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Chemical Shift

Introductory NMR 101

Chemical Shift
Peak Intensity
Spin-spin Coupling
Sample Preparation: Deuterated Solvents

Spin-spin Coupling

Karplus (Garbisch) Relationships: Correlation of Magnitude of J Value w/ Geometry


147
6.5

12

10
5.5
5

4.5

3.5
4
3

2.5

02
0

45

90

135

180

Protocola-c for Computational/NMR Strategy

Spin-spin Coupling

1.

Determine as many experimental coupling constants Jexp( 3J and 4J)


as possible.

2.

Subject each diastereomer to multiconformational search (e.g., Monte


Carlo in MacroModel) to identify the family of stable conformational
isomers and then compute the Boltzmann weighted coupling constants
Jcalc for each diastereomer.

Calculate 2 between the experimental Js and the computed Js. The


isomer with smallest 2 (best fit) is the proposed structure.

2 = (Jexp-Jcalc)2

Extracting Coupling Constants from First Order Multiplets


4096

Spin-spin Coupling

J. Org. Chem. 1994, 59, 4096-4103

A Practical Guide to First-Order Multiplet Analysis in


1
H NMR Spectroscopy
Thomas R. Hoye,* Paul R. Hanson,1a and James R. Vyvyan1b
Department of Chemistry, University of Minnesota, Minneapolis, Minnesota 55455
Received March 11, 1994
The ability to deduce the proper set of coupling constant (J) values from a complex first-order multiplet in a 1H
NMR spectrum is an extremely important asset. This is particularly valuable to the task of assigning relative
configurations among two or more stereocenters in a molecule. Most books and treatises that deal with
coupling constant analysis address the less useful operation of generating splitting trees to create the line
pattern from a given set of J values. Presented here are general and systematic protocols for the converse-i.e., for deducing the complete set of J values from the multiplet. Two analytical methods (A. systematic
analysis of line spacings and B. construction of what can be called inverted splitting trees) are presented first.
A reasonably thorough and systematic set of graphical representations of common doublet of doublets (dd's),
ddd's, and dddd's are then presented. These constitute a complementary method for identification of J's
through visual pattern recognition. These approaches are effective strategies for extraction of coupling
constant values from even the most complex first-order multiplets.

Spin-spin Coupling

Table 7. dddd's Where Jz = Jy and J x = Jw (app tt's).


entry

Multiplet Appearance

8=8

20

6=6

16

5=5

14

4=4

12 J14 = J12 + J12'

3=3

10

2=2

1=1

6 J12 = J14 + J14'

0=0

J14 = J12

J14 = J14'

Spin-spin Coupling

Extracting Coupling Constants from NMR Multiplets: An Addendum


H
OH OH
OPMB
Me

Me

H
Me

Me
H

OH
OH
OPMB

"A Practical Guide to First-Order Multiplet Analysis in 1H NMR Spectroscopy,"


Hoye, T. R.; Hanson, P. R.; Vyvyan, J. R. J. Org. Chem. 1994, 59, 4096-4103.
"A Method for Easily Determining Coupling Constants. An Addendum to "
Hoye, T. R.; Zhao, H. J. Org. Chem. 2002, 67, 4014-4016.

Spin-spin Coupling

Spin-spin Coupling

Two Steps to Identify all Js in a Multiplet


1. Assign each peak in the multiplet one or more component numbers

from 1 to 2n (arbitrarily) from left to right by analogy to the examples shown below.

a) ddd

1 2 3 4

b) ddd

5 6 7 8

c) dddd
1

2
3

45

9 1213 14

10

11

15

16

Spin-spin Coupling

2. Systematically identify the J's by the following series of steps. Adopt the

convention that J1 J2 J3 J4 Jn. Appreciate that for J3 and beyond it is


necessary to have first determined the previous coupling constants (e.g., both J 1
and J2 must be known before J3 can be determined). {1 to x} is the distance in Hz
between component 1 (i.e., the lefthandmost peak) and component x.
i)

{1 to 2} is J1

ii)

{1 to 3} is J2

iii)

remove from further consideration the component corresponding to (J1 + J2)

iv)

{1 to next higher remaining component (i.e., 4 or 5)} is J3


corollary: one of {1 to 4} or {1 to 5} is J3

v)

remove from further consideration the components corresponding to the remaining combinations
of the first three J values [i.e., (J1 + J3), (J2 + J3), and (J1 + J2 + J3)

vi)

{1 to the next higher remaining component} is J4


corollary: one of {1 to 5} through {1 to 9} is J4

Spin-spin Coupling

Application to a dddd (24 = 16)

J2
J1

2
3

4 5

6
7
8

9
10
11

12 13

14
15

16

assign 2n components (or "units of intensity")

Spin-spin Coupling

Application to a dddd (24 = 16)


J3
J2

J1

J2
J1

2
3

4 5

6
7
8

9
10
11

12 13

14
15

16

assign 2n components (or "units of intensity")

Spin-spin Coupling

2. Systematically identify the J's by the following series of steps. Adopt the

convention that J1 J2 J3 J4 Jn. Appreciate that for J3 and beyond it is


necessary to have first determined the previous coupling constants (e.g., both J 1
and J2 must be known before J3 can be determined). {1 to x} is the distance in Hz
between component 1 (i.e., the lefthandmost peak) and component x.
i)

{1 to 2} is J1

ii)

{1 to 3} is J2

iii)

remove from further consideration the component corresponding to (J1 + J2)

iv)

{1 to next higher remaining component (i.e., 4 or 5)} is J3


corollary: one of {1 to 4} or {1 to 5} is J3

v)

remove from further consideration the components corresponding to the remaining combinations
of the first three J values [i.e., (J1 + J3), (J2 + J3), and (J1 + J2 + J3)

vi)

{1 to the next higher remaining component} is J4


corollary: one of {1 to 5} through {1 to 9} is J4

Spin-spin Coupling

Application to a dddd (24 = 16)


vi)

J4

v)

J3

J2

v)

J3

J2

v)

J3

J1

iv)

J3

iii)

J2
J2

ii)
i)

J1

J1

J1

2
3

4 5

6
7
8

9
10
11

12 13

14
15

16

Spin-spin Coupling

Assigning Component #s is Harder for Some Multiplets (e.g., dddddd)

H
H

Ha
Me

O
Me H
Hb

PMB

Resolution Enhancement: Relative Line Intensity Now Easier


H
H

Ha
Me

3
2

J1 J2 J5
J3 J6
J4

J total = 43.7 Hz (observed: 44.0 Hz)

PMB

Me H
Hb

J = 4.1, 7.0, 7.0, 7.0, 9.3, and 9.3 Hz

dddddd

Spin-spin Coupling

Splitting Tree: to Confirm the Assignments


H
H

Ha
Me

O
Me H
Hb
dddddd

PMB

Spin-spin Coupling

Spin-spin Coupling

Spiruchostatins A and B: A Challenging Opportunity to Test the Method

H D
N

NH
S

Me

Me

Me

NH
O

OH
O

Spiruchostatin A

Mimics transforming growth factor-






1. Masuoka, Y.; Nagai, A.; Shin-ya, K.; Furihata, K.; Nagai, K.; Suzuki, K.; Hayakawa, Y.;
Seto, H. "Spiruchostatins A and B, novel gene expression-enhancing substances produced by
Pseudomonas sp.," Tetrahedron Lett. 2001, 42, 41-44.

Strategies for Ferreting Out the Js


To overcome peak broadening:
a) Variable temperature NMR
b) Resolution enhancement

To overcome peak overlap:


a) Mixed solvents: benzene-d6 titration
b) Complementary field strengths

Spin-spin Coupling

Spin-spin Coupling

Variable Temperature NMR


H
O

N
H
H

Me
N

H
O

2''

OH

H
O

H
i-Bu

H
H
H

OH

H O

H
H
O

4''

3'

7'''

3'

2'''

6'''

2'''

2''

OH

7'''

6''

60 C

25 C
3.5

3.3

3.1

2.9

2.7

2.5

2.3

Spin-spin Coupling

Resolution Enhancement Gives Critical 3-H (ddddd) Js


3'''-H
(ddddd 1.9, 1.9, 1.9, 3.8, 7.0)
For easy deconvolution of

J1

first order Js see:

J2

Hoye, T. R.; Zhao, H.

Et

S
Me

NH
O

J4

67, 4014-4016.

NH
S

J3

J. Org. Chem. 2002,

H
N

Me
3'''
O

OH
O

J5

60 C
5.53

5.52

5.51

5.5

5.49

5.48

5.47

Spin-spin Coupling

Resolution Enhancement (contd)


7'''-H
(ddd 2.9, 8.2, 11.4)

3'-H
(dd 3.9, 15.0)

3.154

3.134

3.114

3.094

3.074

3.054

5.63

5.62

5.61

5.6

S 7''' H

H
H
6''' H
4'''H
H

i-Bu
OH
H
H

6'''-H
(dddd 2.4, 9.6, 12.0, 15.0)

5.64

3.034

4'''-H
(ddd 2.1, 2.1, 15.4)

5.65

H
3' H
N

3.174

Me
H

H O

5.59

5.58

2.52

2.5

2.48

2.46

2.44

Spin-spin Coupling

Overcome Peak Overlap by Mixed Solvent ( 17 % Benzene-d6 in CDCl3)


H
O

N
H
H

Me
N

H
O

OH
2'' a
17 % C6D6

60 C

H O

H
H
H

S 7''' H

H
i-Pr
OH
H
H
H

6''' H
O

245

7''' (dddd
3.0, 3.0, 9.2, 13.1)

195

145

2'' b


7'''

6''' (dddd
3.2, 5.5, 6.5, 13.1)

95

6'''

45

-5

2.7

2.65

2.6

2.55

2.5

0 % C6D6

2.8

2.75

2.7

2.65

2.6

2.6

2.58

2.56

2.54

2.52

2.5

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