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Chem 325

2-D NMR TECHNIQUES


avcg181.001.001.2rr.esp

3.5

COSY
4.0

4.5

F1 Chemical Shift (ppm)


NOESY 5.0

5.5

HETCOR 6.0

6.5

7.0

7.5

7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5


F2 Chemical Shift (ppm)

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COrrelation SpectroscopY (COSY)
COSY allows us to easily determine which peaks in the 1H
NMR are coupled to which other peaks, i.e. what is splitting
what.
(old method: peak-by-peak decoupling)

2D experiments are performed by initiating specific sequences


of RF pulses to which the sample is exposed. The NMR
measurement is made and an FID is collected. The sequence is
then repeated with a slight variation in the pulse sequence.

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COSY
Recall that in NMR experiment, we can saturate a
particular nucleus by irradiating it with an intense rf pulse.
This has the effect of averaging the nuclear spins to zero, or
erasing the peak from the spectrum.

The COSY experiment relies on the fact that when a


particular peak is erased in this way, it can no longer couple
with neighboring hydrogens.
The COSY experiment is performed by irradiating a
particular peak, and looking for changes in the other peaks.

Anything that was coupled to the irradiated peak is then


observed in the COSY experiment.

This process is repeated and each peak in the spectrum is


sequentially irradiated.

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COSY
The COSY spectrum is really a 3-D plot with the x- and y-axes
both chemical shift, and the z-axis is the signal.

The spectrum is rarely visualized in this way. More common to


show the view from above, with the peaks drawn with contour
lines.

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Contour Maps

5
COSY
The two axes now both correspond to the 1H NMR spectrum.

The magnitude of the z-axis is represented by the number


and spacing of the contour lines.

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COSY: 2-Nitropropane
CH3

H3C C NO 2

doublet

septet

7
CH3
-CH -CH3
H3C C NO2

-CH3

Points on diagonal:
Hs correlated with
themselves! Not
important.

-CH

8
COSY
(3-methyl)butyl ethanoate
3
1
O O CH2 2 CH3
C CH2 CH
4
6 1
CH3 CH3
1

3
4 6

t s d

9
6 1
4 2 3

3
O O CH2 CH31
C CH2
2
CH

6 4
CH3 CH3 1

10
COSY

Significant OFF-DIAGONAL spot shows that two Hs


are correlated: exchanging magnetization info, thus must
be COUPLED.
COSY: confirms coupling interactions
Useful for complex spectra: many peaks overlapping,
unresolvable multiplet patterns, many coupling constants
with similar values.

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COSY Example
The following molecule has a complex 1H NMR. It is nearly
impossible to determine what peaks are splitting one another
in this spectrum. c
d b

e a
OH
f f
g g

h h
i j i

1.00 2.00 0.72 1.96 2.02 2.03 0.99 1.02

8.5 8.0 7.5 7.0


Chemical Shift (ppm)

12
COSY Example
The following molecule has a complex 1H NMR. It is nearly
impossible to determine what peaks are splitting one another
in this spectrum. c
d b
Ha
e a
OH
f f
g g
Hj
h h
i j i

1.00 2.00 0.72 1.96 2.02 2.03 0.99 1.02

8.5 8.0 7.5 7.0


Chemical Shift (ppm)

13
COSY Spectrum
avcg271.001.001.2rr.esp

1D 1H NMR Spectrum
7.0

7.1

7.2

7.3

7.4

7.5

7.6

F1 Chemical Shift (ppm)


7.7

7.8

7.9

8.0
Correlations 8.1

8.2

8.3

8.4

8.5

8.6

8.7
8.5 8.0 7.5
F2 Chemical Shift (ppm)

14
Diagonal Peaks
avcg271.001.001.2rr.esp

A peak will always


correlate with itself,
so peaks along the 7.0

diagonal do not tell 7.1

us anything useful. Weak


7.2

7.3

We ignore these. 7.4

7.5

7.6

All other peaks are

F1 Chemical Shift (ppm)


7.7

useful. Strong 7.8

7.9

8.0
Notice that some 8.1

peaks are strong 8.2

and some are weak. 8.3

The strength is 8.4

related to the 8.5

magnitude of J. 8.6

8.7
8.5 8.0 7.5
F2 Chemical Shift (ppm)

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Off-Diagonal Peaks
avcg271.001.001.2rr.esp

In this spectrum, the


strong peaks
probably arise due to 7.0

correlations between Weak


7.1

ortho substituted 7.2

7.3
protons. The weak 7.4

ones are likely due to 7.5

meta coupling. 7.6

F1 Chemical Shift (ppm)


7.7

c Strong 7.8

d b 7.9

8.0
e a
OH 8.1
f f 8.2
g g
8.3

h h 8.4

i j i 8.5

8.6

8.7
8.5 8.0 7.5
F2 Chemical Shift (ppm)

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COSY
avcg271.001.001.2rr.esp

Every peak has a 7.0

mirror image opposite 7.1

the diagonal line. 7.2

7.3

7.4

7.5

7.6

F1 Chemical Shift (ppm)


7.7

c 7.8

d b 7.9

8.0
e a
OH 8.1
f f 8.2
g g
8.3

h h 8.4

i j i 8.5

8.6

8.7
8.5 8.0 7.5
F2 Chemical Shift (ppm)

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COSY
avcg271.001.001.2rr.esp

We make correlations
by drawing vertical
and horizontal lines 7.0

from the peak to see 7.1

which two protons are 7.2

7.3
coupled. 7.4

7.5

7.6

F1 Chemical Shift (ppm)


7.7

c 7.8

d b 7.9

8.0
e a
OH 8.1
f f 8.2
g g
8.3

h h 8.4

i j i 8.5

8.6

8.7
8.5 8.0 7.5
F2 Chemical Shift (ppm)

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COSY
avcg271.001.001.2rr.esp

In this image, we
see that it is a
triplet coupled to
a doublet. 7.25

7.30

7.35

7.40
This guy is meta

F1 Chemical Shift (ppm)


to the peak on 7.45

the x-axis
7.50

This guy is ortho 7.55

to the peak on the This means that 7.60

x-axis these two must be


7.65
ortho to each other.
Lets check. 7.70

8.20 8.15 8.10 8.05 8.00


F2 Chemical Shift (ppm)

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COSY
avcg271.001.001.2rr.esp

Zoom
**
7.0

7.1

7.2

7.3

7.4

7.5

7.6

F1 Chemical Shift (ppm)


7.7

7.8

7.9

8.0

8.1

8.2

8.3

8.4

8.5

8.6

8.7
8.5 8.0 7.5
F2 Chemical Shift (ppm)

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COSY
avcg271.001.001.2rr.esp

* *
There is a strong 6.90

cross peak 6.95

connecting these 7.00

7.05

two hydrogens. 7.10

7.15

7.20

F1 Chemical Shift (ppm)


This confirms our 7.25

7.30
suspicion. 7.35

7.40

7.45

7.50

7.55

7.60

7.65

7.70

7.75

7.65 7.60 7.55 7.50 7.45 7.40 7.35 7.30 7.25 7.20 7.15 7.10 7.05 7.00
F2 Chemical Shift (ppm)

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Back to 1H NMR
The COSY tells us that the following peaks are ortho to another.
As expected, the triplets are coupled to 2H and the doublets to 1H.
c
d b
Ha e a
OH
f f
g g

h h
Hj i j i

1.00 2.00 0.72 1.96 2.02 2.03 0.99 1.02

8.5 8.0 7.5 7.0


Chemical Shift (ppm)

22
Back to 1H NMR
We see 2 sets of d-t-t-d combinations, one worth 4H and the other
8H.
c
d b
Ha e a
OH
f f
g g

h h
Hj i j i

1.00 2.00 0.72 1.96 2.02 2.03 0.99 1.02

8.5 8.0 7.5 7.0


Chemical Shift (ppm)

23
Back to 1H NMR
We see 2 sets of d-t-t-d combinations, one worth 4H and the other
8H.
c
We can assign the d b
4H group to the e a
Ha OH
phenol ring. f f
g g

h h
Hj Hc i j i

Hb
He Hd

1.00 2.00 0.72 1.96 2.02 2.03 0.99 1.02

8.5 8.0 7.5 7.0


Chemical Shift (ppm)

24
Back to 1H NMR
We do not have enough information to assign the 8H set. If we
knew one, we could figure out the rest.
c
Hf or Hi ?? d b

e a
Ha OH
f f
g g

h h
Hj Hc i j i

Hb
He Hd

1.00 2.00 0.72 1.96 2.02 2.03 0.99 1.02

8.5 8.0 7.5 7.0


Chemical Shift (ppm)

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NOESY
COSY: 1H-1H correlations via spin coupling interactions, nuclei
must be closely connected by bonds.
NOESY is a type of 2D NMR that is also a 1H-1H correlation. It
correlates nuclei that are physically near each other in space, but not
necessarily coupled to one another.
It takes advantage of the Nuclear Overhauser Effect, recall from our
discussion of 13C NMR. When a proton is in close proximity to
another proton, they can influence the relaxation rates of one
another even if they are not coupled. This effect is removed when
one proton is saturated.
So in NOESY, we see correlation peaks due to nuclei that are
spatially near to each other, but not coupled. A THROUGH-SPACE
EFFECT.
Sometimes we see coupled peaks too, but we can rule these out with
the COSY spectrum.

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NOESY
avcg272.001.001.2rr.esp

As with COSY,
the diagonal 7.0

NOESY 7.1

peaks are 7.2

meaningless. 7.3

7.4

7.5

Peaks can be 7.6

F1 Chemical Shift (ppm)


positive (red) or 7.7

7.8

negative (blue). COSY


7.9

NOESY 8.0

interactions are 8.1

positive (red) while 8.2

8.3

COSY usually are 8.4

blue/red. 8.5

8.6

8.5 8.0 7.5


F2 Chemical Shift (ppm)

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NOESY
avcg272.001.001.2rr.esp

OH
a
With NOESY we now
see peaks correlated 7.0

to the OH 7.1

7.2

7.3

c 7.4

d b 7.5

e a 7.6

OH

F1 Chemical Shift (ppm)


f f Lets see this 7.7

g g 7.8

in more detail! 7.9


h h
8.0
i j i
8.1

8.2

8.3

8.4

8.5

8.6

8.5 8.0 7.5


F2 Chemical Shift (ppm)

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NOESY
avcg272.001.001.2rr.esp

The NOESY is telling OH


a
us that the OH is
Hd
close to Hb no 7.10

surprise there. Hb 7.15

c He 7.20
d b
7.25
e a
OH
f f
7.30

g g

F1 Chemical Shift (ppm)


7.35

h h
7.40
i j i Hc
7.45

7.50

It is also indicating an 7.55

interaction between Hf 7.60

the OH and this peak. 7.65

This peak is likely Hf.


7.92 7.91 7.90 7.89 7.88 7.87 7.86 7.85 7.84 7.83 7.82 7.81
F2 Chemical Shift (ppm)

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Back to 1H NMR
We can now assign all protons
Hi and Hj are close to c
each other as well, but d b

not coupled. We should Ha e


OH
a

see a NOESY signal f f


g g

Hi Hf h h
Hj Hc i j i

Hh
Hg Hb
He Hd

1.00 2.00 0.72 1.96 2.02 2.03 0.99 1.02

8.5 8.0 7.5 7.0


Chemical Shift (ppm)

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NOESY
avcg272.001.001.2rr.esp

Hj Hf
There is indeed a
NOESY peak here. 7.0

7.1

He 7.2

7.3

c 7.4

d b 7.5

e a 7.6

OH

F1 Chemical Shift (ppm)


7.7
f f
g g 7.8

7.9
h h
8.0
i j i
Hi 8.1

8.2

8.3

Another possible thru-space Assignments 8.4

correlation: Hf and He? Complete! 8.5

8.6

8.5 8.0 7.5


F2 Chemical Shift (ppm)

31
1H 13C Correlations
There are a number of heteronuclear 2D NMR methods that allow
correlations between carbon and hydrogen nuclei.

HETCOR (HETeronuclear CORrelation) and HSQC


(Heteronuclear Single Quantum Correlation). Both correlate
carbon nuclei with attached hydrogen nuclei. The HSQC
experiment is a more modern and more sensitive method and is
replacing HETCOR (although the HSQC experiment takes longer).

Pulse sequences become


very complex:

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HETCOR
3
O O CH2 CH31
C CH2
2
CH

6 4
CH3 CH3 1

1
3
2
6

No diagonal line!

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HETCOR of Menthol

In HETCOR, there
are no cross peaks
to worry about.

Unambiguous
assignments of C,H
connectivities

Intensity of spot
related to
magnitude of
coupling constant J

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