NMR

1
HL Chemistry - Option A Modern Analytical
Chemistry
NUCLEAR MAGNETIC RESONANCE
2
Different Types of NMR

• Electron Spin Resonance (ESR)
• 1-10 GHz (frequency) used in analyzing free
  radicals (unpaired electrons)
• Magnetic Resonance Imaging (MRI)
• 50-300 MHz (frequency) for diagnostic imaging of
  soft tissues (water detection)
• NMR Spectroscopy (MRS)
• 300-900 MHz (frequency) primarily used for
  compound ID and characterization

3
NMR in Everyday Life
Magnetic Resonance Imaging
4
NMR Spectroscopy
5
Explaining NMR
UV/Vis spectroscopy
Sample
6
Explaining NMR
7
Principles of NMR

• Measures nuclear magnetism or changes in nuclear
  magnetism in a molecule
• NMR spectroscopy measures the absorption of light
  (radio waves) due to changes in nuclear spin
  orientation
• NMR only occurs when a sample is in a strong
  magnetic field
• Different nuclei absorb at different energies
  (frequencies)

8
Bigger Magnets are Better
Increasing magnetic field strength
low frequency high frequency
9
Different Isotopes Absorb at Different Frequencies
2H
15N
13C
19F
1H
30 MHz 50 MHz 125 MHz 480 MHz
500 MHz
low frequency high frequency
10
Which Elements or Molecules are NMR Active?

• Any atom or element with an odd number of
  neutrons and/or an odd number of protons
• Any molecule with NMR active atoms
• 1H - 1 proton, no neutrons, AW 1
• 13C - 6 protons, 7 neutrons, AW 13
• 15N - 7 protons, 8 neutrons, AW 15
• 19F 9 protons, 10 neutrons, AW 19

11
NUCLEAR SPIN
The nuclei of some atoms have a property called
SPIN.
These nuclei behave as if they were spinning.
.. we dont know if they actually do spin!
This is like the spin property of an electron,
which can have two spins 1/2 and -1/2 .
Each spin-active nucleus has a number of spins
defined by its spin quantum number, I.
The spin quantum numbers of some common nuclei
follow ..
12
Spin Quantum Numbers of Some Common Nuclei
The most abundant isotopes of C and O do not have
spin.
Element 1H 2H 12C 13C 14N 16O 17O 19F Nuclear
Spin Quantum No 1/2 1 0 1/2 1 0 5/2
1/2 ( I ) No. of Spin 2 3 0 2
3 0 6 2 States
Elements with either odd mass or odd atomic
number have the property of nuclear spin.
The number of spin states is 2I 1,
where I is the spin quantum
number.
13
THE PROTON
Although interest is increasing in other
nuclei, particulary C-13, the hydrogen nucleus
(proton) is studied most frequently, and we will
devote our attention to it first.
14
NUCLEAR SPIN STATES - HYDROGEN NUCLEUS
The spin of the positively charged nucleus
generates a magnetic moment vector, m.
m


The two states are equivalent in energy in
the absence of a magnetic or an electric field.
m
1/2
- 1/2
TWO SPIN STATES
15
THE RESONANCE PHENOMENON
absorption of energy by the spinning
nucleus
16
Nuclear Spin Energy Levels
N
-1/2
unaligned
In a strong magnetic field (Bo) the two spin
states differ in energy.
1/2
aligned
Bo
S
17
Absorption of Energy
quantized
Opposed
-1/2
-1/2
DE
DE hn
Radiofrequency
1/2
1/2
Applied Field
Bo
Aligned
18
THE ENERGY SEPARATION DEPENDS ON Bo
- 1/2
kBo hn
DE
degenerate at Bo 0
1/2
Bo
increasing magnetic field strength
19
The Larmor Equation!!!
DE kBo hn can be transformed into
gyromagnetic ratio g
g n 2p
gB0 n 2p
frequency of the incoming radiation that will
cause a transition
Bo
strength of the magnetic field
g is a constant which is different for each
atomic nucleus (H, C, N, etc)
20
A SECOND EFFECT OF A STRONG MAGNETIC FIELD
WHEN A SPIN-ACTIVE HYDROGEN ATOM IS PLACED IN A
STRONG MAGNETIC FIELD
.. IT BEGINS TO PRECESS (that means spin)
OPERATION OF AN NMR SPECTROMETER DEPENDS ON THIS
RESULT
21
N
w
Nuclei precess at frequency w when placed in a
strong magnetic field.
RADIOFREQUENCY 40 - 600 MHz
hn
NUCLEAR MAGNETIC RESONANCE
If n w then energy will be absorbed and the
spin will invert.
NMR
S
22
Resonance Frequencies of Selected Nuclei
Isotope Abundance Bo (Tesla)
Frequency(MHz) g(radians/Tesla)
1H 99.98 1.00 42.6 267.53 1.41
60.0 2.35 100.0 7.05 300.0 2H 0.0156 1
.00 6.5 41.1 7.05 45.8 13C
1.108 1.00 10.7 67.28 2.35
25.0 7.05 75.0 19F 100.0 1.00 40.0
251.7
41
23
POPULATION AND SIGNAL STRENGTH

• The strength of the NMR signal depends on the
  Population Difference of the two spin states

Radiation induces both upward
and downward transitions.
induced emission
resonance
For a net positive signal there must be an
excess of spins in the lower state.
excess population
Saturation equal populations no signal
24
Typical 1H NMR Spectrum
25
CLASSICAL INSTRUMENTATION
typical before 1960
field is scanned
26
Continuous-Wave NMR
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NMR Magnet
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NMR Magnet Cross-Section
Sample Bore
Cryogens
Magnet Coil
Magnet Legs
Probe
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A Simplified 60 MHzNMR Spectrometer
hn
RF (60 MHz) Oscillator
RF Detector
absorption signal
Recorder
Transmitter
Receiver
MAGNET
MAGNET
1.41 Tesla (/-) a few ppm
S
N
Probe
30
Fortunately, different types of protons precess
at different rates in the same magnetic field.
Bo 1.41 Tesla
N
59.999995 MHz
EXAMPLE
59.999700 MHz
To cause absorption of the incoming 60 MHz the
magnetic field strength, Bo , must be increased
to a different value for each type of proton.
59.999820 MHz
60 MHz
S
Differences are very small, in the parts per
million range.
31
IN THE CLASSICAL NMR EXPERIMENT THE INSTRUMENT
SCANS FROM LOW FIELD TO HIGH FIELD
HIGH FIELD
LOW FIELD
NMR CHART
increasing Bo
UPFIELD
DOWNFIELD
scan
32
NMR Spectrum of Phenylacetone
NOTICE THAT EACH DIFFERENT TYPE OF PROTON COMES
AT A DIFFERENT PLACE - YOU CAN TELL HOW MANY
DIFFERENT TYPES OF HYDROGEN THERE ARE
33
MODERN INSTRUMENTATION
PULSED FOURIER TRANSFORM TECHNOLOGY
FT-NMR
requires a computer
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FT-NMR
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A Modern NMR Instrument
Radio Wave Transceiver
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An NMR Probe
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NMR Sample Probe Coil
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PULSED EXCITATION
N
n2
n1
BROADBAND RF PULSE
contains a range of frequencies
n3
(n1 ..... nn)
S
All types of hydrogen are excited simultaneously
with the single RF pulse.
39
FREE INDUCTION DECAY
( relaxation )
n1
n2
n3
n1, n2, n3 have different half lifes
40
COMPOSITE FID
time domain spectrum
n1 n2 n3 ......
time
41
FOURIER TRANSFORM
A mathematical technique that resolves a
complex FID signal into the individual
frequencies that add together to make it.
( Details not given here. )
DOMAINS ARE MATHEMATICAL TERMS
converted to
TIME DOMAIN
FREQUENCY DOMAIN
FID
NMR SPECTRUM
FT-NMR
computer
n1 n2 n3 ......
COMPLEX SIGNAL
Fourier Transform
individual frequencies
a mixture of frequencies decaying (with time)
converted to a spectrum
42
The Composite FID is Transformed into a classical
NMR Spectrum
frequency domain spectrum
43
Fourier Transformation
iwt
F(w) f(t)e dt
Converts from units of time to units of frequency
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FT NMR
Free Induction Decay
FT
NMR spectrum
45
COMPARISON OF CW AND FT TECHNIQUES
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CONTINUOUS WAVE (CW) METHOD
THE OLDER, CLASSICAL METHOD
The magnetic field is scanned from a low field
strength to a higher field strength while a
constant beam of radiofrequency (continuous wave)
is supplied at a fixed frequency (say 100 MHz).
Using this method, it requires several minutes to
plot an NMR spectrum.
SLOW, HIGH NOISE LEVEL
47
PULSED FOURIER TRANSFORM (FT)
METHOD
FAST LOW NOISE
THE NEWER COMPUTER-BASED METHOD
Most protons relax (decay) from their excited
states very quickly (within a second).
The excitation pulse, the data collection (FID),
and the computer-driven Fourier Transform (FT)
take only a few seconds.
The pulse and data collection cycles may be
repeated every few seconds.
Many repetitions can be performed in a very short
time, leading to improved signal ..
48
IMPROVED SIGNAL-TO-NOISE RATIO
By adding the signals from many pulses together,
the signal strength may be increased above the
noise level.
signal
enhanced signal
noise
1st pulse
2nd pulse
add many pulses
noise is random and cancels out
etc.
nth pulse
49
INTEGRATION
50
NMR Spectrum of Phenylacetone
Each different type of proton comes at a
different place . You can tell how many different
types of hydrogen there are in the molecule.
51
INTEGRATION OF A PEAK
Not only does each different type of hydrogen
give a distinct peak in the NMR spectrum, but we
can also tell the relative numbers of each type
of hydrogen by a process called integration.
Integration determination of the area
under a peak
The area under a peak is proportional to the
number of hydrogens that generate the peak.
52
Benzyl Acetate
The integral line rises an amount proportional to
the number of H in each peak
METHOD 1
integral line
integral line
simplest ratio of the heights
55 22 33 5 2 3
53
Benzyl Acetate (FT-NMR)
Actually 5
2 3
33.929 / 11.3 3.00
21.215 / 11.3 1.90
58.117 / 11.3 5.14
METHOD 2
assume CH3 33.929 / 3 11.3
digital integration
Integrals are good to about 10 accuracy.
Modern instruments report the integral as a
number.
54
DIAMAGNETIC ANISOTROPY
SHIELDING BY VALENCE ELECTRONS
55
Diamagnetic Anisotropy
The applied field induces circulation of the
valence electrons - this generates a magnetic
field that opposes the applied field.
valence electrons shield the nucleus from the
full effect of the applied field
magnetic field lines
B induced (opposes Bo)
fields subtract at nucleus
56
PROTONS DIFFER IN THEIR SHIELDING
All different types of protons in a molecule have
a different amounts of shielding.
They all respond differently to the applied
magnetic field and appear at different places in
the spectrum.
This is why an NMR spectrum contains useful
information (different types of protons appear in
predictable places).
57
CHEMICAL SHIFT
58
PEAKS ARE MEASURED RELATIVE TO TMS
Rather than measure the exact resonance position
of a peak, we measure how far downfield it is
shifted from TMS.
reference compound
tetramethylsilane TMS
Highly shielded protons appear way upfield.
TMS
Chemists originally thought no other compound
would come at a higher field than TMS.
shift in Hz
downfield
0
n
59
REMEMBER FROM OUR EARLIER DISCUSSION
Stronger magnetic fields (Bo) cause the
instrument to operate at higher frequencies (n).
field strength
frequency
hn Bo
NMR Field Strength
1H Operating Frequency
constants
60 Mhz
1.41 T
100 MHz
2.35 T
n ( K) Bo
300 MHz
7.05 T
60
HIGHER FREQUENCIES GIVE LARGER SHIFTS
The shift observed for a given proton in Hz also
depends on the frequency of the instrument used.
Higher frequencies larger shifts in Hz.
TMS
shift in Hz
downfield
0
n
61
THE CHEMICAL SHIFT
The shifts from TMS in Hz are bigger in higher
field instruments (300 MHz, 500 MHz) than they
are in the lower field instruments (60 MHz, 100
MHz).
We can adjust the shift to a field-independent
value, the chemical shift in the following way
parts per million
shift in Hz
chemical shift
d
ppm
spectrometer frequency in MHz
This division gives a number independent of the
instrument used.
A particular proton in a given molecule will
always come at the same chemical shift (constant
value).
62
HERZ EQUIVALENCE OF 1 PPM
What does a ppm represent?
1 part per million of n MHz is n Hz
Hz Equivalent of 1 ppm
1H Operating Frequency
1
(
)
n MHz n Hz
60 Mhz 60 Hz
106
100 MHz 100 Hz
300 MHz 300 Hz
ppm
0
1
2
3
4
5
6
7
Each ppm unit represents either a 1 ppm change in
Bo (magnetic field strength, Tesla) or a 1
ppm change in the precessional frequency (MHz).
63
NMR Correlation Chart
-OH
-NH
DOWNFIELD
UPFIELD
DESHIELDED
SHIELDED
CHCl3 ,
TMS
d (ppm)
12
11
10
9
8
7
6
5
4
3
2
1
0
H
CH2Ar CH2NR2 CH2S C C-H CC-CH2 CH2-C-
CH2F CH2Cl CH2Br CH2I CH2O CH2NO2
C-CH-C
RCOOH
RCHO
CC
C
C-CH2-C C-CH3
O
Ranges can be defined for different general types
of protons. This chart is general, the next slide
is more definite.
64
APPROXIMATE CHEMICAL SHIFT RANGES (ppm) FOR
SELECTED TYPES OF PROTONS
R-CH3 0.7 - 1.3
R-N-C-H 2.2 - 2.9
R-CC-H
R-CH2-R 1.2 - 1.4
4.5 - 6.5
R-S-C-H 2.0 - 3.0
R3CH 1.4 - 1.7
I-C-H 2.0 - 4.0
H
R-CC-C-H 1.6 - 2.6
Br-C-H 2.7 - 4.1
6.5 - 8.0
Cl-C-H 3.1 - 4.1
R-C-C-H 2.1 - 2.4
R-C-N-H
RO-C-H 3.2 - 3.8
5.0 - 9.0
RO-C-C-H 2.1 - 2.5
HO-C-H 3.2 - 3.8
R-C-H
HO-C-C-H 2.1 - 2.5
9.0 - 10.0
R-C-O-C-H 3.5 - 4.8
N C-C-H 2.1 - 3.0
O2N-C-H 4.1 - 4.3
R-C-O-H
R-C C-C-H 2.1 - 3.0
11.0 - 12.0
F-C-H 4.2 - 4.8
C-H 2.3 - 2.7
R-N-H 0.5 - 4.0 Ar-N-H 3.0 - 5.0 R-S-H
R-O-H 0.5 - 5.0 Ar-O-H 4.0 - 7.0
1.0 - 4.0
R-C C-H 1.7 - 2.7
65
Characteristic Chemical Shifts
66
YOU DO NOT NEED TO MEMORIZE THE PREVIOUS CHART!
IT IS USUALLY SUFFICIENT TO KNOW WHAT TYPES OF
HYDROGENS COME IN SELECTED AREAS OF THE NMR CHART
C-H where C is attached to an electronega-tive
atom
CH on C next to pi bonds
aliphatic C-H
alkene C-H
benzene CH
aldehyde CHO
acid COOH
XC-C-H
X-C-H
2
3
4
6
7
9
10
12
0
MOST SPECTRA CAN BE INTERPRETED WITH A KNOWLEDGE
OF WHAT IS SHOWN HERE
67
DESHIELDING AND ANISOTROPY
Three major factors account for the resonance
positions (on the ppm scale) of most protons.
1. Deshielding by electronegative elements.
2. Anisotropic fields usually due to pi-bonded
electrons in the molecule.
3. Deshielding due to hydrogen bonding.
We will discuss these factors in the sections
that follow.
68
Chemical Shifts

• Key to the utility of NMR in chemistry
• Different 1H in different molecules exhibit
  different absorption frequencies
• Arise from the electron cloud effects of nearby
  atoms or bonds, which act as little magnets to
  shift absorption n up or down
• Mostly affected by electronegativity of
  neighbouring atoms or groups

69
Spin-Spin Coupling

• Many 1H NMR spectra exhibit peak splitting
  (doublets, triplets, quartets)
• This splitting arises from adjacent hydrogens
  (protons) which cause the absorption frequencies
  of the observed 1H to jump to different levels
• These energy jumps are quantized and the number
  of levels or splittings n 1 where n is the
  number of nearby 1Hs

70
1H NMR Spectra Exhibit...

• Chemical Shifts (peaks at different frequencies
  or ppm values)
• Splitting Patterns (from spin coupling)
• Different Peak Intensities ( 1H)

71
Spin-Spin Coupling
H
H
H
H
C - Y
C - CH
C - CH2
C - CH3
J
singlet doublet triplet
quartet
72
Spin Coupling Intensities
1 1 1 1 2 1 1 3 3 1 1 4 6 4 1 1 5 10 10 5 1
3 3
2
1 1
1 1
1 1
Pascals Triangle
73
NMR Peak Intensities
Y
Y
Y

C - CH
C - CH2
C - CH3
AUC 1 AUC 2 AUC 3
74
DESHIELDING BY ELECTRONEGATIVE ELEMENTS
75
NMR Units of Measurement

• Energies 10-6 eV
• Wavelength 30 cm - 100 cm
• Frequency 108 - 109 Hz
• Parts per million (d) 0 - 12 ppm (for 1H)

nobs - nref
x 106
ppm
nref
ppm is proportional to frequency
76
DESHIELDING BY AN ELECTRONEGATIVE ELEMENT
d-
d
Chlorine deshields the proton, that is, it
takes valence electron density away from carbon,
which in turn takes more density from hydrogen
deshielding the proton.
C
H
Cl
d-
d
electronegative element
NMR CHART
highly shielded protons appear at high field
deshielded protons appear at low field
deshielding moves proton resonance to lower field
77
Electronegativity Dependence of Chemical Shift
Dependence of the Chemical Shift of CH3X on the
Element X
Compound CH3X
CH3F CH3OH CH3Cl CH3Br CH3I CH4
(CH3)4Si
Element X
F O Cl Br
I H Si
Electronegativity of X
4.0 3.5 3.1 2.8
2.5 2.1 1.8
Chemical shift d
4.26 3.40 3.05 2.68
2.16 0.23 0
most deshielded
TMS
deshielding increases with the electronegativity
of atom X
78
Substitution Effects on Chemical Shift
most deshielded
The effect increases with greater numbers of
electronegative atoms.
CHCl3 CH2Cl2 CH3Cl
7.27 5.30 3.05 ppm
most deshielded
-CH2-Br -CH2-CH2Br -CH2-CH2CH2Br
3.30 1.69 1.25
ppm
The effect decreases with incresing distance.
79
ANISOTROPIC FIELDS
DUE TO THE PRESENCE OF PI BONDS
The presence of a nearby pi bond or pi system
greatly affects the chemical shift.
Benzene rings have the greatest effect.
80
fields add together
81
ANISOTROPIC FIELD IN AN ALKENE
protons are deshielded
H
H
Deshielded
shifted downfield
fields add
CC
H
H
secondary magnetic (anisotropic) field lines
Bo
82
ANISOTROPIC FIELD FOR AN ALKYNE
H
C
C
H
secondary magnetic (anisotropic) field
Shielded
hydrogens are shielded
Bo
fields subtract
83
HYDROGEN BONDING
84
HYDROGEN BONDING DESHIELDS PROTONS
The chemical shift depends on how much hydrogen
bonding is taking place.
Alcohols vary in chemical shift from 0.5 ppm
(free OH) to about 5.0 ppm (lots of H bonding).
Hydrogen bonding lengthens the O-H bond and
reduces the valence electron density around the
proton - it is deshielded and shifted
downfield in the NMR spectrum.
85
SOME MORE EXTREME EXAMPLES
Carboxylic acids have strong hydrogen bonding -
they form dimers.
With carboxylic acids the O-H absorptions are
found between 10 and 12 ppm very far downfield.
In methyl salicylate, which has strong internal
hydrogen bonding, the NMR absortion for O-H is at
about 14 ppm, way, way downfield.
Notice that a 6-membered ring is formed.
86
Applications

• Determination of exact structure of drugs and
  drug metabolites - MOST POWERFUL METHOD KNOWN
• Detection/quantitation of impurities
• Detection of enantiomers (shift reagents)
• High throughput drug screening
• Analysis/deconvolution of liquid mixtures
• Water content measurement

87
NMR vs. IR

• NMR has narrower peaks relative to IR
• NMR yields far more information than IR
• NMR allows you to collect data on solids
  liquids but NOT gases
• NMR is more quantitative than IR or UV
• NMR samples are easier to prepare
• NMR is much less sensitive than IR or UV
• NMR spectrometers are very expensive

88
IR vs. NMR
Absorbance