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Multidimensional NMR Experiments

Chem 8361/4361:Interpretation of Organic Spectra

© 2009–2013 Andrew Harned & Regents of the University of Minnesota

2D NMR SpectroscopyGeneral Information

– More complicated experiments to set up than 1H and 13C– Changes in pulses (#, length, angles, mixing times, etc.)– Observe effects based on relationship of nuclei

**Can be homonuclear (same nuclei) (e.g. H–H) or heteronuclear (different nuclei) (e.g. H–C, H–P, etc.)**

– Will only go over the what the experiments tell you and how to interpret, and only for the most common and widely used for solving organic structures

– DEPT, H–H COSY, HMQC (HETCOR), HMBC, INADEQUATE (C–C COSY)

– There is a whole alphabet soup of other experiments (both 1D and 2D)

– EXSY, TOCSY, HOHAHA, INEPT, WATERGATE, and many more

http://www.chem.ox.ac.uk/spectroscopy/nmr/acropage.htm

2D NMR SpectroscopyNumber of Protons on Carbon

DEPT (Distortionless Enhancement by Polarisation Transfer

– Used to be known as APT (Attached Proton Test)– DEPT is 1H-detected; APT is 13C-detected

– Tells you how many protons are attached to a particular carbon– negative peaks = CH2

– positive peaks = CH and CH3 (distinguishable with further processing)– “missing” peaks = carbons w/o protons

– With a little help from IR and chemical shift of 1H and 13C, can get a rough idea of molecular weight

2D NMR SpectroscopyNumber of Protons on Carbon

DEPT (Distortionless Enhancement by Polarisation Transfer

1

1 = Carbon spectrum

2

2 = ↓ CH2 ↑ CH, CH3

3

3 = ↑ CH

135ºpulse

90ºpulse

– Tells you which protons are coupled to one another– Very useful when peaks are overlapping in 1H NMR and you are unable to calculate coupling constants, or when there are a lot of similar coupling constants– Cross peaks are coupled to each other

– Newer method is DQF (Double Quantum Filtered)-COSY– same information, but looks “cleaner”

2D NMR SpectroscopyWho is Talking to Who?

1H–1H COSY (Correlation Spectroscopy)

C C C

H

1 bond H–H coupling

H

2D NMR SpectroscopyWho is Talking to Who?

1H–1H COSY (Correlation Spectroscopy)

1H1H

4H2H 2H 1H

3H3H

2H

– Overlapping protons and a lot of similar coupling constants

Raffinose–a trisaccharide

2D NMR SpectroscopyWho is Talking to Who?

1H–1H COSY (Correlation Spectroscopy)

Raffinose–a trisaccharide

2D NMR SpectroscopyWho is Talking to Who?

1H–1H COSY (Correlation Spectroscopy)

4H

1H

1H2H2H1H

3H3H

2H

2D NMR SpectroscopyWho is Talking to Who?

1H–1H COSY (Correlation Spectroscopy)– DQF-COSY: Double Quantum Filtered COSY – cleans up the spectrum by reducing noncoupled systems (e.g. CH3 singlets)

CH2

CH2

H3C CH3

HO

Ipsenol

2D NMR SpectroscopyWho is Talking to Who?

1H–1H COSY (Correlation Spectroscopy)– DQF-COSY: Double Quantum Filtered COSY – cleans up the spectrum by reducing noncoupled systems (e.g. CH3 singlets)

CH2

CH2

H3C CH3

HO

Ipsenol

2D NMR SpectroscopyWho is Talking to Who?

1H–1H COSY (Correlation Spectroscopy)

C6H10O2

2D NMR SpectroscopyWho is Talking to Who?

1H–1H COSY (Correlation Spectroscopy)

O

O

– Tells you which protons are coupled to one another– Very useful when peaks are overlapping in 1H NMR and you are unable to calculate coupling constants, or when there are a lot of similar coupling constants– Cross peaks are coupled to each other

Recall...1H–1H COSY

C C C

H

H

2 & 3 bond H–H coupling

H

– Tells you which protons are coupled to one another– Very useful when peaks are overlapping in 1H NMR and you are unable to calculate coupling constants, or when there are a lot of similar coupling constants– Cross peaks are coupled to each other

Recall...1H–1H COSY

C C C

H

H

2 & 3 bond H–H coupling

H

4H

1H

1H

2H2H1H

3H

3H

2H

This can still causeambiguities!

2D NMR SpectroscopyWho is Talking to Who?

1H–1H TOCSY (Total Correlation Spectroscopy)

– Tells you which protons are in the same spin system (a continuous chain of spin-spin coupled protons)– Magnetization from HA is transferred to HB, which then transfers to HC and on down the line

– Can be run as either a 1D or 2D experiment– Running as a 1D experiment greatly simplifies spectra with severe signal overlap– Related experiment (HOHAHA) gives essentially the same information– Can also observe one-bond 1H–13C couplings (HMQC-TOCSY, hetero-TOCSY, HEHAHA) - will not discuss

C C C

HA HB

C C

HC HD HE

1D TOCSYSpin System Identification

1H–1H TOCSY (Total Correlation Spectroscopy)– Irradiate at frequency of proton of interest– Wait a period of time (typically 20 to 400 ms) and then collect1D spectrum– Only observe protons to which magnetization has been transferred– Short periods of time (20 ms) will only give rise to “single step” transfers; longer periods of time allow magnetization to propagate further

α- and β-lactose

1D TOCSYSpin System Identification

O

H4

O

H3

HO

H2

H1

OHH5

OH

OHO

HO

H

H

HO

H

HOHH

OH

β-lactose4.67 ppm

H6,H6'

1D TOCSY

Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.

O

HN

OO

HN

OO

N3

OO

OO

O

OO

O2A B,C D

12

34

56

1D TOCSY

Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.

O

HN

O

O

HN

O

O

N3

O

O

O

O

O

O

O

O

2

A

B,C

D

1

234

5

6

2D TOCSYSpin System Identification

1H–1H TOCSY (Total Correlation Spectroscopy)– Cross peaks are in the same spin system

O

OHHO

N3O

O

12

3 4

56

COSY TOCSY

Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.

N

N

23

45

6

7

8

9 10

1112

13

17

19

2925

23

2D TOCSY– Cross peaks are in the same spin system

Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.

Intermediate in biomimetic synthesis of manzamine

N

N

23

45

6

7

8

9 10

1112

13

17

19

2925

23

2D TOCSY– Cross peaks are in the same spin system

Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.

Intermediate in biomimetic synthesis of manzamine

N

N

23

45

6

7

8

9 10

1112

13

17

19

2925

23

2D TOCSY– Cross peaks are in the same spin system

Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.

Intermediate in biomimetic synthesis of manzamine

New DevelopmentsDeconvolution via MDEC

MDEC (Multi Frequency Homonuclear Decoupling)– Conceptually the same as the homonuclear decoupling experiment mentioned earlier, but allows multiple frequencies to be decoupledat the same time

J. Am. Chem. Soc. 2009, 131, 15994–15995

(a) 1H NMR(b) irr @ H-1(c) irr @ H-1/H-7(d) irr @ H-1/H-3a/H-7

H-2 (dddd)

H-2 (app dt)

H-2 (dd, J = 3.3, 12.2 Hz)

H2

H

Me

H1

OHH3b

H3a MeMe

H7

123

7

OH

X

X

X

New DevelopmentsDeconvolution via MDEC

1D-TOCSY-MDEC

J. Am. Chem. Soc. 2009, 131, 15994–15995

123 4

O

O

Me

H

H

H

MeMe

H

6

(a) 1H NMR(b) 1D-TOCSY irr @ H-3(c) 1D-TOCSY irr @ H-3 with MDEC @ H-1b, H-2b, H-3

H-2aX

X

X

2D NMR SpectroscopyWho is Talking to Who?

1H–13C COSY– HETCOR (Heteronuclear Correlation)

– older experiment; 13C-detected– HMQC (Heteronuclear Multiple Quantum Correlation) and HSQC (Heteronuclear Single Quantum Correlation)

– newer experiments; 1H-detected; largely replaced HETCOR– Both give same information, experimentally very different– Peaks have one-bond coupling (i.e. attached directly)– Compliments DEPT– Particularly useful for diastereotopic protons

C C C

H

1 bond H–C coupling

2D NMR SpectroscopyWho is Talking to Who?

HMQC

C C C

H

1 bond H–C coupling

2D NMR SpectroscopyWho is Talking to Who?

HMQC

C C C

H

1 bond H–C coupling

DiastereotopicProtons

2D NMR SpectroscopyWho is Talking to Who?

HMQC

Can “see into” multiplets

H2C

O

CH3

H

HH3C

H3C

Caryophyllene Oxide

2D NMR SpectroscopyWho is Talking to Who?

HMQC

O

O

2D NMR SpectroscopyHO

Cl

2D NMR SpectroscopyHO

Cl

2D NMR SpectroscopyHO

Cl

2D NMR SpectroscopyWho is Talking to Who?

1H–13C COSY (Long Range)

– COLOC (Correlated spectroscopy for Long range Couplings)– older experiment; 13C-detected

– HMBC (Heteronuclear Multiple Bond Coherence)– newer experiment; 1H-detected; completely replaced COLOC

– Both give same information, experimentally very different– Peaks have two- or three-bond coupling– “Sees through” heteroatoms and quaternary carbons– Can be very complicated, but is very powerful

C C C

H

2 and 3 bond H–C couplings

H1

2 3C O C

H

H1

2 3C C C

H

HO

1

2 3

2D NMR SpectroscopyWho is Talking to Who?

HMQC

C C C

H

1 bond H–C coupling

2D NMR SpectroscopyWho is Talking to Who?

HMBC

C C C

H

2 and 3 bond H–C couplings

H1

2 3

2D NMR SpectroscopyWho is Talking to Who?

OCH3

OH

OH

OCH3

or

2D NMR SpectroscopyWho is Talking to Who?

OCH3

OH

OH

OCH3or

2D NMR SpectroscopyWho is Talking to Who?

OCH3

OH

OH

OCH3or

2D NMR SpectroscopyWho is Talking to Who?

OCH3

OH

OH

OCH3or

2D NMR SpectroscopyWho is Talking to Who?

OCH3

OH

OH

OCH3or

2D NMR SpectroscopyWho is Talking to Who?

13C–13C COSY

– INADEQUATE (Incredible Natural Abundance Double Quantum Transfer Experiment)– tells what carbons are attached to each other– if you know what type of carbon it is (C, C=O, CH, CH2, CH3, etc.) from DEPT, you can almost write down the entire gross structure by running two NMR experiments

– BUT it is 13C–13C coupling– probability of one 13C is 0.01– two next to each other 0.01x0.01 = 0.0001 (~1 molecule in 10,000)

– Need lots of sample and instrument time to overcome– In our facility: 80% v/v, overnight, 500 MHz = nothing

C C C

1 bond C–C coupling

ON

2D NMR SpectroscopyWho is Talking to Who?

INADEQUATE

C C C

1 bond C–C coupling

2D NMR SpectroscopyWho is Talking to Who?

INADEQUATE– Cross peaks show up as doublets = JCC – Diagonal is midway between the two doublets

5 4 1 9 103 11 2 15 126,714

2D NMR Spectroscopy

OH

CH C CH CH2 C CH2

CH3,CH3,CH2,CH3

2D NMR Spectroscopy

2D NMR Spectroscopy

C C,CH

2D NMR Spectroscopy

C CCH CH CH2 CH2 CH3CH3 x2

O

Br

WhichIsomer?

2D NMR Spectroscopy

O

Br

2D NMR Spectroscopy

O

Br