3 - NMR Data and Molecular Structure

3 - NMR Data and Molecular Structure

1. Chemical shift, 2. Integration

• Spin-spin coupling, J

• Chemical and magnetic equivalence

• Strong and weak coupling, / J

3-NMR Data and Molecular Structure (Dayrit) 2

Do we need to do both 1H and 13C ?

• Good 1H and 13C NMR data are essential for the determination of structure. In many cases, one experiment provides information that the other does not have. The 1H and 13C NMR data must be consistent.

• Carbon atoms form the backbone of organic compounds. Protons surround the carbon backbone and are exposed to the chemical environment.

H-bondsolvent



• Comparison of 1H and 13C NMR data: The chemical shift range of 1H is fairly narrow (~12 ppm).

1H NMR signals often overlap.

The chemical shift range of 13C is wide (~200 ppm). There is less overlap in 13C NMR: 1 peak 1 C

13C chemical shifts are more predictable than 1H because carbons are less affected by chemical environment (e.g., solvent, temperature, intermolecular interactions).

Direct nuclear coupling (through space) is observed for 1H-1H interaction (known as dipolar coupling, NOE). This is not observed for 13C.



• Comparison of 1H and 13C NMR data: Indirect spin-spin coupling (J-coupling) is observed for both

1H and 13C. This information is very important for the determination of the compound’s bonding arrangement, configuration and conformation: 1H - 1H 1H - 13C: heteronuclear coupling 13C - 13C: observed only in fully labeled compounds


Information which can be obtained from 1H NMR spectra:

Data Inference

Chemical shift Chemical environment: this is determined by type of bond, inter- and intramolecular interactions, configuration, conformation, and chemical exchange.

Integration Relative number of nuclei.

Spin-spin coupling, nJ

Magnitude depends on number of intervening bonds, n, and dihedral angle between bonds.

Basis for many 2-dimensional experiments.

Temperature dependence

Chemical exchange Kinetics


Information which can be obtained from 13C NMR spectra:

Data Inference

Chemical shift Relative electronegativity of groups bonded to carbon.

Integration Not applicable to standard 13C NMR spectrum. Relative number of nuclei for inverse-gated 13C NMR.

Spin-spin coupling, nJ

nJCH is the basis of many 2-dimensional NMR experiments.


Larmor frequencies at 2.35 T

MHz 25 40 96 100 13C 31P 19F 1H

Larmor frequency

The Larmor frequency, 0 (Hz), refers to the absolute

frequency of the nucleus of in the absence of electrons. It is determined by the magnetogyric ratio of the nucleus:

o = (/2) B0

(Jacobsen 2007)

Larmor frequency: (MHz)

Chemical shift: (Hz) or (ppm)

13C


Chemical Shift

• The Larmor frequency, , differentiates among different

types of nuclei (isotopes) only; it does not differentiate among individual atoms of the same isotope in a compound.

• Various nuclei in a compound can be differentiated according to their individual chemical environments which arise from the shielding provided by the electrons which surround each nucleus. This is the chemical shift, (in Hz):

= (/2) B0 (1 - )

where , the shielding factor, is a dimensionless number and has values in the order of 10-6.


Chemical Shift

• The magnitude of the Larmor frequencies at the typical NMR magnetic fields (e.g., 2.35 T) are in MHz. In contrast, the shielding factor, , exerts a much smaller influence on the frequency of the individual nuclei in the order of Hz, that is 106 times less.

• For example, in absolute frequencies at 2.35 T, two 1H nuclei in different chemical environments may resonate at 100.000 100 and 100.000 200 MHz. The difference in their frequencies, therefore is 0.000 100 MHz, or 100 Hz.

• 100 Hz/100 MHz = 1.00 x 10-6, or 1.00 ppm. (The meaning of the term “ppm” as used here reflects the factor of 10-6 in the differences in the frequencies of the individual nuclei. It is not a concentration term.)

= (/2) B0 (1 - )


Chemical Shift

• The absolute chemical shift, (in Hz), depends on the strength of the external magnetic field, B0.

, Hz = (/2) B0 (1 - )

, ppm = [( TMS - sample ) / TMS] x 106

• However, for purposes of spectral assignments, it is more convenient to assign the positions of the signals using values which are the same regardless of the magnetic field strength. (This is important since NMR data are produced using instruments of different magnetic field strengths.) Thus, another convention for stating the chemical shift was developed:


Chemical Shift

•By convention, the position of is made by referencing it to a standard compound, tetramethylsilane (TMS). The chemical shift in relative to TMS can be calculated from the frequency values in MHz.

•TMS is called an internal reference, and is assigned a position of 0 (0 ppm) for both 1H and 13C.


CH3

Si CH3

CH3

H3C


Chemical Shift

• is independent of B0.

• TMS is the standard internal reference used in organic solvents (0 ppm). In aqueous solvents, other reference compounds are used, such as 3,3,3-trimethyl-silylpropionate (TSP).

• The residual proton (1H) signals from the deuterated solvent are sometimes used as the chemical shift reference. This is a secondary reference, and it should be noted that the assigned values sometimes differ, and that the chemical shift may be temperature dependent.



Chemical Shift

• Negative chemical shifts are possible. This simply means that their shielding factor, , is higher than that of TMS.

• The unit of “ppm” comes the factor 106. For example, on a 1H spectrum, the following might be the absolute frequencies of TMS and the sample at 100 and 400 MHz:

At 2.35 T: TMS = 100.000 357 25MHz s = 100.000 348 50MHz = 8.75 ppm

At 9.4 T: TMS = 400.001 429 00 MHz s = 400.001 394 00 MHz = 8.75 ppm


Effect of B0 on chemical shift, and

(Jacobsen 2007)

0 ppm ()10 ppm

0 ppm8 ppm

0 ppm6.67 ppm

0 ppm4 ppm

0 ppm3.3 ppm


Chemical Shift• The field felt by the shielded nucleus can be expressed in terms of a “local magnetic field”:

Blocal = B0 (1 - )

• That is, the electrons which surround each nucleus alter its magnetic field by an amount represented by , the shielding factor.

• Since is of the order of 10-6, this means that there is only a small absolute difference between the Blocal values among

nuclei of the same type. This difference is the chemical shift.

• At 2.35 T, the range of chemical shifts for 1H is about 1500 Hz, while for 13C the range is 6250 Hz.


Shielding factor,

The shielding factor, , has several components:

= dia + para + N + R + e + i + x

• dia + para : inductive effects due to electronegativities of substituents

• N : anisotropy; depends on position of nucleus in space relative to chemical bonds

• R : special case of anisotropy due to the aromatic ring current

• e : special case of anisotropy due to electric fields in regions around electronegative groups

• i : intermolecular bonding interactions, such as hydrogen-bonding and solvent effects (generally for 1H only)

• x : various contributions, such as isotope effects, shielding due to proximity to heavy metals


13C chemical shifts of Alkanes

CH4

-2.3H3C CH3

7.3 15.4

15.9 13.0

24.8 24.1

25.0

14.2

22.8

34.8 11.8

32.0 22.3

30.1

31.3

27.7

32.2

23.1

14.2

n-hexane n-heptane

14.1

23.1

32.4

29.5 29.5

32.1

22.8

14.1

n-octane

= dia + para + N + R + e + i + x


halides

carbon

= dia + para + N + R + e + i + xInductive effects

on Carbon


Effects of Anisotropy on shielding: N, R and e

• A magnetic field causes electrons to move in opposition to it. This in turn gives rise to electron-induced fields. Chemical-shift anisotropy (CSA) arises from the motion of electrons in response to the external magnetic field.

• The induced field can increase or decrease the chemical shift of a surrounding nucleus depending on its position in space relative to the electric field.

• CSA is most readily observed in 1H where CSA effects can range from a fraction to several ppm.

= dia + para + N + R + e + i + x


= dia + para + N + R + e + i + x

Effects of Anisotropy on shielding: N, R and e

There are three types of CSA:

• N : due to the location of the nucleus in space with respect to

the axis of a chemical bond

• R : due to the location of the nucleus in space with respect to

the plane of an aromatic ring

• e : due to the location of the nucleus in space with respect to

an electronegative group.

• CSA is a separate contribution from the inductive effect which

is due to dia + para.


Chemical Shift Anisotropy: Cyclic Alkanes

1H, :

O

H

OCH3OH

H

H

HO

H

HO

H

HO

4.69

3.97

5.18

3.78

O

OCH3

HOH

H

H

HO

H

HO

H

HO

equatorial is approx +0.48 ppm(deshielded)

H

HR

+

+

_

+

+

_


Chemical Shift Anisotropy: Cyclic Alkanes13C, :

CX C

X

X ppm ppm

H 27.1 27.1CH3 33.2 28.4CH2CH3 40.1 35.5CH=CH2 42.1 37.0F 91.0 88.1Cl 59.8 60.1Br 52.4 55.4I 31.2 38.3


Chemical Shift Anisotropy: Alkenes and Carbonyls


1H, :

6.83 6.28transcis

CO2RH

RO2C H

CO2RH

H CO2R

ca. 9 - 10

R H

5.06

6.27

5.16

HH

H

H

H

H

HHO 3.75

H OH 3.53 1.32 1.03

H H


Chemical Shift Anisotropy: Alkyne

1H and 13C, :

1H, 13C,

CH3 0.91 15.4

CH3 1.71 18.7

CH3 1.80 3.7


Chemical Shift Anisotropy: Aromatic ring


Chemical Shift Anisotropy: Aromatic ring

1H, : 13C, : 128.0

126.0

128.3

122.4126.3

126.3

130.1

131.9


13C NMR Chemical Shifts


1H NMR Chemical Shifts


1H NMR Chemical Shifts

(from: Becker, High Resolution NMR)

13C NMR Chemical Shifts


• Integration involves the measurement of the area under the peak in order to approximate the relative number of nuclei. It is a standard technique for 1H NMR analysis.

• Integration often does not give exact whole-number ratios.

• The proper settings of the pulse delay and phasing of the spectrum during processing are essential for accurate integration.

• Using the standard broadband proton-decoupled 13C pulse sequence, integration of carbon atoms cannot be performed because the peak areas are not related to the number of nuclei. 13C can be integrated using a special pulse sequence called inverse-gated decoupling.

Integration


• All nuclei which possess a magnetic moment, , can interact with each other in two ways:

1. Indirect interaction: nuclear spin-spin coupling, nJ2. Direct interaction: nuclear Overhauser effect, NOE

• Nuclear interactions are weak and involve energies in the order of a few Hz.

• Nuclear interactions, both indirect and direct, are very important probes of the molecular structure.

Internuclear interactions


• Nuclear coupling arises from the interaction between nuclei which are transmitted through the bonding electrons. These perturbations occur as each nucleus undergoes spin transitions.

• Nuclear spin-spin coupling is classified as indirect (or through-bond) coupling.

Spin-spin coupling, J

HC

CH

(Jacobsen 2007)

HC

CH

B0

Hb

Ha


Spin-spin coupling, J: General considerations

J is designated according to:

• the number of intervening bonds, n

• whether the coupling is homonuclear or heteronuclear.

For example:

• directly-bonded 1H and 13C nuclei, C-H: heteronuclear, 1JHC

• geminal protons, H-C-H: homonuclear, 2JHH

• vicinal protons, H-C-C-H: homonuclear, 3JHH

• directly-bonded carbons, -C-C-: homonuclear, 1JCC


Effect of number of bonds on J value (Hz).

nJABnJHH

nJHCnJCC

1JAB - 125 ~ 250 30 ~ 1702JAB 0 ~ 40 -10 ~ +40 < 203JAB 0 ~ 18 1 ~ 10 0 ~ 5

4JAB* 0~ 7 < 1 < 2

* These values are usually observable only in conjugated systems.

Spin-spin coupling, J: nJ


Spin-spin coupling, J : Effect of hybridization

The larger is the s orbital component of the bond, the larger is the coupling constant: sp > sp2 > sp3.

• C-C-H (sp3): 1JHC ~ 125

• C=C-H (sp2): 1JHC ~ 160

• CC-H (sp): 1JHC ~ 250

• H-C-H (sp3): 2JHH ~ -18 to -8

• C=C< (sp2): 2JHH ~ -4 to 4HH

• H-C-C-H (sp3): 3JHH ~ 0 to 15 (depends on dihedral angle)

• H-C=C-H, cis (sp2): 3JHH ~ 4 to 12

• H-C=C-H, trans (sp2): 3JHH ~ 14 to 19


The effect of the environment on the chemical shift and 1H-1H coupling

• Chemical equivalence: Refers to nuclei which have the same chemical shift, for example, protons which are bound to the same carbon nucleus. This does not include overlap of chemical shifts due to accidental equivalence.

• Magnetic equivalence: Having the same (spatial) environment or coupling relationships with other nuclei in the molecule. Only those nuclei with the same chemical environment and coupling relationships are magnetically equivalent. Magnetically equivalent nuclei are degenerate and do not couple with each other.


Chemical equivalence and magnetic equivalence:

• Chemically equivalent and Magnetically equivalent:

• Chemically equivalent but not Magnetically equivalent:

RC

Ha

HbHc

R

Ha

Hb

Hc

HO2C

R

CH3

Ha Hb

Hc


Spin-spin Coupling. Examples of equivalence

H

H

C6 symmetry axis. Chemical Shift Equivalence: Yes.Magnetic Equivalence: Yes. Spin system: A6 (singlet)

H

H

CH3

Chemical Shift Equivalence: No. Magnetic Equivalence: No.Spin system: AB

H

CH3

H

H

Chemical Shift Equivalence: Yes. Magnetic Equivalence: No.Spin system: AA'



H (c')

NO2

(c) H

H (b')

H (a)

(b) H

H (a')

NO2

(a) H

H (b')

OH

(b) H



C

H

HH

Free rotation. Chemical Shift Equivalence: Yes.Magnetic Equivalence: Yes. Spin system: A3

H H

HHChemical Shift Equivalence: Yes.Magnetic Equivalence: No.Spin system: AA'BB'

*

H H

HCl Chiral center:diastereotopicChemical Shift Equivalence: No.Magnetic Equivalence: No.Spin system: ABX



H3C

H3C H Free rotation.CSE: Yes.ME: Yes. Spin system: A6M

H3C

H3C

H3C H

H

*Restricted rotation; next to chiral center: diastereotopicCSE: No.ME: No. Spin system: A3B3M


J(1H-1H) coupling

Relative intensities within a multiplet for first order coupling with magnetically equivalent nuclei calculated with the Pascal triangle.

Number of coupled magnetically

equivalent spins

Relative intensities of multiplet Multiplet pattern

0 1 singlet

1 1 1 doublet

2 1 2 1 triplet

3 1 3 3 1 quartet

4 1 4 6 4 1 quintet

5 1 5 10 10 5 1 sextet

6 1 6 15 20 15 6 1 septet

(Jacobsen 2007)

First-order splitting patterns: Multiplicities

(Jacobsen 2007)


First-order splitting patterns: Multiplicities


H3C

O CH3

CH3HH

H


Typical values for JHH

H C C H

O

3J= 3 ~ 7 Hz 3J= 4 ~ 10 Hz

C C

C

H

H

3J= 11 ~ 18 Hz (trans)

C C

H

H

C C

HH

3J= 6 ~ 14 Hz (cis)

3J= 0 ~ 9 Hz(Karplus relationship)3J= 7 Hz (free rotation)

H C C HVicinalcouplings

2J= 0 ~ 3.5 Hz

Geminalcouplings

C

H

H2J= -12 ~ -20 Hz

C

H

H


3Jaa'= 10 ~ 13 Hz3Jae'= 2 ~ 5 Hz3Jee'= 2 ~ 5 Hz2Jae= -11 ~ -14 Hz

Ha'

He'He

Ha

3J(trans)= 3 ~ 9 Hz

3J(vic)= 5 ~ 12 Hz

2J(gem)= -4 ~ -10 Hz

H

H H

Aliphatic ring couplings

5J(para)= 0.1 ~ 1 Hz

4J(meta)= 2 ~ 3 Hz

3J(ortho)= 7 ~ 10 Hz

H

H

H

H

Aromaticcouplings

Typical values for JHH


H

H

-2.00

0.00

2.00

4.00

6.00

8.00

10.00

0 90 180 270 360 450

Dihedral angle

3J(H

H)

3J (1H-1H) and the Karplus relationship.

3JHH’ = 9 cos2 - cos - 0.28


H

H

3J (1H-1H) and the Karplus relationship.

3JHH’ = 7 - cos + 5 cos 2

(Jacobsen 2007)


JHH and chemical shift difference,

The appearance of a J-coupled 1H multiplet depends on the ratio between the frequency difference of the coupling nuclei and the J-coupling constant:

( / J) both values in Hz

• If this ratio is greater than 10, the coupling is first order (weakly coupled) and it can be analyzed in a fairly straight-forward manner.

• If this ratio is < 10, the coupling appears more complex and is classified as second order (strongly coupled).


c. 2nd order: J < 1 (strongly coupled)

b. 2nd order: J ~ 4

a. 1st order: J 10 (weakly coupled)

Effect of B0 on J splitting order

(Jacobsen 2007)

Second order:

J < 1

First order:

J 10


Some common spin systems.

Number of spins 1st Order 2nd Order

2 AX AB

3 A2X, AMX ABX, ABC, A2B

4 A2X2, A3X A2B2, ABCD

Note! The difference between 1st and 2nd order systems alsodepends on the strength of the external magnetic field. By usinghigher field magnets, some 2nd order systems can become 1st order.


Solving an NMR structure is like putting allthe pieces of a puzzle together . . . . .

1H shifts13C shifts

integration

J coupling

nOe

DEPT

HMBC

HMQC

exchange

TOCSYOthers:IR, UV,etc.


Reporting NMR Data:

1H:Label ppm multiplicity J (Hz) integration assignment

13C:Label ppm DEPT assignment


SummaryNMR is a powerful technique for the determination of chemical

structure.

Structural Information NMR Data

Bonding relationships Chemical shift, spin-spin coupling(homonuclear and heteronuclear)

Chemical formula Integration, multinuclear NMR

Conformation Spin-spin coupling, nOe

Relative configuration Spin-spin coupling, nOe

Dynamic phenomena Kinetic studies, relaxation time

Intermolecularinteraction

nOe


Analysis of 1H NMR for 2-butanol.

2-Butanol (d/l)

H3CCH3

HO

H

H

H1

23

4

de

CH3

HHCH3

OHH

1 a

4 f

de

a

bc

f

b c

*

1H Spin system: chemical equivalence magnetic equivalencea (3H)d, ef (3H)

yes yesyes noyes yes


1H at 60 MHz

H3CCH3

HO

H

H

H1

23

4

de

a

bc

f*

3.8 ppm, 1H, br q

1.7 ppm, 1H, br s

1.1 ppm, 3H, d

1.5 ppm, 2H, q

0.9 ppm, 3H, t


2-Butanol (d/l)

H3CCH3

HO

H

H

H1

23

4

de

CH3

HHCH3

OHH

1 a

4 f

de

a

bc

f

b c

*

Hn , ppm Integ multiplicity (J) .

a 1.1 3 d (Jab= 9)

b 3.8 1 br q: q (Jab= 9), d (Jbd= 2), (Jbe~0)

c 1.7 1(1.5~4) br s

d 1.5 1 q (Jdf= 9), d (Jbd= 2), (Jed~ 0)

e 1.5 1 q (Jfe= 9) (Jed~ 0) (Jbe~0)

f 0.9 3 t ~ d,d (Jf/ed= 9)


H3CCH3

HO

H

H

H1

23

4

de

a

bc

f*

Hb: 3.8 ppm, 1H, br q

I I I I I Jab = 9II II II II Jbd = 2

Hc 1.7 ppm, 1H, br s

Ha: 1.1 ppm, 3H, d II I Jab= 9

Hd:1.5 ppm, 1H, qd

I I I I I Jdf = 9II II II II Jbd = 2


H3CCH3

HO

H

H

H1

23

4

de

a

bc

f*

He: 1.5 ppm, H, q

Hf: 0.9 ppm, 3H, t

I I I Jfd=9

I II I Jfe=9

I I I I I Jef = 9


Analysis of 1H NMR for 1-butanol.

1H Spin system: chemical equivalence magnetic equivalence

h

e da

g f

43

21H3C

H

H

H

H

OH

HH

1-Butanol

bc

fg

e d

1 b,c

4 h

CH2OH

HHCH3

HH

b,c yes no

d, e yes no

f, g yes no


1H at 60 MHz

h

e da

g f

43

21H3C

H

H

H

H

OH

HHbc

C7H14O2

C9H10O2

3 - NMR Data and Molecular Structure

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