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PARAMAGNETIC RELAXATION REAGENTS
NUCLEAR MAGNETIC RESONANCE STUDIES
OF
PREFERENTIAL SOLVATION
BY
HANS
G
1986
I
4 1 \
NMR Research Group
Department of Organic Chemistry
University of Umeå
PARAMAGNETIC RELAXATION REAGENTS
NUCLEAR MAGNETIC RESONANCE STUDIES
OF
PREFERENTIAL SOLVATION
BY
HANS GRAHN
1986
AKADEMISK AVHANDLING
Som med tillstånd av rektorsämbetet vid Umeå Universitet för
erhållande av Filosofie Doktorsexamen vid MatematiskNaturvetenskapliga fakulteten i Umeå, framlägges till offentlig
granskning vid Kemiska Institutionen, hörsal C, Lu 0, fredagen den 16
maj, kl.10.00.
PARAMAGNETIC RELAXATION REAGENTS
Nuclear Magnetic Resonance Studies
of Preferential Solvation
Hans Grahn, NMR Research Group, Department of Organic Chemistry,
University of Umeå, S-901 87 Umeå, Sweden.
ABSTRACT
The interactions between neutral paramagnetic relaxation reagents
(PARR's) and certain aromatic compounds have been studied by
and
13c spin-lattice relaxation time measurements. In media such as
cyclohexane and carbon tetrachloride, Cr(acac) 3 becomes preferentially
solvated by aromatic solutes. The solvation is significantly
suppressed in a more interacting solvent like dichloromethane.
Paramagnetic induced chemical shifts of the aromatic outer sphere
ligand indicate in addition to relaxation data, a preferential
orientation caused by dipole-dipole interactions. For benzene or for
several alkylated benzenes which have small or no permanent dipole
moments, the interaction is electrostatic, i.e. of a dipole-dipole
induced type and where the easily polarizable aromatic ring is
preferred in the solvation sphere.
Carbon tetrachloride is shewn to have a specific PARR interaction.
If co-ordination number, solution structure etc., are to be determined
using weakly interacting substrates, this solvent should be avoided.
A multivariate statistical approach is also reported, where 1 i
electron-nuclear relaxation data and induced shifts of monosubstituted
arcmatics have been related to different physical descriptors. Most of
the variance in relaxation and shift data is best described by the
dipole moment. The results support a dipole-dipole interaction as the
preferred solvation mechanism.
The preferential solvation of several organic substrates with the
diamagnetic Co(acac) 3 is studied by varying the substrate
concentration in cyclohexane. By the use of ^ C o shift, it is shown
that proton donating solutes such as chloroform and methanol have a
specific solvation. The order of preference is close to that obtained
in Cr(acac) 3 solutions.
ISBN 91-7174-235-2
CONTENTS
page
LIST OF PAPERS
7
GENERAL INTRODUCTION
9
NUCLEAR SPIN RELAXATION
11
MOLECULAR MOTION
14
RELAXATION MECHANISMS
14
Dipole-dipole (DD) interactions
15
Nuclear quadrupole (Q) relaxation
16
Chemical shift anisotropy (CSA)
16
Scalar coupling (SC)
16
Spin-rotation (SR)
17
ELECTRON-NUCLEAR RELAXATION
17
A BRIEF REVIEW OF TOE USE OF PARR's
18
LSR-PARR comparison
20
PARR STRUCTURE AND CHEMICAL PROPERTIES
20
APPLICATIONS
21
Magnetic resonance imaging
23
Major requirements cn PARR's
23
COMMENTS ON TOE RESULTS
24
Results of T^e studies in papers I-III
25
Results of paramagnetic induced shift
32
studies in papers I-III
A multivariate approach to preferential
34
solvation studies
A ^Co diamagnetic study of preferential
35
solvation
SHORT SUMyiARY
39
ACKNOWLEDGEMENTS
40
REFERENCES
41
LIST OF PAPERS
This thesis is based on the following papers and will be referred to
by the Roman numerals I-V.
I
U. Edlund and EL Grahn, "The Interaction Between Paramagnetic
Relaxation Reagents and Carbon Tetrachloride",
Org. Magn. Reson. 18, 207 (1982).
II
EL Grahn, U. Edlund and G. C. Levy, "Preferential SolvationOrientation of Aromatic Substrates toward a Paramagnetic
Relaxation Reagent, Tris(acetylacetonato)chranium(III )",
J. Magn. Rescan. 56, 61 (1984).
III T. A. Holak, D. W. Aksnes, H. Grahn and U. Edlund,
"Solvation of Alky 1aromatic Hydrocarbons towards a
Paramagnetic Relaxation Reagent, Tris (acety lacetonato)
Chrcmium(lll)",
Magn. Reson. Chon. 24,
V
(1986), in press.
H. Grahn, "Evaluation of Relevant Molecular Descriptors for
the Solvation of Paramagnetic Relaxation Reagents",
To be published.
IV
H. Grahn, U. Edlund and T. A. Holak, "A ^9Co NMR Chemical
Shift and Relaxation Study of Preferential Solvation toward
Tris (acetylacetonato)cobalt(III )",
Submitted to Magn. Rescn. Chem.
7
GENERAL INTRODUCTION
The enormous growth of chemical applications in NMR seem to be
never ending. The expansion is taking place over a wide front and the
NMR method has beccme a routine spectroscopic technique suitable for
both liquid and solid state work.^'^ in medicine, NMR has recently
-a
been developed as a new imaging technique.
One of the basic physical phenomena in NMR is the relaxation
process, Which takes place after the perturbation of the nuclear spin
system by a radiofrequency pulse. The study of relaxation processes in
molecular systems can give valuable information about the structure
and conformation and also about molecular dynamics.^ In this work, we
have mainly used the relaxation time parameters,
to study the
interactions between various organic molecules and certain organometallic additives that are commonly used in NMR.
When a substance is dissolved in a liquid, several processes take
place. Bonds between the ions or molecules of the substance are broken
and the solute is dispersed homogeneously throughout the solvent
medium. If the liquid is composed of mixed solvents, the solute is
often preferentially solvated by one component of the mixed solvent
(Figure l).5
Bulk solvent
50%
Q)
(
50%
SOLUTE
Figure 1. Preferential solvation by benzene in a benzene-cyclohexane
mixture.
9
This phenomenon plays an important role for example in the inter­
pretation of several homogeneous catalysis reactions. Thermodynamic
methods were first used to study the concept of preferential solvation
in mixed solvent systems. However, these methods often focused on the
properties of the bulk solvent, rather than on the solvation shell
itself.
NMR has been shown to be a very sensitive method for the study of
solvent molecules in the outer solvation sphere.^ Although inter­
actions in charged metal-complex systems have been extensively inves­
tigated, this is not the case for neutral metal.complexes of the type
outlined in Figure 2. The following abbreviations of these metal
complexes will be used throughout the summary.
n
Mn
R
R'
R"
A b bre via tion
Cr3*
H
H
H
Cr(pdo )3
Cr3*
ch3
ch3
H
C r(acac )3
Cr3*
ch3
ch3
ch3
Cr(Meacac)
H
Cr(hfac )3
Cr3*
Cr3*
C(CH3)3
C(CH3)3
H
Cr(dpm )3
Fe3*
ch3
ch 3
H
Fe(acac)3
Gd3*
ch3
ch3
H
GtKacaclj
Gd3*
C(CH3)3
n -C 3F 7
H
Gd(f od )3
Ni2*
ch3
ch3
H
N i(acac )2
Cu2*
ch3
ch3
H
Cu(acac)2
Figure 1. Paramagnetic metal complexes used in 1SMR.
10
These compounds are paramagnetic and sometimes have a dramatic
influence on the NMR parameters. Some of the effects are used to probe
preferential solvation and will be explained in the summary. The only
interaction mode that has been clearly proven in the presence of these
neutral transition metal carpiexes and organic substances is hydrogen
boiding involving the ligand carbon/Is in the metal complex.
Before proceeding further, it should be noted that the definition
proposed by Langford and Stengle of the second co-ordination sphere is
used. 7k
Hence, the first co-ordination sphere is composed of the non-
1abile ligands and the second co-ordination sphere corresponds to the
first solvation sphere of the metal complex.
The scope of this work is to clarify the nature and the properties
of the outer sphere complexes that are formed between several organic
substrates and neutral paramagnetic transition metal ß-diketonato
complexes. These compounds are used in NMR for several reasons.
It is the purpose of this summary to give a better understanding of
the parameters and processes that are dealt with in the study. A brief
introduction will be made on nuclear spin relaxation and paramagnetic
additives and their applications. The summary concludes with a
discussion of the results of papers I-V.
NUCLEAR SPIN RELAXATION
This section presents the relaxation phenomena and different
relaxation mechanisms will be reviewed.
Soon after the first NMR experiment performed by Bloch and Purcell
in 1945,® several useful NMR parameters were determined. NMR chemical
shifts, coupling constants and areas of resonance peaks were found to
be the most powerful tools in the determination of structure,
conformation and composition of molecular systems.^ For a long time,
11
some other important parameters? spin-spin and spin-lattice
relaxation, could only be studied by sophisticated experimental
methods but with the advent of the Fourier transform technique, it
became a routine a matter of routine to measure these parameters.
Relaxation time measurement is an important approach to probe the
structure and conformation of molecules, molecular motion and
molecular interactions. Furthermore, kinetics of molecular systems,
adsorption of molecular species and of course, the mechanism of the
relaxation phenomenal itself are important aspects of the dynamically
processes that are involved.
The radio-frequency (RF) pulse perturbs the thermal equilibrium of
the magnetized nuclear spins. The variation of the measured NMR signal
over time describes the manner in which the system of spins relaxes,
that is, returns to its equilibrium magnetization. This spin state is
described by the Boltzmann distribution, provided that the spin system
is in thermal contact with its environment and that the nuclei are not
interacting strongly with each other. Since the probability of
spontaneous emission is negligible, the return or loss of energy,
must be governed by interactions with fluctuating local magnetic
fields generated by the lattice (the magnetic and thermal
environment). The intensity of these local magnetic fields and their
rates of fluctuation determine the efficiency of the relaxation. The
process is termed spin-lattice relaxation (longitudinal relaxation)
and is an exponential decay process characterized by the first order
time constant, T1# the so-called spin-lattice relaxation time. The T^
process is related to the mean half-time of the spin-lattice
relaxation. Hence, the T1 process quantifies the rate of transfer of
energy to the lattice.
Eqn. 1 describes the rate of return of the Mz'
component (Figure 3) of the total magnetization towards equilibrium
(M0) after an RF pulse.
ay^/dt = -1/Tjl (m ^ - n^)
(D
12
Another relaxation process, the spin-spin relaxation ,T2,
(transverse relaxation) governs the return of the x' and y'
magnetization vectors to their equilibrium value of zero. Daring T2 an
adiabatic exchange of energy among the spins results in a process
where no energy is transferred to other parts of the system. Thus, T2
is an entropy process and the lifetime of this relaxation is given by
dM x*y*/dt
(2)
-1/T2 ^x*y**
Z'
Spin - Spin R e la x a tio n
S p in - L a ttic e
R e la xa tio n
Figure 3. Behaviour of the magnetization vector (M), after a 90° RF
puls created by a small magnetic induction, B^.
13
MOLECULAR MOTION
Both relaxation processes (Tx and T2) occur by the interaction of
the nuclear spin system with fluctuating local magnetic fields. The
fluctuations of these fields is mainly caused by Brownian motion of
molecules i.e. rotational and translational motion. A physical
description of the motions of a molecule can be determined by the
molecular rotation correlation time,
tc
,
which is defined as the time
necessary for the molecule to re-orient through one radian. Factors
such as size and symmetry of the molecule,
intermolecular
interactions, viscosity and temperature all affect the observed spin
lattice and spin-spin relaxation times. Within the extreme narrowing
condition (rapid rotation relative to the inverse of the observed
nuclear resonance frequency) 1/^ increases as tc increases, i.e. as
mobility decreases.
studies are usually appropriate to solve the
desired problem, at least from the organic chemist's points of view,
hence T2 measurements, which are more demanding in experimental set­
up, are used less often.
RELAXATION MECHANISMS12
Some of the physical mechanisms that provide the appropriate
conditions by which nuclei exchange energy with the lattice are
summarized below.
1. Dipole-dipole interactions among nuclei.
2. Intemuclear electric quadrupole interactions.
3. Chemical shift anisotropy interactions.
4. Scalar coupling interactions.
5. Spin-rotation interactions.
The observed relaxation rates (l/T1) within a molecule could be the
sum of different mechanisms as Eqn. 3 shows.
14
l/Ti—l/Ti dd +
1/Ti
q+
1/T-i
CSA +
1/T1
sc +
l/T1
sr + 1/T-l others
Sometimes the relaxation rate is further parameterized. The dipolar
relaxation contribution could, for example, be divided into
and inter-molecular relaxation.
intra-
A brief summary of the above
mechanisms with seme practical examples is given below. It should be
pointed out that the general requirement for spin-lattice relaxation,
is the magnetic interaction which fluctuates at the resonance
frequency.
Dipole-dipole (DD) interactions
Dipole interactions can be understood by the same process that two
bar magnets show when they are brought together. Eqn. 4 describes the
distance dependence of dipolar interactions:
l/T-,00 =^~*
Ys2*2
eff
-6
(rIS i.)
(4)
i=l
where Yj and Ys are the magnetogyric ratios for I and S nuclei, rIS is
the through-space distance between the I nucleus and nucleus
and
is the effective reorientational correlation time. Thus, a DD
relaxation mechanism is of great importance in cases where the
relaxing nuclei is directly bonded to nuclei with strong magnetic
moments, like 1H or 19F. Another way of inducing dipole-dipole
relaxation is by the dipole interaction between unpaired electrons and
the observed nucleus. This is a very effective relaxation pathway
because the magnetic moment of the electron is over 600 times greater
than that of the proton. Although the distance between the unpaired
electrons and the relaxing nuclei may be large compared with internuclear distances, the interaction with the unpaired electrons have
a dramatic effect of reducing the relaxation time. Relaxation of this
kind can occur if dissolved 02 paramagnetic ions (impurities), or a
15
PARR relaxation reagent are present in the solution.
Nuclear quadrupole (Q) relaxation mechanism
Nuclei with spin quantum number V 1 have an asymmetric distribution
of electric charge. The non-spherical charge induces an electric
quadrupole moment, which couples with the time-dependent electric
field gradient. This results in a very effective relaxation pathway.
The nuclear quadrupole spin-lattice relaxation time increases with the
covalent nature of the chemical bond to other nuclei.13 Hence for 14N
in a highly unsymnetrical environment, the relaxation times (T^)are
very short (e.g. Π3c14N, T1Q=22ms).14
Chemical shift anisotropy (CSA) relaxation mechanism
An anisotropic distribution of electrons around a nucleus gives
rise to chemical shift anisotropy. When a molecule tumbles rapidly in
a liquid there will be a modulation of the local magnetic field and
this provides a mechanism for relaxation. Such a mechanism is
pronounced for nuclei with large chemical shift ranges like ^c, 15
15N,16 19pl7 and 31p# Machor showed an unambiguous example of CSA
relaxation for 19F in CHFC12.18 This field dependent mechanism has
also been found to be dominant for the relaxation of 15N in pyridine
at low temperature.
Scalar coupling (SC) relaxation mechanism
Scalar coupling depends on the Fermi hyperfine coupling between
spins A and X , i.e. the coupling interaction through the bonding
electrons between two spins. There are two kinds of scalar relaxation.
Relaxation of the first kind is based on the time dependence of the
coupling constant, J, which gives rise to fluctuating magnetic fields
at nucleus A. The second mechanism depends on the effectiveness of the
relaxation of nucleus
If this nucleus has a quadrupole moment
16
(spin> 1) the mechanism is very efficient and the relaxation time will
be very short for nucleus A, if A and X have similar resonance
frequencies. For example the scalar coupling dominates the relaxation
mechanism in the relaxation of
oi
21
P in PBrç*
Spin-rotation (SR) relaxation mechanism
Spin-rotation relaxation is related to the rotational velocity of a
part of a molecule, or an entire molecule and the influence of this
rotation on a nucleus.22 For very small molecules or groups (e.g. a
methyl group),22 this mechanism becomes important when the SR
interaction approaches the Larmor frequency and hence energy can be
exchanged between spins. The importance of this rate process is
determined by variable temperature
measurements.
ELECTRON-NUCLEAR RELAXATION
As noted earlier dipole-dipole interactions between
nuclei and
unpaired spins are very effective in the process of relaxing nuclei.
When observing a ^2C nucleus, the increment of interaction for
electron-nuclear interactions has been found to be 102 times more
effective than nuclear-nuclear dipolar interactions assuming identical
motion and distance
factors.2^
Due to to diffusion and spin exchange
processes all nuclei in the solution have the same probability to
encounter with the unpaired electron hence, the observed relaxation
rate is a weighted average over each of the different local nuclear
environments. Unpaired spin density in
solution could also be
transferred to the relaxing atom, this mechanism often dominates the
T2 relaxation time.2^
The theoretical treatment of electron-nuclear relaxation is rather
complex, but two equations for spin-lattice and spin-spin relaxation
will be given that are valid within the extreme narrowing limits:
17
1/T^ = (4(S+1)YS2 Yj-2/ 3 fc2 r6) xc
(5)
1/T2e = l/Ti0 + (S(S+l)a2/ YS2)Xq
(6)
where Y is the gyromagnetic ratio of the I or S spins. I is the spin
of the observed nucleus and S is the spin of the metal, r is the
electron-nuclear distance, a the hyper fine electron-nuclear spin
coupling constant and
tq
the molecular correlation time.
In the spin-spin relaxation equation the hyperfine electron-nuclear
spin coupling censtant is given as a. The correlation time Te combines
the electron relaxation time and the exchange lifetime
of the
molecular complex between the ion and the molecule being relaxed as
shown by
l/re = 1/T2S + xh.
(7)
A BRIEF REVIEW OF THE USE OF PARR's
The use of paramagnetic additives in
and
NMR analysis began
in the late 1960's. Compounds such as (Eufdpm^) which form a labile
complex with cholesterol, caused large chemical shift displacements in
the proton NMR spectrum.2^> These shifts originated from the
perturbation of magnetic fields of the unpaired electrons. This alters
the Larmor frequency of each neighbouring nucleus. The degree of
variation depends on the geometry of the complex and the distance
between the perturbed nuclei and the Eu^+ ion. The resulting NMR
spectrum is expanded over a much wider range of frequencies and hence
simplifies the spectral analysis.
Other effects of paramagnetic additives were soon exploited. LaMar
first reported on the effect of a free radical (DTBN, di-tert-butyl
nitroxide)2^ and paramagnetic ions (perchlorates of Mn2+, Cr2+, Fe2+,
Co 2+)28 Qn proton- decoupled
NMR resonances. The main purpose was
18
to quench
variable nuclear Overhauser effects (NOE) vhich distort a
quantitative analysis. In a paper of Natusch's, these results were
confirmed by a theoretical approach.29
Freeman, Pachier and LaMar suggested that a paramagnetic hexaaquochrcmic perchlorate could be used not only to quench the Overhauser
enhancement but also to decrease the relaxation times.2*2 Formic acid
was given as an example of this effect.
Bare za and Engstrom showed that the accumulation time could be
reduced by using 3-diketonates
of Cu2+ and Fe2+ at low
concentrations.
Gansow et al used the co-ordinatively saturated (Cr(acac)3) to
obtain 12C NMR resonances of metal carbonyls.22 The authors pointed
out that the technique could be used to reduce the possibilities of
saturation.
1o
NMR using paramagnetic relaxation reagents, was found to be
useful in several biosynthetic studies. Compounds such as
tryptophane,22 cholic acids,2^ helicobasidin2^ and alkaloids2^ were
synthesized and characterized by use of 12C NMR and Cr(acac)3-
LaMar demonstrated how the simultaneous use of a shift reagent
(Eu(fod)3) and a relaxation reagent (Gd(fod)3) could overcome problems
found in structural studies in solution.2^ In a later work Gd(dpm)3
was suggested as an effective relaxation reagent.
OQ
In a discussion of the pros and cons on the use of lanthanide
chemical shift reagents vs. relaxation reagents, Levy and Kanoroski
made an interesting comment.39 The 12C NMR lanthanide shifts could be
of both pseudo-contact and contact origin. The contact shifts may be
large and of opposite sign to coincident pseudo-contact shifts. With a
non-shifting relaxation reagent, such complications do not arise.
19
LSR-PARR comparison
In this thesis only paramagnetic relaxation reagents have been
studied. Only minor or no 1inebroadening effects were observed. A
canparison between lanthanide shift reagents (LSR)^ and paramagnetic
relaxation reagents (PARR) can be made on the basis of Eqn. 5,6.
The LSR reagent should be anisotropic and induce minor line
broadening. Hence, the electron relaxation time should be very fast
(T2s~ 1 0 - 1
3 s ).
Quite contrary, the PARR should be isotropic, to prevent dipolar
shifts? relax slower (T2s ^10~6) and not form any specific complex
with the solute.
PARR STRUCTURE AND CHEMICAL PROPERTIES
Paramagnetic relaxation reagents normally consist of a paramagnetic
metal ion in complex with an organic ligand. Tris- 3-diketonates are
the most oormonly used chelates and their general structure is given
in Figure 1. Also Cr(lll) and Fe(lll) complexes of the ligands
ethyl enediaminetetraacetic acid (EDTA) and diethy lenetriaminepentaacetic acid (DTPA) have been used for -^C NMR spectrometry in
aqueous solutions.
41 4 ?
'
The paramagnetic ions belong to the transition elements, which
means that they can have a partially filled d-electron shell. The
first row of transition metal ions contain partially filled 3d
electron shells and may consequently be interesting for relaxation
purposes. As described by Hund's rule, the five degenerate 3d orbitals
are composed such that each orbital must contain one unpaired electron
before the orbitals are filled (spin paired).
The magnitude of T ^ relaxation is in part proportional to the
20
square of the effective magnetic moment t eff, modified as a result of
different electron spin relaxation times. Hence, the most favoured
ions are Mn^+, Cr^+ and Fe^+, which have 5, 3 and 5 unpaired electrons
respectively in their 3d orbitals.
The lanthanides have partially filled 4f orbitals and may possess
paramagnetic properties. The largest relaxation enhancement is noticed
using Gd^*, which has an effective magnetic moment of 7.9 (the
corresponding values for Cr2-1” and Cu2"1" cire 3.8 and 1.7 respectively)
As mentioned in a previous section, some lanthanides have very
short electron spin relaxation times and are used as lanthanide shift
reagents (LSR). Ions as Dy2+, Ho2+ and Eu3+ are used as LSR, 4 2 but are
poor spin relaxing agents.
Usually PARR^s are divided into two classes according to their
complexation ability:
a) Co-ordinatively saturated chelates as Cr(acac)g and Fe(acac) 3
are only capable of forming second co-ordination sphere comp­
lexation.^ Although these reagents are relatively shift inert, both
specific4^ (hydrogen bonded) and non-specific4** (dipoie-dipole or
dipole-induced dipole) complexes can be formed.
b) Co-ordinatively unsaturated chelates as Gd(dpm) 3 and Ni(dpm) 3
are capable of forming both first and second co-ordination sphere
complexation because these metal ions can increase their co-ordination
shell including substrate molecules of donor type.4 7
APPLICATIONS
Three of the most extensive applications of non-shifting relaxation
reagents are:
a) to shorten long spin-lattice relaxation times of non-protonated
21
carbons, e.g. carbonyl
c a rb o n s,
48
o r
0f slowly relaxing ^P,
etc.
b) to remove or quench the nuclear Overhauser enhancement in
quantitative
work.49
c) to identify slow relaxing nuclei or nuclei with a negative NOE
factor, e.g.
2 9
si^° and 15N.44,51
There have also been several papers where PARR have been used as
"spin labels". In this case a binding or complexion site (nucleus) in
a substrate will show a shorter electron-nuclear relaxation time,
according to the time averaged internuclear distance between the
nucleus and the paramagnetic ion. An instructive example of this
application of PARR is given by Levy with the system Fe(acac) 3 isobomeol.52 The carbons closest to the hydrogen bonded CH, C-l, C-2
and C-3, have significantly shorter T-^s.
A free radical, 2,2,6,6-Tetramethylpiperidinyl-l-oxy (TEMPO), has
been used as a relaxation reagent (Figure 4). Small amounts of TEMPO
decreases the nuclear relaxation times, especially those of nonprotonated carbon atans.
Figure 4. A free radical, TEMPO, used as a relaxation reagent.
Hofer reported the use of a chiral relaxation reagent (tris(d.ddicampholylmethanato)gadolinium(lll)) that could determine the en­
antiomeric excess of (+) and (-) methylephedrine. The
spin-lattice
relaxation times were shown to differ significantly between the
diastereomeric carpiexes.S3h
22
Magnetic resonance imaging (MRI)
NMR has been found to be a very premising technique to form images
of biological tissues.^ NMR imaging provides an anatomical
description of soft tissues with a far better contrast and resolution
than x-ray computed tomography (CT) in most areas of the body. The
images are obtained as two dimensional pictures of the body (thin
slices) and depend on differences in spin density; spin lattice (T^)
and spin-spin (T2 ) relaxation parameters of water in different
tissues. 5 5
Sometimes it is impossible to resolve differences between various
soft tissues. Therefore, certain contrast media have been used to more
easily obtain information regarding changes in T^ and T2 of the tissue
water. Increased resolution and a reduced examination time are both
streng needs using this technique. Hence, little time can be allowed
for the selection of appropriate pulse delays to optimize the contrast
for a certain tissue.
This is another reason for introducing
relaxation reagents in MRI, which when used in vivo become "MRI
contrast agents".
The most premising contrast agent to date for NMR imaging, appears
to be the gadolinium complex of DTPA. It has been used to provide
contrast enhancement of normal kidney and of human tumor models in
mice. 5 5
Major requirements on PARR's
As shown, there are several requirements on the PARR when it is
used to shorten T^s or to obtain quantitative information. A PARR
should:
- be soluble in appropriate solvents,
- not cause significant linebroadening (to prevent loss of
sensitivity and resolution),
23
- be non-shifting,
- be easily accessible or easy to synthesize and also easy to
eliminate after the measurement,
- be non-interacting i.e. for quantitative work, the ligands
should be inert. All positions in a substrate should be equally
affected.
When PARR^s are used in MRI the following pharmaceutical
considerations must be considered:
easy to store in a form suitable for clinical work,
well tolerated (non toxic) in diagnostic
doses and free
from adverse physiological responses,
quickly excreted,
highly paramagnetic (for low doses),
-
chemically versatile,
for
bonding to biological probes
(selective tissue targeting).
COMMENTS ON THE RESULTS
The work presented in this thesis concentrates on the structure of
the weak second coordination sphere around certain co-ordinatively
saturated transition metal tris (acetyl acetonato) complexes, with a
special attention on the paramagnetic Crfacac)^.
Our interest in this field is primarily in the investigation of
various interaction mechanisms that are valid for in the second co­
ordination sphere. A knewledge of these mechanisms can give important
infoonation regarding the structure; the kinetics of ligand exchange
and the thermodynamic characteristics of these systems. Our
contribution could for instance be used to simplify spectral
assignments and to simplify the interpretation of the catalytic
activity of metal ions in many biological systems.
24
Results of T^e studies in papers I, II and III
To be able to study weak interactions where preferential solvation
occur, the choice of solvent is critical. An incorrect choice of
solvent may result in a carpeting carpiexation of solvent:PARR, which
would be superimposed on the PARR-substrate interaction, thus making a
study of preferential solvation very difficult to interpret.
Before the results of paper I are discussed, some comments must be
made concerning the theoretical treatment of the relaxation data in
systems where co-ordinati ve ly saturated paramagnetic compounds are
used.
Equation 3 of (I) divides the observed relaxation rate into three
contributing relaxation terms:
l/T^bbs) = l/T^C complex) + l/T^free) + l/T^others)
(8)
The first two terms are due to the e1 ectron-nuc1ear interactions and
the remaining one is due to the diamagnetic relaxation pathway
outlined in the previous section. The first addend, which describes a
specific substrate interaction with the PARR,
is extended by
incorporating the equilibrium constant of the substrate :PARR
complexation process. This equilibrium is expressed by an effective
equilibrium constant
having two assumptions, namely that there
are no competing specific sol vent: PARR interactions and that the
separate compìexed species according to Equation 1 in (I) are
described by a binomial distribution. This means that Keff is
expressed as:.^®
This equation is later used to modify the expression of a specific
interaction given by Chan and Eaton^ and is given here:
25
I/T^C complex) = (n[PAHR1 0 /Tl0 e)*(Keff/(l-«eff[S]0))
(10)
This expression is valid under the assumption that the uncomplexed
substrate concentration, [s] , is approximately equal to the initial
concentration, [S]0, of the substrate. One should note that this
expression is dependent on both the PARR and the substrate
concentration. Hence, a specific interaction could then be detected by
a substrate concentration dependent study.
It is interesting to note that this equation is similar to, and
with seme minor restrictions identical to, an equation given earlier
both by Swift and Connick, ^ and by Luz and Meiboom.^ The observed
relaxation rate is then expressed as in Eqn.
8
of (I).
The rate l/T^Qe of a nucleus with spin I in the second co­
ordination sphere is given by the Solomon and Bloembergen equation
(Eqn. 9, I). Since this rate depends on the dipo1e-dipo1e interaction
of the electron spin and the spin of the observed nucleus, the
distance between these spins is important. Also the effective
correlation time of the dipole interaction determines the relaxation
time Tloe.
The second addendin Eqn.
8
corresponds to the relaxation that
arises from the dipole-dipole interaction between the nuclear spin and
the unpaired electron spin in the metal complex in non-specific
complexes. These are formed by stochastic collisions in the solution.
The relaxation expression, conmonly referred to as the Abragams outer
sphere model, ^ is determined by using an inert reference substance
which is similar size to the observed substrate. This reference
substance should of course not form specific outer sphere carpiexes
with the transition metal 3 -diketonates. In many of our measurements,
we have used cyclohexane, which has been shewn to be non-interacting.
Finally, the third addend in Eqn.
26
8
describes the diamagnetic
relaxation pathway. This contribution is easily measured, by simply
observing the relaxation time without PARR.
The aim of the first paper was partly to achive a better
understanding of competition of these electron-nuclear relaxation
pathways. The frequently used solvent carbon tetrachloride has
obviously a preference for weak ccmplexation with the outer sphere of
several chromium relaxation reagents. This could partly quench
substrate:PARR interactions as illustrated by the lack of substrate
concentration dependence on T^, when chloroform has been used as
substrate.
To show this, we have used an approach where the ligand structures
were changed and the Tj_e's were measured at fixed CCl^icyclohexane
ratios. Due to solubility restrictions and sensitivity problems, a
variable concentration study could not be done accurately.
Table 1.
13C T 1e 's of CC14 using various PARRa
_____ T] 0 _____
T1 e(CCl4)/
PARR
CC14
CgHi2
Tie (CgHi2)
Cr(pdo) 3
1.27
1.36
0.93
Cr(acac) 3
1.01
1.27
0.80
Cr(3-Meacac) 3
0.87
1.15
0.76
a [PARR]= 0.03 M
With increased methyl substitution on the ligand, the T^e ratio
decreased. Several explanations point to the fact that this supports a
specific interaction mechanism.
For instance,
the rotational
correlation time t r of the carpiex increases and according to Eqns. 10
27
and 11 this shortens the T-^e.
By the use of paramagnetic induced shifts given in subsequent
papers, we discuss the types of complexes that are possible for the
CC1^:PARR system. Paper I concludes by stating that carbon
tetrachloride should be avoided when co-ordination numbers, solution
structure, etc. are to be determined, having weakly co-ordinating
solutes.
In papers II and III the interest was focused on aromatic systems
and the different interaction modes cn PARR. The apparent equilibrium
constant for benzene was calculated accounting for changes in
viscosity via a T^e - concentration study. A T1e study was also
performed of benzene in different solvents. The studies showed that
Keff for benzene decreased from 0.62 when cyclohexane was used as
solvent to 0.14 when the more interacting solvent carbon tetrachloride
was used. When more competing solvents are used (CCI4 and methylene
chloride), the benzene interaction with Cr(acac)ß is suppressed.
In paper II, several other systems were studied. Polar compounds
including azulene were used to study intramolecular T-^e differences,
when the chrcmium ligand was substituted.
The trend seen from Table 2 shows that the T^e values of the sevenmembered ring carbons are shorter than the values of the five-membered
ring carbons. The trend increases on going from hfac < acac < to 3Meacac.
28
Table 2. 13c Txe#s of azulene in CCI4 , using various PARR2
C-4,8
Tl0
C-5,7
0.81
0.73
0.73
0.67
0.81
1.04
0.62
0.75
0.43
0.42
0.48
0.55
1 . 0 0
1.63
1.62
1.93
1.96
1.71
1.93
1.55
PARR
C-1,3
C-2
Cr(acac) 3
0.82
Cr(3 -Meacac) 3
CrOifac)^
C- 6
C-3a,8a cci4
[PARR] = 0.05M
We then formulated an interaction model, with the PARR metal as
positive centre:
&
Figure 5. Preferential solvation-orientation of azulene towards
Cr(acac)3 *
29
As shown above in Figure 5
the ligands in the first co-ordination
sphere bear a partial negative charge. In the first solvation sphere,
the dipolar substrate molecules orient the positive end of their
dipoles, towards this partial negative charge.
The electron-withdrawing flourinated substituents on the ligand
decrease the che 1 ate-azulene interaction while the opposite is
observed for electron-donating methyl substituents. These outer-sphere
labile complexes are considered to have a preferential orientation.
The proposed model was also used to explain similar behavior of
several other polar aromatic functionalized compounds.
When we examined the carpiexation ability of some nitrobenzenes we
found that even in dichloromethane, the nitro substrate seems to
compete with the solvent. To be able to exclude hydrogen-bonding
effects, we looked for a suitable system to test this hypothesis.
In fact, we found two appropriate compounds, p-nitroto1uene and pcyanoto1uene. These compounds have identical dipole moments, but a pKa
difference of about 10 units. The
T1e's were found to be very
similar and this showed that hydrogen bonding is unlikely to be a
contributing interaction mechanism for acids of this strength.
Another extensive T^e study of several alkyl substituted arcmatics
in solutions containing Cr(acac) 3 was performed in paper III. The
dipole model, suggested in paper II, was shown to have general
applicability. Figure
6
(Scheme 1 ,111), indicates the preferred
orientation of the alkylarcmatic substrates.
In general, the a-carbons have slightly shorter T^e values than the
aromatic carbons. The trend towards decreased relaxation times (T^e)
when more phenyl rings are connected in the a-position, could be
explained by a decreased mutual trans1 ationa1 /rotatiena1 motion.
30
figure 6.
of
13C
electron-nuclear relaxation times
aromatic compounds, studied in paper 111.
A possible contribution to the observed T^e results could arise from
the larger probability of collision between a phenyl group and the
PARR, When the nuirber of phenyl groups is increased in the substrate.
The trends of decreased
going from toluene to tetraphenyl-
31
methane, could also be taken as support for excluding any hydrogen
bond interactions among these very weak acidic substrates. In figure 1
(III), this is shown by a plot of the T^e of the para-carbons in
phenyImethanes as a function of their van der Waals volume. The plot
yields a straight line, also including tetraphenylmethane.
Results of paramagnetic induced shift studies in
papers I, II and III
Although one of the criteria of PARR's is to be a non-shifting
reagent, i.e. the magnetic anisotropy tensor should be zero (see
above), the sensitive NMR method is found to be capable of detecting
induced shifts in the second solvation sphere. The maximum induced
molar 13C shift (ppm/mol of Cr(acac)3) was found to be about 3 ppm for
azulene, when Cr(acac)^ was used in a non-interacting solute (Schone
3, II). An analysis of ccrrbined induced shift data can give valuable
information concerning the nature of the outer co-ordination sphere
similar to the use of relaxation times. However, if dipolar effects
are the predominant interaction mechanism, as shown by the previous
T^e studies,
the interpretation of the induced shifts is more
complicated than the corresponding analysis of relaxation times.
Two mechanisms must be taken into account when treating
paramagnetic shifts; (1) the contact shift, where unpaired cr- and ^ type electron spin density is transmitted by polarization of bending
electrons; (2 ) the electron-nuclear dipolar interaction (through
space), the pseudocontact shift. This interaction arises from the
magnetic dipolar fields that are experienced by a nucleus near a
paramagnetic ion. The latter mechanism is operative for anisotropic
systems and is usually distance dependent by a factor l/r^, where r is
the distance from the paramagnetic centre to the nucleus.
Particular interest has been focused on the large induced shift
observed for carbon tetrachloride which has been noted for several
metal complexes and for free radical additives.^ Our previous study
32
(II) of the system Cr(acac) 3 in dichioromethane and in chloroform,
shows that the short relaxation time for these solutes can only be
partly described by hydrogen bonding. Hence, there must be another
specific interaction involving the halogen atcm.
When spin density is transferred to substrates in the second co­
ordination sphere and a contact shift is observed, a weak, short-lived
binding situation is formed. Two possible mechanisms can explain the
transmission of spin density from the metal nucleus to the outer
ligands. First, there can be a direct spin de localization due to an
overlap between the
0
or
the tt-system of the substrate with the
chelate ligands. The other possible mechanism of transmitting spin
density is by polarization.
These types of mechanisms have been studied recently for a variety
of ha logenated hydrocarbons, using 1-chiorobutane as solute.
3
The
transfer of spin density was interpreted to proceed by direct
deloca1ization. Based on this proposal a general donor-acceptor model
was claimed to be the dominant mechanism for the outer sphere
interactions between Cr(acac) 3 and the CX- hydrocarbon.
We believe that it is not possible to exclude other types of
interactions. A pseudo-contact shift could for example, be induced by
an electrostatic dipo1 e-dipo1 e interaction, which creates anisotropy
in the Cr(acac) 3 system, resulting in an induced shift.
For carbon tetrachloride and its ha logenated analogs a donoracceptor interaction to Cr(acac) 3 has been claimed.
By this
complexation, a transmission of spin density was claimed to be
transmitted from the paramagnetic center to the ligands. This
interaction was reported to be dominant. However, in paper (IV) a 59Co
shift study of
Co(acac)y
the diamagnetic analog to Cr(acac)3 , shewed
a larger shift change than was to be expected. This observation can be
explained, together with the short T^e and large paramagnetic shift of
33
CCI4 in the presence of Cr(acac)3 , by a comparatively strong PARRsubstrate ccmplexaticn.
In (65) it is suggested that the electrostatic interactions
determine the orientation of the outer 'sphere ligands and that donoracceptor interactions are the valid mechanism in the complex formation
with Cr(acac)3 * It is, perhaps, not adequate to envisage a strict
distribution of effects in this way. A more vigorous study is clearly
needed to disentangle the contact and pseudo-contact mechanisms in
this case.
A multivariate approach to preferential solvation
In paper IV, another approach was used for the study of outer
sphere complexation to PARR's. The multivariate partial least squares
method PLS,^ was applied to relate physical molecular parameters to
T1e and induced shift data. This method has been successfully used in
interpreting other NMR parameters such as the chemical shift.67
The basis for the present study was to examine whether physical
descriptors for the substrates, that would be expected to govern
rotational/translational motion, could explain the T^e data. It was
also of interest to study whether the factors, expected to contain
information about electronic properties,
would be more important for
the induced shifts. The factors which contain information about
electronic properties will, of course, also contain information about
the possibilities of orbital overlap between different complex
fragments (e.g. inner and outer sphere ligand hetero-atoms).
The statistical model of the T^e and induced shift data, contained
two main effects. For the first effect, the dipole moment was found to
be a significant descriptor to account for most of the variance in T^e
and the induced shift process. Concerning the second effect, however,
the shift data was best described by electronic descriptors; on the
34
other hand, variables such as log P and density, had significance for
the relaxation data.
The
results support our previous
interpretations about the interaction mechanisms between aromatic
substrates and PARR.
The approach gives a possibility to predict the catalytic activity
in seme homogeneous catalysis reactions by use of the known relation
between NMR parameters and molecular properties of the substrate.
A diamagnetic approach to preferential solvation (Paper V)
In the previous studies v/e have used relaxation data and induced
shifts as probes for the interactions in the second co-ordination
sphere of several chromium complexes. A direct study of the nucleus
would give additional information about the structure and binding
forces in the complexes. Owing to the paramagnetic properties of the
chromium nucleus, such a study is of course impossible. Another
approach would be to use a diamagnetic nucleus in a similar chelate
system. The very shift-sensitive cobalt-59 nucleus is an ideal nuclei
for these purposes.Several ^ C o NMR studies of charged cobalt
chelates have earlier been used to investigate second sphere
interactions and have shewn to be powerful probes for studying these
interactions.
CoCacac)^ was chosen as the natural diamagnetic analog to
Cr(acac)3 « Special attention was given the weak molecular
interactions, such as dipole induced-dipole interactions, that were
studied in papers II and III. Emphasis was also directed toward the
somewhat puzzling interactions shown by the altylhalides.
The experimental study was designed to investigate weak electro­
static interactions, hence the choice of solvent was therefore
critical. Despite Co(acac) 3 solubility restrictions, we decided to use
cyclohexane as solvent, because of its inertness towards the reagent.
35
We examined the ^ C o chemical shift as a function of solvent
composition. A deviation from a straight line would indicate a
preferential solvation and conclusions about the nature of interaction
could be drawn. The substrates studied were protic and aprotic, hence
a variation of interactions could be expected.
A 6 (ppm)
-10
-20
-30
-50
-60
-70
-80
-90
-100
-110
0.2
0.4
0.6
0.8
Mole f r a c t i o n c y c lo h e x a n e
Figure 7.
^Co
chemical shifts of Co(acac) 3 in various organic
compounds plotted against the molar fraction of cyclohexane. (See
Figure 1 (V) for a list of symbols a-k).
36
From Figure 7 it can be seen that at solute concentrations ex­
ceeding a bulk molar fraction of 1 :1 , the first solvation sphere is
fully occupied, leading to a straight line in the plot. An estimation
of the order of preference to participate in the solvation sphere was
made by using the bulk sol vent: solute composition, at which both
solvent and solute contribute equally to solvate the chelate. We then
obtained a similar trend as expected, based on our previous T^e and
induced shift studies. It should also be noted that our earlier
observed interaction of carbon tetrachloride toward Crfacacjg
persisted for the diamagnetic experiment.
In paper V, the results for compounds capable of hydrogen bonding
to acetylacetonates are especially noted. We noted an upfield shift,
going through a maximum. Substrates which have a larger hydrogen
bonding ability acquire maximum shifts at lower solute concentrations.
Unfortunately, due to solubility restrictions, this condition could
only be shewn far PhOH and MeQH in a more interacting solvent such as
CC14. The observed trend in figure 2 was explained by changes in the
bulk solvent phase, similar to the observations noted by Langford et
al
for the chloroform-MeOH system.
At decreased alcohol
concentrations, the R-CH is preferred in the solvation sphere, giving
rise to shifts towards higher field. At higher alcohol concentrations,
self aggregation competes with the che late-so lute association
resulting in a non-regular ideal solution. The dilution study was
supplemented by a sol vent-isotope effect study for methanol and
chloroform (Table 1, V), which even showed a secondary isotope effect
in the methanol succession.
In the suirmary of relaxation mechanisms above, it was mentioned
that nuclei with spin V
1
have an electric quadrupole relaxation
moment. Diamagnetic Co III complexes are normally considered to relax
through time modulations of the coupling of the nuclear spin, with the
quadrupole tensor by rotational motion. Accordingly, an expression of
the spin-lattice relaxation in such systems will have a strong
37
dependence on Tr, the rotational correlation time, as shewn by eqn.
1
(V). The quadrupolar coupling constant (e^qQ/ti) in this equation, is a
measure of the asymmetry of the system and is zero for a highly
symmetric situation. We measured this constant for Co(acac) 3 by
ccrnbining eqn. 1 and 2 in V, assuming that the rotational diffusion of
Co(acac) 3 is isotropic. Hence, by measure of the 1^C
carbon of Co(acac) 3 in CCI4 , we could estimate
of the methine
eff. From the line
width of Co(acac) 3 (Table 2, V), we calculated T2 by the relation
1/2 = (l/Tr)T2. Finally, these values used in eqn.
1
gave a quadrupole
coupling constant of 5.2 MHz.
Another mechanism has been claimed to be operative for similar
chelates. Asyirmetric vibrations of the complex, excited by collisions
with solvent molecules, could be induced and this could lead to
nuclear spin relaxation. Co(acac) 3 was compared with Co(trop) 3 which
was found to have a larger quadrupolar coupling constant, when
assuming a mechanism described above. According to crystal data, the
reverse would have been expected. However, the study was performed in
chloroform and the positively charged tropolonato ligands could
increase the hydrogen bond accepting ability of the oxygen atoms. This
could lead to a disturbance in the 0 ^ symmetry, which could in turn
explain the observed behaviour.
Our conclusion about the relaxation is well explained by a static
quadrupolar interaction, which is modulated by the reorientation of
the chelate.
38
SHORT SUMMARY
In this thesis the interactions between several organic substances
and neutral paramagnetic relaxation reagents have been studied using
NMR techniques. A specific interaction between certain PARR's and
carbon tetrachloride was found. The interaction mechanisms between
several aromatic solutes and Cr(acac) 3 were also studied. For solutes
uncapable of hydrogen-bond donation, the mechanism was found to be of
a dipole-dipole type. The positive end of the solute dipole orients
towards the PARR chelate. This model explains the preference of
benzene and alkylbenzenes to occupy the PARR solvation shell. The
study was extended to a large number of alkyl-aromatic compounds and
the results were in accordance with our earlier findings. Hence, the
interaction towards Crfacac)^ is purely electrostatic when hydrogenbonding solutes are excluded.
A maltivariate approach was used to relate paramagnetic induced
NMR relaxation and shift data to physical descriptors, that were
expected to have relevance to motional behaviour and electronic
structure of the aromatic solute. The results supported our earlier
interpretations that the interaction is of a dipole-dipole type. In
the future development of catalytic reactions this model may be of
significant importance.
The diamagnetic analog to Cr(acac)3, namely Cotacac^, was studied
by varying the solute concentration in cyclohexane. The preferred
solvation was found to be most pronounced in hydrogen-bond donating
solutes. The order of preference is close to that found for Cr(acac)3 .
The
relaxation is suggested to be controlled by modulation of the
static quadrupolar tensor of CoCacac^.
39
ACKNOWLEDGEMENTS
I would like to express my gratitude to my supervisor and friend
Ulf Edlund, who introduced me to this subject and who has created a
most inspiring and highly interactive atmosphere during these years.
I also wish to thank Svante Wold, Bo Norden and Bertil Eliasson for
helpful discussions and suggestions.
To all my other NMR colleagues and friends having some share in
this work I convey my gratitude!
My special thanks goes to my friend and co-author Tadeuz Holak, for
a fruitful col laboration during his stay here in the sunnier 1983.
Finally, financial support fron Bengt Lundqvist Memorial Foundation
is gratefully acknowledged.
40
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