Document Text Contents
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Essential Practical NMR for
Organic Chemistry
i
Essential Practical NMR for Organic Chemistry S. A. Richards and J. C. Hollerton
© 2011 John Wiley & Sons, Ltd. ISBN: 978-0-470-71092-0
Page 2
P1: OTE/OTE/SPH P2: OTE
fm JWST025-Richards October 7, 2010 7:16 Printer: Yet to come
Essential Practical NMR for
Organic Chemistry
S. A. RICHARDS
AND
J. C. HOLLERTON
A John Wiley and Sons, Ltd., Publication
iii
Page 108
P1: JYS
c07 JWST025-Richards October 2, 2010 18:41 Printer: Yet to come
Further Elucidation Techniques – Part 1 103
R
O
CH3
R
OH
CH3
Structure 7.1 Keto-enol exchange.
Remember that any proton which is acidic enough is prone to undergo deuterium exchange. Methylene
protons alpha to a carbonyl for example, may exchange if left standing with D2O for any length of time,
as they can exchange via the keto-enol route (i.e., Structure 7.1).
Note that deuterium exchange of the -OH leads to incorporation of deuterium alpha to the carbonyl
in the ketone form. This may happen, even if there is no evidence of any enol signals in the spectrum
initially, i.e., it can occur even when the equilibrium is heavily in favour of the ketone. Aromatic protons
of rings which bear two or more -OH groups are also prone to undergo slow exchange, as are nitrovinyl
protons.
7.3 Basification and Acidification
This topic has been dealt with quite extensively in Section 6.6.6 so we won’t go over the material again
but there is perhaps one other type of problem that may be worth looking at with a view to solving by a
change of pH. Consider the two structures in Structure 7.2.
Whilst the preferred method of differentiating these structures would be by an NOE experiment, it
would be possible to accomplish this by running them in DMSO and then adding a drop of base to each
solution and re-running. (Note: DMSO is the preferred solvent for this experiment as both the neutral
and the charged species would be soluble in it.) In both cases, the phenoxide ion (Ar-O−) would be
formed and the extra electron density generated on the oxygen would feed into the ring and cause a
significan upfiel shift of about 0.3–0.4 ppm in any protons ortho- or para- to the hydroxyl group. In
the example above, the compound on the left would show such an upfiel shift for only a single doublet
(a), whilst the compound on the right would show an analogous upfiel shift for both a narrow doublet
(b) and a doublet of doublets (c).
Caution should be exercised if attempting any determination of this type as it is not the preferred
method and it is always safest if both compounds to be distinguished are available for study in this way.
OH
O
CH3
CH3
O
OH
CH3
CH3
bc
a
Structure 7.2 Compounds which show one or two upfield shifts.
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104 Essential Practical NMR for Organic Chemistry
7.4 Changing Solvents
If a signal of particular interest to you, is obscured by other signals in the spectrum, it is often worth
changing solvent – you might be lucky, and fin that your signal (or the obscuring signals) move
sufficientl to allow you to observe it clearly. You might equally well be unlucky of course, but it’s worth
a try.
Running a sample in an anisotropic solvent like D6-benzene or D5-pyridine, can bring about some
even more dramatic changes in chemical shifts. We tend to use benzene in a fairly arbitrary fashion, but
in some cases, there is a certain empirical basis for the upfiel and downfiel shifts we observe.
For example, benzene forms collision-complexes with carbonyl groups, ‘sitting’ above and below the
group, sandwich-style. When the carbonyl is held rigidly within the molecule, either because it forms
part of a rigid system, or because of conjugation, we can generally expect protons on the oxygen side of a
line drawn through the carbon of the carbonyl, and at right angles to the carbonyl bond to be deshielded.
Conversely, those on the other side of the line are shielded.
7.5 Trifluoroacetylation
This is quite a useful technique which can give a rapid, positive identificatio of -OH, -NH2, and -NHR
groups in cases where deuteration would be of little value. Even though the technique can be a little
time-consuming and labour-intensive in terms of sample preparation, it can nonetheless yield results in
less time than it would take to acquire definit ve 13C data – particularly if your material is limited.
Consider Spectrum 7.3. The bottom trace shows the ordinary spectrum of cyclohexanol, run in CDCl3.
Distinguishing it from chlorocyclohexane is not easy (without the use of 13C NMR) – the chemical shift
of the proton alpha to the functional group would be similar in both compounds, and in the case of the
alcohol, the -OH need not show coupling to it. Furthermore, in problems of this type, the -OH proton
itself may well be obscured by the rest of the alkyl signals or combined with the solvent water peak.
Integration of the alkyl multiplet before and after deuteration will not necessarily be very reliable, since
looking for 1 proton in a multiplet of 10 or 11, will give only a relatively small change in integral
intensity (and let us not forget that water in the CDCl3 which will absorb in this region, along with any
water that may be residual in the compound).
The top trace shows what happens when the sample is shaken for a few seconds with a few drops of
TFAA. The reaction shown in Structure 7.3 occurs.
The resultant spectrum is clearly very different from the alcohol, as the trifluoroaceti ester function
is far more deshielding with respect to the alpha proton than is the -OH group. A downfiel shift of
>1 ppm can be seen. This clearly distinguishes the alcohol from the analogous chloro compound which
would of course give no reaction.
This is a relatively quick and convenient technique, the reagent reacting quite readily (assuming no
great steric hindrance of course) with alcohols, primary and secondary amines. (Note the possibility of
complication if you react a secondary amine with TFAA – it will yield a tertiary amide!) If the reaction
is a little slow, as is often the case with phenolic -OH groups, you can ‘speed it up a little’ by gentle
warming, more shaking, and even adding a drop of D5-pyridine to base-catalyse the reaction.
Use of this reagent is however, somewhat limited. You can only use it in solvents which don’t
react with it (D4-methanol, and D2O are obviously out of the question), or contain a lot of water, i.e.,
D6-DMSO. Another slight drawback is that the cleaving of the anhydride liberates trifluoroaceti acid,
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Index 215
radical scavengers 21
referencing see spectrum referencing
relative quantificatio 157–8
relaxation delays 27, 39, 160–1
residual solvent signals 15–16, 18
restricted rotation 78–82
ROESY see rotating frame Overhauser effect
spectroscopy
roofin 52–3, 55, 67, 95
room temperature (RT) shims 28
rotameric forms 78–82
rotating frame Overhauser effect spectroscopy (ROESY)
116, 123–4, 149, 179, 186–7, 195, 198, 201, 204
RT see room temperature
safety issues 163–6
cryogens 165–6
magnetic field 163–5
sample-related injuries 166
salts 96–100, 173, 196–7
sample depth 18–19
sample preparation 11–21
contamination 20
filtratio 19–21
magnetic fiel homogeneity 11, 18–20
mixed solvents 17
number of transients 12–13
quantities of sample 12–13
residual solvent signals 15–16, 18
sample depth 18–19
solvents 13–18
spectrum referencing 17–18
sample-related injuries 166
selective population transfer (SPT) 119–20, 125
semi-empirical prediction 171
sensitivity of NMR technique 1–2, 3
13C NMR spectroscopy 127–8, 133
high performance liquid chromatography 143–4
quantities of sample 12–13
spinning of samples 31
see also signal-to-noise ratio
shielding substituents 52–3
shimming
high performance liquid chromatography 143–4
interpretation of spectra 83–4, 91
spectrum acquisition 18, 28–30
29Si-H couplings 91–2
signal-to-noise ratio (SNR) 1–2, 3, 10
13C NMR spectroscopy 127–8, 134, 136
instrumental elucidation 115
number of transients 12–13, 23–4
quantities of sample 12–13
sample depth 18
simulation software 171–2
sinc function 25–6
117/119Sn-H couplings 91
SNR see signal-to-noise ratio
software tools 167–72
acquisition software 167
13C NMR spectroscopy 169–70
1H NMR spectroscopy 170–1
prediction software 168–71
processing software 167–8
simulation software 171–2
structural elucidation software 172
structural verificatio software 172
solvent suppression 145
solvents
chemical elucidation 104, 109
interpretation of spectra 44–6, 81
mixed solvents 17
residual signals 15–16, 18
sample preparation 13–18
spectrum referencing 17–18
spectral interpretation see interpretation of spectra
spectral width 25
spectrum acquisition 23–31
acquisition time 25
frequency locks 30–1
number of increments 27–8
number of points 24
number of transients 23–4
pulse width/pulse angle 25–7
relaxation delay 27
shimming 28–30
spectral width 25
spinning 31
tuning and matching 30
spectrum referencing 17–18, 39, 128–9
spin choreography 4
spin decoupling 111–12
spin quantum numbers 1–2
spin–spin coupling 7–9, 49, 52
spinning of samples 31
spinning side bands 83–4
splitting 7–9, 51
SPT see selective population transfer
stabilized free radicals 20–1
stack plots 114
structural elucidation software 172
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216 Index
structural verificatio software 172
substituent effects 48–56
superconducting NMR magnets 4–5
tautomerism 120–1
tetramethyl silane (TMS) 6, 17–18, 39, 91–2
TFAA seetrifluoroaceti anhydride
TFAE see(–)2,2,2,trifluoro-1-(9-anthryl ethanol
thiophenes 57
three dimensional (3-D) NMR 149
three-bond coupling 64–5, 92–6, 133–4, 136, 153
time-domain data 4
TMS seetetramethyl silane
total correlation spectroscopy (TOCSY) 116, 123, 149
1,2,4-tri-substituted benzene systems 55–6
trifluoroaceti acid 16
trifluoroaceti anhydride (TFAA) 101, 104–5
(–)2,2,2,trifluoro-1-(9-anthryl ethanol (TFAE) 106–7
3-(trimethylsilyl) propionic-2,2,3,3-D4 acid (TSP) 17–18
triple bonded systems 57–64
TSP see3-(trimethylsilyl) propionic-2,2,3,3-D4
acid
tuning 30
two dimensional (2-D) NMR 111, 112–16
diffusion ordered spectroscopy 148–9
INADEQUATE 147
J-resolved 147–8
problems and solutions 179, 186, 195
processing 33, 37
spectrum acquisition 25, 27–8, 31
two dimensional (2-D) NOESY 116, 122–3
two dimensional (2-D) proton–carbon correlated
spectroscopy 130–7
vertical scaling 41–2
vicinal coupling 64–5, 92–6, 133–4, 136, 153
virtual coupling 76–7
WATERGATE pulse sequence 145
WET pulse sequence 145
Z test 72–4
zero fillin 33
zwitterions 96–100
P1: OTE/OTE/SPH P2: OTE
fm JWST025-Richards October 7, 2010 7:16 Printer: Yet to come
Essential Practical NMR for
Organic Chemistry
i
Essential Practical NMR for Organic Chemistry S. A. Richards and J. C. Hollerton
© 2011 John Wiley & Sons, Ltd. ISBN: 978-0-470-71092-0
Page 2
P1: OTE/OTE/SPH P2: OTE
fm JWST025-Richards October 7, 2010 7:16 Printer: Yet to come
Essential Practical NMR for
Organic Chemistry
S. A. RICHARDS
AND
J. C. HOLLERTON
A John Wiley and Sons, Ltd., Publication
iii
Page 108
P1: JYS
c07 JWST025-Richards October 2, 2010 18:41 Printer: Yet to come
Further Elucidation Techniques – Part 1 103
R
O
CH3
R
OH
CH3
Structure 7.1 Keto-enol exchange.
Remember that any proton which is acidic enough is prone to undergo deuterium exchange. Methylene
protons alpha to a carbonyl for example, may exchange if left standing with D2O for any length of time,
as they can exchange via the keto-enol route (i.e., Structure 7.1).
Note that deuterium exchange of the -OH leads to incorporation of deuterium alpha to the carbonyl
in the ketone form. This may happen, even if there is no evidence of any enol signals in the spectrum
initially, i.e., it can occur even when the equilibrium is heavily in favour of the ketone. Aromatic protons
of rings which bear two or more -OH groups are also prone to undergo slow exchange, as are nitrovinyl
protons.
7.3 Basification and Acidification
This topic has been dealt with quite extensively in Section 6.6.6 so we won’t go over the material again
but there is perhaps one other type of problem that may be worth looking at with a view to solving by a
change of pH. Consider the two structures in Structure 7.2.
Whilst the preferred method of differentiating these structures would be by an NOE experiment, it
would be possible to accomplish this by running them in DMSO and then adding a drop of base to each
solution and re-running. (Note: DMSO is the preferred solvent for this experiment as both the neutral
and the charged species would be soluble in it.) In both cases, the phenoxide ion (Ar-O−) would be
formed and the extra electron density generated on the oxygen would feed into the ring and cause a
significan upfiel shift of about 0.3–0.4 ppm in any protons ortho- or para- to the hydroxyl group. In
the example above, the compound on the left would show such an upfiel shift for only a single doublet
(a), whilst the compound on the right would show an analogous upfiel shift for both a narrow doublet
(b) and a doublet of doublets (c).
Caution should be exercised if attempting any determination of this type as it is not the preferred
method and it is always safest if both compounds to be distinguished are available for study in this way.
OH
O
CH3
CH3
O
OH
CH3
CH3
bc
a
Structure 7.2 Compounds which show one or two upfield shifts.
Page 109
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c07 JWST025-Richards October 2, 2010 18:41 Printer: Yet to come
104 Essential Practical NMR for Organic Chemistry
7.4 Changing Solvents
If a signal of particular interest to you, is obscured by other signals in the spectrum, it is often worth
changing solvent – you might be lucky, and fin that your signal (or the obscuring signals) move
sufficientl to allow you to observe it clearly. You might equally well be unlucky of course, but it’s worth
a try.
Running a sample in an anisotropic solvent like D6-benzene or D5-pyridine, can bring about some
even more dramatic changes in chemical shifts. We tend to use benzene in a fairly arbitrary fashion, but
in some cases, there is a certain empirical basis for the upfiel and downfiel shifts we observe.
For example, benzene forms collision-complexes with carbonyl groups, ‘sitting’ above and below the
group, sandwich-style. When the carbonyl is held rigidly within the molecule, either because it forms
part of a rigid system, or because of conjugation, we can generally expect protons on the oxygen side of a
line drawn through the carbon of the carbonyl, and at right angles to the carbonyl bond to be deshielded.
Conversely, those on the other side of the line are shielded.
7.5 Trifluoroacetylation
This is quite a useful technique which can give a rapid, positive identificatio of -OH, -NH2, and -NHR
groups in cases where deuteration would be of little value. Even though the technique can be a little
time-consuming and labour-intensive in terms of sample preparation, it can nonetheless yield results in
less time than it would take to acquire definit ve 13C data – particularly if your material is limited.
Consider Spectrum 7.3. The bottom trace shows the ordinary spectrum of cyclohexanol, run in CDCl3.
Distinguishing it from chlorocyclohexane is not easy (without the use of 13C NMR) – the chemical shift
of the proton alpha to the functional group would be similar in both compounds, and in the case of the
alcohol, the -OH need not show coupling to it. Furthermore, in problems of this type, the -OH proton
itself may well be obscured by the rest of the alkyl signals or combined with the solvent water peak.
Integration of the alkyl multiplet before and after deuteration will not necessarily be very reliable, since
looking for 1 proton in a multiplet of 10 or 11, will give only a relatively small change in integral
intensity (and let us not forget that water in the CDCl3 which will absorb in this region, along with any
water that may be residual in the compound).
The top trace shows what happens when the sample is shaken for a few seconds with a few drops of
TFAA. The reaction shown in Structure 7.3 occurs.
The resultant spectrum is clearly very different from the alcohol, as the trifluoroaceti ester function
is far more deshielding with respect to the alpha proton than is the -OH group. A downfiel shift of
>1 ppm can be seen. This clearly distinguishes the alcohol from the analogous chloro compound which
would of course give no reaction.
This is a relatively quick and convenient technique, the reagent reacting quite readily (assuming no
great steric hindrance of course) with alcohols, primary and secondary amines. (Note the possibility of
complication if you react a secondary amine with TFAA – it will yield a tertiary amide!) If the reaction
is a little slow, as is often the case with phenolic -OH groups, you can ‘speed it up a little’ by gentle
warming, more shaking, and even adding a drop of D5-pyridine to base-catalyse the reaction.
Use of this reagent is however, somewhat limited. You can only use it in solvents which don’t
react with it (D4-methanol, and D2O are obviously out of the question), or contain a lot of water, i.e.,
D6-DMSO. Another slight drawback is that the cleaving of the anhydride liberates trifluoroaceti acid,
Page 215
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ind JWST025-Richards October 8, 2010 10:19 Printer: Yet to come
Index 215
radical scavengers 21
referencing see spectrum referencing
relative quantificatio 157–8
relaxation delays 27, 39, 160–1
residual solvent signals 15–16, 18
restricted rotation 78–82
ROESY see rotating frame Overhauser effect
spectroscopy
roofin 52–3, 55, 67, 95
room temperature (RT) shims 28
rotameric forms 78–82
rotating frame Overhauser effect spectroscopy (ROESY)
116, 123–4, 149, 179, 186–7, 195, 198, 201, 204
RT see room temperature
safety issues 163–6
cryogens 165–6
magnetic field 163–5
sample-related injuries 166
salts 96–100, 173, 196–7
sample depth 18–19
sample preparation 11–21
contamination 20
filtratio 19–21
magnetic fiel homogeneity 11, 18–20
mixed solvents 17
number of transients 12–13
quantities of sample 12–13
residual solvent signals 15–16, 18
sample depth 18–19
solvents 13–18
spectrum referencing 17–18
sample-related injuries 166
selective population transfer (SPT) 119–20, 125
semi-empirical prediction 171
sensitivity of NMR technique 1–2, 3
13C NMR spectroscopy 127–8, 133
high performance liquid chromatography 143–4
quantities of sample 12–13
spinning of samples 31
see also signal-to-noise ratio
shielding substituents 52–3
shimming
high performance liquid chromatography 143–4
interpretation of spectra 83–4, 91
spectrum acquisition 18, 28–30
29Si-H couplings 91–2
signal-to-noise ratio (SNR) 1–2, 3, 10
13C NMR spectroscopy 127–8, 134, 136
instrumental elucidation 115
number of transients 12–13, 23–4
quantities of sample 12–13
sample depth 18
simulation software 171–2
sinc function 25–6
117/119Sn-H couplings 91
SNR see signal-to-noise ratio
software tools 167–72
acquisition software 167
13C NMR spectroscopy 169–70
1H NMR spectroscopy 170–1
prediction software 168–71
processing software 167–8
simulation software 171–2
structural elucidation software 172
structural verificatio software 172
solvent suppression 145
solvents
chemical elucidation 104, 109
interpretation of spectra 44–6, 81
mixed solvents 17
residual signals 15–16, 18
sample preparation 13–18
spectrum referencing 17–18
spectral interpretation see interpretation of spectra
spectral width 25
spectrum acquisition 23–31
acquisition time 25
frequency locks 30–1
number of increments 27–8
number of points 24
number of transients 23–4
pulse width/pulse angle 25–7
relaxation delay 27
shimming 28–30
spectral width 25
spinning 31
tuning and matching 30
spectrum referencing 17–18, 39, 128–9
spin choreography 4
spin decoupling 111–12
spin quantum numbers 1–2
spin–spin coupling 7–9, 49, 52
spinning of samples 31
spinning side bands 83–4
splitting 7–9, 51
SPT see selective population transfer
stabilized free radicals 20–1
stack plots 114
structural elucidation software 172
Page 216
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216 Index
structural verificatio software 172
substituent effects 48–56
superconducting NMR magnets 4–5
tautomerism 120–1
tetramethyl silane (TMS) 6, 17–18, 39, 91–2
TFAA seetrifluoroaceti anhydride
TFAE see(–)2,2,2,trifluoro-1-(9-anthryl ethanol
thiophenes 57
three dimensional (3-D) NMR 149
three-bond coupling 64–5, 92–6, 133–4, 136, 153
time-domain data 4
TMS seetetramethyl silane
total correlation spectroscopy (TOCSY) 116, 123, 149
1,2,4-tri-substituted benzene systems 55–6
trifluoroaceti acid 16
trifluoroaceti anhydride (TFAA) 101, 104–5
(–)2,2,2,trifluoro-1-(9-anthryl ethanol (TFAE) 106–7
3-(trimethylsilyl) propionic-2,2,3,3-D4 acid (TSP) 17–18
triple bonded systems 57–64
TSP see3-(trimethylsilyl) propionic-2,2,3,3-D4
acid
tuning 30
two dimensional (2-D) NMR 111, 112–16
diffusion ordered spectroscopy 148–9
INADEQUATE 147
J-resolved 147–8
problems and solutions 179, 186, 195
processing 33, 37
spectrum acquisition 25, 27–8, 31
two dimensional (2-D) NOESY 116, 122–3
two dimensional (2-D) proton–carbon correlated
spectroscopy 130–7
vertical scaling 41–2
vicinal coupling 64–5, 92–6, 133–4, 136, 153
virtual coupling 76–7
WATERGATE pulse sequence 145
WET pulse sequence 145
Z test 72–4
zero fillin 33
zwitterions 96–100
