Pulsed NMR experiments
Introducing the Chemical Shift
Problems, Problems, Problems……

• Until the mid 1970’s all NMR spectrometers worked by shining a RF freq on sample and slowly scanning the magnetic field
• One passage took ca. 12min
• Lots of those minutes were expended on scanning through regions with only empty baseline

• Recall the thinking on Fourier Analysis
• Measure all frequencies at once (better use of time) deconvolute later
• How to do this? Hold magnet constant and irrad with a short pulse that contains all the relevant RF frequencies
• All the magnetic moments oscillating at characteristic RF freq should come into resonance (absorb energy)
• In returning to equilibrium, they should release energy, oscillating at their proper frequencies
• Oscillating magnets should induce an AC voltage in a nearby coil
• Thank you Professor R. Ernst

z
Z
M
X
RF pulse with whole range of frequencies x y
Y
Recall that this is vector resultant from individuals all oscillating around Z at
Larmor frequency
Absorbs energy
Destroys Boltzmann excess
M Still has precessional torque around z (field) axis

Z y
X
X
Y x-Pulse tips the ensemble of M down to the y axis of the x-y plane.
Another effect is to start them precessing about z at the same time point, therefore with the same phase. This is called coherence

z z z z y x z y x z y x y x y time x y x

z z
z z y x z y x z y x y x y time x y x

z z z z y x y x z y x y time x z y x And we are left to see the oscillation of the projection that remains in x,y plane x y

If we apply a second field at the same frequency, but from a different direction, the same kind of torque is experienced by I. This amounts to perturbing the population equilibrium
H
0

Induction!!!
H
0
This “perturbation” acts like any other momentum vector in the H
0 field and begins to precess about z
(what frequency?)
The secret is creation of a phase-coherence that starts off the individual vectors comprising I same phase y having the
This induced precession can be detected by contriving to have a sensing coil at right angle to H0.
Coil produces voltage at same periodicity.

• The Chem ical shift makes NMR useful in Chem istry (they named it after us)
• Arises from the electrons surrounding our nuclei, responding to a magnetic field.
• Induced circulation of electrons, Lenz’s law; this circulation generates a small magnetic field opposed to H
0
• The small negative field diminishes the H
0 experienced by a nucleus. This differentiates sites, based on chemical nature
• Effect grows directly proportional to H
0

W.G. Proctor, F.C Yu; Physical
Review , 77 , 717 (1950)
W.C. Dickinson; Physical Review , 77 ,
736 (1950)
An early example, revealing the sorting out by chemical environment, and response proportional to number of hydrogen atoms

• Bulk Susceptibility is corrected for by internal shift reference
• Shielding by electron cloud is experienced at the nucleus
• Induced circulation of electrons such that a “current flow” is set up, generating a magnetic field counter to H
0
(Lenz’s Law)
• Implies that if we know about the electron cloud distribution, we could Predict chemical shifts
• Predicts direct proportionality of the chemical shift (when expressed in Hz) to the applied field. The ppm scale normalizes out this effect. This means that a 3ppm shift on a 100 MHz instrument is
300 Hz from TMS. The same 3ppm signal on a 500 MHz instrument is 1500 Hz from TMS.

Chemical shift is the ultimate precessional frequency of the vector component of M in the plane perpendicular to H
0
H
0
(Z)
Y
 t
X
After a pulse…
H
0
(Z)
Y
X
 t
Precesses at a frequency 
This is in units of
(radians)/sec
At some time, has distinct angle and as a vector in x,y can be resolved into x, y components.
The receiver works by counting how many times this electric vector whizzes past in a unit of time

•Our vector picture can help
Rotates at  H
0
MHz
Stands Still!
Now, more than one chemical shift wil move with just a difference from  H
0
What if we could contrive to measure once every  H
0 seconds
?
Strobe effect
Is The Rotating Frame
Don’t have to distinguish
25000002 from 25000005
Hz, but 2 cf. 5
Imagine a “blinking eyeball”, (strobe effect) blinks at Larmor frequency ……

What would our “blinking eyeball” receiver in the X,Y plane see, watching this Vector over time?
Seems to “die away…
Time
The strobe effect cancels out the Larmor (MHz) frequency, leaving behind the chemical shift frequency
Because the nuclear spin is also spiraling back to the Boltzmann equilibrium, leaving less “signal” in the x,y plane. (The red vector is
“seen” by the x,y plane detector)

• The real triumph of the shift theory is in its relationship to electronegativity and hybridization and easy prediction of trends based on qualitative notions from structural theory.
• Withdrawing electron density diminishes the screening ability of the electron cloud and the nucleus goes to higher field.
• Feeding in electron density sends nucleus to lower field.
• “Moving” electrons have some real consequences on nearby chemical shifts.

10
CH=O
Acids, H-bonded OH
8 aromatic alkenyl
6
CH
2 allylic, acetylenic,  to carbonyl
CHX CHR-O
CHR-N methylene methyl
2 ppm from TMS
4 0
1 H
OH, br, variable, SH sh. ca  1.5
C=O aldehyde, ketone
C=O,
C=O, amide acid heteroaromatic
CH aromatic, alkene
CR(-O)-O
O-subs
N-subs
200 160
O-subs aromatic, alkene alkene
120
C-subs aromatic,
80 40
Alkyl
0
13 C

15
Taken from G. Levy in Concepts in Magnetic Resonance , 6 , p 338 (1994) Shifts vs. NH
3
380.4 to scale to nitromethane=0.0
(liq) Subtract
See also G.C. Levy and R.L. Lichter, “ 15 N Nuclear Magnetic Resonance Spectroscopy”, J. Wiley and Sons
(1979); also a massive collection of tabulated data in NMR: Principles and Applications 18, in the
Chemistry Library at Temple

• 13 C Shift is sensitive to branching, e.g.branched hydrocarbons
• 
Kth
Carbon =
B s
N
KP

 4
2
D
M
A
SM
 
S
N
K 3
  s
N
K 4
 number of carbons P bonds away
D
M
 number of carbons bonded to Kth carbon, with M attached carbons
S = number of carbons bonded to Kth carbon
• Sterics, electronegativity, strain, hybridization all contribute to the observed value for chemical shift

• More Reliable in 13 C
• Best used as general predictive for trends. Evaluate for consistency
• Here probably separation into resonance, inductive would help
• Changes in hybridization
• Other contributor is steric compression effect (branching?),  shielding effect

Electronegativity
Effects on 13 C
Shifts
No
Surprises
Here

• Sometimes prediction works
• Better for carbon than for proton
• Multiple substitution can lead to push-pull deviations due to resonance, etc.
• Protons have larger relative effects on them from anisotropic neighboring fields mostly because the range of the shift domain is so small.
• Best efforts are in interpolation schemes based on mapping of assigned shifts in chemical-bond space
• The good news is that relevant model compounds are really effective in predictive value

Anisotropic Shielding Near

Electrons
Shielding Region
0
H
Increases the total field felt at H by ca.
1.5 ppm
Deshielding Region
Induced Current Induced Magnetic Field
Pronounced effect for aromatic, in line with e circulation

Above, below plane shielded
+
+
Nitriles, acetylenes isonitriles
+
In plane deshielded
+
+
+
+
Carbonyl, alkene +
+
+
+
• Effects are ca. 2 ppm at most.
+
Small pos
C
O
• Most Significant when a nucleus is fixed in geometry with respect to the neighboring field.
Polarized effect
Best description is in
L.M. Jackman, S. Sternhell, Applications of Nuclear
Magnetic Resonance Spectroscopy in Organic
Chemistry, Pergamon Press, (1969) ch.2

1.27
H
O
1.67
H
O
-.7 (to higher field)
H
H
Shielding by cyclopropyl ring
Use for both assigning signals, and interpreting the structure

18-Annulene
Also for porphyrins, etc
H
0.2 ppm
-3 ppm
L.M Jackman, F Sondheimer,
A.A Bothner-By, Y. Gaoni, R.
Wolovsky, Y. Amiel, D.A. Ben-
Efraim, J Amer. Chem Soc . 84 ,
4307 (1962)
H
The shift anisotropy cone from the aromatic ring current requires a deshielding region outside and a shielding on the inside. An excellent review of the use of this probe is found in W. LeNoble, Highlights of Organic Chemistry, Marcel Dekker , (1974) ch. 9

• Here is a dramatic example
H
OH
H
 3.88
H
 0.55

• Anisotropic has shifts differ according to the angle of the molecule compared to H
0
• Solids
• Preserves all the information about the interaction
• Isotropic has motions fast enough to average the chemical shift, and remove the dependency on the angle
• Liquids
• Simple enough to understand because some information is lost
Imagine frozen cyclopentadiene. Its grid has angle w.r.t. magnetic field
Different interaction of electrons with
H
0
--Different chemical shifts!
H
0

The same average shift for the same chemical-electronic environment
Here the CH
2 s are all the same, as are all the CH next to the methylene, etc.
How do we know what “same” means?
H
0
Magnetic field

• The Chemical shift implies that we see
(potentially) a different signal for every different chemical environment.
• Chemical environment here is the electronic structure (electrons, hybridization, charge, polarizability etc.) These are all things able to be predicted to some extent by theory.
• What do we mean by “different”?

• Isochronous (same frequency)
• Only if the atoms are exchanged by any* symmetry operation for the molecule. Example C
2
, C
6
• Could be made equivalent in rapid chemical process, e.g rotation, exchange
• True always in achiral solvents
• *Atoms only exchanged by mirror plane symmetry are enantiotopic. Non-equivalent in chiral solvents
• For molecules as units, similarly, enantiomers are only distingushed with different shifts in chiral solvents.
Diastereomers, like other isomers have different shifts regardless of solvent.

Some definitions and examples…
Homotopic
Enantiotopic
Diastereotipic
H
3
C
H
3
C
H
3
C
H
OH
CH
3
CH
3
CH
3
In any solvent
In chiral solvent
In normal solvent
In any solvent
A test for enantiotopic protons or 13 C
Draw two structures, successively replacing A, then B.
If the two structures are enantiomers , then the signals will be enantiotopic .
The carbon they are attached to is termed “ prochiral ”.
Relationship Example: 2CH
3
Appearance

• Number of symmetry different positions can differ for isomeric possibilities--rule structures out
• Symmetry, Symmetry, Symmetry…..but….

H O
H
H
3
C
O
H
3
C
O
H
CH
3
These methyl groups are not chemical shift equivalent--No matter how fast they rotate, they never see the same environment

H
H
H
H
OH
OH
Ha,b are diastereotopic
C
2
H d
H
OH
H e
H and never have same chemical shift
Hc are equivalent except in chiral solvent
H c
H e a
H
H
H
OH
H
OH
H
Ring flipping only able to distinguish at low temperature (use highest symmetry)
H H
Meso
H d b
H
H
H
H
H
R,S pair
OH c
H
Ref: E. Eliel and S. Wilen,
Stereochemistry of Organic
Compounds , J. Wiley & Sons
(1994) ch. 6
R. Silverstein, G.C. Bassler, T.
Morrill, Spectrometeric
Identification of Organic
Compounds , Wiley, (3rd Ed is
1974) ch. 4

How many
13 Carbon signals would we predict for these compounds?

Two protons or carbons that are technically not exchanged by a symmetry operation can be nevertheless equivalent, if they are exchanged by a chemical process on a time scale faster than the NMR time scale.
Example, ring flipping of conformers; rotation of methyl groups.
H
H
H
H
H
H
H
O
H
H ax
H eq ax, eq. H not symmetry equivalent but you could only see the difference at low temperature
Ha
O
Hb
At room temperature, motions make it seem
“flat” with Ha, Hb at same shift.

•Imagine two signals that are chemically changing their identities.
•They have chemical shifts,  1,  2
•These shifts are also separated by a given number of Hz; (  =  1 2)
•Remember, that Hz has units of 1/sec.
•The chemical shift difference in Hz can be compared to a “chemical lifetime” or its reciprocal the reaction rate constant k . k has units of 1/sec.
•If the reaction rate k is faster than  , we can only observe a signal at the average of the two chemical shifts. Intensity will be the sum.
•We can address this experimentally by making k smaller (lower the temperature) or making  bigger (use a higher field NMR magnet)
•Practically, the relevant time scale for exchange here is 10s of msec.

A B

An irony, samples appear “colder” w.r.t. kinetics on higher field NMR systems

Tabulate
Observation or Fact Inference about Structure
Step 1.
Do we have enough Data? What questions do we need to address?
Molecular Weight (mass Spec)?
Inventory proton,carbon counts into shift categories, number of unique signals
Assess purity , can we “ignore” some signals?
From above, can we write down Molecular Formula ?
UV chromophore?

Step 2. Tabulate Obvious features
Check the IR spectrum, and 13 C NMR for Functional groups (C=O, CN, OH etc.
Mass Spectrum--Any Fragments or losses that are structurally useful? (loss of water, CO
2 tropylium, acylium present?
, CH
2
=CH
2
;
Evaluate chromophore, from UV if available
Are there obvious 1 H NMR signals by inspection ?
(methyls, methoxys, aromatics,
Evaluate exchangeable H from mass spec, or 1 H NMR
(D
2
O exchange)

Step 3. Start putting the pieces together
From the list of inferences in our table write out fragments that must be present.
Some must be at ends, some must be internal
Compare to molecular weight and deduce formula
Can we infer the presence of heteroatoms?
Compute DBE
Specify Fragments from 1 H NMR spin patterns
Recognize that some of the parts and fragments overlap or are redundant. Tabulate this
Write down trial structures . Cross check against data.
Formulate questions . (how can I exclude ….?; how could I distinguish A from B, etc. Symmetry comes in.

Step 4. Confirmatory
Exact Mass
Comparison with known structure
Literature, data bases
“Fingerprint” available?

The steps discussed frame a sort of inductive reasoning
Your knowledge of Chemistry, e.g. valence, what bonds to what, molecules you know, provide for inductive reasoning.
These two converge when you can write down a reasonable structure that agrees with all the data.