a study of hydrogen bonding
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Rochester Institute of TechnologyRIT Scholar Works
Theses Thesis/Dissertation Collections
3-1-1968
A Study of Hydrogen BondingMary Ann Conklin
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Recommended CitationConklin, Mary Ann, "A Study of Hydrogen Bonding" (1968). Thesis. Rochester Institute of Technology. Accessed from
A STUDY OF HYDROGEN BONDI NG
MARY ANN CONKLIN
MARCH, 1968
THESIS
SU BM I TTED I N PART I AL FULF I LU~ENT OF THE
REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE
APPROVED:
Earl Krakower Project Advisor
Robert L. Craven Sta ff Cha j rman
T. E. Strader Li brary
Rochester Institute of Technology Rochester, New York
Acknowledgements
The author is grateful to the Institute
faculty for accepting her in their Master's program
and for giving her valuable training during her
residence at Rochester Institute of Technology.
The author wishes to express her esteem of
Dr. Earl Krakower and her appreciation of his efforts
in making bhis work come to its conclusion. Much of
the credit for this thesis must be given to his
dedication to productive and fine research, his thor
oughness and conscienciousness in scientific endeavor,
and his ability to communicate his purpose in the
research project to the author.
The author also wishes to thank Dr. Louis Daignault
for the mass spectrometric analyses. She is grateful for
all he taught her and values her association with him.
Thanks are extended to Frederick Delles who aided
the author particularly in the early stages of the work;
and to Mitchell Bogdanowicz for his help in the gas
chromotography experiments.
Dr. Harry Agahigian is also acknowledged for the
very fine NMR training he gave the author prior to the
commencement of this research.
This dedication, to Robert Frost, is .madesince the
poet well expresses the author's feelings in his''Reluctance"
and his "Road Not
ABSTRACT
The proton magnetic resonance technique lends itself to the
study of hydrogen bond equilibria. Through PMR spectra, hydrogen
bonding can be detected. The specific proton which participates
intimately in the hydrogen bond may be identified.
The following work has investigated hydrogen bonding systems
in which the proton donor is trifluoroacetic acid and the proton
acceptor is an N-heterocycl ic base, such as quinazoline, quinoline,*
and isoquinol ine.
From measurements of the chemical shift versus concentration, and
from measurements of the line width at half peak amplitude versus
concentration for the time average exchange signal, the extent of
hydrogen bonding may be determined and the participating equilibria
may be characterized. Two equilibrium constants have been calculated
using the PMR data obtained in this study.
Solvent effects upon the hydrogen bonding equilibria have been
noted in several cases. These effects were similar to those found in
otheV previous investigations and can be explained.
The effect of hydrogen bonding upon the N-heterocycl ic ring has
been observed. The ring protons are chemically shifted upon hydrogen
bond association of the N-heterocycle with the acid. This observation
reveals a charge redistribution in the heterocycle upon complex
formation. There is insufficient data to calculate the charge densities
of these systems, however.
TABLE OF CONTENTS
IV. APPENDIXES ..
V. BIBLIOGRAPHY
Page
I . I NTRODUCT I ON
A. The Hydrogen Bond I
B. Magnetic Properties of Nuclei 7
C. NMR Applications to Hydrogen Bonding 18
D. Charge Density Considerations 30
II. EXPERIMENTATION
A. Synthesis and Preparation Techniques 36
i. Quinazoline 36
ii. Quinoline 39
iii. Isoquinoline 39
iv. Trifluoroacetic Acid 40
v. Chloroform 40
vi. Acid-base mixtures 40
B. Instrumentation 41
I I. RESULTS AND DISCUSSION
A. Acid-base Systems. Two Component Systems 45
B. Solvent Effect
i. Three component system 56
i i . Two component system
a. Dimethy I su I foxide-tri f I uoroactic Acid 60
b. Chloroform- isoqu inol i ne 61
c. Chemical Shift of N-heterocycl ic Ring Protons 63
List of Illustrations
Figure Title to follow
page
I Preparation of Quinazoline 37
II Block diagram R-20 43
III Trifluoroacetic acid spectrum 45
IV Chemical Shift vs Concentration
Trifluoroacetic-Carbon Tetrachloride 45
V Quinazoline spectrum . 46
VI Quinoline spectrum 46
VII Isoquinoline spectrum 47
VIII Chemical Shift vs Concentration
Quinazoline-Trifluoroacetic acid 47
IX Chemical Shift vs Concentration
Quinoline-Trifluoroacetic acid 47
X Chemical Shift vs Concentration
Isoquinoline-Trifluoroacetic acid 47
XI Illustration of line width vs
concentration 53
XII Width vs Concentration
Quinoline-Trifluoroacetic acid 53
XIII Width vs Concentration
Isoquinoline-Trifluoroacetic acid 53
XIV Chemical Shift vs Concentration
three component system 59
XV Chemical Shift vs Concentration
comparison plot for the two and
three component systems 59
XVI Chemical Shift vs Concentration
Trifluoroacetic -Dimethyl sulfoxide 60
XVII Chemical Shift vs Concentration
Isoquinoline-Chloroform 62
Figure Title to follow
page
XVIII N-hetero ring protons
Chemical. Shift vs Concentration
Quinazoline-Trifluoroacetic acid 63
IXX N-hetero ring protons
Chemical Shift vs Concentration
Quinoline-Trifluoroacetic acid 65
XX N-hetero ring protons
Chemical Shift vs Concentration
Isoquinoline-Trifluoroacetic acid 65
XXI N-hetero ring protons
Chemical Shift vs Concentration
three component system 65
INTRODUCTION
The Hydrogen Bond
The formation of a hydrogen bond results from an interaction
between a donor molecule, A-H, and an acceptor group, B. This inter
action usually involves two functional groups: the acidic (e.g.,car-
boxyl or hydroxyl group) and the basic (e.g., nitrogen in N-heterocycl es)
The proton donor, A-H, and the proton acceptor, B, molecules have
strongly electronegative atoms between which the hydrogen atom lies.
A stable hydrogen bond will only be formed if the charge distribution
of the A-H bond orbital is such that the proton is sufficiently un
screened. The molecules associate rapidly and reversibly to form
molecular aggregates known as complexes. The hydrogen lies between
the two electronegative atoms and shares an electron pair with each (30).
This association is written as:
A-H + B * A-H...B (C)
The bond formed is relatively weak; usual bond energies are in the 2-15
Kcal/mole range (17,31). For example, the dimer of trifluoroacetic acid
gas has a bond energy 6.85 0.2 Kcal per hydrogen bond per mole;
aniline in solution has a bond energy of 1.93 Kcal/mole while methanol
in carbon tetrachloride has a bond energy 13 Kcal/mole (13).
It is difficult to suggest a universally acceptable definition of
a hydrogen bond. However, Pimental and McClellan offer their criteria
for hydrogen bond formation:
"A H-bond exists between a functional group, A-H, and an atom
or group of atoms, B, in the same or different molecule when
(a) there is evidence of bond formation (association or
chelation); and (b) there is evidence that this new bond
linking A-H and B specifically involves the hydrogen atom
already bonded toA."
(54)
2
There are three theories of hydrogen bonding (36): the electro
static approach (52); valence-bond approach (17); and the molecular-
orbital approach (45).
The Is configuration of hydrogen (with the 2s and 2p orbitals
having too high energies) allows hydrogen to form only one covalent
bond (17,31).
The electrostatic approach considers the case of two dipoles and
their attraction.
-A-i+H &S~3t.
The closer B approaches H the stronger the electrostatic link between
them is. Some pairs of electrons, such as those found in N-heterocycl ics,
often determine the strength and direction of hydrogen bonds. This
approach has been supported by studies about solvent effects of H
bonding (48). The electrostatic approach is supported theoretically by
quantum mechanical rules (52). Another supporting evidence is that
hydrogen bonds are formed by fluorine; e.g., HF and specifically a
symmetrical H-bond is formed in HF . There is a possibility that the
nature of the actual hydrogen bond lies somewhere between the electron-
pair structure and the ionic structure. The electrostatic approach
provides an explanation as to the fact that only electronegative atoms
form such bonds (31).
The valence bond approach presents possible structures contributing
to the hydrogen bond, such as
covalent A-H bond
ionic A-H bond
covalent H-B bond
ci7;
(1) A-H B
(2) A H . . . . B
(3) A"HB+
(4) AH . . . B
3
Proponents of this approach indicate that the covalent contribution
may be significant (17,18). This treatment has received experimental
support from studies on the proton accepting power of a series of
compounds (49). The order of proton accepting power or hydrogen bonding
strength is the reverse of the order of magnitude of electrostatic
attraction. It was suggested that, for atoms having non-bonding or
lone pair electrons, a possible contribution is made by the charge
transfer force arising from stabilization due to electron migration
from a base to an anti-bonding hydroxyl orbital f an acid (48). The
proton donor and proton acceptor act as electron acceptor and electron
donor. Further work in the vacuum ultraviolet region was suggested
for examination of a possible resonance between structures A-H B
and A H B which if found would support this approach.
The molecular orbital approach (53) considers the molecular orbital
on either side of the hydrogen atom. The molecular orbital contains
two electrons by which the hydrogen is weakly bonded to both the
electronegative atoms, A and B. The electron pair in the A-H bond
are tightly drawn to the electronegative atom. This bonding electron
pair is pulled from the first valence shell into the second valence
shel I of hydrogen. The hydrogen then may form a weak bond with some
electron-pair donor such as nitrogen (44).
Certain conditions are necessary in the potentially hydrogen
bonded system for the association. They include a geometrical config
uration which allows H bonding and an electron affinity of the atoms
sharing the hydrogen. How our choice of compounds would fit these
criteria will be discussed later.
4
The particular arrangement of the three atomic centers involved
in the hydrogen bond is not yet established. The linearity of A-H...B
is said to be energetically favored (54), but work revealing that cyclic
dimers are often formed by hydrogen bonding molecules supports a non
linear arrangement of the three atomic centers. One example is the
dimer of acetic acid which is known to be self-associating.
H .0...H-C1 H
I // \ I
H-C-C C-C-H
\ SH
0-H...0'H
There are two types of hydrogen bond. The first, and most common,
is the intermolecular hydrogen bond in which the groups, A-H and B,
are in different molecules. Intermolecular hydrogen bonds can produce
polymers; that is, the complexes are not restricted to dimer size.
An example of intermolecular hydrogen bonding is given by trifluoro
acetic acid and quinoline.
0. .0
Xc^
tF-C-F
or by trifluoroacetic acid itself.
F O...H-0. F
I sf \ \
F-C-C C-C-F
I \ #F 0-H...0 F
The other class of hydrogen bonding is intramolecular, where the
groups A-H and B are part of the same molecule. Intramolecular hydro
gen bonding is also called chelation and is commonly found in ortho-
5
compounds where five-, six-, or seven-membered rings are formed by this
chelation. For example, 5,8-d ihydroxy-a-naphthoquinone is known to
Form intramolecular hydrogen bonds:
In contrast to intermolecular hydrogen bonding, the species
resulting from intramolecular hydrogen bonding does not have an
increased molecular weight, increased melting or boiling point, nor
decreased vapor pressure.
It shall be shown in subsequent discussion that certain properties
of intermolecularly hydrogen bonded systems are remarkably concentra
tion dependent. Such concentration dependence either does not exist
or is very small for intramolecu larly bonded systems.
Association in hydrogen bonding is a rapid and reversible process.
For a two component system there should be several equilibria operating
at once. Possible processes include:
A-H + B - AH . . . B
A-H. . . B
->
A . . .H B
A . . . H B->
+ H +BH+
B + B B + H +B
A-H + f- + H-A 43
The formation of a hydrogen bond is sensitive to several variables;
e.g., temperature, concentration, and solvent (if the hydrogen bond
system is in solution). Often the presence of hydrogen bonding in a
6
system is detected by the sensitivity of the acid-base system to these
(variables.
The hydrogen bond can alter the mass, shape, atomic and electronic
arrangements of the molecule. Hence, hydrogen bond formation modifies
!both physical and chemical properties. It is this feature that makes
the following work possible.
Proton magnetic resonance spectroscopy. PMR, is a useful technique
which is applicable to the study of hydrogen bonding. PMR directly
indicates the role of the hydrogen atom in hydrogen bond formation
and supplies information about the electronic charge distribution of
the hydrogen bond system (55).
Magnetic Properties of Nuclei
The PMR technique involves radiof requency-induced transitions
between energy states of a nucleus polarized by a magnetic field. The
nucleus giving rise to the PMR spectrum possesses angular momentum
and spin.
The maximum measurable vector of the angular momentum of the
nucleus must be, according to quantum mechanical rules, an integral or
half-integral of h/2ir or tf; h being Planck's constant, tf is called the
modified Planck's constant. This maximum measurable vector of the
angular momentum, the spin quantum number, is designated by I. If
1=0, the nucleus does not give rise to a NMR signal. The nucleus may
have (2 1+ I) states; the permitted values of the moment along any
one direction may be described by the magnetic quantum number, m.
m = I, (I - I), (1 -
2), ... (-T + I), - I.
The magnetic moment of the nucleus is parallel to the spin
quantum number. When the spin quantum number is zero, the magnetic
number is zero. When I has a finite value, the magnetic vector, u, is
described by my/ 1.
8
The magnetic properties of the nucleus may be described by a
ratio since the vectors y and I are parallel.
h"
P= J-(I'K) = /(I %-) Equation I
}f is the magnetogyric ratio.
The spin of the nucleus is related to the electrical quadruple
moment, which describes the distribution of electric charge about the
nucleus. The electrical quadruple moment, 0, measures the non-sphericity
of the electric charge distribution.
Only nuclei with I > I possess electrical quadruple moments; that
is, hydrogen H having 1 = { does not possess an electrical quadruple
moment so that PMR investigations should not involve any direct
interaction of the spin with the electric charge distribution. However,
14nitrogen N possessing a spin 1=1, has an electric quadruple moment,
Q = 2 x I0"2.
The nucleus in a homogeneous external field H with the magnetic
moment vector u in the z direction possesses energy-
yH . y may
have (2 1+ I) distinct, equally-spaced states which are separated by
The nucleus which absorbs radiof requency quanta will undergo
transitions between energy levels expressed by different magnetic
quantum numbers; e.g., m = 0 and m =-{ if 1 = i for the nucleus. From
the Bohr relation E = hv where E is the energy of the transition, h is
the Planck constant, and v is the frequency of the radiation absorbed,
since the neighboring energy levels are separated by y H / 1.
hv = yH / 1 Equation 2
pHov
= tt~ = Ht*t Equation 3
Ih o JhM
This frequency may also be expressed in terms of the magnetogyric ratio.
^ =
IH=
24mT)Equation 4
/Ho2tt
Equation 5
v is the frequency of the radiation required for the nucleus in the
magnetic field H to undergo the transition between neighboring levels.
If the environment of the nucleus is ignored, the transition
occurs at a characteristic frequency which is pnoportional only to the
external applied magnetic field, H,and the magnetogyric ratio, o .
The magnetic environment of the nucleus, however, may be effected
by neighboring nuclei and electrons. In solids, where molecular
translation and rotation are inhibited, the magnetic moments of
neighboring nuclei alter the magnetic field felt by the nucleus in
question. The strength of the field due to a neighboring nucleus at
distance R is within + 2y/R and- 2y/R ; the spectral signal of the
nucleus in question would be broadened since the resonance condition
occurs over a range of frequencies. In liquids and gas samples, however,
where molecules translate and rotate freely, this magnetic dipole
broadening cancels out to zero. Due to rapid molecular motion, there
fore, this dipole-dipole interaction may be neglected.
Electrons about the nucleus in question also alter the magnetic
field felt by the nucleus. The magnetic field induces an orbital
motion thereby setting up currents within the molecule and a secondary
magnetic field, each of which is proportional to the external field.
The molecule acquires a diamagnetic moment because of this induced
10
motion of its electrons. The field felt by the nucleus is proportional
to and slightly smaller than the external field.
H. = H ( I -
cr-) Equation 6local o
The parameter, <^, is the screening constant and is dependent upon
the electronic environment of the nucleus. Non-equivalent nuclei
experience different diamagnetic electron screening and, as a result,
give rise to different resonance frequencies. This change in the
resonance frequency is called the chemical shift, ?. Each chemically
distinct nuclei exhibits a characteristic chemical shift. The chemical
shift is proportional to the external magnetic field, H,and may be
expressed in gauss, or hertz (where one hertz is equal to one cycle
per second. )
The resonance frequency of the nucleus is also effected by inter
actions known as electron-coupled spin interactions or spin-spin
coupling. This interaction between nuclear spins of non-equivalent
nuclei occurs through the bonding electrons; it is independent of the
external magnetic field. The energy of the interaction is proportional
to the product of nuclear spin-vectors. - The proportionality constant,
J, is known as the spin-spin coupling constant.
If the interaction of two non-equivalent nuclei is considered, one
nucleus via the bonding electrons feels the spin orientations of the
second nucleus corresponding to (2 1 + I). If for the second nucleus
I = i then the first nucleus sees 2{{) + I or 2 orientations and its
resonance frequency signal will be split into a doublet, or into two.
This multiplicity of the PMR signal of equivalent nuclei is thus
determined by the neighboring group of equivalent nuclei. The neighboring
1 1
group because of spin-spin coupling splits the peak of the nuclei in
question into (2n 1+1) multiplets, where I is the spin quantum number
of the neighboring nuclei and n is the number of nuclei on the neigh
boring group.
In summary of the foregoing discussion, the magnetic nucleus, i,
giving rise to the PMR absorption signal undergoes transitions between
energy levels. The Hamiltonian operator, ~)\ ,describes these levels
and is given by
X= ^f I Y. H (I -o-.) I(i) Equation 7
i
orJ^
=j-; I Y. H. T(i) Equation 8
i
The Hamiltonian operator, 2 , describing the spin-spin coupling between
nuclei, i and j, is given by
J( =.f. J.. I(i) I(j) Equation 9J J
So long as dipole-dipole interaction is neglected (which it may be if
molecular motion is high and this effect is reduced to zero), the
complete Hamiltonian to be used shall be
Equation 10
Now, it has been stated above that PMR spectroscopy involves the
transitions of a nucleus in a magnetic field between energy levels
designated by the magnetic quantum numbers; e.g., m = + , m = 0 when
I=i. These transitions require the absorption and release of energy.
The transfer of this energy is accomplished in part by nuclear
precession, a property of the magnetic nucleus.
12
When a nucleus, i, is in a magnetic field, H., it precesses about
an axis parallel to the direction of the field. This is illustrated
below:
The angular velocity of the precessing nucleus is id. . This u.,
the Larmor precession frequency, depends upon the magnitude of the
angular spin momentum, 1., and the magnetic moment, y., of the nucleus,
or the magnetogyric ratio of the nucleus V. . w. depends also on the
field seen by the nucleus, H..
u. = V.H.I ii
Equation 11
This nuclear precession is an integral part of one relaxation
mechanism. Relaxation of the nucleus begins as soon as it absorbs
energy. Atoms or molecules move rapidly as a result of thermal energy
Such thermal motions set up oscillating magnetic fields which may have
the same frequency vector as the precessing nuclei. The effect of such
thermal motion could be then to change the magnetic quantum number of
the precessing nuclei. That is, transfer of energy from the relaxing
nucleus may occur by its transition from one state to another because
of the magnetic field induced by thermal motion of neighboring magnetic
nuclei and molecules. Eventually thermal equilibrium with the other
degrees of freedom is established. This relaxation depends on
temperature, concentration, and viscosity. It is called longitudinal
13
relaxation, or the spin-lattice relaxation time, T., explained here,
in part, by one of many relaxation mechanisms.
The second form of relaxation is called transverse relaxation,
or the spin-spin relaxation time, T. If several nuclei precess about
axes parallel to the same magnetic field and these nuclei do so in phase,
there results a rotating magnetic vector perpendicular to the axis
of the magnetic field. When this precession of the nuclei fall out of
phase, the rotating magnetic vector would diminish to zero. The rate
of this type of relaxation is known as T. Any factor which tends to
hasten the loss of phase of the several precessing nuclei shortens the
spin-spin relaxation time, T?. Such factors include a non-homogeneous
applied field, and non-homogeneous internal field within the sample as
effected by sample viscosity. These relaxation mechanisms have an
effect on the character of the PMR signal. The line width of the PMR
signal is determined by, among other effects, the relaxation times. The
line width is of the order I /T and; especial ly noticeable in viscous
liquids or solids, when T is decreased, the line width becomes very
broad.
Because the PMR technique involves the placement of molecules in a
magnetic field, an essential part of the background is a discussion of
magnetochemical properties of molecules.
An applied magnetic field polarizes a molecule placed in it by
inducing electronic orbital currents and spin alignments within the
molecule. Aspects of the magnetic susceptibility of molecules are
relevant to the understanding of PMR spectroscopy. The magnetic field,
H, and the induced magnetic moment per unit volume, M, are related by
H = XyM Equation 12
14
where X is the volume magnetic susceptibility and depends only on the
substance placed in the magnetic field.
The induced magnetic moment is parallel to the field when X is
positive. In this case the substance is said to be paramagnetic; para
magnetism usually occurs in substances having electrons with unpaired
spins. Substances are diamagnetic when X is negative.
The molar magnetic susceptibility, X, may be defined by
X = v Equation 13m
where M is molecular weight and d is density.
In substances having little symmetry, the relationship H = X M
may not hold, and magnetic susceptibility may have to be expressed by
three vectors alonq three directions I, 2, and 3: X = l/3(X. + X + X,),a ' '
m I 2 3
The substance is said to be diamagnetical ly anisotropic if
X. =
Xy r X.,.
The Bloch equations apply to the macroscopic moment, M, when all
nuclei are acted on by the same field, H . M is the resultant magnetic
moment per unit volume, for several nuclei of magnetogyric ratio, J ,
in a magnetic field, H, acting in the z direction and i>5 is the
angular frequency of Larmor precession.
iM = YMH =a) M Equation 14
dt o o
Since M has components M,
M,
Mr x' y'
z
Equation I 5x
Equation I5y
-rr~~
0 Equation I5z
dMX
dt=
u Mo y
dM
to Mdt O X
dMz
0
These equations for the x, y, and z components of the magnetic moment
per unit volume must be modified by consideration of fluctuations and
relaxation effects so that since M approaches M,
zrK o'
dMz
M - Mz o
dt T
dMX
dt
M
u M - =*
o y T2
dM
Y -
dt
M
-uM- /
ox T
Equation I6z
and
Equation I 6x
Equation I 6y
where T. is the longitudinal relaxation time and T is the transverse
relaxation time.
In a case of rapid molecular motion the local magnetic field
changes rapidly and the above equations must be modified. The corre
lation time, / ,is introduced by Bloch as a measure of the fluctuation
rate of the local magnetic field. If the fluctuations are very rapid,
then
w"/ < < Io'c
the/decay of all components is equal; M,
M,
M becomes identical and' K ^ x' y'
z *
T.=
V
If H. is a field perpendicular to H and is rotating with angular
frequency, u), then it has component
(H.) = H. cos cj t Equation 17I x I
^
(H.) =-H. sin u t
I y I
16
The complete Bloch equations follow:
dM M
- = Y(M H + M H. sin wt)- -^ Equation I8x
v
y o z I TM
dt
dM M
-j^- = YW H. cos tot- M H ) - =^ Equation 1 8y
dt z I x o T_'
dM M_
M
-rr- = )f(-M H, sin tut- M H. cos u>t)
-
^dt x I x I T.
Equation I 8z
These Bloch equations refer to a fixed coordinate system described by
directions x, y, and z. The coordinate system may be allowed to rotate
about the z axis with angular velocity -to. The new vectors of the
macroscopic moment, the in-phase component of M, u, which is parallel
to the direction of the applied field, H,and the out-of-phase com
ponent, v, which is perpendicular to the direction of H., may be related
to the fixed macroscopic moment vectors by
M = u cos cut- v sin cot Equation 1 9x
xM
M =-u sin <jjt
- v cos tot Equation 1 9y
Substitution of these relationships into the Bloch equation yields
-rr + ^ + (to -
to)v = 0 Equation 20dt T o
N
dv v
-rr + zr- - (oi -
to)u + vH.M = 0 Equation 20vdt T o I z
M
dM M - M
-rr- +-^f
- Yh.V = 0 Equation 20zdt T. I
^
If the rf field H. is not large, M is nearly M the equilibrium value
of that polarization so that
dv v-rr + =r-
- (to -
to)u + vH.M = 0 Equation 20vdt T o I z
M
17
becomes
dv. + Y_ _ ( _ u)u + vH M = o Equation 2I\
dt T o I o
18
NMR Applications to Hydrogen Bonding
The formation of the hydrogen bond changes the physical and chemical
roperties of the molecule. Hydrogen bond formation thus affects a
change in the electron distribution of the molecule. As previously
stated, the electron environment of the proton influences the magnetic
field the proton experiences. That is, the hydrogen in the unassociated
molecule experiences a different magnetic shielding than the hydrogen
in the associated state.
There would be, upon hydrogen bond formation, two possible effects:
(ignoring the possibility of intermolecular, donor-acceptor, electron
currents) (55).
(I) The proton of the acid, A-H, experiences a field due directly
to currents induced in the B atom of the base; this may lead
to a contribution to the proton chemical shift.
(2) The base atom, B, disturbs the electronic structure of the
A-H bond and, thereby, alters the magnetic susceptibility
of the proton. A change in the shielding constant results;
this change would be reflected in the chemical shift of the
proton (55).
Upon hydrogen bond formation there is a down-field shift of the
A-H proton PMR signal unless the base B is an aromatic pi-electron
system (54,60). This implies that in association there is a decrease
in the diamagnetic shielding; i.e., the proton is more"bare"
because
the proton's electron environment has been repulsed by the base electrons
(66).
This downfield shift due to association has been observed frequently
(41,42,43). In a proton study of quinoxaline
in inert solvent, dichloromethane, CH_CI,
and in trifluoroacetic acid, CF-COOH, Blears and Danyluk (14) noted
19
downfield shifts for all protons when the protonating solvent was used.
They attributed the deshielding to the formation of a conjugate acid
with the heterocyclic nitrogen accepting the proton. Upon association,
the charge density about the ring is changed, and this alters the
shielding of the ring protons. This change in electron distribution is
not yet we I I understood.
Rapid equilibria between the species (conjugate acid and base, the
salt, the original base and acid) in acid solutions was indicated,
according to Blears and Danyluk, by the symmetry of their spectra, type
AA'BB'. A more complicated spectra, type ABCD, wou I d have been expected
if the protonated heterocycle lifetime were significantly greater than
the exchange rates between it and the proton donor, or it and possible
tautomers (14).
It may be added here that the ABCD pattern arises from four non-
equivalent nuclei of the same species and a AB arises from four nuclei,
two of which are equivalent to each other and non-equivalent to the
remaining two. The more complicated spectrum would appear when the life
times of the four-equivalent nuclei are long enough for a characteristic
signal to appear for each.
It is assumed that the proton exchanges between the heterocycle
and the acid, and that it spends about equal time with each. When the
mean lifetimes of the protonated heterocycle and the acid are long
compared with the exchange rate time, sharp resonance peaks are
observed for the species. But when the lifetimes are shorter and compare
with the time of exchange; a single resonance peak is observed at a
chemical shift intermediate between the chemical shifts of the two
species (62).
20
This is to be expected upon consideration of the Bloch equations.
A case of a proton exchanging between two sites is pictured in figures
(a) through (d) below. Figure (a) depicts the spectrum when the life
time of either site is long; figure (d) depicts the spectrum when
exchange is rapid and lifetimes are short.
T(.u -
to. ) = 10a b
(b)
"y(co -
to, ) = 2a b
(d)
The hydrogen bond system is in a state of dynamic equilibria where
the hydrogen atom of the acid may be in any one of several chemical
environments.
ft) CF-jCooU + C.FjtOOH
21
0---H-0
o -
u-o
& /w <LP3 COO VA
<X*l <TT3 f3
<^x Cv CN
c^ 6 ^ VA -ft
+ CF3CQOV-\
6 - U-&
o
W-o>^F3
QC')A- (Lv\COo\A
..H-On
o"
x<2>
+ CF3Coov\VA-O
o
Nc-cr,
(W .. ^]
5Jp-CF
\AO-
0."^)
. u-o\
C-C.F.
o
'\&H- Os.
O'/C-^3
22
tS) \+- O
o
N
C-CF,// 3
E)fe>Uv...
ft"
] ;=
r h'7^ H
B\AV
+
ft"
o>
.?
C.-CF7
Qa.E)<s
') VA\.7o-C - C F,
-K
uv-V- CF3COO
QC) .*
rvi U .... o
C-^F,//
r>l Hv C_ F3 COO
*-)VI'..
.-O.
C-CF
//
-V- C F3 C OO
0-BWV
+ "% B A- "Vv\
G) A- f^-W P\- V-\ + C\
*The quinazoline equilibria are represented in this manner because
it is not yet known whether nitrogen 1 or nitrogen J>, or both
participate in the hydrogen.
23
Should the exchange of the proton between these various species occur
rapidly, the resonance signal of the proton in any one of its environ
ments cannot be separated from the signals of the proton in the other
possible species. That is, the resonance signals of the proton involved
in rapid equilibria may coalesce. The rapid equilibria cause only a
time-average environment of the proton to be detected, and one resonance
signal often called the "exchange-averagepeak"
results.
Because the width of the proton resonance signal may be thus
effected, it is well to consider the Bloch equations which, modified,
describe the system undergoing such equilibria or proton exchange.
The Bloch equations for the in-phase, u, and out-of-phase, v,
components of the macroscopic moment are expressions of a complex
equation. A complex moment, G, is defined by
G = u + iv Equation 22
so the equation becomes
|j + [j- - i(u -
co)]g =
-iVH(MoEquation 23
This equation for G describes the macroscopic moment, M, where all
nuclei see the same field, H .'o
However, nuclei in different chemical environments experience
different fields due to the shielding effect,
H. = H (I -<P) Equation 6i o
^
where <r> is the screening or shielding constant.
The resonance frequencies of non-equivalent nuclei are corres
pondingly different; if the Larmor frequencies are designated to. and
uD for different environments A and B. Then the macroscopic momentsD
will be independent and described by equations.
24
I - i ( co-
to) G. = - i V M . H Equation 24
i\A
dG- i ( ok -
to)
B
\K M. H. Equation 24a
B
In order to modify these expressions to allow for exchange between
environments A and B, the populations of the nuclei in these positons
need be considered. If /. is the mean lifetime of the nuclei in AA
and Tais the mean lifetime of the nuclei in B, the population at
D
A, p., and at B, pRshould satisfy
pA+
pb= ' Equation 25
and may be related to the lifetimes of the nuclei in these two states
by
r, rB
The Bloch equations then become
dG
B^A
+
nEquation 26
d*- i (w. -
to)
"A
A
C C
irH.Mo + -I -A.
1A ^B rA
Equation 27
dG
T2L B
- i (to_ -
to)
GA GRGD
=-iJH.M + ^A
- j-
B 'B TA rB
The total complex moment, G, is given by the sum G. + G .
G =-i^H.M
"I o
r +7 rA B A B
f-- i(coA-to)
uA
ji (toR
-
to)
I + = i (to. -
co) i (toR-
to) rBi i
Equation 28
25
If the lifetimes of the nuclei are very short, then this expression for
"he total complex moment becomes
G =-iVh.M
I o
^A+ %
ri- i (to -
to) r*+ri
T2B
i(coB- . to)'B
Equation 29
The imaginary part of the complex moment represents a mean resonance
signal with frequency
mean PAUA+
VbEquation 30
and with width
'A
VEquation 31
The transverse relaxation time, T, may be quite smaller than the
longitudinal relaxation time, T. ; and the two signals may not collapse
completely, but will instead produce a wider exchange-average peak.
This occurs when the exchange of the proton is not rapid enough to give
complete collapse.
JB(co - to
)2
- 7l) Equation 322 2
'A PB A B 8
A B
The exchange between sites as described by the above expressions
is precisely the circumstances of the proton in hydrogen bonding.
The line broadening effect due to hydrogen bond formation may
thus be explained. The degree of downfield shift varies for the protons
of the N-heterocycles depending upon which ring they are on. The
degree of shift may be used as a qualitative indication of the relative
electron densities of the carbon atoms to which the ring protons are
bonded (46). Also, the degree of PMR signal shift upon association is
26
thought to correlate with the hydrogen bond strength. The shielding
of the protons in the N-containing ring is effected by several factors
in that ring, namely; (I) the electric field of the ring nitrogen,
(2) the magnetic anisotropy of the nitrogen, (3) the diamagnetic
anisotropy of the pi-electron cloud, and (4) the pi-electron density
of the ring and the charge.
Nitrogen possesses a quadruple moment, 0, which it is recalled from
above, a measure of the non-sphericity of charge. This environment
*
about nitrogen would effect especially those protons nearest nitrogen.
Line spectrum may be broadened due to quadrupolar relaxation.
The downfield shift of all the heterocycle's protons may be
explained by the delocal i zation of the charge deficiency, and the
coincidental deshielding of the pi-electron cloud.
The PMR signal of the carboxyl proton of the acid in the system
also experiences a downfield shift upon hydrogen bonding. This proton,
since it is directly involved in the hydrogen bond, is expected to
exhibitthe greatest chemical shift dependence on concentration (65).
Upop hydrogen bond formation the polarity of the A-H bond increases (3).
The greatest downfield shift occurs when the proton is deshielded to
the greatest extent; this occurs when the hydrogen bond association is
the strongest (22,27,41).
The PMR signal of the acid proton involved in the hydrogen bond
may shift upfield upon association with an aromatic base (60). This
is caused by induced diamagnetism by the pi -electrons. The applied
magnetic field causes the pi-electrons to circulate around the entire
ring skeleton. Because of the circulating pi-electrons a secondary
or local magnetic field is set up which augments the applied field
27
outside of the ring but in the same plane. Above and below the
romatic ring, the secondary field opposes the applied field (28).
hould there be an association between the proton donor and the pi-
electron cloud, as in (a) the acid proton would be in the area and
the acid proton signal would appear upfield (60).
A/-, N..H-A
H
(a) (b)
The hydrogen bond shift is temperature and concentration dependent;
a feature that has often been used to identify the intermolecular
interaction as association or hydrogen bond formation (45). Early
workers (8,50) using ethanol observed the temperature deoendence of
the hydroxyl proton chemical shift, and the temperature independence
of the CH, and CH proton chemical shifts. Increased temperature caused
the hydroxyl chemical shift to move upfield as did dilution by inert
solvent. This can now be explained as the disassociation of hydrogen
bonded species causing the upfield (toward chemical shift of unassociated
states) shift. Solvent dilution, since it produces the same effect
as temperature increase, may be used more conveniently.
Often to obtain the chemical shift for the non-associated state,
the compound is successively diluted with inert solvent and the results
are extrapolated to infinite dilution.
It has been noted that the temperature dependency of the chemical
shift of acid-base systems may not be entirely due to a shift in the
hydrogen bond equi I ibria. The slight te-'ioerature deoer.dency of the
28
chemical shift of the proton participating in the hydrogen bond may
arise from temperature dependent changes in the effective length of
the bond H...B (28,68).
Chemical shifts are also susceptible to changes in solvent (64).
The equilibrium constant of association can be estimated from the
chemical shifts measured as a function of concentration (35,54).
For this calculation the unassociated and the complexed species
are assumed: ( I ) to have characteristic precessional frequencies,
v and v ; (2) each species has a lifetime longer* than 3 x 10 sec;
and (3) the observed frequency, v', is a weighted arithmetic mean of
these.
C = moles of complex
A =moles of acid or proton donor
B =moles of proton acceptor
v' =
a VC+
VAEquation 33 (35)
v. and v are obtained by extrapolation to infinite dilution of a plot
of values from a PMR study of pure acid.
vc(O (A + B - C)
K "
(A - C)(B - C)Equation 34
For systems in which the proton donor is self-associating another
expression may be used (54).
A' = moles of proton donor not associated with base
Y = fraction ofA'
which is monomer
A = A' + C
M = moles of monomer,Ya'
v' is measured PMR frequency
v1 = ( jA v + (G-jv Equation 33
29
v is characteristic precessional frequency; a weighted average
frequency of monomer ncjquency of monomer not hydrogen bonded to B.
Qv' = v + (v. - v) Equation 35
I I I Ic
.. ,,
l=
TTi r ix + Equation 36v'
- v K(v. -
v) dC v - vM
A A
A plot of : versus-rr-
should be straight line, from whichv - v do
v. - v and K may be determined (68).
From temperature dependence studies the enthalpy of association
AH may be estimated (35) by use of the expression
AH/RT2
= OlnK/aT)P
30
Charge Density Considerations
Other protons in the system experience altered resonances upon
hydrogen bond formation. The ring protons of the aromatic base show
a change in chemical shift as association occurs. This change in the
chemical shift may be used as an indication of a redistribution of
the heterocyclic pi -electrons.
Recall that the chemical shift is a function of the applied field,
H,and a local factor, the screening constant, er-. (See equation 8)
The shielding constant at nucleus I is the sum several contributions.
An expression of these combined contributions has been proposed.
<r = <^''
+ (r'''
+ Il'2+<rl'rIn3
1 d P2t\ Equation 37 (63)
/T- I Iwhere d
'
is the diamagnetic contribution from the electrons on
atom I,
CT* 'is the paramagnetic contribution from these electrons.
I 20-
'is the contribution from the electrons on atom 2, that is, a
neighboring anisotropy effect. <EP'
is the contribution due to ring
or non-localized electronic currents. These contributions determine the
screening constant which, in turn, determines the chemical shift (II).
The importance of ring currents in determining aromatic proton
chemical shifts has long been recognized and estimates of the contribution
have been attempted.
The theoretical contribution of the pi-electron ring current of
benzene to proton shielding has been estimated as -2.24 to -2.76 ppm.;
estimates based on experiment evaluate the contribution to be between
-1.48 to -1.44 ppm. (II). Despite this discrepancy, the contribution
is seen to be large enough that one wou I d expect detectable changes
in the -chemical shift upon redistribution of pi-electron density.
31
Conversely, one would expect changes in the electron distribution
to be indicated by changes in the shielding parameters of ring
protons.
Quantitative effects of the charge density distribution on
chemical shifts of ring protons are difficult to determine, but it
is valuable to correlate the order of chemical shifts with the order
of charge densities. This correlation is based on the assumption
that the chemical shift of the proton is displaced by an amountpro-
portional to the pi -electron density on the ring carbon atom to which
it is attached.
Early workers recognized this interrelationship of ring electron
distribution and ring proton chemical shift. Shifts of aromatic
protons upon dilution with solvent were attributed to a "ringcurrent"
effect (65).
Much work has been done to correlate the chemical shift of
aromatic nuclei with the known inductive and resonance effects of ring
substituent groups. Taft, et.al. (67) investigated substituted
f I uorobenzenes in carbon tetrachloride. Electron withdrawing groups,
or deactivating meta directors, were found to cause the fluorine
resonance to shift upfield, while electron releasing, or activating
ortho-para directors, caused a downfield shift of para fluorine and
an upfield shift of meta fluorine. Comparative results were found by
Corio and Dai ley (19) who studied substituted benzenes. The ortho, meta,
and para protons exhibited a shift to high field of the chemical shift
when electron withdrawing groups were substituted, and a low field
change in chemical shift when electron releasing groups were placed
on the ring. The meta directing groups shifted the meta and para
32
protons equally, but shifted the ortho proton a great deal. The
Corio and Dai ley qualitative determination of electron density (19)
indicated q < q = q : that is, the charge density at the meta
x> ttiNp' '
and para positions are about equal and both are greater than the
electron density at the ortho position.
In the attempts to correlate electron density with chemical
shifts several important conditions must be met. The degree of
hybridization of the attached ring carbon atom must remain unchanged.
There must be no change in the contribution to cr of the sigma bond
between the ring carbon and proton. Buckingham points out that this
second condition might not be met in reality. He states that
although inductive effects of substituents do contribute to pi-electron
distribution, since the protons are removed from the ring by the sigma
bonds, it is "dangerous to try to correlate proton signals with
pi-electron densities as the associated carbonatoms."
(16) Buckingham
concludes that the chemical shifts can be better accounted for in
terms of the electrostatic field created in the molecule.
Proton-transfer studies involving aromatic heterocycles have detected
alterations of ring proton chemical shifts due to hydrogen bonding (43,65).
These changes have been attributed to redistribution of pi-electron
density upon formation and dissociation of the hydrogen bond.
The first problem to be considered in this study is whether or
not the acid-base interaction is indeed the expected hydrogen bond
association. The second problem is to characterize, or find out as
much as possible about this association and the corresponding equilibria.
33
Many studies have shown that hydrogen bonds form between weak
iroton acidsand electron donor molecules such as those containing
luorine, oxygen, or nitrogen; or even aromatic hydrocarbons (69).
The bases used in this work are all aromatic N-heterocycles; the
molecules are planar and have their electronegative atom, the nitrogen,
in easily accessible positions on the two fused six-membered rings.
The study of these compounds should prove interesting because of
the effects of the nitrogen lone pair electrons in the ring pidistri-
bution and because of theoretical aspects regarding N-hetero aromatic
systems. The nitrogen in the pyridine ring causes reduction of the
pi-electron density at the carbon atoms relative to the carbons in the
benzene ring (46).
The outstanding feature common to these chosen bases, or proton
2 2 3acceptors, is the nitrogen in the ring. Nitrogen (Is
,2s
, 2p ) has
two sigma bonds, one pi bond, and one lone pair of electrons (32).
Quinoline, benzo(b) pyridine, or l-azanaphthalene occurs in coal
tar and distillation residues of petroleum. It is a weak base, pKa4.9l
(37,69). Spectra of quinoline have been obtained and characterized
(12,28,33,43,55,65).
Isoquinoline or 2-azanaphthalene, Beilstein #3078, is found in
nature as a constituent of coal tars. Although it does not occur in
biological systems itself, many compounds of biochemical interest
contain the isoquinoline unit. It is a weaker base than quinoline,
pKa. = 5'. 36 (27,69). Spectra of isoquinoline have been obtained and
studied (13,55).
Quinazoline, I,3-diazanaphthalene,
Beilstein #3480, is the third
base studied in this work. It is the strongest base of this series,
pKa= 3.51.
34
Quinazoline provides a good starting point for a series of hydrogen
bond studies because of the relationship of its structure to many
biologically important molecules (51).
The dynamic equilibria of biological systems depends a great deal
upon hydrogen bonding. In fact Pauling has written "... the significance
of the hydrogen bond for physiology is greater than that of any other
structuralfeature."
(51) The more information concerning the hydrogen
bond aptitude of individual components of those systems, such as the
N-heterocycl ics, the more light will be shed on biological processes.
The hetero ring of quinazoline
of purines commonly found in DNA
>)
))
resembles one ring
It is this particu lar
ring
N
which, by hydrogen bonding, participates in holding the
two strands of the DNA helix together.
unit
There is also a structural relationship to the pteridines, base
Nwhich have been found to be effective against
Npernicious anemia and some types of leukemia (I).
Folinic acid, which has many functional groups to
which it may attribute its activity
0 H H
I IN- CH2M,h70>-C-N-CCHCHC0oH
I 2 2 2
CO H
is necessary in mammalian cell division; a part of its complex structure
resembles the quinazoline N-hetero ring. There is a whole class of
naturally occurring materials called quinazoline alkaloids (10).
35
The PMR spectrum of quinazoline in inert and polar solvent has
ieen obtained and studied (6,13,28). It is considered afirst-
order spectrum (28) and has been analyzed as such.
Trifluoroacetic acid, CF-COOH, is an organic acid, pKa= 0.588
(25 C. ) (40). It has been used in hydrogen bond studies before (43),
and is the proton donor used throughout this work.
Chloroform, one solvent considered in this work, is able to form
hydrogen bonds by donating its single hydrogen. It has been shown to
associate with acetone and other oxygen-containing acceptor molecules
(23,30). PMR hydrogen bond studies of chloroform systems have been
conducted (27).
Chloroform is weakly self-associating but correction can be made
by studying it in inert solvent (41). The infinite dilution shifts of
chloroform in inert and in proton accepting solvents are first
obtained; the difference between these values is the chemical shift
between unassociated chloroform and the acid-base complex.
This work begins with the synthesis (where necessary) and purifi
cation of the molecules to be studied. Once this task has been
accomplished, the acid-base systems shall be studied neat and in
solution by (i) varying the mole fractions and concentrations to determine
the sensitivity of the spectra to this variable, and (ii) measuring
and varying cell temperatures to detect and identify the hydrogen bonded
species.
36
EXPERIMENTAL
Quinazoline preparation (5).
Reaction diagram, figure I.
4-Ch I oroqu i nazo I i ne
4-Hydroxyquinazol ine, Aldrich m.p. 218-218.5,21.9 g. (0.15 mole)
was mixed with phosphorus pentachloride, Eastman Organic Chemical,
50.0 g. (0.24 mole) in phosphorus oxychloride, \80 ml. The mixture
was refluxed for three hours; then the phosphorus oxychloride was
distilled off. The residue was mixed with chloroform, 170 ml. and
poured onto ice, 262 g. Ammonium hydroxide, Baker Analyzed Reagent,
0.898 sp. gr., 48 ml. was added to adjust to the pH 8. The mixture was
then extracted four times with 50 ml. of chloroform. The yellow residue,
23 g., was chromatographed on an alumina column, Alcoa F-20, 146 g.,
56 x 2 cm. The benzene eluents yielded 12.3 g. of a creamy white solid,
98-9
C, 40 yield.
Hydrazine Derivative
4-Chloroquinazol ine, 10.0 g. (0.06 mole) in 15 ml. chloroform was
added slowly to p-tol uenesu I fony I hydrazide, m.p.|ll-2 C, I I.I g.
(0.06 mole) in 40 ml. chloroform. The mixture was kept at 26 C. for
17 hours. The creamy white precipitate was collected and washed with
chloroform; air dried, m.p. 157-160 C, yield 24 g. (0.071 mole).
Ouinazol ine
A hydrazine derivative, 17.0 g. (0.05 mole) was added slowly to
sodium hydroxide, 500 ml. (20.0 g. sodium hydroxide, 150 ml. water,
37
350 ml. ethylene glycol) (2) and stirred for three hours at 86 C.
The reaction was quenched by the addition of 200 g. of ice (9,57).
Quinazoline was extracted twelve times with 50 mj. chloroform.
The reddish brown oil 7.7 g. (0.05 mole) v/as chrornatographed on an
alumina column, Alcoa F20, 77 g., 29 x 2 cm. Benzene eluentswere
collected; the pale yellow white solid residue, 3.2508 g. (0.025 mole)
m.p. 43-4 C, was then vacuum distilled twice, m.p. 45.8 - 46.7 C.
The distillate gave a single peak on the Perkin-EJmer gas chromatograph
800 record using a Carbowax 20 M column at 200 C. The fragmentation
pattern from the CEC 104 mass spectrometer indicated no fragments
other than those accounted for by quinazoline, molecular weight 130.15.
Elemental analysis: Calculated: ft? = 73.I0;$H = 4.84;$N = 21.68
Found: fc = 73.50;$H = 4.61 ;%H= 21.45
Quinazol ine
Quinazoline, Aldrich Chemicals, was vacuum distilled twice at
1 .25 mm'.- 1 .30 mm. pressure. The center fraction, b.p. 70.0 C,
was reserved for investigations. This distillate, m.p. 46-.5-47.8 C.
gave a single peak on the Perkin Elmer gas chromatograph 800, Carbowax
20 M column, 200 C. The fragmentation pattern from the CEC 104 mass
spectrometer indicated no fragments other than those accounted for
by molecular weight 130.15.
Elemental anahysis: Calculated: %C = 77. I0;#H = 4.84; %H = 21.68
Found: %C = 73.78;$H = 4.64;$N = 21.15
38
PREPARATION OF QUINAZOLINE
+ PCI,
POCI, solvent
:MH2NH-S02{? "'V-CH3
V
NHTos
I
OH
NHNHS02-(/J-CH3
39
Qu i nol ine
Quinoline, Eastman Organic Chemicals, was vacuum distilled twice
at 5 mm.- 8 mm. pressure. The center cut, b.p. 99-99.5 C. was
25.4reserved for instrumental investigations. This sample
n^"
'= 1.6220
gave the expected NMR spectrum, a single peak upon gas chromatography
on the Perkin Elmer 800, Carbowax 20 M column,185
C. The fragment
ation pattern from the CEC 104 mass spectrometer indicated no fragments
other than those accounted for by quinoline, molecular weight 129.15.
Elemental Analysis: Calculated: C = 83.70?*; H = 5.60?; N = 10
Found: C = 81.01?; H = 5.43?
C = 83.16?; H =
N = 10.45?
N = 10.61?
Isoquinol i ne
Isoquinoline, Aldrich Chemicals, was vacuum distilled twice at
4 mm. -5 mm. pressure. The center fraction, b.p. 91-92 C. was reserved
254
for instrumental investigations. This sample, n_. = 1.6199, gave
the expected NMR spectrum. The fragmentation pattern from the CEC
104 'mass spectrometer indicated no fragments other than those accounted
for by isoquinoline, molecular weight 129.15.
Elemental Analysis: Calculated: C = 83.70?; H = 5.60; N = 10.80?
Found: C = 83.02?; H = 5.41?; N - 10.67?
Gas chromatography on the Perkin Elmer 800 Carbowax 20 M, 185 C.
revealed an impurity, possibly quinoline, of about 3?.
A sample of isoquinoline was purified by preparative gas chroma
tography on the Varian 1520, Carbowax 20 M column at 225 C. This
sample was used to make several acid-base mixtures and the instrumental
results were consistent with those results using isoquinoline, twice
distilled and not purified by g3S chromatography.
40
Trifluoroacetic Acid
Trifluoroacetic acid, Eastman Organic Chemicals, 110 g. was
distilled with 7 g. trifluoroacetic anhydride, Eastman Organic
Chemicals. The fraction b.p. 70.5-71.0 C. was reserved for
instrumental investigations.
Chloroform
Chloroform, Baker Analyzed Reagent, was purified by the techniques
ot Fieser (25), and as recommended in Weissburger's, Techniques in
Organic Chemistry, VII.
Preparation of Acid-base Mixtures
The two-component mixtures were prepared in small 3 or 10 ml.
vials with plastic stoppers. The base component was weighed into the
vial and then the more volatile trifluoroacetic acid was added. A
Mettler semi-automatic balance 170 g. limit, 0.1 mg. was used for
weighing. The sample mixtures were prepared in open air.
The three-component mixtures were made following the above
procedure except that the solvent, dimethy I sul foxide, was added last.
The total moles of isoquinoline and trifluoroacetic acid were calculated;
then the proper amount of dimethy I sul foxide to be added was calculated.
A pre-weighed amount of dimethy I sul foxide was added to the chilled
binary mixture; the weight of d imethy I su I foxide actually added was
determined by weight difference (weight of vial containing all three
components minus the weight of the vial containing two components).
The sample mixtures were pipetted into an NMR sample tube already
containing the reference tetramethy I si I ane. The tube was immediately
stoppered.
41
Instrumentation
The nuclear magnetic resonance experiments were performed on
an Hitachi Perkin-Elmer High Resolution Nuclear Magnetic Resonance
spectrometer, model R-20, frequency 60 MHz for hydrogen. The block
diagram of the instrument is illustrated in figure II. Two major
units comprise the R-20; the operating console and the magnet console.
The magnet console consists of a permanent magnet of 14,092
gauss and is thermostated to a constant 34 C. (so long as room
temperature is within the range 18 -28 C. ) to maintain field and
resolution stability. Normal thermal drift and external disturbances
are compensated for by a closed loop field locking system which keeps
an external control water sample in resonance by adjusting the
magnetic field. This control sample is positioned within I cm. from
the measured sample.
The magnetic sweep is accomplished by a linearly varying R.F.
field. The abscissa sweep spectrum may be observed in two ways on the
operating console: using an oscilloscope, or a recording chart which
lies on a flat bed x-y recorder. The recording charts are calibrated
within 0.2? or 0.2 Hz. For example, when a sweep width of 600 Hz
is used with the tetramethy I si I ane peak at the 0 Hz position on the
chart the chemical shift of a resonance signal at 600 Hz would be
within 1.2 Hz of its true position. This hydrogen bond study often
employed 1200 Hz sweep widths. Chemical shifts of the time average
exchange peak were observed in the range 700-1200 Hz. The maximum
instrument chart error would then be 2.4 Hz for the extreme low
field shift.
42
The recording chart speed may be set at 30, 60, 125, 250, 500,
1000, 2000, and 4000 seconds for the full chart abscissa; and the
bscissa may be set to represent 30, 60, 120, 600, and 1200 Hz sweep
w;idth. The chemical shift and line width parameters may be read with
accuracy from the calibrated chart (see above) or may be determined
by use of an electronic digital counter, with accuracy to 0. I Hz.
Line widths were determined by use of the digital counter, Model
TR 3824X.
The resolution attained is 0.3 Hz and, under normal operating
conditions where room temperature changed not more than 1 C, is
stable.
Also, the spectrum is reproducible. For five successive sweeps
at 250 second sweep time the average deviation is 0.4 cps., providing
room temperature does not change by more than I C.
The sensitivity specification for the R-20 is a signal to noiee
ratio of 12/1 on the largest peak of I? (volume) ethylbenzenedeutero-
chloroforrn quartet. These experiments were run when operation at a
20 to 25:1 signal to noise level was obtained.
The operating console also contains a series of dials which make
it possible to:
(I) select the input frequency level; the H| level used in these
experiments was 3.2 x10^
micro-volts.
(2) select the sensitivity; the sensitivities most often used
in these experiments were in the range 5 to 100. Sensitivitywas adjusted according to the concentration of the sample.
(3) select the mode of representation, either dispersion or
absorption peaks. The absorption signal was recorded in this
work.
(4) integrate the spectrum. Integration was not necessary for
these experiments and, therefore, was not carried out.
(5) select the band pass width. In recording the spectra the
. usual setting was 0.1 second on the time constant dial.
43
Sample tubes were 15 cm. long and 5 mm OD glass cylinders with
a rounded closed end. The usual sample size was 0.5 ml., and never
less than 0.3 ml .
4.99/67MC
5M1C
/^VCD
r
SV/EEP
CCT
PEC-Q
/-/
777'
D6CAP
6E7Z
CRO
B
EM
98KC
OSC
A DP.
---59.9/ic--
MULTI
x /2
033
MOp B.P.F
MEASURME,
n
b"tlKCy-\ <
/OOKCt/KC
L.
r"
ATT
J
BALANCED
MOO,
\
N
IOOKC
B.P.F.
ZKCKC
V-F
CONV.
f/U(E_PN_ REU/V/t]
E1UL Tl.
x 12
59.9MC S.S.B
MOP.
60MC
B.P.F,
CONTROL
/OOKC
OQC
STABIL IZEP
SUPPLIES.
H.T, & CT.
-*- TO UNITS
MAQENT
TEMP.
CONTROL
TO MAC?NET
FIG. // BLOCK DIA&RAM OF
tHANNEL
'RIDGE
60,005
rI
COMC
R.EAMP,
D\CSL
5KC9
MPI0\5KC\PHA&
ftriP\BM.\ PST.
^0
/
wf
\|
O II
^//^BALANCEWPICATOR INTEGRATOR
MACrNET
5KC FIELD
MOP
5RC PHASE
SHIFTER
DC. AMP
C R 0
U'R(?
^RfC.
D~
RECORQER
(CALIBRATEP
CHART)
ERROR OUTPUT
WNEL 0LOCK-
ON /ND/CATOR
HIGH FREQ. COMPENSATION
R^20H.R. NMR SPECTROMETER
45
RESULTS AND DISCUSSION
Acid-base; Two Component Systems
Qui nazo I ine-Tri f I uoroacetic Acid
Quinoline-Trifluoroacetic Acid
I soqu i no I i ne-Tr i f I uoroacet i c Ac i d
The PMR spectrum of trifluoroacetic acid consists of a single
resonance signal at 690 Hz from tetramethy I si lane. The full line width
at half the signal amplitude, Av,, is 0.6 Hz for liquid trifluoroacetic2
*
acid (Figure III). This sample is a mixture of trifluoroacetic acid
monomers, dimers, and higher order mers formed by hydrogen bonding.
The observed resonance signal is therefore a time average exchange
peak which results from the rapid equilibria A and B. See chart
following pg. 20. An infinite dilution study of trifluoroacetic acid
in carbon tetrachloride indicated the chemical shift of the monomer f0
be 606 Hz from tetramethy I si lane (Figure IV).
The PMR spectra of the bases, quinazoline, quinoline, and iso
quinoline consist of a series of resolved signals upfield from the
trifluoroacetic acid resonance. These spectra have been previously
characterized (12,13,55). The proton signal assignments are illustrated
in Figures V, VI, and VI I.
The PMR spectrum of quinazoline results from the two hetero-ring
proton spins and the four aromatic non-hetero-ring protons. The two
hetero-ring protons give rise to singlets at low field relative to
the other proton signals.
There has been some dispute concerning the relative chemical
shifts of. the H-2 and the H-4 of quinazoline. Black and Hefferman
Figure III tlo follow page 45
F-C-C
O
xo-H
Lj''
Figure IV to follow page 45
Chemical Shift vs Concentration Trifluoroacetic acid-Carbon
Tetrachloride reference tetramethy I si I ane at 60 MHz
720
"j". 7:i: -j7
7-;:-:;;77--:- ;. oo - 6
710
; v t:--:: 77 0 7.-
. .
-
.
;-
_ ..
N 7001
. ._ .
,
X;...-
: ,
'
.
'
'9o
"
j.::".'-
: .s --::.......... -';.!.'"
>. . '..
VD
690 XT -.-.- .. .
'
.. 7,. .._ ... '..... *. . -
' '
+-
..--.i.-.:_--.:r::L-.:-:.::-l::
-.'-
7j---.--
; -.. ..A.:. -\ -y yro
0)
c .y.... . \ . . .-'. . . . . \ y. . . . .
'
.. '. y. y >...''. y y y y ; ..:.(. .
ro 680yyyy.r.yy .
i '.:--!:; : :: -y -:j-.: ;. :;
. . -y_\yy y'-\. ::
w. .,.-_...-.
-----
"'- '-: !
'----!
:--'
- -P- -[
>~
sz 670 , _ . .... :. ..l_...; ._.:_!.. . .'.t-
...... ;...'.'.+ -
j- - -
,
- - -
f-
i- - ,_ . . ~ . -- ; . . . . .
j. . ... -
o . . [ t . ._ | . _ | . . 1.._ .
.\.... ^ ... . . . _ . . I
F ,
..-.(...-. .. ,._
--'_;" -
7 .
' !"
roi_ .
-
. . . i . ; _L. . i . _ . . ;+-
660 - - - -; - i ----.1 - ;-..:. -_ ,-.
-[ p
<d' *
T"
-
' - -- |-
p- -- - - - -
;- '- j. - - -
--
';.:__.::.._'_'..,
7 . . :;: L _.:.;; :'.":. _\ :.;/.:_ ". :.;". '..:_..
B:... :;::.!..:.::[ ::
-
. . .
; " '
. ;:-
. .
--.:-
_ , .
o1_s-
6507"
7777 - -
.
- '!'-'--'":-
N-- - - - ...
...;. . -. '--- . .
,.... - .... ......... ....
X 7 ; ;'
"
: -..-', .:-:-..-..'-.:..-:.:.
-.._.;..-
'. / 7 -.\ :;"
. :.": . --;. 'y . y y :
c: 640. . . ._ _.- _ ......... -~
y~ "
~.~ - -----. ... ~~
\ ., iry.'-.y
+-.._-..:.:-.-.._ *--.-- -- -
'- - . _
s-.... .:: .-.j;:.;..:.| :.:-. _--r.:::..;.i_. -..:.
'
". .... '-. .
sz
en630 ::..-
1:
ro
-;-
,.-:_-::
;z--.---\-:----yv-
.
.-
o
V 620,
. . . : L .
-
7- -
- .
-
j-
SZ
O
-
\
- -- . ...j
= -_.f_. __.
: ... . ... __...(
610.::i:...-:'-':--.-.:-;:-::-.-:-r-::- r:"
-r:-
y.'r:r::,:.- ----_- -.- ---------
-"PPry- :--
r
_.-"_--
>
y yj-"-":-
L;-^7-
t-
.9.
600- '''-' --- -
-,' - -- .'_'..__ -- r--~,~ - - _
-j --
. : !'
:'
.. i ::..::: yyyyyyy.y.: .-.:.::. :...: ..:
590
0.0 0.2 0.4 0.6 0.8
Mole fraction Carbon tetrachloride
1.0
46
report two resolved signals, 562 Hz for H-2 and 554 Hz for H-4 from
tetramethy I si lane at 100 M Hz; that is, they report that the H-4 absorbs
at higher field than the H-2. Two independent groups (6,38) report
strong evidence that the H-4 absorbs at lower field than the H-2.
This study found that both H-2 and H-4 give rise to a resonance
chemically shifted 545 Hz from tetramethy I si I ane. The high field
triplet is assigned H-6. The remaining protons, H-5, H-7, and H-8
give rise to resonances which lie between the H-4 and the H-6
resonances (13).
The PMR spectrum of quinoline consists of many resolved signals
resulting from the three protons on the hetero ring and the four
protons on the adjacent ring (Figure VI). The proton in the two
position gives rise to a quartet at low field; the proton on the
eight position gives rise to a multiplet immediately upfield from the
H-2 quartet. The highest field quartet is due to H-3. The resonance
of the H-4 is found between. the H-8 resonance and the nearly coin
cidental H-5, H-6, and H-7 signals. The H-4 doublet is difficult to
identify because it is not signficantly downfield from the other
aromatic non-hetero ring proton signals. Spin-spin coupling constants
have been suggested for this system (61):
|J34| = 8.3 Hz |J23| = 4.4 Hz |J24| = 1.7 Hz
There is also evidence of cross-coupling between H-4 and H-8
|J48| ='0.8 Hz
The PMR spectrum of isoquinoline is similar to the spectra of
quinoline and quinazoline in that the protons a to the nitrogen are
at low field relative to the other protons of the system (Figure VII).
IC j
Figure V ;to follow page 46
2. 1
.f\.
../W^v-A/v.-
R 1
ijI
JJiiillll
M HI I
77 . I
7; 'ill1
i ' :i
' v
(i v,
P^-pf-y
IOC
^"'Figure VI
0
:o to follow page 46 <1C0
j q?'+*/*'
"\<*-.>v-';/'I
S1.I1
'.iil
8
vw
if!ii i ;
! !
f I
i 1
\'
1
\\fA.n<v.'
yM
V K/'7/7iW r y
' >V^.-^v-l7.'
47
The low field singlet is due to the H-l. The doublet, high field of the
H-l singlet, is due to the H-3. The H-4 gives rise to the resonance to
i
the low field side of the remaining signals but is nearly coincidental
with them.
In the two component acid-base system, the singlet at low field
is identified as the time average exchange peak. The series of
resonances upfield is identified as being due to the base protons. The
entire spectrum is modified considerably when the concentration of
acid and base is changed.
The chemical shift and half-line width of the time average exchange
peak is concentration dependent as can be seen in figures VIII through
XI. In the acid-base system the proton may be in any one of several
environments as seen in the equilibria A through E (page 21-22).
Each existing species among which the acid proton is rapidly
exchanging contributes to the observed time average exchange signal.
As the relative concentrations of the acid and base are altered, the
concentrations of these different species also changes, e.g., the
complexes formed in equilibria QaC, QC, and IC, may be formed in
greater quantities as the base concentration increases from 0.0 to
0.5 fraction. This change in the relative proportions of the various
species is revealed in the time-average exchange signal. For example,
as the mole ratio quinol ine/tri f I uoroacetic acid is increased from
0.0 to 0.3 equi I ibri urn (QC) is shifted toward complex formation. In
the complex, the H-bonded proton is less shielded than in the unassoc-
iated trifluoroacetic acid. As more of the complex is formed, the
acid proton is further deshielded and the time average exchange peak
is shifted to low field. Conversely, as the complex dissociates, the
ico,---
r Figure VII to follow page 47
J\> J jK^/K,
H
!<!
p
t
i^\vv-^ '--V.^-^.sJ^^/.OJ.
-
Figure VIII to follow page 4-7
Quinazoline - Trifluoroacetic acid
Chemical Shift vs Concentration Time average exchange peak
1100
Is!
X
o
oc
ro
1050
- 1000V)
>-
JZ+-
0)
Ero
l_+-
CD
EO
N+-
l_
0)
x:
CO
ro
o
E0>
SZ
o
950
900
850
800
750
725
r -"-!
G
0,. \. :
lr._::--
[
K7:7v|t 7 -i
p 7777f! - -- Vi ' 1-
G
::7 77.
7-K:.-(.-:.:.-;:
.
t _
:t.
7 :::
...,.
.:::.:(.
-
r-L
0.0 0.2 0.4 0.6
Mole fraction Quinazoline
0.8 1.0
Figure IX to follow page 47
Qu i nol i ne -
Chemi
Trifluoroacetic acid
cal Shift vs Concentration Time average exchange peak
1000
8
N
X
o
ro
d)
c
ro
sz+-
<D
Ero
+-
EO
i_
<DSZ
sz
in
ro
o
E(!)
SZ
o
950
900
850
800
750
;;;;:!
"
'
. : . / . r
1.... yy.y j
^vt"- - \;y:
. "-..;
: 7
- ".-,"'
:_."-f
7-
;,-"..;. t-.P. - .--
: i-1-. \y
:...:. a -.. G ..--.;~.:-.-.;-----:.-
- - ii -:7-
'
,
777, 7:7;/: r,:"": 7 :-7;,.-.l-.
:"
:.,
7'
/ |- . . .
,. . .
J- .
-^- . .
;;.r.-. :-:-.. r: ...:.-. G . .
. 7' y .;._.._ : . .
-.;.L-.--.i:.. O .yy.Ayyy .
-r -.::-;.::.-. .-!-. :i:.: I :..:::.., --.;:.
-; j.:
G
O
r-; : 1 .
GO
..-.
77 "-
G
O
700
650
7 Q'
7 ji.
0.0
,...
1
0.2
. _l_;.:---.
0.4 0.6
Mole fraction Quinoline
0.8 1.0
Figure X to follow page 47
Isoquinoline - Trifluoroacetic acid
Chemical Shift vs Concentration Time average exchange peak
1100.---,..-.---:.-;'-: ~'::r::l-y '
-'. ......|.--... .
..... yr. .. .
-.<-. -::::.L
:' '
".'
''
\-:;1;;j _7;.4__
; j ; . ; 7 -..-..-'; 7'
.: .-... :77- ]p-.y: .7
;g
N
:<:'
' ! .
,--..--.
f..... . .
j. .
j |
..... _ .
r
>: 1050 '- ; -- :-r-- --
7--
...-.:-:_-; \y.yzy. [y: ._;_:._7;__ -.--;..;.-. ---..:.: J;i-.'7-..-7^_--::
o-
, - --,.... : - . S ...!-..1
. ( .
,-
VO :-:_::- 7: -..;... .: [:_. . . ..<yy_. 7 ytyil-.: . ;..-;_:.\~z.. yy.p.zryyr \..y.yy.zz.L..::._-.--7-.._
+-" " '
-7:
--' ' --
r_ :_ --;
-
' '"
r-
--i- ' '- ! yy '
ro-
1- -- :"-...- J - _
'
:-_;..._.-. _ ,_ip^.._:: [.__-.__. ._..._. . .-..,..
oc
-..-' -!.."
''
t_ -f
:-;-
-I .
'.!-
: Pro - - - : : . . . j. . _
,. 1 _ . . : . [ i . .._
< :...,...
!. 7 :
"
1 1.!"
f J"-" '
"%j"
i
' "
_
f"
in1000
>---'--
|- -
-[ -,-
-| 1 - - j-''
-~1-:pp.;--..:<:p
- -
7j\ -;;\pp~
y.^rrr. . ,.
:
.-.r
sz - - - i - - - - - - t - - . .- - j. - -.1 ,
. - J j. . ... . \ ... .S-l-% -- j .. - : - ."-.._._.
+-^
_ ... .
'["
i 1
~
-
' ' i'
tr ;
~ t~
CD" -
!" *
"1 ' i " " " ! - 1 ._-.-. l ... [. - - ,- - .. - . - . -
P- - -- - .'-.. -...'. | 1 -r . . . , . ._..._.1 . L i.. - ..,...-.. - --
ro . .... l , . .-..,..
-
._;
-
-_.r-
GL+-
i:
'
'
7.-.7I-
:
'
-
7"
'P'
"'>- '
~
... -. - -: -7fl)+-
950 -: -.
':
r- - I -
-! -;-;--
E ... ; ..::::.:.!
. :..[ -. : .: . yyy .'{.;. \:.:r..\ yrr.:'::.yy y _ .yy.y.y
r.'
. . \:... :_ ;-.--. r . .
'
;.-;' -
()
U -
r- - 1 -
;-
[- - -
; - - - - - - - - - - -
;- \ - - -
,; - ;
;- - -
s-1
- 1 |-
'--; '-
7 i -
'
1 -
.
N-.
"
....::."-;--. :.. r. s ::-. .::.--,--. r. .--; ;-.--; -.:.:: r .-yy.J;.-:-.-.-
,-...rr :.. ....
-...-
-.,
r:
H~-,_._i_.r. .l . .r._. .. r i J..j..: :r. i
.:; ..7":.[. :.
:-.:"'
\yy.y-. _ ..y.
I_-- - - "
; |'
;' " "
f' '
:' " " * ' "
r ;' " "
;" ......
a) -
-y- -r-.r-i-..,... .! ; . .
.., ;. i.
t -ji--- --.--.
sz - ; ! - i ... 1. .. I -
(... ......I ; . _. . . [
a900 -- '- -
yr\yz yy\ zyyy\rr zrzyi yrrP:r~y. yy.-rrr'rry 'yy-yyr:~" 7 '"
r
4-..... ;.-[_--.-- - - .-----.-:-.----.-:-.-. 4_-..l.....l !..._..__;.,.
H- '
..
;-"' / ,
: '(
- - 1 -
-J.-
r. -
sz: r j r ;
'" " -'
<
(t
'
['-
tn l ! '-- -r-- ' _..
- - f . 1r q ..|
. ; . .
_,. .
ra
o 850.
A' ' '''
- '
.-".-
1 r- -
,
- ;-_
--
,Y : i
-
. j '-!;..[ i
' ' "
1 .
-
b0)
A '..
-[-
'.
-|!-...!_
x-. . . 1 f. - -:- [ . .1 .,. 1. -
-7I-
-l -
.-'..,-,...
o :-.-. ,-. "-,- 7 ;-"-
7-: -:-...^-: P\ --:-!-
,T. '7
800
-_"--?-:-
-:^.:-..i r -r.:r. r7"
; ;_/-; .
-
.:.:.:..j.:..:: :-
.-/7 -
;."
. ;.:l: r .;-.[. -.:. :t
..
::.:;/:::- -
:..;.-.:-:--};:::..: . .--:::.-.:::; . :
,
-[- ----;----;-7---L--
r.....T.-..!.:..__. -7---;_--.---,--
--;.L.-.-7-_..--:.---!-r-..-_:.^:;....;.
77.77-f:777;]:. :0, ...777:77:[::::::,:7-::7:--:i:-:-.7:-:;;,;:.:,| 777:77^7777:7
750
::.r:::-': O, , -----,
- ...
, ,
. . . - : ['--
-
-: -T: - ';-
-;! f7 -1
--:--
;- :. "-
-t.'.: .-.
700
0.0 0.2 0.4 0.6
Mole fraction Isoquinoline
0.8 1.0
48
protons are shielded further by their electronic environment and the time
average exchange signal shifts to high field.
The formation of a salt from 0.3 to 0.9 mole fraction quinoline,
and 0.25 to 0.9 mole fraction isoquinoline prevented chemical shift
measurements throughout the entire concentration range. The complete
association of the acid-base ion pairs is thought to occur at a 1:1
mole ratio of base to acid (42,43).
From 0.0 to 0.5 mole fraction base, the predominant equilibria
(C) and (D)
B + H-A t B...H-A t [W"...A~~]
would be progressively shifted to the right, as evidenced by the down- '
field shift of the time average exchange signal. As seen in figures i
VIM, IX, and X only a small amount of base is needed for the complex
to be formed.
The complex dissociates into ions in excess base and the time
average exchange signal shifts to high field when equilibrium E
operates:
[BH+...A~] tBH+
+
The extrapolation of the chemical shift versus concentration graph to
infinite dilution of acid in base may be taken to be the chemical
shift of the base cation. In the quinol i ne - tri f I uoroacetic acid system,
this acid cation is called the quinol inium ion; in the
isoquinol ine-trif luoroacetic acid system the cation is the isoquinol inium
ion.
The time average exchange signal is a weighted sum of the signals
of the unassociated trifluoroacetic acid, v., and of the complex, v~.
That is, the chemical shift,v'
,of the observed peak may be given as (35)
v' = | vc + ^-=-^ VA Equation 33
49
pon rearrangement, this relationship becomes a means by which complex
toncentration can be estimated:
v1-
vAC = A Equation 37
VC~
VA
Since the chemical shift observed for the acid is a result of
monomer, dimers, and polymers, the chemical shift for the acid-base
hydrogen bonded species is considered essentially equal to that of the
acid (42). That is, the time average exchange peak is the weighted
sum(35) :
, _
C A - C - H HV
~
AVC+
A VA+
A VH
where H represents the hydrogen bonded species. Since v.,= v.
this beomes
iC A - C - H . H
V =
A VC+
A VA+
A VA
which rearranges tov'
- VAC = A Equation 37
VC"
VA
The resonance frequency of the complex, v, is found by extrapolating
the plot of the chemical shift vs. concentration to the expected minimum
at 0.5 mole fraction (43).
The calculation of theequi I ibrium constant for equilibrium QE of
the quinol ine-trif I uoroacetic acid system follows.
[qh+...a_] * [qh+] + [a-]
K_ CQH+]rA-][QH...AJ
v1 is the observed frequency of the time average exchange signal, v
is the frequency of the complex ion-pair, found by extrapolation to 0.5
mole fraction to be 1112 Hz from tetramethy I si lane. V(,H+ is the
50
frequency of the quinol inium ion, found by extrapolation to 1.0 mole
fraction quinoline to be 700 Hz from TMS. C is the concentration of
the complex ion-pair and QH is the concentration of the quinol inium
ion. The observed frequency is the weighted sum given as
Assuming a total of 100 moles initially,
CqI + CtfaI = 100
and
[TFAl = Cc3 + Tqh+J
At 0.90 mole fraction quinoline and 0.10 mole fraction trifluoro
acetic acid,v' = 992 Hz using 10.0 moles of acid initially.
tc - qh+3 . roH+D
%,
.
VQH+VC
1
C
C
V-
V
QH C
v'-
vc[QH +}
C 700 - 1112 412
rQH+l992-11.2 120
[tfa"] = c + Cqh+3
10 moles= C + TQH+3
c = io - Tqh+]
C = 3.43CQH+3
3.43[QH+
J = 10 -
QH+
rQH+3 =
j= 2.26 moles
= 3.43
51
7.74 moles
u. CQH+] Fa~1 C2.26ir2.26"] _ ,,
KE"
QH+...A-}"
CT7741
= '66
= 6.6 x10"'
A similar calculation for the equilibrium IE of the isoquinol ine-
trif I uoroacetic acid system follows:
ClQH+...A\] ^ Dqh+3 + Ta"!
K =ClQH+DfA"3
[|QH+...A"1
v' is the observed frequency of the time average exchange signal and
at 0.05 mole fraction trifluoroacetic acid v= 985 Hz. v is the
frequency of the complex ion-pair, found by extrapolation to 0.5 mole
fraction to be 1112 Hz. vjir\|-i+l's ~^e frequency f the isoquininol inium
ion, found by extrapolation to 1.0 mole fraction isoquinoline to be
750 Hz.
The observed frequency is the weighted sum
DQH+...A"3 - C|QH+J v C IOH+3 v
r.QH+...A-l(IQH...A)
C|QH+_A-;jU0H
Equation 33
Assuming a total 100 moles initially
Ciq] + Ttfa] = ioo
CtfaI = Dqh+...a""3 + r IQH+
1
vc ^iqh+...a"3
Cioh+...a-1 W^lC IQH+1 v
'-
vc
= 2.97
52
v -
Ciqh+D Ta~3KE
"
r + ^[IQH ...A J
DQH+...A~] + ClQH+] = 5 moles
ClQH+...A~] = 5 - ClQH+D
OQH+...A"] = 2.97 C IQH+1
2.97DQH+T) = 5 - ClQH+]
DQH+] =
~y= 1.26 ClQH+...A"3 = 5 - 1.26 = 3.74
Ke=
CL26^I.263= A25'__ 4>25x
|0-l
The value of the equilibrium constant for the qu i nol ine-tri f I uoroacetic
_2
acid system, found in a previous study (43)- K = 6.3 x 10,differs
from the value found here. The previous work (43) involved chemical
shift measurements at 40 M Hz, while this work was done on a 60 M Hz
instrument. Due to stability factors introduced in modern instrumen
tation the work is sufficiently more refined and therefore the chemical
shift measurements obtained would appear to be more reliable than
those obtained with the 40 M Hz instrument.
A comparison of the equilibrium constants for the quinol ine-
tri f I uoroacetic acid system, K = 6.6 x 10,and the isoqui nol ine-
tri f I uoroacetic acid system for which K = 4.3 x 10,corresponds to
their relative base strengths. Quinoline is the stronger of the two
bases and is therefore the better proton acceptor. The quinol inium
ion would be expected to be more stable than the i soquinol in ium ion.
This is revealed in the equilibrium constant calculation. For both
systems the complex ion-pair is favored, but it appears to be less
favored in the case of quinoline.
53
The equilibrium constants for equilibria C and D were not
ii
calculated using the above procedure. Due to the nature of the
i
Chemical system no reliable data could be obtained over this region.
j
A computerized calculation using iterative procedure is needed for
the refinement of the data regarding equilibria C and D and would be
useful for the calculations involving equilibrium E.
The half-line width of the time average exchange peak is con
centration dependent as seen in figures XI, XII, and XIII. Line widths
were measured for the qui nol i ne-acid and isoquinoline acid systems.
Line widths were not measured for the quinazol i ne-tri f I uoroacetic
acid series since the mixtures were very viscous and additional line
shape broadening resulted.
The line widths were obtained using the electronic digital
frequency counter and are accurate to 0. I Hz. The spectrum was
expanded to the minimum sweep width which fully presented the time-
average exchange signal; this sweep width used is 30 Hz full scale
(XI).
As stated in the introduction, there are several causes of line
broadening. Should the lifetimes of the acid proton in its different
magnetic environments be long compared to the exchange rate but not
long enough to produce resolved resonance peaks representing each
environment, (i.e., fXto -
w, ) = /2),a broad signal appears. That
a b
is, when the predominant equilibrium is slow, there will be exchange
broadening of the time average exchange peak. The types of equilibria
operating should be related to the concentration of the system. For
example, in high acid concentration equilibrium C:
B + A-H ^ B...H-A
Figure Xi
Time average exchange signal
Quinoline-Trifluoroacetic acid
Traces of actual resonance signals. Chemical
hertz, from tetramethylsilane. The resonance
are not relative from one trace to another.
shifts in
intensities
Trifluoroacetic acid
1.0000 mole fraction
0.8 Hz
690 Hz
Quinoline-Trifluoroacetic
0.19^-1 mole fraction
Quinoline
Quinoline-Trifluoroacetic
0.9170 mole fraction
Quinoline
968 Hz
Figure XII to follow page 53
Time average exchange peak Width at half amplitude vs
Concentration Quinoline-Trifluoroacetic acid
. L :
'"\
o
IT-
F,o
0-
o
24
22
20
18
-_:..-..
i -
l- ---
....
f_
y-
T-"
- -"f:
f- ...-.
16
14
12
.10
8
-fyy
o'
-
; 7 ,
-
^ ---|-,,_,- *E-~ ' - P^yFyyy P:P
:"l~'"c
P
.
>. ... . _. ..
i_-...[
..[._.._ ....
'
. i
6-- - - - i - -
...- - L I 1 -
i i'
-r.Ay. O^P^
0..0 0..2
7 \.'---^M:-B^-^-FFp
4
2
0
^pFFyPpFp^APlPzFzF^FpF.M:^^
Pv.
0..4 0..6 0.8 1.0
Mole fraction Quinoline
Figure XIII to follow page 53
Time average exchange peak Width at half amplitude vs
Concentration Isoquinoline-Trifluoroacetic acid
i .-71
: i .>
. . _ * :'. -
'
-V-
-;-.r--
T.;L-.r 7::.-7 : i ::
16
7 "77
.-. 7
:--(
-
-
.:.
! .. . . yyy y
|7 '7-1j
-
:- - i
- - - , - -- . . .
_r.
... _ - ._.
..^. _ . . :.. : --7 .
[---
14O [Ay~--
{y-prPr <
-
f- - '. --
j ...-;'....i .
;
^
- -:- 7--:1.-,. _ .._... ._
\zy:
y
.777 O-:.
t.--.! ".
-I"
i . . .-;_:. .
-
':
- - 7."
.77 ;
' ' '
A
- -
r 7: p| : . : . 77, ,. .
1'.-' 1 : -
,.: .
1 : ..".-.. | . .
-\
[ _r. . . .
O . . . . ^ . .. : - -
1 [ 1 _. 1 ! - .... . . ;
12
: .
:-: r.r
7- .6? ._
_
-
1 . : -, : .
1 . : .
. . (.-
rl
- ,._:_.-
-
1'
- '. :
'..A. .
10
:Pyy:-'-r
::y7o::":"-tTr77n77:
[zyj.rz.z.y.
r r'.... .rr:f_
:-._; -::. 7V :_-r:
7 -77--"!.:777 7 ;-7-
8f o 777- ; . r; ": :.-.
'
i : ; . J:7;77| : 7: : :77:|'777-7- :"77
777.7:-'
['-'-'"-
ayy '.y . y ... f _ _ 'yy. yy :..:-.:;:.--!.: : - 1- -_- t: h .:::..: i "-"-"-
6---;-~--
._ L-
--_-;-
l : .-. ... ....
"T-f
Tf-7 7.77! .r
"7~77-
. 7 . '.77"
7-
z
;;;- -~-
\:;!"
-
-.:-.:7:-
7.7-
A-'z\z-y'y f -
7-0-..7-7-7
l_ 'SEP'. TiZW
'.'.-'
\r:.:.-''
a - y -
'
1"_" ' ~
7. !;":.:
4
?
-_-_:.:.-.::.-.
:.:!-
l
"---7- --- :l _-_.-;-;_
r _. . .
:77T 77,
. 1
b.-. .-. -.--7.-
-
: :' -
zzz : i
--.-7:::-.-:...._
-&-
.:.-:
0-- - - - 7" "~~ . _-.- - . ~-.-~7--
.7.777--.-.-.j--.--~7.-j.--7-
. [Z Pi ~Z7 P.-
'"-77
0.0 0.2 0..4 0,6 0,8
Mole fraction Isoquinoline
1-.0
i 54
is more likely than equilibrium E:
BH+...A"3 -
BH+
+
i The line width dependency on concentration may then be a means
i
of characterizing the equilibria of the system.
Equilibrium processes resulting from the formation of an H bond
are usually rapid and would not, therefore, be considered to contribute
extensively to the exchange broadening. The dissociation of the
complex into the protonated base and trifluoroacetic acid conjugate
base is also considered a rapid process(42,43).*
The greatest line widths occur in the high acid concentration
range where equilibrium D between the hydrogen bonded acid-base
species and the ion-pair complex, operates.
[b...h-a~] ^ Cb-h+...a"]
This slower equilibrium is the reason for the exchange broadening.
An interesting note is that as the base concentration is increased
just beyond the region of maximum line width, a drastic decrease in
line width occurs. This would indicate that faster equilibria begin
to operate at this point. The equilibrium C
B...H-A ^ B-H+...A"}
would be shifted toward ion pair formation upon addition of base.
Once the complex is formed, the rapid dissociation process becomes
possible. This shift to greater concentration of the ion pair
does indeed occur, as indicated by the formation of the insoluble
salt beyond the 0.3 mole fraction base region.
Another cause of line broadening is the quadruple relaxation
mechanism. Nitrogen (1=1) possesses an electric quadruple moment,
which imparts an asymmetrical charge distribution about the nucleus.
55
Spin-spin interactions with a nitrogen nucleus influence the spin-spin
relaxation time, T and therefore alter the line width of the proton
signal. Notice that the maximum line width for both the quinol ine-acid
and isoquinol ine-acid systems occur in the 0.7 to 0.8 mole fraction
acid range. The quinol i ne-acid systems show the more dramatic line
broadening, the maximum line width being at least 22 Hz. Whereas, the
maximum line width for the i soqui nol ine-tri f I uoroacetic acid system
is about 14 Hz. Of the two bases, quinoline is the stronger. The
hydrogen bond association between the quinol ine ^nd acid is no doubt
stronger than that of the isoquinoline. The proton is probably held
closer to nitrogen in the quinoline molecule than is possible in the
isoquinol ine-acid association, and as such, is more subject to the
strong quadruple relaxation mechanism.
It is suggested here that if the line width vs. concentration
measurements could be made for the qui nazo I ine-acid system, an even
greater maximum width of the time average exchange peak would be
observed since quinazoline is the most basic of the three.
The fully protonated base ion would show a very broad signal
due to the strong quadruple effects of nitrogen. This work was conducted
at room temperature, and no resolved signal was observed for either
the quinol inium ion orthe isoquinol ium ion. Signals of the protonated
bases may be detected if the equilibria are sufficiently slowed, as
they should be at decreased temperatures. Low temperature experiments
are planned.
56
Acid-Base-Solvent: Three Component System
The high resolution NMR technique used in this study requires
samples in liquid state. Unfortunately, the acid-base two component systems
form salts in the mole fraction ranges 0.30 to 0.85 quinoline for
quinol ine-trif I uoroacetic acid; 0.25 to 0.92 isoquinoline for isoquinol ine-
tri f I uoroacetic acid; and 0.45 to 1.00 quinazoline for quinazoline-
tri f I uoroacetic acid. In order to study the acid-base systems over the
complete concentration range, 0.0 to 1.0 mole fraction of one component,
a search for a solvent was made. The salt dissolved most easily in
dimethylsul foxide but even in DMSO, a 70 mole percent solvent was
required to dissolve the salt formed throughout the 0.0 to 1.0 acid/
base range.
The isoquinol ine-tri f I uoroacetic acid system was selected for the
preliminary solvent study since isoquinoline is the weakest base in
this series. The isoquinol ine/tri f I uoroacetic acid mole ratio was
varied as in the two component system and the concentration of dimethy I -
sulfoxide was held at 70 mole percent for all solutions in the series.
The plot of chemical shift versus i soquinol ine/tri f I uoroacetic acid
concentration may be seen in Figure XIV. The expected low field shift
between 0.0 to 0.5 mole fraction isoquinoline did not occur (42).
When the chemical shift is plotted as a function of the mole
fraction trifluoroacetic acid in the three component system and this
plot is compared with the chemical shift versus concentration of the
two component acid-base systems, as in Figure XV, the effect of the
solvent can be clearly observed. There is still a low field shift;
however, the low field shift in the three component system is remarkably
less than that of the two component system. One reason for this
57
apparent decreased chemical shift dependency on concentration is the
dissociation of the isoquinol ine-acid complex due to the increased
dielectric constant of the mixture. Dimethy I sul foxide has a dielectric
constant 48.9(20
C.) and 45.5(40
C. ) (39). Another reason is
the dilution of the acid-base mixture in the large amount of dimethyl-
sul foxide.
The solvent, dimethy I su I foxide, is not an inert solvent. Rather
it is anticipated that DMSO participates in the hydrogen bonding.
Dimethy I sul foxide is known to be a strong electren donor, or base.
DMSO has been used as a basic solvent in hydrogen bond studies because
of the availability of the electrons in the p-orbital of its oxygen
and because it does not self-associate (4). A recent NMR study of
succinimide and dimethy I sul foxide found the N-H proton chemical shift
to be concentration and temperature dependent (56). These
observations are indicative of hydrogen bond associations. DMSO is
known to form strong hydrogen bonds with phenols and mineral acids
(39) as evidenced by the downfield shift of hydroxyl proton in NMR
studies. There has been no evidence, however, that proton transfer to
the sulfoxide oxygen occurs, only that hydrogen bond complexes form.
For example, the association of acetic acid and DMSO is thought to
form 1:1 and 2:1 complexes as shown below:
and
CH3-C
^0-H...CCHT1
3
)=S
Ch
CH,1 3
CH^1 3
0 0-H. ..0 0-H...0
CH,\ 3
=s
I
CH3
(72)
58
The isoquinol i ne-tri f I uoroacetic acid-dimethyl sul foxide system,
then, may be viewed as several competing equilibria. Not only
(A)
CF3COOH + CF COOH ^ CF.
/.0...H-0
C-CF.
0-H...0x
(B)
CF COOH
/
CF, CF, CF,J,
3 ' 3I
3
,c c. c
0 N0...H-0 0...H-0 N0
(C)+ CF,COOH
N 3 .H-0
CF,
Ao
(D)
and
(E)
but also
(H)
CF3C00H
?F3
N ...H-0^
0
CF.
i+..:</ \
CH-S-CH3
Ji ,0
CF,-(/ ^3N0-H...0=S
CH
++ CF COO
.59
The low field shift for the three component system would not be as
great as it is for a system in which there are only equilibria A, B,
C, and D since equilibria E operates in the three component system.
Recall that the resonance signal observed is a time average
exchange peak. The environment of the proton in the DMSO complex
contributes to this signal. The proton involved in a DMSO-acid
complex would not be as deshi elded as a proton involved in the
isoquinoline complex. Since proton transfer to the DMSO is unlikely
(4), the proton would remain closer to the shielding environment
of the acid then it does in the isoquinol ine-acid system where proton
transfer to the base is likely.
Line width measurements, AvL, were not possible for this2
three component system due to viscosity broadening of the mixtures
at34
C.
o
-P
r-l
o
H
BCD
o
Figure XIV to follow page 59
Isoquinoline-Trifluoroacetic acid -Dimethyl sul foxide
Time average exchange peak
Chemical Shift vs Concentration
800
....
750
700'
0)
c3
rH
co 0
650
x:-p
o>
ens
p
CD Q^ 600 ;
o
u
H
N
-P
I 550
cH
P
<H 7H \
x:
CO500
450
0\
400";"
"""
0.0 0.2 0.4 0.6 0.8 1.0
Moles Isoquinoline / Moles Trifluoroacetic acid
Figure XV to follow page 59
Time average exchange peak
Chemical Shift vs Concentration
Trifluoroacetic acid-Isoquinoline O.
Trifluoroacetic acid- Isoquinoline-DliSO <
Trifluoroacetic acld-Dimethylsulfoxide ?
OVO
-P
rj
CD
C5
HH
W
H
&-P
CD
Be>
-P
0)
-P
O
Jh
<H
N
P
CD
.3
H
P
H
CO
Hcj
o
H
B0)
1100
1000
900
800
700
600
500
1+00
77''tr-.!77-''
'I'
Fp:F F:\~F'
o :.
.77:^77-:C? 77.._
77777- 7:i O
"- -^ .-7.-77-.7-_. 77 ~
|,7.-r._.|. .::;:::.-.:: ^
PFF-rFFo7- -,7"-P-~
--.-:}--
: D O :.."-..
--7-7-^-D 777 r-7777777-777
-U-y , . . .,.777777777
'
7 ,7
7v_~."
"~.Trri.""t~ i _
l*t
77777777-;--'
<j<p7717:777777 -\ .
P' P\P--"PPzEzyrPy
7-07.:07.:.,: .-:--_::-.777: 0:.7: .. .. - ,::_ ..
,
:_.-^-^ ,
-7- ___..,_.-
7
:"-.::[77: 7:777'
-.
'
7 77 1_'
7 ._:_;:. . . _
7770.---7-71 ..-y-
-7*--:i -' -
: : ..
i- d<
777.1.7 ::.!.-;:;-..r.:7:!.;.-:.;7;
'^rl :-"T""-i"-rr-t-"."-f < \ -
1.0 0.8 0.6 0.*f 0.2
Mole fraction Trifluoroacetic
0.0
60
Dimethylsul foxide-Trif luoroacetic Acid System
The PMR spectra of each of these components indicates a
resonance signal at 690 Hz for trifluoroacetic acid and at 163 Hz
for dimethylsul foxide.
Trifluoroacetic acid is a known proton donor in hydrogen bond
systems and DMSO is a known electron donor as previously discussed.
This binary system gave the expected chemical shift vs. concen
tration plot (Figure XVI). Association does occur as evidenced by
the drastic low field shift of the acid signal a*s the 0.5 mole
fraction range is approached from either concentration extreme. The
methyl protons of DMSO did not show any modifications in their spectral
signal .
No line width measurements were taken because of the viscosity
of the system.
Figure XVI to follow page 60
Trifluoroacetic acid - Dimethylsulfoxid:
Chemical Shift vs Concentration
o
vD
4^>
crj
CD
%H
H
W
H
>>^-P
0)pir
cti
U-P
0
-p
Bo
u
N
-P
UCD
H
P
<H-
CO
H
o
H
Bo
&o
8^0
800
750
700
650
600
550
,i:: 7: 0 ::.;:: ay 7.77(77;:: -.!..::-7-7|.7 .. -. i -
-
.. :. .7 z\...y.
y '"P''[-'P{.E r'~PJPPPr O 7"y-_'."7".;
- -
.~-;-v-:l--: ...;..y3^i;:....:.o
- ; ,-'-
-r"
'. . - .
- -
7 / .
" - -
\- ~
. 7
'
'" ~~
- -
\ *'('
'
' * r
{'
p K ' i . -.'. P.L"'
7..['. \: '. '.
yyyF'F'.-T'yyWp
'
'/ P y"' "y\
"
T\.F^PPF^^r 4""ife777'
- ,- - ! / -
' '
- 7~77rn. ".7; .f
~
~""| 7 7" "
7 7 : ; 7 7" '
7 77"
V~
7"
",
PP-;
-..:-.-:
-7--.-7:7::-
--,-:..-.-.-
7777:"
O -EEyPy~--~P~--^
yEPrryyyyyyyFEy. P'yyy yyPzPP QO ..-
-
---
--
.: , . - !-
- -
\ :'>::V:-: -:.;1-._--. ; -. ^
7 .
'"'
"
"':"
r~-T~ I" ^
:
ro"-. "..... ....
'
: '':. ; .. PJ -
.. [:.,';\ [_ "-.F\
"
..
-
-
o
-"
- -
--
l- - \ -
PEPPPPaFeeFF.-'
:- T -r -
'
- 7-
. .
(i.
|__ , _ .. j. _ ._
... ! . 7.7-7 L._,7i. | - _. l 7- ... :. 7, .,. 7. .. 7 - . o-
7-. i 7777-j"7::-
-"; 7 7::p:-. : ! --. -.!
7-J."
.
"\-777 7;".--
77-;"7-77-;777^t77-77:7"7777
"
-77--" -
.
-
-;"
j~
O
777J. .7
"
j -7-7.-1. 7. "|-7:-
-f i ;h-
:.K-:
500
o.o 0.2 0.4 0.6 0.8
Mole fraction Dimethylsulfoxide
1.0
61
Isoquinol ine-Ch loroform Solvent Effectsi
I The study of the isoquinol ine-ch loroform system was first under-
I
taken in an attempt to find an inert solvent for the acid-base systems.
Since isoquinoline does not self-associate, no significant change in
the spectrum was expected upon dilution with an inert solvent.
However, changes did occur for this isoquinol ine-ch loroform
system throughout the concentration range. As shown in Figure XVII,
the chemical shifts of all the hetero-ring protons and the chloroform
proton are concentration dependent.
The N-hetero-ring protons appear to be identically influenced by
the chloroform. This may be due to a ring current effect often
observed for aromatic molecules (15,65) and is not necessarily
indicative of a hydrogen bonding association. When a molecule such
as isoquinoline participates in hydrogen bond formation the N-hetero
ring protons are dissimilarly affected; this is shown by this work
as well as others (42,60,64).
It is now known that chloroform is capable of forming hydrogen
bonds. Chloroform can self-associate and forms weak hydrogen bonds
(26). The question that arises fromfhis study is whether the association
is indeed hydrogen bonding.
The usual association shift is to low field as the complex is
formed. The chloroform proton is observed to shift to high field in
the intermediate concentration range. The chloroform proton apparently
is not participating in the usual hydrogen bonding.
One explanation of the data is that the chloroform proton associates
with, or at least is effected by the pi-electron cloud of the N-hetero
ring of isoquinoline. The chloroform proton could approach the iso
quinoline molecule from the top or bottom of the planar molecule as
62
in figure (a) on page 22 of introduction. The proton would be then
subject to diamagnetic shielding by the pi-electron current (15).
The isoqu inol ine-ch lorof rom association, although small in
comparison to the base - trifluoroacetic acid association, was
sufficient to indicate that chloroform would not be suitable for
further work since it is not an inert solvent.
Figure XVII to follow page 62
Isoquinoline - Chloroform
Chemical Shift vs Concentration Ring and chloroform protons
--.. --,--
j-",
r~--
560 -_ j _ -_7!
7-:_I;i7_-_- '
'r_'_-_-: -
.7.
-
.--".7ovO
-p
ctf
o h-7%/-,:-^0:,-,,_.r .:.-::..;.
:->;.-
,^77 7.
H
7~"~
"
"O~ "" """ " ~
"""''
f """ ^ """
'"- "" -- r-
54o _.;_.._ __
. -.Ss!/ |"--
..x,.7| "'7 : -.77-:""-
:"
-j7.37-7 -..''
H
w --:
Hyy-'
_-- 7- -.\".
-,>
-r'
._____ - ..
^. _ ...
{>> - .- _: 1-
^^- - - ...!..j. . . .
^ -7 77 77 7.:.7I7-
-. - - /\ - 1.. ..... ..;....-.... . ; -
,...
-PL ... - 7 . 7. :. -7
-
O ^\- -
|...... - . . -
(D 777 777 7 -.7-7 h -\7-- r-
". -[-- - --(---r-
,
- ;- -
,
E - -
-.7.-
7-J-.7-77-yy-TSt-:;!::::-;-;.:-
-777-77:777777: .ztryy.
U 520 -'[-: - | -
!"
"07.' " '"" '"
"' 7
P i_-..77 :; 7 yy 0777' ;:.;
i:7^^7 .7 .7.
7:7777-
._ _:. ::. ., 7
<D
-P fc-^FF ----t -.-: ---_ ..
- "--
-
^>^73t: " ^-
:o"
0ri3 Q -7 -::--...
-ry:.~.:.-
.A..z-.. -.--. 77...-
..:t. .:_7:7.7 ..: -zzyy 7.-77
<H
-
tjr,E- 7.7::-77i::::._ ... ; 77777::. ... yyy
-
.... 7,"- mP.. 7.7 7 7! O 7 ".
7-
77: 7 77-7- :r-;-
7..:-:. 7 -77
N 500-U1
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_ _-'7 7' '" '
+5 - - ^. '. ;.-.-..,..; t . . -
f-J ,- ... ; .---< . .- .... - ^\ . .. ._. -..;...
"
.. . . ; ;
<D r - - - -- -- - !-^. 7 -'- - ;. ;..._..._ 7 .. . . .
,d[yrr- -.-
:. 7 : . 7 . \X -. .
i -
. .._.::
-
;. 7777.7.;-:-
77777O77-
Ay : .
d Az.y.-yyyyry;---
-77-7-7-
0\. 7777:7:7.7777:7. 7. 0 7:7. 7.777 7O::..
H__: :;.7.::7.-.-.:...7.7: . -_,..-tX 7 7._..__.7:37777.7 :_:._..:3:7 .: : .7:7.
p
480r F- -
:
-
!^\Q-
l
-
- !-.
H- -
'
1 r- .
(. P- - .
;...
...
Z^^-.._.... : 1 . ,
CO
77777^7^
H
o L_". :..: i :[ .:::::.:. 1 p~
:::pppp :-"::.--..-..! ::*.:.-. r [:i\ _ 77777 :; . pplpep 7. r::.:\ ;. :i-; ; 77::-.. ;_-_..:
B<D 460 7 77___ 7. 7 7_71 i_ 777.7 ~__L ..77 _ 1 : 7 77 1.7 .
"7" " '
I"
'."lII".*! *,*.L"*.Tr
_7____
" "
"!
,3'- - - - ..-.---
r-- . - .
j.- - . .
,- - -..
j- -i - ....
r- -- - -
U
%F^F&^^^440
:HCI3S^A"
; 7-^A -'.;;...; .|.7:777 :[777777i.7 77:!77:77!:7 7707:7
420 - ' -"- '--;--}- -- \ - - -
yy-y 7 ,-- -
0.0 0.2 0.4 0.6 0.8
Mole fraction Isoquinoline
1.0
63
Chemical Shift of N-heterocycl ic Ring Protons
I The base spectrum also is concentration dependent. The chemical
shifts for the hetero-ring protons change upon addition to acid to
the N-heterocycl ics.
The chemical shifts were very difficult to measure because the
base spectra are complicated by overlapping signals and because the
spectra were drastically modified as hydrogen bonding and protonation
occurred. The results (which should be further investigated) perhaps
at higher H. frequencies are shown in figures XVIII, IXX, XX, XXI,
and XXI I.
However, qualitative conclusions may be drawn from these data.
There is insufficient information for any quantitative results. Also,
the magnitude of ring proton shifts is thought to be medium dependent
and consequently charge density arguments may not be supported by the
data presented here (42,60,64).
The two N-hetero protons of quinazoline seem to be similarly
influenced by the formation of the hydrogen bond. Each exhibits a very
slight high field shift toward higher quinazoline concentrations.
The limited range of concentration over which liquid samples were
possible prohibited measurements beyond 0.45 mole fraction quinazoline.
However, the chemical shifts observed were all downfield of the chemical
shift of 1.0 mole fraction quinazoline. The quinazoline N-hetero
ring protons are more deshielded as acid concentration is increased.
(Figure IXX)
'
This would indicate that the electron density is reduced somewhat
at the 2 and 4 ring carbons in the associated quinazoline. The
decrease in the charge density seems to be about equal for both sites.
Quinazoline ~ Trifluoroacetic acid
N-hetero ring protons
Chemical Slri ft vs Concentration
it::
OvO
fi-P
o <a
H CD
FSN Cj
-P H
fl) W
"ft
CD+5 B<H cd
H *H^"PW CD
-P
H
o
H
BCD
.d
o
610
600
590
580
570
560
550
'54o
? E3
o
D
cSP-
E3
O
-Qr
_^o
7 77-7T7 7.
777
CD.
D?
0
O O
"O
7-7
77:
37X
:2f747
.:.-.t:
-
.-.:..t.....
0.0 0.2 0.4 0.6 0.8
Mole fraction Quinazoline
a
1.0
64
An important implication may be drawn from this observation.
The effects of ring substituents on ring proton chemical shifts seem
to be about equal for meta and para positions, whi le the ortho
position is effected differently (19,67).
The H-2 and H-4 are ortho and para to nitrogen I: in quinazoline
they are both ortho to nitrogen 2. If the hydrogen bond association
hence the effect upon pi-electron redistribution, was through nitrogen
I, the H-2 and the H-4 chemical shifts should be changed dissimilarly.
That is, the A6 would be greater or less than A6.. However, if the
hydrogen bond association involves the nitrogen, to which H-2 and H-4
are both ortho, the effect on the chemical shifts would be about the
same for each proton. More experimentation is necessary, but at this
point, the data leads to suspicions that the nitrogen in position 3
is the one which participates in hydrogen bonding.
The N-hetero ring protons of quinoline also exhibit concentration
dependent chemical shifts. (Figure XX)
Because of the formation of insoluble salt in the intermediate
range the plot is not continuous; nevertheless, between high quinoline
concentrations to high acid concentrations there is a downfield shift
for all N-hetero ring protons. The shift of the H-2 is approximately
10-15 Hz; for the H-3 the change is about 50 Hz; and the chemical
shift of the H-4 is about 80 Hz. At high acid concentrations, the H-4
signal becomes nearly coincidental with that of the H-2.
These observations compare with previous studies that have found
that positions meta and para to the position of disturbance are
subject to greater modification in their chemical shifts (19). It
65
certainly seems from this that the charge density of the 4-carbon is
decreased to a greater extent than that of the 2-carbon. However,
since the magnitude of the change is medium dependent, no definite
conclusions may be drawn.
The N-hetero ring protons of isoquinoline exhibit similar changes.
(Figure XXI )
At low acid concentrations, the chemical shift of the H-l and
H-3 fluctuate about the values obtained for neat isoquinoline. At
high acid concentrations, however, both are shifted downfield. The
H-l is effected less, the change being~
20 Hz. The H-3 is shifted a
great deal, 50-60 Hz; the chemical shift of the H-3 becomes coin
cidental with that of the H-l. This indicates that for some reason the
H-3 has been deshielded.
The N-hetero ring protons of isoquinoline exhibit an interesting
solvent effect. (Figure XXII) At high acid concentrations, the H-3
is shifted 60 to 70 Hz upfield by the addition of dimethy I sul foxide
to the system. This observation would parallel the findings of
Krakower and those of Schaefer who noted the medium dependency of
N-hetero ring proton chemical shifts (42,64). The change in chemical
shift due to solvent for the H-l is not proportional to the change
for the H-3. This leads to doubts about whether the chemical shifts
of ring prorons can justifiably be used to determine even qualitative
charge density distributions.
wchesibimsimmoFiBB,,
Figure IXX to follow page 65
N
X
O
VO
CDc
10
in
>
sz+-
CD
Eroi_+-
CD
EO
1_
CDx:
to
550
540
530
520
510
500
490
480
470
460
450
~
440
<dsz
O
430
420
410
400
Quinoline - Trifluoroacetic acid
Ring protons Chemical Shift vs Concentration
H-2 OH--3a
....7.3
Q -
l . -. ; -
_
1. . I
7-
"
.-. ;
"
'
;-
j
H-4 ? H--8 0
.7, .. t- _')
'_ \ _ I'
0 j '. i'."
1 yy 1: ".. 7. .
"
.!
"
7: ;.'. .7 . i
Q O S. Oi-7-7
I-- -
!i::.- " ( 77
D
-7 :: (.:
...77.L
^30
7;:~
[-. 1
7 '-- ::7-
--.--[--.- - O
1\ \:z: . i O"-
.- : | : :. . .
'
:.-.:!
' -u-
~_,
. 7. . . L.zz : 7. y :'.:..: 7. ~T *
-7""
. . .
y .".
'
i:A-EfFa-
\'
,\ . 1
\ 7-
7:7'
O77 :.-. 77-j.:
Fee ..... 15... -
,
77f
- -
-t- -
1- -
r
h"
'
.
i :.7-i *, 1
r- - -
1-7-7"-F-PEP
1
. .7...(_..-
'
... . j. .
:.-
. , 1 ;'
. ... 0 .
'
- -
;- - - - -
r- 1 - - - -
;- - *
1- ...
j-- - -
!
'L-'
i-
-1- '-
--I
i 777 :[7 -77- 0- ;/
'i7i7.:~~" ' "
t11"
~:~_,,
..- j-..
-77 "t "^ .
-'
7 77 r~i"
7 1 7 ::::."
~~:.7
~:~T~~:
:. 73
v
7 v y
77-;
"-'
-~-.y
v v ,
-
;
[:'-.-
: j -
- V- -
:i '.. .
' 7i~
7*
D
-T-H--0
---Oh
. . j .
7"'
.77
- -
j- -
777?
'
y -7
""7:7 i
D
'_"_'.
77.7:77"
.7
::::-::!'
~~'.'\ ~~E'"\
" '
'.'
. 7"
.7 j
7 7"
\
v. .
"" "
i
v - !
: A
777 -7-
. 37 ...
1~"
I
7 :
^ _t. ...!_. _
-
i- -
1--
- i
t'
\ ....
. . . . .
:FF.77:1 7 77"7|
. ._
"
7t- -
J
7~
'777.71
" - - -
1 03-.
777... .. -i .
..y ": 1 77^
...
j - > -
~~i -r.-..:-.--
1
- - (-:-
'--- -'--
0.0 0.2 0.4 0.6
Mole fraction Ouinoline
0.8 1.0
Figure XX to follow page 65
1 1 soqui no I ine - Trifluoroacetic acid
N-hetero ring protons Chemical Shift vs Concentration
590-
580
N
X21 570
O
(0 560
CO
y-
EO1_H-
550
N-f-
l
540
CDSZ
c
5304-
H-
sz
CO 520
(0
V
E(11
510sz
O
500
0.0
H-1 a
H-3
0.4 0.6 0.8
Mole fraction Isoquinoline
Figure XXI to follow page 65
Isoquinoline-Trifluoroacetic acid-Dimethyl sulfoxide
N-hetero ring protons
Chemical Shift vs Concentration
580 ... ,
.7 .. GG 7. . ...77:7:77:7 77777 7I7777777 :7:-7'
. .7
7777[777-77:o::"-7.
N
:--:!:-'F::^
@
^7^^"^
-
?""
-
' F-F^FP P- .:.,
570-
7
-:77:-o7.-7.77. eGS-4T4-
-
.:-...tr-..:,|r.,-r-:-: -.: 7
<l,. ... .._ . .
. _ __ . . !__._.._|^
... _, f .
^
. _ ...
-7.-77 "..;..: 00"
:PP 7 7777;77-:7:|777 7 ;7 7-7
O
p
E cd 70.-
7.-77 7 -.-;--. ',7 .7
7-.J--7.-
yy.77..-
7 .7 .-[.77-7 .O.-.7.7:.77.77 ;.",.:
O
U CD550
"-
,
"
--7 7-
777 7 77377-7.-7. -..7777.0777.. Ij" "
: .
- 7" ~-.7 7
7-
cdtsl H
N"
.
. ;.. . .:.: . : 7[-.7 : \~y. yy. _7- .37 j z: 37.77. .7077
! - i i - ; - -
[- i ;
' - - - -
P -H
Jh K> J^v.;:.::;77:7.3
0.'
-.7 -.'77 . ;::::::.:
'
r zyzz:\.:: .z:z. .].yy .7 --7-7.7
CD r.7-
. 77 ...:.:7 077- -
17:7-7-
77---
[-
-_ \---_ [ .-y.zy'y.";~
..-.'>;..-.-. . -7-7-777.
-P
. . 1 . . .7 '. _ . .
,_. _
T... _ :.._.:.. ', . . . . .
.--. r 7..7;
.. -_.> 7 .-,. ..:,..
'
1 . L ..7 . ,. ; :...::._. ..r .....
rrr.
H CD
P 05
J^O_^:
-
_
.
7-7-J7'
---.j:
- 77-
'-"-- " " ;-- ; --7-
Or 7
- 7.7- 77 ...... ....-r..|3 . -
"
_.. .|.7 . .. _.. _. 7__ .
_
. _..
H P520
----
Baa+^|h- --:-'-.--'-.-
-:- -
w +i
h . :__ L :..._.....;
3.. ..-_....- J. _ . . _ _. 7 1 : .... 7 .... . .
03
O 51Q7
.07_77 7___.0- 7_-.-i__73.-___-...-._37 .-7.77777 77 _ _ .
H;-- . ...;.(T>
'-
..00 Q , ...... i ,- . . . . ,
6 1 G_l_---t '" -.-
1 , ;
CD77 7 7.77 777-70:7377:3.-77737:777:.7-|.7.7...7-7-7777777-3777 77 7
"
:
O 500(__;:;.
7--777... 7:7777-7-77777:177:77.7 77:7; 777.77: 77. :!:.. 7. .yy 77
777 7
0 --r 1 777 t. { ..__: i_3 ::.._!.. j . ::::. 7::33i.:._: :.:_b zz.aaaa aa ya yy .z.y
0.0 0.2 0.4 0.6 0.8
Mole fraction Isoquinoline
1.0
DMSO
H-l
H-3
70fo 60% 50%
O
D
e
Appendixes
Tabulated data in support of figures
IV, VIII- X, XII - XXI.
Trifluoroacetic acid - Carbon Tetrachloride
Chemical Shift vs Concentration
Chemical shift in hertz from tetramethylsilane at 60
Mole fractions Chemical Shift
Trifluoroacetic Carbon Tetrachloride Hz
1.0000 0.0000 690
0.6.75 0.3825 704
0.3143 0.6857 714
0.2695 0.7305 -71 4
0.14S0 0.8520 71 4
O.0839 0.9161 714
0.0231 0.9769 697
0.0031 0.9969 606
Quinazoline - Trifluoroacetic acid^-^
11
Time average exchangepeal"
(tae) and ring proton peahs
Chemical Shift vs Concention
chemical shift in hertz from tetramethysilane at 60 MHz
Mole fraction
Quinazoline Trifluoroacetic
Chemical shift, Hz
tae H-2 H-4
0.0107 0.9893 748 572 598
0.0870 0.9130 742 573 598
0.1484 0.8516 792 570 594
0.2170 0.7830 864 572 599
0.2299 0.7701 876 572 600
0.2933 0.7077 954 576 606
0.3585 0. 641 5 1010 568 594
0.3957 0e6043 1044 568 592
0.4223 0. 5777 1060 564 588
1.0000 0.0000 - 545 545
Quinoline - Trifluoroacetic acid
Time average exchangepeak-
Chemical Shift vs Concentration
chemical shift in hertz from tetramethylsilane at 60 MHz
Line width at half peak amplitude vs Concentration
Mole fraction Chemical shift width
Quinoline Trifluoroacetic Hz Hz
0.0000 1.0000
0.0954 0.9046
0.1332 0.8668
0.1712 0.8.288
0.1871 0.8129
0.1888 0.8112
0. 1 941 0.8059
0. 2037 0.7963
0. 2084 0.7916
0.2305 0.7695
0.2675 0.7325
0.3024 0.6976
0.8918 0.1082
0.8925 0.1075
0.9170 O.0830
0.9330 0.0670
0.9655 0.0345
654 0.6
726 1.4
79 3.1
782 9.7
806 13.5
806 15.0
812 16. 5
830 18.3
836 21.9
858 19.5
904 8.0
952 3.6
1014 1.4
1010 1.8
968 3.1
922 2.9
754 1.3
Isoquinoline - Trifluoroacetic acid
Time average exchange peak
Chemical Shift vs Concentration
chemical shift in hertz from tetramethylsilane at 60 MHz
Line width at half peak amplitude vs Concentration
Mole fraction
I soquinoline Trifluoroacetic
0.0960 0.9040
0.1070 0.8930
0.1093 0.8907
0.1350 0.8650
0.1713 0.8287
0.1901 0.8099
0.1912 0.8084
0.1918 0.8082
0.1991 0.8009
0.1993 0.8007
0.2049 0.7951
0.2053 0.7947
0.2120 0.7880
0.2206 0.7794
0.2319 0.7681
O.9326 0.0674
0.9417 0.0583
0.9460 0.0540
0.9532 0.0468
Chemical shift
Hz
width
Hz
718 .0.6
737 1.2
738 1.3
748 2.1
780 4.2
814 7--5
81 4 8.4
812 8.5
828 8.8
829 9.0
830 11.3
830 12.2
838 12.7
850 13.2
864 11.6
1100 0.9
964 1.4
1080 1.0
969 1.0
Isoquinoline - Trifluoroacetic acid - Dime thylsulfoxide
Time average exchange peal-
Chemical Shift vs Concentration
Chemical shift in hertz from tetramethlsllane at 60 kHz
Moles IQ/Moles TFA Mole fraction Chemical
Isoquinoline Trifluoroacetic DMSO Shift
Hz
0.0000
0.0960
0.2066
0.3921
0.5275
0.5973
0.6888
O.7636
0.7964
0.8916
o.ooco 0.3333 0.7012 764
0.0289 0.3013 o. 7007 758
0.0339 0.2645 0.7016 750
0.0973 0. 2026 0.7001 727
0.1425 0.1575 0.7000 686
0.1651 0.1342 0.7007 656
0.1980 0.1037 0.6983 604
0.2187 0.0788 0.7025 544!
0.2322 0.0679 0.6999 518
0.2627 0.0361 0.7012 418
0.3125 0.0848 0.6027 506
0.3615 0.0405 0.5980 398
0.3742 0.0279 0.5979 348
0.3924 0.1038 0.5038 656
0.4345 0.0646 0. 5009 504
0.4132 0.0600 0.5268 496
7 j. fluoroac e ti c acid
Time average exchange psak
Dime thy1sulfoxide
600
550
N
: vO ^OO
P
a
EH
o 450
fH
pen
<H 0)
H ^
CO
Hcd
o
H
B<D
O
DMSO 0.6983DMSO 0.5979D77S5 0. 5009
0.7012 mole fraction o
0.6027 mole fraction a
0.5268 mole fraction <
4oo
35o;
0.08 0-.06. o.o4 0.02 0,00
Trifluoroacetic acid - Dimethylsulfoxide
Chemical Shift vs Concentration
Chemical shift in hertz from tetfamethylsllane at 60 MHz
Mole fraction Chemical Shift
Dimethylsulfoxide Trifluoroacetic Hz
0.1128 0.8872 704
0.3000 0.7000 756
0.4935 0.5065 829
0.6950 0.3050 776
O.7012 0.2988 764
O.8970 0.1030 540
0.0000 1.0000 690
;l soqui no I ine - Chloroformi
i
Ring proton and Chloroform proton peaks
Chemical Shift and Line Width vs. Concentration
Chemical shift in hertz from tetramethy I si I ane at 60 MHz
Mole fraction Chernica 1 Shift
Isoquinol ine H-1 H-3 CHC
Hz width Hz width Hz
0.000 - - - - 434
0.008 551 2 509 7'
433
0.016 550 2 507 6 432
0.024 549 2 506 7 432
0.032 549 2 506 7 432
0.040 549 2 505 6 432
0.048 547 2 503 7 430
0.055 546 2 503 7 430
0.063 547 2 503 7 430
0.070 547 2
'
504 7 431
0.103 545 2 502 7 432
0.292 529 3 488 7 432
0.496 521 2 480 7 440
0.697 516 2 476 7 450
Quinoline ~ Trifluoroacetic acid
'Ring protons
Chemical Shift vs Concentration
chemical shift in "hertz from tetramethylsilane at 60 MHz
Mole
quinoline
fraction
trifluoroacetic
Chemical
H-2 H-3
shift :
H-4
7n Hz
H-8
0.0954 0. 9046 548 476 540 -
0.1332 0.8668 544 471 544 -
0.1712 O.8288 538 468 538 -
0.1871 0.8129 546 469 542 -
0.1888 0.8112 546 468 542 -
0.1941 0.8059 546 471 541 -
O.2037 0.7963 550 472 546 -
0.2084 0.7916 546 469 541 ~
0.2305 0.7695 5br4 463 537 -
0.2675 0.7325 54o 462 536 -
0.3024 0.6976 544 467 540 -
O.8918 0.1082 526 419 462 486
0.8925 0.1075 525 41 8 460 483
0.9170 O.O83O 527 419 451 488
0.9330 0.0670 525 415 459 486
0.9655 0.0345 522 412 456 486
1.0000 0.0000 540 416 460 494
Isoquinoline - Trifluoroacetic acid
N-hetero ring protons
Chemical Shift vs Concentration
Chemical shift in 'hertz from tetramethylsilane at 60 MHz
Mole fraction
Isoquinoline Trifluoroacetic
0.0960 0.9040
0.1350 0.8650
0.1713 O.8287
0.1901 0.8099
0.1912 0.8084
0.1918 0.8082
0. 2049 0.7951
0. 2053 0.7947
0.2120 0.7880
0.2206 0. 7794
0.2319 0.7681
0.9326 0.0674
0.9360 0.0640
0..941 7 0.0583
0.9460 0.0540
0.9935 0.0065
0.9999 0.0001
1.0000 0.0000
Chemical
H-1
Shift
H-3
570 562
570 564
570 570
574 574
576 576
576 576
576 576
575 575
576
'
576
576 576
575 575
552 509
552 509
548 505
552 508
556 514
554 512
551 510
Isoquinoline - Trifluoroacetic acid --Dimethy I sul foxide
N-hetero ring protons
Chemical Shift vs Concentration
Chemical shift in hertz from tetramethy I si lane at 60 MHz
Mole fraction
soqui no I ine Trifluoroacetic DMSO
0.0973 0.2026 0.7001
0.0339 0.2645 0.7016
0.1425 0.1575 0.7000
0.1651 0.1342 0.7007
0.1980 0.1037 0.6983
0.2187 0.0788 0.7025
0.2322 0.0679 0.6999
0.2627 0.0361 0.7012
0.3742 0.0279 0.5979
0.3615 0.0405 0.5980
0.3441 0.0569 0.5990
0.3125 0.0848 0.6027
0.4575 0.0435 0.4990
0.4134 0.0599 0.5267
0.4353 0.0646 0.5001
Chemical
H-1
Shift
H-3
578 510
578 507
572 508
568 507
562 505
556 505
558 505
558 507
570 520
570 524
570 519
574 520
569 520
570 520
572 520
Bibliography
i
i
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