Chapter 13 - Department of Chemistry, Michigan State University

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John E. McMurry
www.cengage.com/chemistry/mcmurry
Chapter 13
St t
Structure
Determination:
D t
i ti
Nuclear Magnetic
g
Resonance Spectroscopy
Revisions by Dr. Daniel Holmes – MSU
Paul D. Adams • University of Arkansas
The Use of NMR Spectroscopy




Used to map carbon-hydrogen framework of
molecules
Used to determine relative location of atoms
within a molecule
Most helpful spectroscopic technique in organic
chemistry
h i t
Depends on very strong magnetic fields




Earth’s magnetic field is ~0.00006 Tesla
Refrigerator magnet is ~0.005 Tesla
MRI range ffrom 1.5
1 5 – 3.0
30T
Tesla
l
Largest NMR Magnet at MSU is 21.2 Tesla
The Use of NMR Spectroscopy
The Use of NMR Spectroscopy






Otto Stern, USA: Nobel Prize in Physics 1943, "for his contribution to the
development of molecular ray method and his discovery of the magnetic
moment of the proton"
Isidor I. Rabi, USA: Nobel Prize in Physics 1944, "for his resonance method
for recording the magnetic properties of atomic nuclei"
Felix Bloch, USA and Edward M. Purcell, USA: Nobel Prize in Physics
1952, "for their discovery of new methods for nuclear magnetic precision
measurements and discoveries in connection therewith"
Richard R. Ernst, Switzerland:
S
Nobel Prize in Chemistry
C
1991
1991, "for
f his
contributions to the development of the methodology of high resolution
nuclear magnetic resonance (NMR) spectroscopy
Kurt Wüthrich,
Wüthrich Switzerland: Nobel Prize in Chemistry 2002,
2002 "for
for his
development of nuclear magnetic resonance spectroscopy for determining
the three-dimensional structure of biological macromolecules in solution"
Paul C. Lauterbur, USA and Peter Mansfield, United Kingdom:
g
Nobel Prize
in Physiology or Medicine 2003, "for their discoveries concerning magnetic
resonance imaging"
Why This Chapter?

NMR is the most valuable spectroscopic
technique used for structure determination


Through-bonds and through-space
More advanced NMR techniques are used in
biological chemistry to study protein structure
and
d ffolding
ldi
Hadjuk et al. J. Am. Chem. Soc. 2000, 122, 7898
13.1 Nuclear Magnetic Resonance
Spectroscopy

1H
or 13C nuclear spins (or any NMR active nucleus like
15N,
N 31P,
P 29Si,
Si 2H,
H or 11B) will
ill align
li parallel
ll l tto or against
i t an
external magnetic field

Parallel orientation is lower in energy making this spin
state more populated

At 21
21.2
2 T (900 MHz),
MHz) the excess population is only
0.014%, which means there are only 140 spins out of a
million aligned with the field
13.1 Nuclear Magnetic Resonance
Spectroscopy


Radio energy of exactly correct frequency (resonance)
causes nuclei
l i tto fli
flip iinto
t anti-parallel
ti
ll l state
t t
Energy needed is related to molecular environment
(proportional
(p
p
to field strength,
g , B))

Frequency of transition: =-B0
13.2 The Nature of NMR
Absorptions


Electrons in bonds shield nuclei from magnetic field
Different signals appear for nuclei in different
environments
The NMR Measurement


The sample is dissolved in a solvent that does not have
a signal itself (CDCl3) and placed in a long thin tube
The tube is placed within the magnet
The NMR Measurement

A radiofrequency pulse (10-15 s) is transmitted to the
sample nuclear spins ‘flip’
sample,
flip to higher energy state if in
resonance with pulse




Nuclei relax back to equilibrium, which is detected as
microscopic
i
i voltage
lt
oscillations
ill ti
iin th
the NMR probe
b
The oscillations decay over time (Free Induction Decay or
FID)
Pulses repeated many times and data summed to get
improved Signal compared to the Noise
Fourtier Transform is used to convert the FID to a
spectrum with frequency vs. intensity
13.3 Chemical Shifts

The relative energy of resonance of a particular nucleus resulting
from its local environment is called chemical shift




Beff = Bapplied – Blocal
The more electron density around the nucleus, the greater the
g of that nucleus ((Blocal is larger)
g )
shielding
Shielded nuclei appear to the right of the NMR spectrum and are
called upfield
Deshielded nuclei appear to the left and are called downfield
13.3 Chemical Shifts



Nuclei that absorb on upfield side are strongly shielded.
Chart calibrated versus a reference point
point, set as 0
0, tetramethylsilane
[TMS]
Any difference in the electron density about a nucleus will mean a
difference in chemical shift

Electronegative atoms (e.g. Cl, O, N) will deshield a neighboring
nucleus
Measuring Chemical Shift



Numeric value of chemical shift: difference between
strength of magnetic field at which the observed nucleus
resonates and field strength for resonance of a
reference (TMS)
 Difference is very small but can be accurately
measured
 Taken as a ratio to the total field and multiplied by
06 so tthe
e sshiftt is
s in pa
parts
ts pe
per million
o (pp
(ppm))
10
Resonances normally occur downfield of TMS, to the
left on the chart
Calibrated on relative scale in delta () scale
 Independent of instrument’s field strength

500.0005 MHz and 300.0003 MHz both equal 1 ppm
13.4 13C NMR Spectroscopy:
Signal Averaging and FT-NMR





Carbon-13: only carbon isotope with a nuclear spin
 Natural
N t l abundance
b d
1
1.1%
1% off C’
C’s iin molecules
l
l
 Sample is thus very dilute in this isotope
Sample is measured using repeated accumulation of
data and averaging of signals, incorporating pulse and
the operation of Fourier transform (FT NMR)
All signals are obtained simultaneously using a
broadband excitation pulse
Frequent repeated pulses give many sets of data that
are averaged
d tto reduce
d
noise
i
Fourier-transform of averaged pulsed data gives
p
((see Figure
g
13-6))
spectrum
13.4 13C NMR Spectroscopy:
Signal Averaging and FT-NMR
13.5 Characteristics of 13C NMR
Spectroscopy


Is not quantitative when run using standard
conditions
Provides a count of the different types of
environments of carbon atoms in a molecule


Look for any type of symmetry (e.g. a symmetry
plane, a rotation axis) in the molecule you are
investigating
g
g
Any carbons that are related by symmetry will
give rise to one resonance
13.5 Predict Number of 13C
Resonances
13.5 Predict Number of 13C
Resonances
7 unique carbons
5 unique
niq e carbons
13.5 Predict Number of 13C
Resonances
13.5 Predict Number of 13C
Resonances
7 unique carbons
4 unique carbons
13.5 Predict Number of 13C
Resonances
13.5 Predict Number of 13C
Resonances
C60: Buckminsterfullerene
1 carbon resonance at 143 ppm
0 proton resonances!
13.5 Characteristics of 13C NMR
Spectroscopy





Provides a count of the different types of environments of
carbon atoms in a molecule
13C resonances are 0 to 220 ppm downfield from TMS
(Figure 13-7)
Chemical shift affected by electronegativity of nearby
atoms
 O, N, halogen decrease electron density and shielding
((“deshield”)
deshield ), moving signal downfield to the left
left.
sp3 C signal with no electronegative group is around  0
to 9; sp3 C signal with electronegative resonates between
 5 to 110; sp2 C:  110 to 220
C(=O) at low field,  160 to 220
Characteristics of 13C NMR
Spectroscopy (Continued)
 13C
chemical shift regions
Characteristics of 13C NMR
Spectroscopy (Continued)

Spectrum of 2-butanone is illustrative- signal for
C=O carbons on left edge
Characteristics of 13C NMR
Spectroscopy (Continued)

Spectrum of para-bromoacetophenone is
illustrative- signal for C=O carbons on left edge
Characteristics of 13C NMR
Spectroscopy (Continued)

Spectrum of methyl propionate
Characteristics of 13C NMR
Spectroscopy (Continued)

Spectrum of methyl propionate
2
Characteristics of 13C NMR
Spectroscopy (Continued)

Spectrum of methyl propionate
4
2
Characteristics of 13C NMR
Spectroscopy (Continued)

Spectrum of methyl propionate
1
2
4
Characteristics of 13C NMR
Spectroscopy (Continued)

Spectrum of methyl propionate
1
2
3
4
13.6 DEPT 13C NMR
Spectroscopy



Improved pulsing and computational methods
give additional information
DEPT-NMR (distortionless enhancement by
polarization transfer)
Normal spectrum shows all C’s then:



Obtain spectrum of all C’s except quaternary
(broad band decoupled)
Ch
Change
pulses
l
tto obtain
bt i separate
t iinformation
f
ti
for CH2, CH
Subtraction reveals each type (See Figure 1310)
13.6 DEPT 13C NMR
Spectroscopy
6-methyl-5-hepten-2-ol
CH’s
CH3’s
CH2’s
13.7 Uses of 13C NMR
Spectroscopy




Provides details of structure
E
Example:
l product
d t orientation
i t ti iin elimination
li i ti ffrom 1
1-chlorohl
methyl cyclohexane
Difference in symmetry of products is directly observed in the
spectrum
1-methylcyclohexene has five sp3 resonances ( 20-50) and
two sp2 resonances  100-150
13.8 1H NMR Spectroscopy and
Proton Equivalence




Proton NMR is much more sensitive than 13C and the
active nucleus (1H) is essentially 100% of the natural
abundance
Shows how many kinds of nonequivalent hydrogens are in
a compound
d
Theoretical equivalence can be predicted by seeing if
p
g each H with “X” g
gives the same or different
replacing
outcome
Equivalent H’s have the same signal while nonequivalent
are different

There are degrees of nonequivalence
Nonequivalent H’s


If replacement of each H with “X” gives a different
constitutional isomer,
Then the H’s are in constitutionally heterotopic
environments and will have different chemical
shifts – they are nonequivalent under all
circumstances
Equivalent H’s


Two H’s that are in identical environments (homotopic)
have the same NMR signal
Test by replacing each with X


if they give the identical result, they are equivalent
Protons are considered homotopic
Enantiotopic Distinctions



If H’s are in environments that are mirror images of each
other they are enantiotopic
other,
Replacement of each H with X produces a set of
enantiomers
The H’s have the same NMR signal (in the absence of
chiral materials)
Diastereotopic Distinctions



In a chiral molecule, paired hydrogens can have different
environments and different shifts
Replacement of a pro-R hydrogen with X gives a different
diastereomer than replacement of the pro-S hydrogen
Diastereotopic hydrogens are distinct chemically and
spectroscopically
Homotopic, Enantiotopic, or
Diastereotopic?
Homotopic, Enantiotopic, or
Diastereotopic?
enantiotopic
ti t i
Homotopic, Enantiotopic, or
Diastereotopic?
enantiotopic
ti t i
di t
diastereotopic
t i
Homotopic, Enantiotopic, or
Diastereotopic?
enantiotopic
ti t i
di t
diastereotopic
t i
di t
diastereotopic
t i
Homotopic, Enantiotopic, or
Diastereotopic?
enantiotopic
ti t i
diastereotopic
di t
diastereotopic
t i
di t
diastereotopic
t i
Homotopic, Enantiotopic, or
Diastereotopic?
enantiotopic
ti t i
diastereotopic
di t
diastereotopic
t i
diastereotopic
di t
diastereotopic
t i
Homotopic, Enantiotopic, or
Diastereotopic?
enantiotopic
ti t i
diastereotopic
di t
diastereotopic
t i
diastereotopic
di t
diastereotopic
t i
homotopic
13.10 Integration of 1H NMR
Absorptions: Proton Counting




The relative intensity of a signal (integrated area) is
proportional to the number of protons causing the signal
This information is used to deduce the structure
For example in ethanol (CH3CH2OH), the signals have
the integrated ratio 3:2:1
For narrow peaks, the heights are the same as the areas
and can be measured with a ruler
2,2-dimethylpropanoate
13.9 Chemical Shifts in 1H NMR
Spectroscopy

Proton signals typically range from  0 to  10

Downfield signals are H’s attached to sp2 C

 electrons in alkenes and, especially, aromatics circulate when exposed
to an external magnetic field to further deshield the protons.

Upfield signals are H’s attached to sp3 C

Electronegative atoms attached to direct C cause downfield shift
13.9 Chemical Shifts in 1H NMR
Spectroscopy
13.9 Chemical Shifts in 1H NMR
Spectroscopy
1.0
13.9 Chemical Shifts in 1H NMR
Spectroscopy
1.8
1.0
13.9 Chemical Shifts in 1H NMR
Spectroscopy
1.8
61
6.1
1.0
13.9 Chemical Shifts in 1H NMR
Spectroscopy
63
6.3
1.8
61
6.1
1.0
13.9 Chemical Shifts in 1H NMR
Spectroscopy
72
7.2
63
6.3
1.8
61
6.1
1.0
13.9 Chemical Shifts in 1H NMR
Spectroscopy
72
7.2
63
6.3
1.8
6.8
61
6.1
1.0
13.9 Chemical Shifts in 1H NMR
Spectroscopy
72
7.2
63
6.3
1.8
6.8
61
6.1
3.8
1.0
13.9 Chemical Shifts in 1H NMR
Spectroscopy
13.11 Spin-Spin Splitting in 1H
NMR Spectra

Peaks are often split into multiple peaks due to
interactions between nonequivalent protons on adjacent
carbons, called spin-spin splitting




This is a through-bond interaction and transmitted via the
b di electrons
bonding
l t
The splitting will be one more peak than the number of H’s
on the adjacent carbon (“n+1 rule”)
The relative intensities are in proportion to a binomial
distribution (Pascal’s Triangle) and are due to interactions
between nuclear spins
p
that can have two p
possible
alignments with respect to the magnetic field
The set of peaks is a multiplet (2 = doublet, 3 = triplet, 4 =
quartet)
Simple Spin-Spin Splitting




An adjacent CH3 group
can have four different
spin alignments as
1:3:3:1
This gives peaks in ratio
of the adjacent H signal
An adjacent CH2 gives a
ratio of 1:2:1
The separation of peaks
i a multiplet
lti l t iis measured
d
in
and is a constant, in Hz

J (coupling constant)
Rules for Spin-Spin Splitting



Equivalent protons do not split each other
The signal of a proton with n equivalent
neighboring H’s is split into n + 1 peaks
Protons that are farther than two
t o carbon atoms
apart do not split each other
13.12 More Complex Spin-Spin
Splitting Patterns


Spectra can be more complex due to overlapping
signals, multiple nonequivalence
Example: trans-cinnamaldehyde
13.12 More Complex Spin-Spin
Splitting Patterns
13.12 More Complex Spin-Spin
Splitting Patterns
H
J = 16 Hz
6.1 ppm
13.12 More Complex Spin-Spin
Splitting Patterns
H
J = 16 Hz
J = 7 Hz
6 1 ppm
6.1
13.12 More Complex Spin-Spin
Splitting Patterns
H
J = 16 Hz
J = 7 Hz
6 1 ppm
6.1
13.13 Uses of 1H NMR
Spectroscopy


The technique is used
y likely
y
to identify
products in the
laboratory quickly and
easily
Example:
regiochemistry of
hydroboration/oxidation
of methylenecyclohexane
13.13 Uses of 1H NMR
Spectroscopy


The technique is used
y likely
y
to identify
products in the
laboratory quickly and
easily
Example:
regiochemistry of
hydroboration/oxidation
of methylenecyclohexane
13.13 Uses of 1H NMR
Spectroscopy



The technique is used
y likely
y
to identify
products in the
laboratory quickly and
easily
Example:
regiochemistry of
hydroboration/oxidation
of methylenecyclohexane
Only that for
cyclohexylmethanol is
observed
X
13.13 Uses of 1H NMR
Spectroscopy

Could we have used 13C to find the answer?
13.13 Uses of 1H NMR
Spectroscopy

Could we have used 13C to find the answer?

Not without running a DEPT (the CH3 would be distinctive)
Let’s Work Some Problems
Predict the splitting pattern
Let’s Work Some Problems
Predict the splitting pattern
CHBr2CH3
CHBr2CH3
Let’s Work Some Problems
Predict the splitting pattern
Let’s Work Some Problems
Predict the splitting pattern
CH3OCH2CH2Br
CH3OCH2CH2Br
CH3OCH2CH2Br
Let’s Work Some Problems
Predict the splitting pattern
Let’s Work Some Problems
Predict the splitting pattern
ClCH2CH2CH2Cl
ClCH2CH2CH2Cl
Let’s Work Some Problems
Predict the splitting pattern
Let’s Work Some Problems
Predict the splitting pattern
(Red is split by Blue)
Let’s Work Some Problems
Predict the splitting pattern
Let’s Work Some Problems
Predict the splitting pattern
(Red is split by Blue)
Let’s Work Some Problems
Predict the splitting pattern
Let’s Work Some Problems
Predict the splitting pattern
Let’s Work Some Problems
How would you distinguish between these isomers?
Let’s Work Some Problems
How would you distinguish between these isomers?


The compound on the left has two vinylic
protons with chemical shifts around 5-6 ppm; the
one on the right will not.
The compound on the right will not have
protons above 1.5 ppm.
Let’s Work Some Problems
How would you distinguish between these isomers?
Let’s Work Some Problems
How would you distinguish between these isomers?


The compound on the left,
left diethyl ether
ether, has two
proton resonances: a quartet and a triplet.
The compound on the right, methoxypropane,
has at 4 proton resonances: a singlet, a triplet, a
multiplet, and another triplet.
Let’s Work Some Problems
How would you distinguish between these isomers
Let’s Work Some Problems
How would you distinguish between these isomers?

Both compounds will have three proton
resonances with the same splitting pattern:
singlet, quartet, and a triplet.

The CH2 group of the left compound, ethyl
acetate, will have a chemical shift around 4 ppm,
while the CH2 group of right compound,
compound 2butanone, will be around 2.2 ppm.
Let’s Work Some Problems
How would you distinguish between these isomers?
Let’s Work Some Problems
How would you distinguish between these isomers?

Each compound will have 4 proton peaks


The left
f compound will have two methyl singlets
The right compound will have a methyl singlet
and a methyl doublet
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