Multidimensional NMR

Experiments
Chem 8361/4361:
Interpretation of Organic Spectra
20092013 Andrew Harned & Regents of the University of Minnesota
2D NMR Spectroscopy
General Information
More complicated experiments to set up than
1
H and
13
C
Changes in pulses (#, length, angles, mixing times, etc.)
Observe effects based on relationship of nuclei
**Can be homonuclear (same nuclei) (e.g. HH) or heteronuclear
(different nuclei) (e.g. HC, HP, 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, HH COSY, HMQC (HETCOR), HMBC,
INADEQUATE (CC 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 Spectroscopy
Number of Protons on Carbon
DEPT (Distortionless Enhancement by Polarisation Transfer
Used to be known as APT (Attached Proton Test)
DEPT is
1
H-detected; APT is
13
C-detected
Tells you how many protons are attached to a particular carbon
negative peaks = CH
2
positive peaks = CH and CH
3
(distinguishable with further
processing)
missing peaks = carbons w/o protons
With a little help from IR and chemical shift of
1
H and
13
C, can get a
rough idea of molecular weight
2D NMR Spectroscopy
Number of Protons on Carbon
DEPT (Distortionless Enhancement by Polarisation Transfer
1
1 = Carbon spectrum
2
2 = ! CH
2

" CH, CH
3
3
3
= " CH
135
pulse
90
pulse
Tells you which protons are coupled to one another
Very useful when peaks are overlapping in
1
H 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 Spectroscopy
Who is Talking to Who?
1
H
1
H COSY (Correlation Spectroscopy)
C C C
H
1 bond HH coupling
H
2D NMR Spectroscopy
Who is Talking to Who?
1
H
1
H COSY (Correlation Spectroscopy)
1H
1H
4H
2H 2H 1H
3H
3H
2H
Overlapping protons and a lot of similar coupling constants
Rafnosea trisaccharide
2D NMR Spectroscopy
Who is Talking to Who?
1
H
1
H COSY (Correlation Spectroscopy)
Rafnosea trisaccharide
2D NMR Spectroscopy
Who is Talking to Who?
1
H
1
H COSY (Correlation Spectroscopy)
4H
1H
1H
2H
2H
1H
3H
3H
2H
2D NMR Spectroscopy
Who is Talking to Who?
1
H
1
H COSY (Correlation Spectroscopy)
DQF-COSY: Double Quantum Filtered COSY cleans up the
spectrum by reducing noncoupled systems (e.g. CH3 singlets)
CH
2
CH
2
H
3
C CH
3
HO
Ipsenol
2D NMR Spectroscopy
Who is Talking to Who?
1
H
1
H COSY (Correlation Spectroscopy)
DQF-COSY: Double Quantum Filtered COSY cleans up the
spectrum by reducing noncoupled systems (e.g. CH3 singlets)
CH
2
CH
2
H
3
C CH
3
HO
Ipsenol
2D NMR Spectroscopy
Who is Talking to Who?
1
H
1
H COSY (Correlation Spectroscopy)
C
6
H
10
O
2
2D NMR Spectroscopy
Who is Talking to Who?
1
H
1
H COSY (Correlation Spectroscopy)
O
O
Tells you which protons are coupled to one another
Very useful when peaks are overlapping in
1
H 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...
1
H
1
H

COSY
C C C
H
H
2 & 3 bond HH coupling
H
Tells you which protons are coupled to one another
Very useful when peaks are overlapping in
1
H 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...
1
H
1
H

COSY
C C C
H
H
2 & 3 bond HH coupling
H
4H
1H
1H
2H
2H
1H
3H
3H
2H
This can still cause
ambiguities!
2D NMR Spectroscopy
Who is Talking to Who?
1
H
1
H TOCSY (Total Correlation Spectroscopy)
Tells you which protons are in the same spin system (a continuous chain
of spin-spin coupled protons)
Magnetization from H
A
is transferred to H
B
, which then transfers to H
C

and on down the line
Can be run as either a 1D or 2D experiment
Running as a 1D experiment greatly simplies spectra with severe signal
overlap
Related experiment (HOHAHA) gives essentially the same information
Can also observe one-bond
1
H
13
C couplings (HMQC-TOCSY,
hetero-TOCSY, HEHAHA) - will not discuss
C C C
H
A
H
B
C C
H
C
H
D
H
E
1D TOCSY
Spin System Identication
1
H
1
H TOCSY (Total Correlation Spectroscopy)
Irradiate at frequency of proton of interest
Wait a period of time (typically 20 to 400 ms) and then collect
1D 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
!- and "-lactose
1D TOCSY
Spin System Identication
O
H
4
O
H
3
HO
H
2
H
1
OH
H
5
OH
OH
O
HO
H
H
HO
H
H
OH
H
OH
!-lactose
4.67 ppm
H
6
,H
6'
1D TOCSY
Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.
O
H
N
O O
H
N
O
O
N
3
O O
O
O
O
O O
O
2
A B,C D
1
2
3 4
5
6
1D TOCSY
Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.
O
HN
O
O
HN
O
O
N
3
O
O
O
O
O
O
O
O
2
A
B,C
D
1
2
3
4
5
6
2D TOCSY
Spin System Identication
1
H
1
H TOCSY (Total Correlation Spectroscopy)
Cross peaks are in the same spin system
O
OH HO
N
3
O
O
1
2
3 4
5
6
COSY TOCSY
Claridge, T. D. W. High-Resolution NMR Techniques in Organic Chemistry, 2nd Ed., Elsevier, 2009.
N
N
2
3
4
5
6
7
8
9 10
11
12
13
17
19
29
25
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
2
3
4
5
6
7
8
9 10
11
12
13
17
19
29
25
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
2
3
4
5
6
7
8
9 10
11
12
13
17
19
29
25
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 Developments
Deconvolution via MDEC
MDEC (Multi Frequency Homonuclear Decoupling)
Conceptually the same as the homonuclear decoupling experiment
mentioned earlier, but allows multiple frequencies to be decoupled
at the same time
J. Am. Chem. Soc. 2009, 131,
1599415995
(a)
1
H 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)
H
2
H
Me
H
1
OH
H
3b
H
3a
Me
Me
H
7
1
2
3
7
OH
X
X
X
New Developments
Deconvolution via MDEC
1D-TOCSY-MDEC
J. Am. Chem. Soc. 2009, 131, 1599415995
1
2
3
4
O
O
Me
H
H
H
Me
Me
H
6
(a)
1
H NMR
(b) 1D-TOCSY
irr @ H-3
(c) 1D-TOCSY
irr @ H-3 with
MDEC @ H-1b,
H-2b, H-3
H-2a
X
X
X
2D NMR Spectroscopy
Who is Talking to Who?
1
H
13
C COSY
HETCOR (Heteronuclear Correlation)
older experiment;
13
C-detected
HMQC (Heteronuclear Multiple Quantum Correlation) and
HSQC (Heteronuclear Single Quantum Correlation)
newer experiments;
1
H-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 HC coupling
2D NMR Spectroscopy
Who is Talking to Who?
HMQC
C C C
H
1 bond HC coupling
2D NMR Spectroscopy
Who is Talking to Who?
HMQC
C C C
H
1 bond HC coupling
Diastereotopic
Protons
2D NMR Spectroscopy
Who is Talking to Who?
HMQC
Can see into
multiplets
H
2
C
O
CH
3
H
H
H
3
C
H
3
C
Caryophyllene Oxide
2D NMR Spectroscopy
Who is Talking to Who?
HMQC
O
O
2D NMR Spectroscopy
HO
Cl
2D NMR Spectroscopy
HO
Cl
2D NMR Spectroscopy
HO
Cl
2D NMR Spectroscopy
Who is Talking to Who?
1
H
13
C COSY (Long Range)
COLOC (Correlated spectroscopy for Long range Couplings)
older experiment;
13
C-detected
HMBC (Heteronuclear Multiple Bond Coherence)
newer experiment;
1
H-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 HC couplings
H
1
2 3
C O C
H
H
1
2 3
C C C
H
H
O
1
2 3
2D NMR Spectroscopy
Who is Talking to Who?
HMQC
C C C
H
1 bond HC coupling
2D NMR Spectroscopy
Who is Talking to Who?
HMBC
C C C
H
2 and 3 bond HC couplings
H
1
2 3
2D NMR Spectroscopy
Who is Talking to Who?
OCH
3
OH
OH
OCH
3
or
2D NMR Spectroscopy
Who is Talking to Who?
OCH
3
OH
OH
OCH
3
or
2D NMR Spectroscopy
Who is Talking to Who?
OCH
3
OH
OH
OCH
3
or
2D NMR Spectroscopy
Who is Talking to Who?
OCH
3
OH
OH
OCH
3
or
2D NMR Spectroscopy
Who is Talking to Who?
OCH
3
OH
OH
OCH
3
or
2D NMR Spectroscopy
Who is Talking to Who?
13
C
13
C 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, CH
2
, CH
3
, etc.)
from DEPT, you can almost write down the entire gross structure by
running two NMR experiments
BUT it is
13
C
13
C coupling
probability of one
13
C 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 CC coupling
O
N
2D NMR Spectroscopy
Who is Talking to Who?
INADEQUATE
C C C
1 bond CC coupling
2D NMR Spectroscopy
Who is Talking to Who?
INADEQUATE
Cross peaks show up as doublets = J
CC

Diagonal is midway between the two doublets
5 4 1 9 103 11 2 15 12
6,7
14
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 C CH CH CH2 CH2 CH3 CH3 x2
O
Br
Which
Isomer?
2D NMR Spectroscopy
O
Br
2D NMR Spectroscopy
O
Br