NMR
Course,
Lecture
14.29 April 14, 1999
4
Lecture
The
4
Chemical
Shift
Chapters (pages) in 'Modern NMR Techniques for Chernistry Research' by A. E. Derorne :
.Notbing
~
unfortunately
Other useful books or scientific
.'Physical
.'Proton
papers related to the topics in this lecture :
Chemistry'
by P. w.
and Carbon-13
NMR
Atkins
: Ch. 20.1
Spectroscopy.
An Integrated
Approach'
by R. J. Abraham
and P.
Loftus : Ch. 2
~
.'Nuclear
Magnetic Resonance Spectroscopy. A physicochemical View' by R. K. Harris :
Ch. 1.8- 1.10 and Ch. 8.1 -8.16
.'N
MR Spectroscopy' by H. Gtinther : Ch. 4.1
.Many
books on chemistry, spectroscopy and physical chemistry in general cover the basics of
NMR including chemical shifts and their origin
Page 111
NMR Lecture 4
14.55 April 12. 1999
With a slight oversimplification one can say that virtually everything that produces a magnetic field will
influence the chemical shiit (the resonance frequency) of a given nucleus.
The most important influence on the resonance frequency of a nucleus :
-A
nucleus is shielded by the electrons surrounding it
-The electrons create a small magnetic field opposed to Bo. the external field coming from the
magnet. due to the circular motion of the electrons around the nucleus induced by BO
-Since the new field is opposed to BO the nucleus will 'feel' a magnetic field slightly smaller
than BO
Bett = BO -Bshield
Bett refers to the 'felt' magnetic field. the one which determines the Larmor frequency. Vo
-The
above formula can also be written as
Beft = BO -BO
* 0"
Where 0" is the shielding constant From this we can see that the Bshield is dependendent on
BO. the external field
-The higher the electron densityaround our nucleus. the higher is Bshield or 0" and the more
shielded our nucleus will be
-For a hydrogen atom where the distribution of electrons is spherical (in atoms. does not
happen in molecules) since there are only s-electrons the 0" is purely due to diamagnetic effects
and therefore O"=O"d
-In
C W NMR the external field Bo must be increased to compensate for Bshield. Therefore.
nuclei experiencing large Bshield are said to resonate upfields. In Fr NMR this corresponds
to small ~values. Normally the right side of the spectrum
-Accordingly.
the left part of our spectrum is called the downfield
region. BO is small in C W
NMR and the ~values are high in Fr NMR
In molecules and in atoms with p-ele(:trons (unsyrnmetric and non-spherically distributed), the
total 0" of a nucleus is also affe(:ted by circulation of ele(:trons within the entire molecule
'--J
These 'molecular' electron movements cause a reduction of 0" for our nucleus and this is called a
paramagnetic shift, O"p
Paramagnetic effects (O"p-term) causes large downfield shifts (to higher vor ppm, to the left in
our spectrum)
If we knew the nature of electronic motion in a molecule (induced by BO) we could calculate allO"
and subsequently all chemical shifts
This we cannot do (except for H2 and LiR) and approximations are made to give a model which
can be used to predict chemical shifts
0" = O"I~Cal + O"I~Cal+ 0",
Here d docal and ~ocal are the local contributions to 0" for a particular nucleus and 0"' can be
solvent effects, anisotropic effects, ring current effe(:ts etc.
For protons the d docal and 0"' terms are most important since paramagnetic effects can not arise
from its own valency electrons (no p-orbitals in H). The neighbouring atoms may however
contribute to the ~ocal term of a proton
Page
1 / 15
NMR Lectln"e 4
14.55 April 12, 1999
The lack of p-orbitals on a hydrogen atom explains w hy virtually all protons resonate within -10
ppm while other nuclei resonate within hundreds or thousands of ppm (C -250 ppm, N 900
ppm, F 800 ppm, Co 18000 ppm etc )
How do all these theories affect a real spectrum?
Practical considerations
.Reducing electron density around a nucleus obviously reduces~ocal .This is very important for
1H resonances
.In 'normal' molecules the H is however not bonded directly to a highly electronegative atom (F,
Cl, O etc). Instead the proton is bonded to a carbon which in tum is bonded to the highly
electronegative atom.
The electronegativity of the substituentaffects the partia! charge on the carbon which then
influences the shielding of the proton
",-..,
The O-values (in ppm) for the serles of compounds (CH3-X) below show that a more
electronegative substituent (higher electron-withdrawing power) reduces the O'~cal for the
protons of the methyl group and accordingly we seehigher chemical shifts, the signal moves
downfield
~
Si(CH3)4
0.00
CH3CH3
0.88
CH31
2.16
CH3Cl
3.05
-Reverse effects, with respect to Ö(lH) versus electronegativity,
CH3-CH2-X where X={F, Cl, Br, I}.
CH30H
3.38
CH3F
4.26
can be observed for
o(CH3-CH2-F)
< o(CH3-CH2-Cl)
< o(CH3-CH2-Br)
< o(CH3-CH2-I)
Other, geometrical, factors are responsible for this
There is also an additive effect when several subtituents are present :
-Higher
(""'
, J
"
number of electronegative substituents on the <x-carbon add to the total deshielding of
thelH
I
CHCl3
I
CH2Cl2
I
CH3Cl
I
I
7.27
I
5.30
I
3.05
I
The effect of the electronegativity of X decreases for protons further away. Protons bonded to
the J3-carbon (3 bonds from X) or to the y-carbon (4 bonds) are less affected then protons
bonded to the a-carbon (2 bonds)
-CH2-Br
-CH2-CH2-Br
-CH2-CH2-CH2-Br
3.30
1.69
1.25
-Linear relationships have been found and NMR chemical shifts have been used to measure
electronegativities of a substituentX :
EX = 0.684 (ÖCH2-ÖCH3) + 1.78
-Caution must be exercised since other effects, like the 'reverseeffect' for ethyl halides above,
may appear, but within a small group of similar molecules the formula can be used
Page2115
NMR Lecture 4
14.55 April 12, 1999
Proton chemical shifts for substituted CH2XY and CHXYZ
following formula and table :
groups can be predicted from the
~H = 0.23 + 1: contributions
Accuracy is approx. :i:O.3 ppm for CH2 groups, less accurate for the CH group
~
Ex. 1: ö(CH2CI2)
Ex.2:
= 0.23+2.53+2.53
ö(CH3CH2CH2CH2Br)
-The hybridization
shift
H-v-.
H
I
,..
H
r-"
= 5.29 ppm
= 0.23+0.47+0.67
Exp. = 5.30
= 1.37 ppm
Exp. = 1.25
state of the carbon atom to which a proton is bonded affects the chemical
H
I
H
H
'\
'"',
""
I
H
H
/
/c=c,
H-C=C-H
H
-Sp3
: mix ofl
s and 3 p orbitals ~ little s-character of the molecular orbital
-Sp2
: mix of 1 s and 2 p orbitals ~ more s-character of the molecular orbital
-sp : mix of 1 s and 1 p orbitals ~ much s-character of the molecular orbital
-The more s-character the closer the electrons are to the C nucleus, and the further away from the
H-nucleus.
This results in a deshielding of the proton
-Expected chemical shifts are therefore :
o(ethyne)
>
o(ethene)
>
O(ethane)
THIS IS NOT THE CASE IN REAL LIFE, HOWEVER!!!
There are other effects which change this order
The correct ranges of chemical shifts are :
ö(ethyne) ~ 2- 3
Ö(ethene) ~ 4- 7
ö(ethane) ~ O -2
Page 3 115
14.55 April 12. 1999
NMR Lecture 4
Chemical shifts of olefinic protons
The effect of substitution for olefmic protons have been investigated and a fonnula proposed :
3H = 5.25 + Zgem+ Zcis + Z trans
Where Zgem.Zcis and ~s
are the contributions (in ppm) for the substituent at that position.
RCIS
.H
",
C'
/
Rtrans
/
:c
"
Rgem
1'"-'-
ICOOH
!
0.97
1.41
0.71
!
Some strongly electronwithdrawing groups (OR, NR, F) have a strong deshielding effect if it
is in the gemmal position (bonded to the samecarbon as the proton) due to inductive effects
The same group has a rather strong shielding effect if it is in cis or trans position (the 'other'
carbon compared to the proton) due to electron-donatingconjugative effects
Anisotropic
effects
Proton chemical shifts are greatly affected by magnetic dipoles at neighbouring atoms or groups
-The magnetic dipoles alter the local magnetic field 'felt' by the proton.
-In
~
our molecule (diatomic, C-H) we get a magnetic moment, ~A, due to the effect the external
field BO has on electrons around atom C. We can consider ~A as a localized point dipole at the
centre of atom C. Please note that 'atom C' is not a carbon atom.
~A(Z) is big, ~A(Y) is small, and ~A(X) is intermediate in the picture on the next page.
-When
our molecule tumbles in solution, the secondary field due to the dipole ~A will increase or
decrease the local, effective, field at atom H.
-We assume that our molecule tumbles freely and no position is favoured. Then we will see the
avecage effect of the secondary field.
-The effects on H of the induced dipole at atom C are clearly not the same for all molecular
orientations.
C is said to be magnetically
anisotropic
if at least one of the ~A(X), ~A(Y) or ~A(Z) is
different from the others. If ~A(X)=~A(Y)=~A(Z) then C is said to be magnetically isotropic and
C will have no effect (on average) on ~ of the H close to it. It is a through-space
not transmitted via bonding electrons.
Page 4 115
efTect, it is
NMR Lectw-e 4
14.55 Apri112, 1999
z
B
/
I
"'\
1-
~
-'\\'1"-
-
/
\
f
I: HI
..
\
,
\
4
I
~-
\ .'
"-"-"- I
.\
/
x
t~1
\
/
/
J L
'I,
,x
I
\
\
I
\t
~)
~~
-"" /L~
\
z
-"..::
~A(z)
i-
-\
-
/
~
I
"r"
I
x
y
~
y
~
z
:'--.
"-/"-<- I
""
~A(x)
Here we see the effect of the secondary field on the local effective magnetic field at atom H when the
molecule (and the molecular coordinate system) is tumbling in solution.
(left) Berr at H is increased due to the secondary field beeing parallell to Bo (H is deshielded)
(middle) The molecule's y-axis is allgned with BO and Berris increased again (H is deshielded)
(right) The molecule's x-axis is aligned with BO and Berr is decreased at atom H (H is shielded)
r
-Many
chemical features (atoms, bonds, functional groups etc) give rise to anisotropic effects.
For instance, even a carbon-carbon single bond is anisotropic :
+
Ha
0.3 nm
K
AO'=+0.14ppm
l... 0.3 nm..1
~
-C-C
-
~
\
.'.,
Hb
AO' = -0.28 ppm
~
'~
~
+
"'"""
Shielding cones showing how the shielding constant is changing due to anisotropic effects.
-The effect on the shielding constantis negative (leading to higher chemical shift) along the axis
of the bond while the effect on the shielding constantis positive in regions perpendicular to the
bond (lower chemical shift)
-The nodal planes where there is no change in O'(AO'= 0) goes along the surface of a cone with a
54.7° angle ('magic angle') to the bond (1-3cos2 ~)
-The C-C bond anisotropic effect is clearly seenin cyclohexane where axial and equatorial
protons have a -0.5 ppm chemical shift difference. At low temperaturethe chair-chair
interconversion is slow and the Aö between Hax and Heq can be measured
Heq
4
H2
Page 5 115
NMR LectW"e4
14.55 Apri112, 1999
On the previous page, it can be seen that it is the shielding cones of the C2-C3 and the C5-C6 bonds
that produce the anisotropic effects on the axial and equatorial protons at C 1
-Heq is in the negative shielding cone of both C-C bonds, while "ax is in the positive region.
-"ax
is shielded by -0.5 ppm compared to Heq
a.-methoxygalactose and fi-methoxygalactose can be distinguished due to the differences in chemical
shifts of the methoxyprotons
~
Other bands give rise to anisatrapic effects as weIl :
+
""""
~
+
The shielding cones for C-C single bond,
C-C double bond and C-C triple bond
+
-
+
The shielding
+
cones for the carbonyl
Page
6 /
15
group and the nitro group
NMR Lecture 4
14.55 April 12, 1999
Another very important contributor to anisotropic effects on chemical shifts :
Ring currents
In an aromatic ring system, a circular movement of the delocalized 7t-electrons will be induced
This cUn'ent will, as we saw before, create a small magnetic field opposed to the external field BO
(in the center of the cicrular path)
Since the aromatic ring is planar, the created field will only be created when the plane of the
aromatic ring is perpendicular to Bo. As a result we have anisotropy and the chemical shiit of
nearby protons will be affected
~
t
B
B due to circulation
of 1t-electrons
Protons located above or below the aromatic system will be in a strong shielding zone leading to
upfield chemical shifts
Protons located in the plane of the ring (the benzene protons) will experience a significant
downfield shift due to the 'reinforced' magnetic field
-The 6 protons of benzene resonate at 7.27 ppm
-The olefmic protons ofcyclohexa-l,3-diene
resonates at 5.86 ppm
-The difference of 1.4 ppm is attributed to the ring current shift
Page 7 115
NMR Lecture 4
14.55 April 12, 1999
Another interesting example :
H
r
r--
I-I
II
H
[16]-annulene
H
[18]-annulene
In [16]-annulene
the 'inner' protons resonate at ö = 10.3 and the 'outer' protons at ö = 5.28
In [18]-annulene,
on the other hand, the 'inner' protons resonate at ö = -4.22 and the 'outer'
protons at ö = 10.75
It is the ring current effect which is responsible for these dramatic differences in ö
This shows that [18]-annulene is aromatic while [16]-annulene is not. According to the '4n + 2'
rule the same result is predicted
The ring current shifts are very important in NMR of ONA and RNA as weIl as in the NMR of
proteins
-All
nucleobases in RNA and ONA (A, C, G, T, U) are aromatic and give rise to ring current
shifts
-Adenine
and guanine give rise to the strongest ring current shifts, cytosine of intermediate
strength and uracil of rather low strength
r'
"
Page 8 115
NMR Lecture 4
14.55 April 12, 1999
The confonnation of ONA is stabilired by both 'vertical interactions' (stacking) and 'horizontal
interactions' (hydrogen bonding)
H
H~N
Distance between
two base planes:
3.4 Ångström
C1'
o
'N-H
,~..r-<
~N-<
CH3
N
H
H
H
'c1'
o
o
H-
N
H
/H
N~H
N'--~>H
>-N,
C1
C
O
I
1
The protons of a nucleobase as well as Hl' are to a large extent within the shielding cone of the
next base and experience an upfield shift
Transitions of a ONA duplex ~ randoffi coil can be ffionitored by NMR. Melting curves from
NMR are as precise as the 'normal' uv melting curve
-When the ordered, stacked structure becomes destacked (randoffi coil) the aromatic and
(
anomeric protons are no longer in the shielding cone of the neighbouring nucleobase ~
downfield shift
-In non-standard structures the (temperature dependent) ring current shifts are used to
determine which nucleobases are stacked to each other
Chemical shifts of exchangeable protons etc
"'"""
-Protons
involved in hydrogen bonds (X-R
Y) are strong ly affected by the electrical dipole
field created (the R-bond is an electrostatic bond) and this leads to downfield chemical shifts
(deshielding) (useful for NMR of ONA and RNA)
-In general, chemical shifts of these protons are very dependent on temperature, solvent, pR etc
-In samples which can form intermolecular R-bonds (R-OR, R-NH2)' the chemical shift of
the R-bonding proton is very rnuch dependent on the concentration
,.-,
-In
-EtOR
in EtOR (neat, many R-bonds) :
8 = 5.3
-EtOH
in CC14 (5%, almost no R-bonds) :
8 = 2.5 (~8 = -2.8)
-Phenol
in CC14 (high conc., many R-bonds) :
8 = 7.5
-Phenol
in CC14 (low conc., almost no R-bonds) :
8 = 4.4 (~8 = -3.1)
samples which can form intramolecular R-bonds, the chemical shift of the R-bonding
proton is on ly little dependent on the concentration
-salicylaldehyde
(neat, many R-bonds) :
8 = 11.5
-salicylaldehyde
in CC4 (5%, still many R-bonds) :
8 = 11.1 (~8 = -0.4)
Page
9 / 15
,
NMR Lecture 4
14.55 April 12, 1999
H
I
14.55 April 12, 1999
NMR Lecture 4
NMR
of carbon-13
The basic theories for chemica! shifts, as weIl as for NMR in genera!, are true a!so for carbon
atoms
One important difference is the relative sensitivity
-The
nuclear spin of 13C, I, is t hut the magnetogyric ratio, y, is only 25% of y for protons
This 1eads to a 1ower sensitivity since AB = ~
27t
Another important aspect concerning sensitivity is the natural abundance
~
-For
hydrogen atoms the natural abundance is 99.98% for lH
-For
carbon atoms the natural abundance is 1.108% for 13C
Taking 'Yand natural abundance into account the relative sensitivity of l3C is ~
compared
to lH
-The
low sensitivity of l3C is an advantage when looking at lH spectra. With a higher
abundance of l3C, the lH spectra would become very complicated due to lH-l3C
couplings.
In a l3C spectrum, all those lH-l3C couplings are observed unIess special precautions are
taken
-The
low sensitivity is naturallya disadvantage when observing l3C
Chemical shifts of carbon atoms
One important difference to 1H is that carbons have p-electrons
-Carbon
-The
resonances are spread out over 200 -300 ppm
local paramagnetic shielding term (~ocal ) is of great importance while
ddocal(the diamagnetic term) is ofsma11 importance contrary to the lH case
"
The chemical shifts of carbon atoms follow roughly the same order as for protons
ö(aldehyde) > o(alkene) > ö(alkyne) > o(alkane) > TMS
Effects of substituents on 13Cchemical shifts are similar to their effects on ör H) but not
identical
-In
CH3-I the 13Cresonancemoves upfield (to -20 ppm) contrary to the lH case. Similarly,
the 'expected' large downfield shifts (from lH analogy) are not seenfor CH3-Cl and CH3-Br
The substituent effect propagatesthrough more bonds for 13Cshifts than for lH
-For lH chemical shifts, the substituent effect is virtually only observed for protons bonded to
the a.-carbon (the carbon carrying the substituent)
-For 13Cchemical shifts, substituent effects are clearly observed at the y-carbon (3 bonds), in
some caseseven at carbons further away
-In acyclic alkanes the effect on the ö- and e-carbonsare small but in cyclic compounds
these effects may be large
Page11/15
14.55 April 12, 1999
NMR Lecture 4
NMR
of carbon-13
The basic theories for chemica! shifts, as weIl as for NMR in genera!, are true a!so for carbon
atoms
One important difference is the relative sensitivity
-The
nuclear spin of 13C, I, is t hut the magnetogyric ratio, y, is only 25% of y for protons
This 1eads to a 1ower sensitivity since AB = ~
27t
Another important aspect concerning sensitivity is the natural abundance
~
-For
hydrogen atoms the natural abundance is 99.98% for lH
-For
carbon atoms the natural abundance is 1.108% for 13C
Taking 'Yand natural abundance into account the relative sensitivity of l3C is ~
compared
to lH
-The
low sensitivity of l3C is an advantage when looking at lH spectra. With a higher
abundance of l3C, the lH spectra would become very complicated due to lH-l3C
couplings.
In a l3C spectrum, all those lH-l3C couplings are observed unIess special precautions are
taken
-The
low sensitivity is naturallya disadvantage when observing l3C
Chemical shifts of carbon atoms
One important difference to 1H is that carbons have p-electrons
-Carbon
-The
resonances are spread out over 200 -300 ppm
local paramagnetic shielding term (~ocal ) is of great importance while
ddocal(the diamagnetic term) is ofsma11 importance contrary to the lH case
"
The chemical shifts of carbon atoms follow roughly the same order as for protons
ö(aldehyde) > o(alkene) > ö(alkyne) > o(alkane) > TMS
Effects of substituents on 13Cchemical shifts are similar to their effects on ör H) but not
identical
-In
CH3-I the 13Cresonancemoves upfield (to -20 ppm) contrary to the lH case. Similarly,
the 'expected' large downfield shifts (from lH analogy) are not seenfor CH3-Cl and CH3-Br
The substituent effect propagatesthrough more bonds for 13Cshifts than for lH
-For lH chemical shifts, the substituent effect is virtually only observed for protons bonded to
the a.-carbon (the carbon carrying the substituent)
-For 13Cchemical shifts, substituent effects are clearly observed at the y-carbon (3 bonds), in
some caseseven at carbons further away
-In acyclic alkanes the effect on the ö- and e-carbonsare small but in cyclic compounds
these effects may be large
Page11/15
NMR Lecture 4
14.55 April 12, 1999
OH
ICHO
48.3
31.4
10.1
0.7
-6.0
-1.9
0.3
0.8
0.2
0.5
The table shows the differences in 13Cchemical shifts (L\5c) for various l-substituted pentanes.The
chemical shifts for pentane are : Ö(C1)=Ö(C5)=13.7
, ö(CV=Ö(C4)=22.6 and ö(C3)=34.5
,-.,
r
-The
substituent effects on the a.- and j3-carbonsare normally deshielding
-The
substituent effect on the 'Y-carbonis shielding (the 'Y-effect)
-The
'Y-effectis very clearly seenin substitutedcyclohexanes
-The 'Y-effectdependson the dihedral angle betweenthe substituent and the 'Y-carbon.The
classical staggeredrotamers gauche- (-600), trans (1800)and gauche+ (+60°) are normally
considered as the only three possible states
-In acyclic compounds the rotations around C-C bonds are generally so fast that we seean
averageeffect only from the three staggeredrotamers
-In cyclic compounds the rotation is restricted and there will only be two possible rotamers for a
dihedral X-C-C-C (where X is an exocyclic substituent)one gauche and trans.
orten one rotamer is highly preferred over the other (dependingon the nature of the endo- and
exocyclic substituents)
-In cyclohexane an axial substituent on the a.-carbon will be gauche to the 'Y-carbonof the
ring and cause an upfield shift of 4-7 ppm for the 'Y-carbon
-Accordingly,
an equatorial substituent on the a.-carbon will be trans to the 'Y-carbonof the
ring and cause an upfield shift of 0-3 ppm for the 'Y-carbon
33.2
r
~CH3
H3C
ty
13
(\
36.2
(H3C)3C
Axial
Equatorial
Page12 115
NMR Lecture4
12:02 PM April 14, 1999
-The 31p chemical shiit is also sensitive to the R-O-P-O and O-P-a-R torsional angles in a
phosphodiester
-The torsional angles and the bond angle not uncorrelated phenomena :
Changing one structural feature is accompanied by a change in the other
-This
interdependence is called the 'stereoelectronic 31p effect'
C
,,\\\\\c
0.."'
it
0-
"'
()
gauche-
p
~
it
-0
0-
gauche-
P-O
rtt
,..0
gauche-
,..0
C \\\\\\"'
f"'
trans
C \\\\\,"'
In practice as weIl as from semiempirica! MO ca!culations we seethat phosphateesterswith both
P-O torsions in gauche conformation (-60° or +60°) resonatesseveral ppm (3-6 ppm) upfield
from a phosphateester which has at least one P-O torsion in trans conformation (-180°)
The AÖ(31p)arising from torsiona! changesare used to monitor DNA and RNA conformation :
In a stacked conformation the ~ and a. torsions (P-O torsions) take up a gauche,gauche
conformation while in a non-stacked (random coil) a!so the gauche,transand trans,trans
conformers exist
These conformationa! changeslead to downfield shifts of the 31p resonanceswhen the
conformation changestoward random coil which can be induced by increasing temperature
f'
'-"
r,
Page
14/14