NMR spectroscopy

its application in pharmaceutical analysis

1H

Bapusaheb Thorat
Professor of Chemistry
Govt. of Maharashtra, I. Y. College, Jogeshwari (E),
Maharashtra 400060

29.10.2008

1H NMR spectroscopy

Questions before a pharmaceutical chemist

(Ref: Pharmaceutical analysis by David G Watson)

Is the identity of the drug in the formulated product

correct?
What is the percentage of the stated content of a drug
present in a formulation?
Does this formulation contain solely the active
ingredients or are additional impurities present?
What is the stability of a drug formulation and hence the
shelf-life of the product?
At what rate is the drug released from its formulation so
that it can be absorbed by the body?
29.10.2008

1H NMR spectroscopy

 Do the identity and purity of a pure drug

substance to be used in the preparation of a
formulation meet specification?
What are the concentrations of specified
impurities in the pure drug substance?
What is the concentration of the drug in a
sample of tissue or biological fluid?
What are the pka value(s), partition coefficients,
solubility and stability of a drug substance under
development?

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1H NMR spectroscopy

Today, the work of a pharmaceutical chemist

involves:
characterization of raw materials and finished products,
determination of impurities, including enantiomeric
impurities, without separation,
fingerprinting mixtures,
quantitative analysis of drugs in formulations without
prior separation.

29.10.2008

1H NMR spectroscopy

The known methods of pharmaceutical analysis

Physical and chemical properties of drug molecules

Titrimetric and chemical analysis
Ultaviolet and visible spectroscopy
Infrared spectrophotometry
Atomic spectrophotometry
Molecular emission spectroscopy
Nuclear magnetic resonance spectroscopy
Mass spectrometry

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1H NMR spectroscopy

29.10.2008

Gas chromatography
High-pressure liquid chromatography
Thin layer chromatography
High-performance capillary electrophoresis
Separation methods

1H NMR spectroscopy

Thalidomide
O

H
N

O
NH

NH
O

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R - isomer

S - isomer

Sedative

Teratanogen

1H NMR spectroscopy

Propranalol

NH

OH

S - isomer,
beta -blocker

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NH

OH

R - isomer,
Contraceptive

1H NMR spectroscopy

Ethambutol
OH

Et
H

NH
NH

Et
H

OH

OH

Et
H
OH

(S,S) -isomer
Tuberculostatic

NH

NH
Et
H

(R,R)-isomer
Cause blindness
Ethambutol

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1H NMR spectroscopy

Chloromycetin
OH

OH

O2N

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OH

OH

HNCOCHCl2

HNCOCHCl2

O2N
(R,R)-isomer
antibacterial

1H NMR spectroscopy

(S,S)-isomer
inactive

10

Penicillamine

R CO2H
HS

H2N

HS
H2N

Anti-arthritic

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CO2H
H

Toxic

1H NMR spectroscopy

11

Ibuprofen
H

Ibuprofen

CO2H

OTC drug

Antipyretic, Antiinflammatory

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1H NMR spectroscopy

12

The two enantiomers of ibuprofen

H
CO2H

R -(-)
Distomer

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HO2C

S -(+ )
Eutomer

1H NMR spectroscopy

13

Chiral drugs
Single enantiomer drugs are called chiral drugs
Chiral drugs have become big business in
recent years. In 2005, its market is $171,865
millions (about Rs 8.5 lakh crores)
Over 80% of new medicines currently in
development are chiral

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1H NMR spectroscopy

14

Interaction of light with matter such as

atoms, ions or molecules.

Electromagnetic Spectrum

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1H NMR spectroscopy

16

Wavelength
l
m

Cosmic

Gam
ma

XRay

UV

Visi
ble

IR

Micr
o

Rad
ar

TV

N
M
R

Radi
o

AC

10-14

10-12

10-9

10-7

10-6

10-4

10-3

10-2

10

103

104

10-8

10-6

10-3

10-1

10-1

1100

103

104

105

10

108

109

10-8

10-2

102

102

106

107

108

1010-

101

105

102

103-5

10

11

nm
Frequency
1023

Energy
e=hv

1019

1017

1015

1013

1012

14371 k
cal

7135 k
cal

12-2
k cal

1011

1010

108

10
6

Radiofrequency waves
wavelength ( )

1012 Ao / 108 / 104 cm / 100 m

Wave-number ( = 1/) 10-4 cm-1

Frequency (c/ )

3 x 106 Hz = 3 MHz

Energy (E = hv)

10-8 eV / 10-4 cal

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1H NMR spectroscopy

18

Matter (Molecules)
Total energy of the molecule = E

electronic +

E Vibrational + E rotational

The magnitude of these energies are in the following order

OH

E elect > E vibr > E rot

NH2

H3C

CN

COOH
Cl
O

1. Above molecule contains s electrons (Single bond), p electrons (Multiple

bonds) and n-electrons (Un shared pair of electrons on elements like N, O,
S, halogens).
The energy required for the excitation of these electrons is in the range of
35-143 K cal.
2. There are C-H, C-C, C=O, C-Cl, etc bonds. These are vibrating with different
frequencies. Such bonds can undergo vibrational excitations. The energy
required for this is in the range of 2-12 K cal.
3. There are several hydrogen atoms which can be oriented in two spin states in
an external magnetic field. They can be flipped. Energy required is of cal.

Summary
Organic Molecule

IR radiation
2.5-15 m
2-12 K cal

UV/ Visible
radiation
200-800
nm
35-143 K
cal

Electronic excitations

p*

p*

etc

UV / visible spectroscopy

Vibrational and rotational

excitation

NMR radiation

C-H, C-OH, etc

Flipping of protons
from a to b spin
states.

IR Spectroscopy

NMR spectroscopy

 The NMR phenomenon was firmly proposed

independently in 1946 by the Physicist Block, Hansen
& Packardat, Stanford University by detecting signals
from proton of water. Purcell, Torrey & Pound at
Harword University detect signal of proton from
paraffin wax. Block, Purcell were get Nobel Price in
Physics at 1952.
The 1991 noble price in chemistry was awarded to
Richard Ernst, for many contributions to NMR,
including development of the Fourier Transform
technique.
Wuthrich explain the structure of polymers by using
NMR technique, for this he awarded Nobel Price in
Chemistry in 2002.

Nuclear Magnetic Resonance spectroscopy

(NMR) The principle
1.

In an applied external magnetic field, radio waves interact

with atomic nuclei whose I > 0, 1H, 13C, 19F, 31P, etc.
(I = spin quantum number / angular momentum).

Nuclei (isotopes)

% natural abundance

Nuclear spin

1H

99.98
0.02
0.00
19.6
80.4
98.89
1.11
99.63
0.37
99.76
0.04
0.20
100.00
100.00

3
3/2
0

0
5/2
0

1/2

2H
3H

10B
11B
12C
13C

14N
15N
16O
17O
18O
19F
31P

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1H NMR spectroscopy

22

Magnetic & Non-magnetic nuclei

Nuclei

1H,13C,17O,19F

2D,10B,14N

12C, 18O

I = , 3/2, 5/2

I = 1, 2, 3

I=0

MAGNETIC

MAGNETIC

NON-MAGNETIC

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1H NMR spectroscopy

23

When the energy of the radiofrequency matches with the energy required to
flip the spin orientation of the nucleus (at resonance), absorption occurs and
a signal is observed.

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1H NMR spectroscopy

28

**Commonly used NMR solvents***

i) Carbon tetrachlorideIt is aprotic and cheap. Its use is rather limited in practice to very non-polar compounds. It is very
hydrophobic; therefore any moisture in the sample is dissolve in it will yield a turbid solution and
homogeneity of the solution and resolution decrease. It has advantage of being non-acidic and hence
can be useful for certain acid sensitive compounds.
ii) Deutero chloroform:It is most useful solvent in NMR. Most of the compounds of varying polarity from nonpolar to
considerably polar are dissolve in it. The signal of CHCl3 at 7.27 causes some problem in the
analysis of the spectra. It is volatile therefore recovery of the sample will be easy if necessary. If the
compounds are sparingly soluble in this solvent then add drop-wise DMSO-d6 to increase the polarity
of the solvent. The single of chloroform is therefore shifted to downfield to 8.38.
iii) DMSO-d6 (deutero dimethyl sulphoxide):DMSO-d6 is very good solvent dissolving relatively insoluble heterocyclic compounds and salts. It has
the following some disadvantageousa) It is very viscous and causes some degree of line broadening.
b) It is mild oxidizing agent has been known to react with some compounds, simple warming of the
solution causes the complete dissolution, as is often required with this solvent.
c) The problem obtained due to restricted rotation becomes worse by using DMSO-d6.
d) DMSO-d6 being nonvolatile therefore removal of it becomes difficult if recovery of sample is
necessary.
e) The main disadvantage of it is affinity toward the water which makes it almost impossible to keep it
dry.
iv) Deutero methanol (MeOH-d4):it is polar solvent used for running the NMR spectra of the salts and extremely polar compounds. It
has high affinity towards water and impossible to keep dry. The major disadvantage of it is to exchange
ionisable protons (-OH, -NH2, and even CONH2) with deuterons. Also - protons of carbonyl can
exchange through keto-enol mechanism.
v) Deutero water:- for polar compounds like salts only.
vi) Deutero benzene:- used in combination with deutero chloroform because it is anisotropic slvent.
vii) Trifluro acetic acid:- used for running the NMR spectra of amines and heterocyclic compounds.

****Chemical shift***

The difference in resonance frequency of a given proton from the some reference standard
(e.g. TMS) is called as its chemical shift.

When the molecules are placed in a magnetic field, its electrons circulate and produced
secondary magnetic fields called as induced magnetic fields. When such molecules are placed
in external magnetic field, the produced magnetic field is in opposite direction to the applied
field so that these molecules are repelled from the applied field. Such induced magnetic field
is called as diamagnetic field. In such case, we have use the high strength magnetic field
i.e. substance can be shielded.
It is also called as diamagnetic shielding.
When molecules are placed in external magnetic field, it produces secondary magnetic field
in the direction of the applied magnetic field so that the strength of applied field goes on
increasing. Such induced magnetic field is called as paramagnetic field. In such cases, we
have used the low field strength magnetic field i.e. substance can be deshielded. It is also
called as paramagnetic deshielding.

Therefore, for the shielded protons higher or stronger field can be applied to produce
resonance i.e. it absorbs at up-field. And for deshielded protons lower field can be applied to
produce the resonance i.e. it absorbs at down field.
Shielding shifts the absorption to right while deshielding shifts absorption to left from the
normal absorption position.
The degree of shielding depends on the circulating electrons density therefore instead of
getting a single line peak; we obtained a complex spectrum (having different resonance
frequencies).

Chemical shift
Such shifts in the position of NMR absorptions due to shielding and
deshielding of protons by induced magnetic field of electrons from the position
of reference protons are known as chemical shift.
The difference in absorption position of particular proton from the absorption
position of a reference proton is called as chemical shift of that proton.
TMS is used as reference in NMR spectroscopy.
CH3
H3C Si CH3
CH3

TMS (tetra methyl silane) is more commonly used as reference because1. It has 12-equivalents protons which gives an intense signal. Therefore even
small quantity of it gives measurable signal.
2. Silicon is more electropositive than the carbon; therefore protons of TMS are
highly shielded.
3. TMS is inert, miscible and volatile, therefore can be easily removed by
evaporization after the experiment (b.p.-27 c). It does not involve any chemical
association with sample. For water soluble compounds the derivative of the
TMS is used as- 4,4-dimethyl-4-silapentane sulphone (DSS).

Scales of measuring the chemical shift:Chemical shifts are measured in Hz (cycle/second). It is generally frequency
difference () between the absorption frequencies of sample and the
reference compound. The magnitude of chemical shift in Hz is depends on
the strength of applied magnetic field or proportional to the radiofrequency
used. Therefore, magnetic field is expressed in the unit which is independent
on applied magnetic field i.e. it is in ppm (part per million).
Chemical shift in ppm = (chemical shift in Hz) x 106/(strength of applied
magnetic field in Hz).
The ppm unit of chemical shift is dimensionless and independent on the
radio frequency of the radio rays and applied magnetic field. Fallowing two
scales are used to- (delta) and (tau).
1. (delta) scale- (delta) = in Hz.106/radio frequency in Hz.
2. (tau) scale- (tau) = 10 - .
The position of the TMS protons is taken at 0.00 ppm in scale whereas on
- scale, it is taken at 10.00 ppm.
Strength of applied magnetic field increases
= 10 -
0
1
2
3
4
5
6
7
8
9
10

10
9
8
Low shielded

2
1
0
More shielded

Factor affecting the chemical shiftThe value of chemical shift is depends on the electronic environment of the proton. The
protons with same electronic environment have same chemical shift value. Same of the
following parameter which affect the chemical shift value are listed below-

a) Electro-negativity of the substituentChemical shift differences in proton resonance are due to the inductive effect. If the electron
density about a proton nucleus is relatively high, the induced field due to electron motions will
be stronger than if the electron density is relatively low. The shielding effect in such high
electron density cases will therefore be larger, and a higher external field (Bo) will be needed
for the rf energy to excite the nuclear spin.
Since silicon is less electronegative than carbon, the electron density about the methyl hydrogens
in tetramethylsilane is expected to be greater than the electron density about the methyl
hydrogens in neopentane (2,2-dimethylpropane), and the characteristic resonance signal from the
silane derivative does indeed lie at a higher magnetic field. Such nuclei are said to be shielded.
Elements that are more electronegative than carbon should exert an opposite effect (reduce the
electron density).
The deshielding effect of electron withdrawing groups is roughly proportional to their
electronegativity. Furthermore, if more than one such group is present, the deshielding is
additive and proton resonance is shifted even further downfield.
In general electron-withdrawing groups decrease the electron density on the carbon atom and
therefore of the protons i.e. protons are deshielded. Whereas, the electro-positivity of the atoms
or groups of atoms increases the electron density around the carbon atom and therefore of the
attached protons i.e. protons are shielded.

b) Van-Der walls deshielding [steric hindrance]

In rigid molecules, the protons occupy a sterrically hindered positions therefore, the
electron cloud of the hindered group will shows electrostatic repulsion with electronic
surrounding of protons and protons get deshielded. But this effect is very small.

c) Magnetic anisotropy:Chemical shift (in Hz) is directly proportional to the strength of applied magnetic field. This
is understandable because is independent on the diamagnetic shielding induced by the Bo.
The electro-negativity does not explain the following chemical shift of the following
examplese.g.
CH3-CH3
CH2=CH2
CHCH
R-CH=O
values
1.50
4.60
2.30
9.97
Hybridization sp3
sp2
sp
sp2
This anemology can be explained on the basis of magnetic anisotropy which can be
observed in the compounds containing -electrons. The bonding electrons also produced
secondary magnetic field. The effect of the secondary magnetic field produced by the
circulation of the bonding electrons can be depends on the orientation of the molecule in
the external magnetic field. The different -values of the ethylene and acetylene can be
explained on the basis of chemical/diamagnetic anisotropy effect.
When olefins are placed in the external magnetic field, the alkenes molecules are oriented
in such a way that the plane of the double bond is perpendicular to the direction of the
applied magnetic field. The circulating -electrons generates the secondary magnetic field
which is diamagnetic (has opposite direction to the applied field) around the carbon atom
and paramagnetic (has same direction to the applied field) in the region of the protons.

Any group held above or below the plane of the bond will experience a shielding effect.
CH3

The aldehydic proton is highly deshielded because of chemical anisotropy of carbonyl group and the electro-negativity
effect of oxygen of carbonyl group.

In case of alkynes, the chemical shift value of proton is 1.5 to 3.5. When the alkyne molecules are placed in external
magnetic field, the alkyne molecules are oriented in such a way that the axis of the plane of triple bond of the molecule
is parallel to the direction of the applied magnetic field. The circulation of the -electrons generates the secondary
magnetic field acts in opposite direction (diamagnetic shielding) to the applied magnetic field Bo. The protons are placed
in the diamagnetic zone of the field therefore chemical shift value of these protons are in the range 1.5 to 3.5 (less) than
the expected.
shielding zone
H

deshielding zone

deshielding zone

H
shielding zone
external magnetic field

In aromatic compounds, e.g.- benzene, the -electrons are localized over aromatic ring. The closed loops of the electrons are involved to circulate electrons in presence of the applied magnetic field Bo, to produces a substantial
electric current called the ring current. The induced secondary magnetic field is diamagnetic at the center of the ring; but
outside the ring it is paramagnetic. The ring current in aromatic ring shows greater deshielding than the compound
containing conjugated double bonds.

fig

29.10.2008

1H NMR spectroscopy

37

In case of substituted aromatic compounds, the electron withdrawing

substituents such as nitro group, carbonyl group, etc. causes deshielding of the
aromatic protons. The deshielding of protons is in the order o>p>m. it causes
deshielding mostly at o- and p- positions because of electron withdrawing
resonance (-R) effect which decrease the electron density at o- and ppositions.

The electron donating groups such as amino group, methoxy group, etc.
causes shielding of the aromatic protons. The order of shielding of protons is
o>p>m because of electron donating resonance (+R) effect which increase the
electron density at o- and p- positions. If the substituent shows electron
withdrawing inductive effect along with electron donating resonance effect,
then p- position is more shielded than o- position.

The chemical shifts of protons are significantly affected by the presence of

charge (positive or negative) on the carbon bearing protons. This can be
explained by comparing the chemical shifts of the protons of cyclopentadienyl
anion, cycloheptatrienyl cation with the protons of benzene.
Since all protons in three species are equivalent, therefore gives a sharp
singlet in each case- cyclopentadienyl anion protons appears at 5.42,
cycloheptatrienyl cation protons appears at 9.17 and protons of benzene
appears at 7.27.

d) Effect of Hydrogen bonding:-

Hydrogen bonding involves the transfer of electron cloud from

hydrogen to neighboring electronegative atom through space which
causes deshielding of proton. As the strength of hydrogen bonding
increase, the chemical shift value of the proton will be shifted towards
downfield. The deshielding is due to the lowering of the electron
density of the proton by the electrostatic force of the attraction.
The position of resonance of OH, NH and SH protons in alcohol,
amines and thiols is unpredictable because extend to which the
hydrogen atom involved in bonding will critically depends on the
concentration, solvent and temperature.
The extend of intermolecular hydrogen bonding is decreased on
dilution by non-polar solvent (polar solvent causes additional
complications) and also with increased temperature. Therefore change
in temperature and solvent, shift the chemical shift value of hydroxyl
proton. But intramoleculer hydrogen bonding is unaffected on dilution
and by varying temperature.

Proton Chemical Shift Ranges*

1H-NMR

/ PMR spectroscopy

1H-NMR

spectrum of a molecule gives all the

information about the hydrogens present in it.
number of signals
position of the signals
intensities of the signals
splitting of a signal

8.0
29.10.2008

7.0

6.0

5.0 4.0

3.0 2.0 1.0

1H NMR spectroscopy

0.0
41

 In a given molecule, protons with the same environment

absorb at the same (applied) field strength; protons with
different environment absorb at different (applied) field
strength.

A set of protons with the same environment are said to be

equivalent.
The number of signals in the NMR spectrum tells us
therefore, how many sets of equivalent protons a molecule
contains.

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1H NMR spectroscopy

42

Number of signals

equivalent and non-equivalent protons

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CH3 CH2 Cl

CH3 CHCl

CH3

CH3 CH2 CH2 Cl

CH3 CHCl

CH2Cl

1H NMR spectroscopy

43

spin-spin coupling
Many 1H NMR spectra exhibit peak splitting
(doublets, triplets, quartets etc)
This splitting arises from coupling with adjacent
hydrogen(s)

29.10.2008

the splittings are n + 1 where n is the number of

equivalent and adjacent hydrogen(s).

1H NMR spectroscopy

44

The molecule Br2CH-CH2Br containing two types of protons, therefore it

gives two signals in its NMR-spectrum. But one of it is split it into three
peaks and other into two peaks i.e. we obtained more number of peaks than
the number of kinds of the protons. It is due to the splitting of the NMRsignals. Such splitting of the NMR-signals was depends on the environment
of the absorbing protons; not with respect to the electrons but with respect to
the number of other nearby protons.
Spin-spin coupling is indirect coupling of protons spin through the inventing
both bonding electrons and linking carbon.
It is occurring because there is some tendency for bonding electrons to pair
its spin with a spin of their nearest proton; the spin of the bonding electrons
have been thus influenced. This electron will affect the spin of the other
bonding electron and so on through it to the next proton. This coupling was
not so important beyond three bonds; there is spin strain in small rings and
bridged system or bond delocalization in aromatic or conjugated system.
Spin-spin coupling is observed only when non-equivalent protons are
present in the neighborhood. Carbon does not affected spin because the
spin quantum number of the carbon is I=0.
HA----C----C----HB
HA C
C HB

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1H NMR spectroscopy

46

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1H NMR spectroscopy

47

Multiplicity the n+1 Rule

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1H NMR spectroscopy

48

Magnitude of Some Typical Coupling Constants

Rules for protons signal splitting:-

i) The spin-spin splitting is expected to observe in only between the nonequivalent

neighboring protons.
e.g.
ClCH2-CH2Cl,
.
(no splitting)

ii) Splitting of one proton by another proton of the same carbon is quite uncommon
because they are generally equivalent.

iii) Mutual splitting of the protons separated by the more than two carbon atoms is
very rear except the allylic and homo-allylic coupling, coupling in alkyne.

iv) The number of peaks into which a proton signal is spitted is equal to one more
than the number of vicinal protons (n).
Number of signals = n + 1.

v) All the peaks of given multiplates (d, t, q, etc.) do not have the same intensity.

vi) The magnitude of the splitting (separation of the peaks) or coupling constants
(distance between the peaks) in the doublets is exactly the same as the separation of
the peaks in triplets.

Integration:It the process by which relative areas under the spectral peaks proportional
to the number of equivalent protons giving the signal, are measured. The
integration of the resonance signal is used to determine the constitution of
the mixtures or percentage of the impurity present.

***Multiplicity and intensity ratio****

The number of the peaks into which a proton signal split is calculated by
using following formula asNumber of peaks = 2nI + 1,
Where, I is the spin quantum number of the proton, and n is the number of
the protons present on the adjacent carbon atom coupling partners.
The intensity of the relative signals of multiplates is given by the coefficients
of the equation (a +b)n, where, n is the number of protons present on the
adjacent carbon atom. The multiplicity ratio can be explained by using
Pascal triangle.
Singlet
(1)
doublet
(1:1)
triplet
(1:2:1)
quartet
(1:3:3:1)
quintet
(1:4:6:4:1)
hexete (1 :5 :10 :10 :5 :1)

Spin-spin coupling Notation/different spin system:For the conventions, the protons are labeled by the letters A, B, and C which have chemical
shifts difference comparable to each other. Those far away in chemical shift from each other
are labeled with the later X, Y, and Z and those intermediates are labeled with the later M, N,
and O. The prime simole is used to designate chemically equivalent but magnetically
nonequivalent protons such as HA and HA.
AB- system:AB system consists of two mutually coupled protons A and B which does not coupled to any
other protons. J = 14-18 Hz.
AX- system:Here we get two separate doublets. The chemical shift value of each signal can be obtained
from the middle of each doublet. The value of coupling constant J can be measured from the
spectrum.
AMX- system:This coupling pattern involves interactions between protons separated by four bonds. Each
proton gives raise to four lines in the signal, so that total 12 lines are obtained. The proton A
coupled with proton X causes the splitting of the signal of into doublet, but proton A also
coupled with proton M, so each line of the doublet is further splits into two lines giving four line
in the spectrum of A. The signal of A has two coupling constants JAM and JAX and is therefore
a doublet of doublet obtained instead of quartet. Similarly the M gives two lines by coupling with
proton X and each line will further spils into two lines by coupling with proton A having two
coupling constants JAM and JMX and give a doublet of doublet. Also the X gives two lines by
coupling with proton A and each line will further spils into two lines by coupling with proton M
having two coupling constants JAM and JAM and give a doublet of doublet.
ABX- system:In such system, value between two out of three nuclei is comparable to their coupling
constants J and these both are coupled with third nuclei as well which is largely separated form
these two. The spectrum of such system also exhibits 12 lines/peaks. The protons A and B by
the spectrum consist of pseudoquartents whereas the X proton gives four to six lines.

Coupling constants
The distance between two centers of peaks in a given multiplates is known as coupling
constant J.
It is expressed in cycle per second or Hz and its range is 0-18 Hz except =CH2, J=42 Hz.
Geminal coupling:The two coupling protons are separated by two bonds i.e. these protons are attached to the
same atom. The value of the geminal coupling constant varies with bond angle- = 125o, J =
0Hz; = 105o, J = 20Hz; and = 109.5o, J = 16-18Hz.
Vicinal coupling:Vicinal coupling is the coupling between two protons separated by three bonds from each other.
the value of vicinal coupling constant varies from 2-18 Hz which depends on the position of
protons in space and in the structure of the molecule.
The J value for anti- and trans- conformations is varies from 5-14 Hz whereas that for cis- and
gauch- conformations is 2-9 Hz.
Long range coupling:Coupling takes place between two protons separated by more than three bonds. The long
range coupling constants are smaller in the absolute magnitude 0-3 Hz than the vicinal and
geminal coupling constants.
1. Allylic coupling:It is the coupling occurs between the two protons separated by one double bond and three
single bonds. Cisoid and transoid.
2. Homoallylic coupling:It is the coupling occurs between the two protons separated by one double bond and four single
bonds in the molecules.
3. Long range coupling in acetylenes, allenes, and cumulenes.
4. W- Coupling.
5. Zic-Zac coupling (coupling between the protons separated by five bonds).

We can derive the following information:

The number of different types of protons (the number of signals)

The environment of the protons (the chemical shift)
The number of protons on the neighbouring carbons (the signal multiplicity)
The number of protons responsible for each signal (the integral)

We shall use Paracetamol as an example

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1H NMR spectroscopy

54

Paracetamol from an NMR Experiment

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1H NMR spectroscopy

55

other applications of 1H-NMR

In structure elucidation
2.15, 2H, pentet
2.75, 2H, triplet
3.38, 2H, triplet
7.22, 5H, singlet

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1H NMR spectroscopy

Br

56

In reaction mechanisms

H3C

CH3

H3C

H
CH3

HF- SbF5
liq . SO2
CH3

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2.8, 6H
2.9, 3H
4.6, 2H
7.7, 2H

CH3

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Electronegativity information

CH3

1.56

4.0

CH3
CH3

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In aromaticity and anti-aromaticity

H
H

H
H

H
H

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H
H

H
H

[18] - Annulene ( Diatropic )

8.9, 12H
- 1.8, 6 H

H
H

[16] -Annulene ( Paratropic )

10.56, 4 H
5.33, 12 H

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59

In stereochemistry

H
H3C
H

Br

Br

Br

H
CH3
H

2.13, 6 H, s
3.21, 4 H, s

CH3

Br
H
CH3
H

1.88, 6 H, s
2.84, 2 H, d
3.54, 2 H, d

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H3C

CH3

H3C

CH3

O
O

CH3
H

Ph
H

Ph

Ph

Ph

COOH

Ph

Ph
COOH

J z

J = 12 Hz

CH3

H
N
O

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CH3

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L
S

H
H

H
L

J H,H = 10 Hz

J H,H = 4-5 Hz
( 60o )

( 180 )

C6D11H
H

H
at R.T

at -66.70

at -1100

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1H-NMR

in optical purity

Shift reagents would

distinguishes enantiomeric
protons.
R

Shift reagents generally used

are europium and
praseodymium complexes of
Hfod (6,6,7,7,8,8,8heptafluoro-2,2-dimethyl-3,5octanedione) and/or HDPM
(dipivalomethane)

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R, R = t - butyl

Ln
3

R = t - butyl, R1 = perfluropropyl

1H NMR spectroscopy

R'

63

 Chiral shift reagent

tris[3-(tertbutylhydroxymethylene)-dcamphorato]europium III
O

C+ + R (C+R)
C+ + S (C+S)

Eu

nR - nS
E P = -----------nR + nS
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Problems
1) A colourless liquid A (molecular formula C9H10O2) gives following spectral data:IR:- (frequency in cm-1)- 1720(s), 1602(m), 1581(m), 1270(s), 1105(s) cm-1.
1HNMR (neat): 1.29[3H, t(J= 8Hz)]; 4.35[2H, q(J= 8Hz)]; 7.40[3H, m]; 8.81[2H, m].
Determine the structure of A.
2) An organic compound A having molecular formula C10H12O2 gives following spectral data:
IR:- (frequency in cm-1)- 1730(s), 1602(m), 1581(m), cm-1.
1HNMR (neat): 2.0[3H, s]; 3.93[2H, t(J= 7Hz)]; 4.30[2H, t(J= 7Hz)]; 7.30[5H, bs].
Determine the structure of A.

3) An organic compound gives following spectral data:

UV: The ultra-violet spectrum exhibits no strong band.
IR:- (frequency in cm-1)- 2985(s), 2950(s), 1460(m), 1380(m), 1820(vs), 1750(s), 1050(s) cm-1.
1HNMR (neat): 1.29[6H, t(J= 7Hz)]; 2.4[4H, q(J= 7Hz)].
Mass (m/z Rel.ab.): 29(38), 57(100), 71(0.6), 73(0.6), 74(0.7).
Determine the structure of the compound and explain the principle ion observed in the mass
spectrum of the compound.
4) An organic compound A exhibits only a singlet at 2.17 in the PMR spectrum and prominent
peaks at m/z 58(M+.), 43(base peak), 39, 27, and 15 in the mass spectrum.
When compound A is treated with benzaldehyde and dilute ethanolic sodium hydroxide, it yields B.
the IR spectra of B exhibits the band at 3025, 1665, 1630, 1600, 1495, 763 and 705 cm-1. The
PMR peaks of B gives following signals:- 7.82[1H, d(J= 18Hz)]; 7.60[5H, m(J= 7Hz)]; 7.05[1H, d(J= 18Hz)].
Deduce the structure of A and B.

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66

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