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Electromagnetic radiation spectrum
NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY
PRINCIPLE AND APPLICATION IN STRUCTURE ELUCIDATION
Professor S. SANKARARAMAN
Department of Chemistry
Indian Institute of Technology Madras
Chennai – 600 036
HISTORICAL PERSPECTIVE
Discovery of NMR phenomenon in 1945
Purcell, Torrey and Pound – Harvard University USA
Bloch, Hansen and Packard – Stanford University USA
When ethanol was placed between pole pieces of an
electromagnet and irradiated with electromagnetic
radiation it absorbed radiation in the radio frequency
region. When the magnetic field was turned off no
absorption was observed.
Purcell and Bloch – Nobel prize in Physics – 1952
For the discovery of NMR.
The first published high resolution NMR spectrum of ethanol at 30 MHz
F. Bloch, W. W. Hansen, M. E. Packard, Phys. Rev. 1946, 69, 127
NMR – magnetic properties of atomic nuclei
Atomic nucleus has mass and it spins on its own axis
Due to the spin, it possesses angular momentum (P)
Due to the charge and the spin it possesses magnetic momentum (m)
Only certain nuclei have non-zero magnetic moment. In others the
“Net magnetic momentum” can be zero
Only nuclei with non-zero magnetic moment are “magnetically active”
Both (P) and (m) are vector quantities and also quantized
The ratio of magnetic momentum to angular momentum is called
“Gyromagnetic ratio”. It is very characteristic of a given nuclei.
Gyromagnetic ration = [g] = (m)/(P)
Basic theory of NMR Spectroscopy
Nucleus should be magnetically active –
non-zero magnetic momentum
According to quantum mechanics angular momentum
can have only certain fixed values (eigen states)
P = (m)(h/2p) where m is the magnetic quantum number of the
nucleus
In the presence of an external magnetic field(m) can have
(2I+1) values, namely (+I), (I-1), (I-2)……..(-I) where (I) is the spin quantum number of the nucleus
For I = ½, two states are possible (+½) and (-½)
For I = 1, three states are possible (+1, 0, -1)
For I = 3/2 , four states are possible (3/2, +1/2, -1/2, -3/2)
Nuclear Spin (I):
A simple way to find out nuclear spin
Atomic mass Atomic number Spin
Even Even zero
Even Odd multiple of 1
Odd Even or Odd multiple of ½
Examples:
I = 0 12C6, 16O8
I = integer 14N7 (1), 10B5 (3), 2H1 (1)
I = half integer 1H1 (1/2), 13C6 (1/2), 15N7 (1/2)
17O8 (5/2) 33S16 (3/2)
Properties of some common NMR nuclei:
Nucleus Spin g Natural
(rad T-1 s-1) abundance (%)
1H ½ 26.7 99.9
2H1 1 4.107 0.015
13C6 ½ 6.72 1.10
19F9 ½ 25.18 100
31P15 ½ 10.84 100
29Si14 ½ -5.32 4.67
NMR of spin ½ nuclei, namely proton and carbon-13
In the absence of external magnetic field the magnetic moment
vectors will be randomly oriented
In the presence of applied external magnetic field (Bo) two
orientations are possible, namely (+1/2) and (-1/2)
The two orientations, one aligning with external field (-1/2)
and another opposing the external field (+1/2),
differ in energy.
The energy difference depends on the strength of applied
magnetic field
E = hn = (h/2p)Bog n = (Bog)/2p
no field
increasing filed strength Bo
E = hn
Nuclear spins in an external magnetic field for I = 1/2
- 1/2
+ 1/2 b
a Bo
Distribution of nuclear spins:
Na / Nb = exp(-DE/kT)
Bo (T) n (MHz) DE (J) Na / Nb T oC
2.35 100 6.7 x 10-26 17 ppm 17
4.70 200 22.5 x 10-26 57 ppm 17
7.0 300 33.5 x 10-26 85 ppm 17
2.35 100 6.7 x 10-26 28
13
-100
+100
Higher the magnetic field strength –
higher the sensitivity and resolution
Lower the temperature –
higher the sensitivity
A 400 MHz NMR instrument is more sensitive
as well as more resolving than a 60 MHz NMR
instrument
The energy gap between the spin states corresponds
to radio frequency region
Application of radio frequency causes the absorption
of the same due to excitation of nuclear spins from
lower energy level to upper energy level when the two
energies match (resonance condition)
The spins in the excited state return back to ground
State by (a) spin lattice relaxation and (b) spin-spin
relaxation
Concept of chemical shift:
n = (Bo g)/ 2p
Nucleus is surrounded by electrons
Electrons have charge as well as spin
The magnetic field due to the spinning electron
shields the nucleus from the external magnetic
field. This is diamagnetic shielding.
The nucleus does not feel Bo, but Beff = Bo(1-s)
Beff is the effective magnetic field felt by nucleus
s is the shielding constant
s - the shielding constant
Characteristic of the chemical environment
of the proton
Depends on the electron density around the protons
n = (Beff g) / 2p = [Bo(1-s) g / 2p]
Since s is different for chemically different protons
the resonance frequency of chemically different
protons will be different – chemical shift
Definition of chemical shift – d:
It is inconvenient to refer to proton frequency as
398.432 MHz
Instead of actual frequencies of resonances, a reference
is taken and the frequencies are calibrated with
respect to the reference
d (in Hz) = n sample – n reference (Spectrometer dependent)
d = (n sample – n reference) x 106 (in ppm)
spectrometer frequency
Chemical shift expressed in d is a dimensionless quantity and
also does not depend on the spectrometer frequency
Reference for 1H-NMR spectroscopy:
Tetramethylsilane (TMS) is used as a reference
The chemical shift of TMS is lower than most protons in
organic molecules, so it is taken as zero
All the protons in TMS are equivalent and hence only one
signal for all the 12 protons – high signal intensity
TMS is a liquid and miscible with most solvents
It is also volatile and hence easy to remove
It is inert and does not react with the samples
0 10 ppm
60 MHz spectrometer
0 10 ppm
400 MHz spectrometer 0 4000 Hz
0 600 Hz
d 2 ppm in a 60 MHz spectrometer is 120 Hz
d 2 ppm in a 400 MHz spectrometer is 800 Hz
Chemical shifts and scan widths
Factors affecting chemical shift:
1. Electronegativity, inductive and resonance effects
TMS = 0.0 CH4 = 0.23 (all in ppm)
MeI 2.2 MeOH 3.4
MeBr 2.6 MeF 4.3
MeCl 3.1 MeNO2 4.3
MeF 4.3
MeCl 3.1
CH2Cl2 5.3
CHCl3 7.2
2. Anisotropic effects:
Spherical electron density – induced magnetic field
will be uniform in space – isotropic effect
For example s –electron – spherical
Non-spherical electron density – induced magnetic
field will be non-uniform in space – anisotropic
Example: p electron cloud of aromatic ring, C=C
and C=O type – most common feature of organic
molecules
H
+
+
shielding
--deshielding
Bo
+
+
H
shielding
-deshielding
-
Bo
d 5.28
d 1.80
Diamagnetic anisotropy in ethylene and acetylene
HH
Bo
HH
+
+
-deshielding
-
Bo
d 7.28
shielding
Diamagnetic anisotropy in aromatic ring
Ring current effect
OH
+
+
shielding
--deshielding
Bo
d 9.5
Diamagnetic anisotropy in carbonyl group
Examples of effect of anisotropy on chemical shift
H H Me Me
1.031.32 1.27 0.70
H H
1.44 2.82
HH
H
7.29
-0.51H8.14-8.67
-4.2
HH
H
HH
H
H 9.3
-3.0
H
H
1.62
1.12
H
NO2
4.23
NO2
H
4.43
H
OH
3.37
OH
H
3.93
Anisotropic effect of sigma bond
CH3 – CH2 - OH
OSPh
OCH2Ph
PhCH2O
PhCH2O
PhCH2O
Solvent effect on chemical shift: (a) in CDCl3, (b) Benzene-d6
Effect of neighboring protons – spin-spin coupling
a
b
d Absence of any interacting protons
No neighboring protons
No spin-spin coupling – only a single peak for each
chemically different proton
Consider two protons Ha and Hb - neighbors
a a
a b
b a
b b
Ha Hb
no spin-spin interaction spin-spin interaction
only two transitionsone for Ha and onefor Hb
four transitions,two each for Ha andHb
Case 1 Case 2
da db
da db
Case 1
Case 2
Jab Jab
http://www.cem.msu.edu/~reusch/VirtualText/Spectrpy/nmr/nmr1.htm
http://www.cem.msu.edu/~reusch/VirtualText/Spectrpy/nmr/nmr1.htm
J spin-spin coupling constant depends on
1. Distance between the coupling partners – intervening bonds
2. Dihedral angle between the coupling partners for vicinal protons
3. Coupling constant is largest when dihedral angle is 180o
and very small when dihedral angle is 90o
4. In freely rotating bonds (like in alkyl chains) average
J values are obtained
http://www.cem.msu.edu/~reusch/VirtualText/Spectrpy/nmr/nmr2.htm#pulse
Spin – spin splitting patterns for I = ½ nucleus like 1H:
The no. of lines from coupling = (2nI+1) = (n+1) for I = ½
Where n is the number of equivalent protons that couple
C C HbHa Ha and Hb - each a doublet with Jab
C C HbHa
Hb
Ha - triplet and Hb - doublet with Jab
C C HbHa
HbHa
Ha and Hb - each triplet with Jab
CH3 - CH2 CH3 - triplet and CH2 - quartet
CH3-CH2-CH2 CH3 - triplet, CH2 - sextet, CH2 - triplet
CH3-CH-CH3 CH3 - doublet, CH-septet
Line intensities of multiplets for spin ½ nucleus
Corresponds to the coefficients of binomial expansion
Can be obtained simply from Pascal’s triangle
1
1 1
1 2 1
1 3 3 1
1 4 6 4 1
1 5 10 10 5 1
1H-NMR chemical shifts of various types of protons
http://www.cem.msu.edu/~reusch/VirtualText/Spectrpy/nmr/nmr1.htm
Magnitude of some coupling constants J in Hz
Chemically equivalent protons –
protons having same chemical environment
hence the same chemical shift (d)
Homo and enantiotopic hydrogens in organic
molecules
isochronous
Magnetically nonequivalent protons –
protons having different magnetic environment
different coupling constant with other protons
diastereotopic hydrogens in organic molecules
For two protons to show spin-spin coupling they have to be
magnetically non-equivalent. They may or may not be chemically
non-equivalent
Parameters obtainable from a 1H-NMR spectrum:
1. Chemical shift values of various protons
2. Coupling constant values from multiplets
3. Relative ratio of signal intensities – area under the peaks
proportional to the number of protons responsible for
each signal
4. Relative mole ratios of components in a mixture
CH3CH2Br
CH3COOCH2C6H5
HCOOCH2CH3
A
C4H8O
B
C4H8O2 CH3COCH2CH3
CH3COOCH2CH3
C5H7NO2 CH3CH2O CH2C
O
N
CH3-CH2-CH(Br)-COOH
C4H7O2Br
H3C CH3
CH2CH3
CH3
CH3
H3C
H
CH3
CH3
Ha and Hb are diastereotopic due to the adjacent chiral center
OH
H
O
Hb
Ha
CH3O
H
H3C H
O
O
CH3
CH3
CH3
H H
H
H3C H
H
O
H
H
H
CH3
O
O CH2CH3O
OCH3CH2
O
OCH2CH3
O
O
CH2CH3
C10H12O3
O H
O
O
CH3
H3C
5H
1H
3H
3H
CH2CH2OH
5H 2H
2H 1H
C9H11Br
5H
2H 2H
2H
CH2CH2CH2Br
C6H5NBr2
2H
1H 2H
NH2
BrBr
H
H
H
Second order spectra:
When the chemical shift values are very close and
the difference in chemical shifts are comparable to J values
one finds second order effects in the NMR spectra
Typically when (Dd)/J is less than 10, second order effects
are seen in the spectra
Unusual intensity of multiplets
More than expected number of lines in multiplets
are characteristic features of a second order spectrum
Examples of spin systems that show second order effects:
Hm
Ha Hx
R
mutually coupled amx spin system
da, dm, dx, Jam, Jax, Jmx
Ha
Hb
X
Y
R
Rmutually coupled ab spin system
da, db, Jab
X
R
Ha
Hb
Y Z
Ha'
Hb'Hb
Ha
X
Y
X
YHa Ha'
Hb Hb'
mutually coupled aa'bb' spin system
da, db, six different coupling constants
Note: Ha and Ha' are chemicallyequivalent but magnetically non-equivalent protons. similarlyHb and Hb' are.
NH3C NH2
C6H8N2
3H 2H
1H 1H 1H
Dimethyl cyclopropanedicarboxylate
Variable Temperature NMR Spectroscopy
Study of dynamic properties of molecules
Conformational changes
Restricted rotation around C-C and C-X bonds
Aggregation phenomena
Fluxional properties of molecules
Temperature range – typically -150 oC to +150 oC
provided solubility and solvent mp/bp permit
Processes with activation barrier typically in the range
of 8-25 Kcal/mole can be studied
Restricted rotation around C-N bond
In amides
H
Me
N
O
Me
H
Me
N
O
MeH
Me
N
O
Me
Activation barrier = 22 Kcal / mole
Conformational changes
Interconversion of chair
form of cyclohexane
H
H
Cyclohexane-d11
Activation barrier = 10 Kcal / mole
H
NHD2
D2
HNH
H
H
D2
D2
HH
H
HH
H
H H
H
H
H
H
HH
H
H
H
H
[18]annulene
Fluxional behaviour of
large annulenes
Bullvalene – most fluxional molecule
Synthesis: Schröder – 1963
C10H10 isomer
C3v symmetry
Degenerate Cope rearrangement [3,3]-shifts
Activation barrier = 11.8 Kcal/mole
HH
HH H
HH
H
Me MeAl
Me
Al AlMe
Me
Me
Me
Me
Me
2
13C-NMR spectroscopy
Carbon-13 nucleus is spin active wih I = ½
Hence C-13 NMR spectroscopy is possible and very useful
in organic structure elucidation
Abundance of Carbon-13 is very low, only about 1.1%
The gyromagnetic ratio of Carbon-13 is also low, it is about
1/4th of proton gyromagentic ratio
Both these factors are responsible for the poor sensitivity of
Carbon-13 NMR spectroscopy, it is about 1/(6400)th of
proton
FT-NMR technique
Two types of NMR spectrometers
Continuous wave (CW)
Fourier Transform (FT)
In CW spectrometer either the magnetic field or the
radio frequency is swept, bringing each nuclei to
resonance one at a time – signals are recorded one at a
time – hence very time consuming because each SCAN
has to be accumulated and averaged
In FT technique a short pulse of radio frequency is
applied that bring all the nuclei to resonance. The nuclei
are allowed to relax to ground state and the resulting
free induction decay is FOURIER transformed
FREE INDUCTION DECAY OF EXCITED NUCLEI - FID
Signal
intenisty
The concept of time domain-frequency domain spectroscopy – FT method
Effect of signal averaging on
S/N ratio
Carbon-13 NMR is usually recorded under conditions
of proton decoupling
That is all the C13-H1 coupling are decoupled by
irradiation (saturation) of all the protons
Therefore only a single signal is observed for each of
the chemically different carbons
From the symmetry of the structure one can easily
predict the number of signals expected for a compound
Groups like acetylene carbon, CN, CO, quaternary carbon
(no protons) are easily detected by Carbon-13 NMR
Broad band decoupling: Carbon-13 spectra are recorded with
simultanous saturation of the proton spins using a second radio
frequency corresponding to the protons. This results in complete
decoupling of the protons and only carbon peaks are seen in the spectrum.
Gated coupling: Decoupler is switched on only during the delay time
and it is off during the data acquisition.
NOE enhancement is retained and the Carbon-13 spectrum is
proton coupled
Off-resonance decoupling: Decoupling with the radio frequency
that is not exactly that of protons but few hundred hertz displaced.
Splitting only due to the protons directly attached to a carbon are seen.
CH3 – quartet, CH2 – triplet, CH – doublet, Quaternary C - singlet
Unlike proton NMR the signal intensities of Carbon-13 spectrum is
usually not quantitative.
1. The relaxation times of Carbon-13 nuclei are much longer than that of
protons.
2. Nuclear Overhauser Effect (NOE).
Relaxation mechanisms:
Spin-Lattice or Longitudinal Relaxation: (T1)
Relaxation by dispersing energy to the surroundings (lattice).
Spin-Spin or Transverse Relaxation: (T2)
Relaxation by dispersing energy to other spin active nucleus.
Nuclear Overhauser Effect:
Enhancement of signal intensities due to heteronuclear coupling
For example: Carbon-13 signal intensities are enhanced due to
irradiation (decoupling) of the protons.
The major relaxation route for Carbon-13 nucleus involves
dipolar transfer of its excitation energy to protons that are
directly attached to it (transverse relaxation).
NOE effect will be maximum for CH3, CH2, CH and none for
Quaternary carbon.
Therefore peak intensities of CH3 > CH2 > CH > C
Relaxation agents:
Paramagnetic relaxation agents such as Cr(acac)3 reduces
the longitudinal relaxation
This allows faster signal averaging
10-100 mM relaxation agent is needed – the solution takes on
a slight pink-purple hue
Net result: Signal intensities of quaternary carbons are
enhanced
O
(a) Spectrum of camphor without relaxation agent
(b) With relaxation agent, Cr(acac)3 added, under otherwise identical conditions
Chemical shift range in 13C-NMR spectrosocpy
O
O CH2CH3O
OCH3CH2
1
2
3
4 5
5 4
2,3
1
CDCl3
O
OCH2CH3
O
O
CH2CH3
1
2 3
4
5 6
6
5
2
3
4
1
NH3C NH2
CH3CH2O CH2C
O
N
Distorsionless enhancement by polarization transfer (DEPT)
2D Correlation Spectroscopy (COSY)
O
HO OH
N3
O
O
H-H COSY of 2-chlorobutane
O
AcO OAc
OHN
OO
O
OAcAcO
N3
A B
N
N
N
N
HMQC NMR of menthol
Het-2D-J resolved
2-chlorobutane
a-Pinene
References:
J. B. Lambert, H. F. Shurvell, L. Verbit, R. G. Cooks, G. H. Stout
Organic Structural Analysis
Macmillan, New York, 1976
W. Kemp
Organic Spectroscopy, 3rd Edition, Macmillan, New York, 1991
D. H. Williams, I. Fleming
Spectroscopic Methods in Organic Chemistry, 4th Edition
Tata McGraw Hill, New Delhi, 1988
R. M. Silverstein, G. C. Bassler, T. C. Morrill
Spectroscopic Identification of Organic Compounds, 5th Edition
John Wiley, New York, 1991
H. Günther
NMR Spectroscopy, 2nd Edition
John Wiley, New York, 1994
Timothy D. W. Claridge, High-Resolution NMR Techniques in Chemistry, Pergamon, 1999
John Wiley, 1998
