult

YamaguchiTetrahedron 1976, 32, 1363Tetrahedron Lett. 1977, 89

Tetrahedron Lett. 1977, 4085

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O

O

H

MeO L2L3

HPh

O

OMeO

PhF3C

H

L2L3

Eu+3

©2019 Gregory R. Cook, NDSU

1° Alcohols

‣ New Chiral Acids for Primary Alcohols

RigueraJ. Am. Chem. Soc. 1998, 120, 4741

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O

OMeO

H

H

L2L3

O

OHOMe

©2019 Gregory R. Cook, NDSU

Amine Derivatives

‣ Amine Analysis - a variety of derivatives

HoyeJ. Org. Chem. 1996, 61, 2056

Fukushi, Yajima, MizutaniTetrahedron Lett. 1994, 35, 599

KabayashiJCS Chem. Comm. 1995, 435

NájeraJ. Org. Chem. 1996, 61, 7285

HeumanJCS Chem. Comm. 1993, 1113.

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PhO

OHCF3MeO

MeOCO2H

NP NOCl Ph

CH3

O

OHH

ArO

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Lanthanide Shift Reagents

‣ Hindkley 1969 - observed that the addition of lanthanide Lewis acids induced large changes in chemical shift.

Eu(dpm)3tris(dipivaloylmethanato) europium

Eu(fod)3tris(heptafluorooctanedionato) europium

Eu(tfn)3tris(tetradecafluorononanedionato) europium

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OEu

O

3

OEu

O

F7C33

OEu

OF7C3

F7C33

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Shift Reagents

‣ Eu(dpm)3-induced shifts of protons in some common

environments

Functional Group Shift (ppm per mol of shift reagent per mol of substrate)

RCH2NH

2 ~150

RCH2OH ~100

RCH2NH

2 30-40

RCH2OH 20-25

RCH2COR’ 10-17

RCH2CHO 19

RCH2CHO 11

RCH2OCH

2R 10

RCH2CO

2CH

3 7

RCH2CO

2CH

3 6.5

RCH2CN 3-7

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Shift Reagents

‣ Shift Reagents

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Shift Reagents

‣ Shift Reagents

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Shift Reagents

‣ Shift Reagents

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Whitesides1970

Chiral Shift Reagents

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O

RO

Eu

3

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Chiral Lewis Base

‣ Lewis Bases - TRISPHAT

LacourChem. Comm. 1997, 2285

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TRISPHAT Shift

‣ TRISPHAT

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TRISPHAT Shift

‣ TRISPHAT

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Review on CSA’SChem. Rev. 1991, 91, 1441

SalvadoriJ. Org. Chem. 1998, 63, 9197

Chiral Solvating Agent - Triazine

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Chiral Solvating Agent - Triazine

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SalvadoriJ. Org. Chem. 1997, 62, 827J. Org. Chem. 1996, 61, 363

Chiral Solvating Agents - Cyclodextrins

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O

BzO OBz

OH

O6

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Chiral Solvating Agents - Cyclodextrins

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CH3

CH3

CH3CH3