Paramagnetic Relaxation Reagents Hans G

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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. Œ 3c14N, 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! 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