First in vivo MRI assessment of a self-assembled metallostar compound endowed with a remarkable high field relaxivity.

{Fe[Gd(2)bpy(DTTA)(2)(H(2)O)(4)](3)}(4-) is a self-assembled, metallostar-structured potential MRI contrast agent, with six efficiently relaxing Gd(3+) centres confined into a small molecular space. Its proton relaxivity is particularly remarkable at very high magnetic fields (r(1) = 15.8 mM(-1) s(-1) at 200 MHz, 37 degrees C, in H(2)O). Here we report the first in vivo MRI feasibility study, complemented with dynamic gamma scintigraphic imaging and biodistribution experiments using the (153)Sm-enriched compound. Comparative MRI studies have been performed at 4.7 T in mice with the metallostar and the small molecular weight contrast agent gadolinium(III)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate ([Gd(DOTA)(H(2)O)](-) = GdDOTA). The metallostar was well tolerated by the animals at the concentrations of 0.0500 (high dose) and 0.0125 (low dose) mmol Gd kg(-1) body weight; (BW). The signal enhancement in the inversion recovery fast low angle shot (IR FLASH) images after the high-dose metallostar injection was considerably higher than after GdDOTA injection (0.1 mmol Gd kg(-1) BW), despite the higher dose of the latter. The high-dose metallostar injection resulted in a greater drop in the spin-lattice relaxation time (T(1)), as calculated from the inversion recovery true fast imaging with steady-state precession (IR TrueFISP) data for various tissues, than the GdDOTA or the low dose metallostar injection. In summary, these studies have confirmed that the approximately four times higher relaxivity measured in vitro for the metallostar is retained under in vivo conditions. The pharmacokinetics of the metallostar was found to be similar to that of GdDOTA, involving fast renal clearance, a leakage to the extracellular space in the muscle tissue and no leakage to the brain. As expected on the basis of its moderate molecular weight, the metallostar does not function as a blood pool agent. The dynamic gamma scintigraphic studies performed in Wistar rats with the metallostar compound having (153)Sm enrichment also proved the renal elimination pathway. The biodistribution experiments are in full accordance with the MR and scintigraphic imaging. At 15 min post-injection the activity is primarily localized in the urine, while at 24 h post-injection almost all radioactivity is cleared from tissues and organs.

Superparamagnetic gadonanotubes are high-performance MRI contrast agents.

We report the nanoscale loading and confinement of aquated Gd3+n-ion clusters within ultra-short single-walled carbon nanotubes (US-tubes); these Gd3+n@US-tube species are linear superparamagnetic molecular magnets with Magnetic Resonance Imaging (MRI) efficacies 40 to 90 times larger than any Gd3+-based contrast agent (CA) in current clinical use.

Synthesis and complexation properties of DTPA-N,N''-bis[bis(n-butyl)]-N'-methyl-tris(amide). Kinetic stability and water exchange of its Gd3+ complex.

A novel DTPA-tris(amide) derivative ligand, DTPA-N,N''-bis[bis(n-butyl)]-N'-methyl-tris(amide)(H2L3) was synthesized. With Gd3+, it forms a positively charged [Gd(L3)]+ complex, whereas with Cu2+ and Zn2+ [ML3], [MHL3]+ and [M2L3]2+ species are formed. The protonation constants of H2L3 and the stability constants of the complexes were determined by pH potentiometry. The stability constants are lower than those for DTPA-N,N''-bis[bis(n-butyl)amide)](H3L2), due to the lower negative charge and reduced basicity of the amine nitrogens in (L3)2-. The kinetic stability of [Gd(L3)]+ was characterised by the rates of metal exchange reactions with Eu3+, Cu2+ and Zn2+. The exchange reactions, which occur via proton and metal ion assisted dissociation of [Gd(L3)]+, are significantly slower than for [Gd(DTPA)]2-, since the amide groups cannot be protonated and interact only weakly with the attacking metal ions. The relaxivities of [Gd(L2)] and [Gd(L3)]+ are constant between 10-20 degrees C, indicating a relatively slow water exchange. Above 25 degrees C, the relaxivities decrease, similarly to other Gd3+ DTPA-bis(amide) complexes. The pH dependence of the relaxivities for [Gd(L3)]+ shows a minimum at pH approximately 9, thus differs from the behaviour of Gd3+-DTPA-bis(amides) which have constant relaxivities at pH 3-8 and an increase below and above. The water exchange rates for [Gd(L2)(H2O)] and [Gd(L3)(H2O)]+, determined from a variable temperature (17)O NMR study, are lower than that for [Gd(DTPA)(H2O)]2-. This is a consequence of the lower negative charge and decreased steric crowding at the water binding site in amides as compared to carboxylate analogues. Substitution of the third acetate of DTPA5- with an amide, however, results in a less pronounced decrease in kex than substitution of the first two acetates. The activation volumes derived from a variable pressure (17)O NMR study prove a dissociative interchange and a limiting dissociative mechanism for [Gd(L2)(H2O)] and [Gd(L3)(H2O)]+, respectively.

Solid-state and solution properties of the lanthanide complexes of a new heptadentate tripodal ligand: a route to gadolinium complexes with an improved relaxation efficiency.

The tripodal ligand (alpha,alpha',alpha' 'nitrilotri(6-methyl-2-pyridinecarboxylic acid)) (H(3)tpaa) forms a Gd(III) complex which has a relaxivity (r(1p) = 13.3 mM(-1) s(-1) at 25 degrees C and at 60 MHz) remarkably higher than those of the currently clinically used contrast agents based on octacoordinate polyaminocarboxylate complexes (3.5-4.7 mM(-1) s(-1)) and a reasonably good thermodynamic stability. The crystal structure of the ligand and of its La, Nd, Eu, Gd, Tb, Ho, Tm, Yb, and Lu complexes have been determined by X-ray crystallography. The neutral H(3)tpaa molecule adopts, in the solid state, a preorganized tripodal conformation in which the three H(3)tpaa arms are located on the same side of the molecule, ready to bind a metal ion in a heptadentate coordination mode. The structures of the Ln(III) complexes vary along the series for their nuclearity and number of water molecules coordinated to the metal, and a tetrameric structure is observed for the La(3+) ion (9- and 10-coordinate metal centers), dimeric structures are formed from the Nd(3+) ion through the Yb(3+) ion (9-coordinate), and a monomeric structure results for Lu(3+) (8-coordinate). The relaxivity studies presented here suggest that the high relaxivity of the Gd(tpaa) complex is mainly the consequence of a shorter bound water proton-Gd(III) distance associated with a probable water coordination equilibrium between tris(aqua) and bis(aqua) complexes, giving raise to a mean number of coordinated water molecules q > 2. Both effects are strongly related to the ligand flexibility, which allows for a large volume available for water binding. The observed rapid water exchange rate is probably due to the presence of a low-energy barrier between 10-, 9-, and 8- coordinate geometries. Although the low solubility of the Gd complex of tpaa prevents its practical application as an MRI contrast agent, the straightforward introduction of substituents on the pyridine rings allows us to envisage ligands with a higher water solubility, containing functional groups leading to macromolecular systems with very high relaxivity.

A model for sequential threading of alpha-cyclodextrin onto a guest: a complete thermodynamic and kinetic study in water.

The first variable-temperature and variable-pressure stopped-flow spectrophotometric study of the sequential threading of alpha-cyclodextrin (alpha-CD) onto the guest dye Mordant Orange 10, S, is reported. Complementary (1)H one-dimensional (1D) variable-temperature kinetic studies and two-dimensional (2D) rotating-frame nuclear Overhauser effect spectroscopy (ROESY) and EXSY NMR studies are also reported. In aqueous solution at 298.2 K, the first alpha-CD threads onto S to form a 1:1 complex S.alpha-CD with a forward rate constant k(1,f) = 15 200 +/- 200 M(-1) s(-1) and dethreads with a reverse rate constant k(1,r) = 4.4 +/- 0.3 s(-1). Subsequently, S.alpha-CD isomerizes to S.alpha-CD (k(3,f) = 0.158 +/- 0.006 s(-1), k(3,f) = 0.148 +/- 0.006 s(-1)). This process can be viewed as a thermodynamically controlled molecular shuttle. A second alpha-CD threads onto S.alpha-CD to form a 1:2 complex, S.(alpha-CD)(2), with k(2,f) = 98 +/- 2 M(-1) s(-1) and k(2,r) = 0.032 +/- 0.002 s(-1). A second alpha-CD also threads onto S.alpha-CD to form another 1:2 complex, S.(alpha-CD)(2), characterized by k(4,f) = 9640 +/- 1800 M(-1) s(-1) and k(4,r) = 61 +/- 6 s(-1). Direct interconvertion between S.(alpha-CD)(2) and S.(alpha-CD)(2) was not detected; instead, they interconvert by dethreading the second alpha-CD and through the isomerization equilibrium between S.alpha-CD and S.alpha-CD. The reaction volumes, DeltaV(0), were found to be negative for the first three equilibria and positive for the fourth equilibrium. For the first three forward and reverse reactions, the volumes of activation are substantially more negative, indicating a compression of the transition state in comparison with the ground states. These data were used in conjunction with DeltaH, DeltaH degrees, DeltaS, and DeltaS degrees data to deduce the dominant mechanistic threading processes, which appear to be largely controlled by changes in hydration and van der Waals interactions, and possibly by conformational changes in both S and alpha-CD. The structure of the four complexes were deduced from (1)H 2D ROESY NMR studies.

EPR spectroscopy of MRI-related Gd(III) complexes: simultaneous analysis of multiple frequency and temperature spectra, including static and transient crystal field effects.

For the first time, a very general theoretical method is proposed to interpret the full electron paramagnetic resonance (EPR) spectra at multiple temperatures and frequencies in the important case of S-state metal ions complexed in liquid solution. This method is illustrated by a careful analysis of the measured spectra of two Gd3+ (S = 7/2) complexes. It is shown that the electronic relaxation mechanisms at the origin of the EPR line shape arise from the combined effects of the modulation of the static crystal field by the random Brownian rotation of the complex and of the transient zero-field splitting. A detailed study of the static crystal field mechanism shows that, contrarily to the usual global models involving only second-order terms, the fourth and sixth order terms can play a non-negligible role. The obtained parameters are well interpreted in the framework of the physics of the various underlying relaxation processes. A better understanding of these mechanisms is highly valuable since they partly control the efficiency of paramagnetic metal ions in contrast agents for medical magnetic resonance imaging (MRI).

Lipari-Szabo approach as a tool for the analysis of macromolecular gadolinium(III)-based MRI contrast agents illustrated by the [Gd(EGTA-BA-(CH2)12)]nn+ polymer.

The parameters governing the water proton relaxivity of the [Gd(EGTA-BA-(CH2)12)]nn+ polymeric complex were determined through global analysis of 17O NMR, EPR and nuclear magnetic relaxation dispersion (NMRD) data [EGTA-BA2- = 3,12-bis(carbamoylmethyl)- 6,9-dioxa-3,12-diazatetradecanedioate(2-)]. The Lipari-Szabo approach that distinguishes the global motion of the polymer (tau g) from the local motion of the Gd(III)-water vector (tau l) was necessary to describe the 1H and 17O longitudinal relaxation rates; therefore for the first time it was included in the global simultaneous analysis of the EPR, 17O NMR and NMRD data. The polymer consists on average of only five monomeric units, which limits the intramolecular hydrophobic interactions operating between the (CH2)12 groups. Hence the global rotational correlation time is not very high (tau g298 = 3880 +/- 750 ps) compared to the corresponding DTPA-BA-based polymer (about 15 monomeric units), where tau g298 = 6500 ps. As a consequence, the relaxivity is limited by the rotation, which precludes the advantage obtained from the fast exchanging chelating unit (kex298 = 2.2 +/- 0.1 x 10(6) s-1).

Molecular dynamics simulations of MRI-relevant GdIII chelates: direct access to outer-sphere relaxivity.

The structure and dynamics of the surrounding water were studied through molecular dynamics (MD) simulations for several GdIII polyaminocarboxylate and polyaminophosphonate complexes in aqueous solution. The radial distribution functions (rdf) show that a few water molecules are bonded to the ligand through hydrogen bonds to hydrophilic groups such as carboxylates and phosphonates. Residence times are of the order of 20-25 ps for the polyaminocarboxylate and 56ps for the polyaminophosphonate chelates. No preferred orientation or bonding of water molecules is observed in the hydrophobic region of the anisotropic macrocyclic complexes. Our rdf allow calculation of the outer-sphere contribution to the nuclear magnetic resonance dispersion (NMRD) profiles using Freed's finite differences method, including electronic relaxation. The results show that the commonly used analytical force-free model is only an empirical relationship. When experimental outer-sphere NMRD profiles are available ([Gd(teta)]- and [Gd(dotp)]5-(teta=N,N',N",N"'-tetracarboxymethyl-1,4,8,11- tetraazacyclotetradecane; dotp = N,N',N",N"'-tetraphosphonatomethyl-1,4,7,10-tetraazacyclododecane) the calculated curves are in good agreement. In the case of [Gd(teta)]-, the comparison with the experimental NMRD profile has led us to predict a very fast electronic relaxation, which has been confirmed by the EPR spectrum.

Self-assembly of multinuclear coordination species with chiral bipyridine ligands: silver complexes of 5,6-CHIRAGEN(o,m,p-xylidene) ligands and equilibrium behaviour in solution.

The complexation reactions between Ag- and a series of enantiopure ligands belonging to the CHIRAGEN (from CHIRAlity GENerator) family (L1, L2, L3, based on (-)-5,6-pinene bipyridine) have been studied in solution. It has been shown that the length of the bridge plays a fundamental role in the self-assembly processes leading to different compounds: mononuclear complexes (with L3), mixtures of polynuclear complexes (with L2) and circular helicates (with L 1). Although the absolute configuration of the chiral centres in all three ligands is the same, the metal-centred chirality of L3 (delta) is inverted with respect to that in the other two complexes with L1 and L2 (delta). The metal configuration is thus opposite in the mononuclear complex with respect to the polynuclear species. Detailed thermodynamic studies were carried out for the Ag+ and L1 ligand system by 1H and 109Ag NMR spectroscopy (as a function of concentration, temperature and pressure). At low temperature and high pressure, the [Ag6L1(6)]6+ hexanuclear circular helicate forms a tetranuclear circular helicate [Ag4L1(4)]4+: 2[Ag6L1(6)]6+ <=> 3 [Ag4L1(4)]4+. The thermodynamics parameters, obtained by temperature and pressure variation, have the following values: K298 = (8.7 +/- 0.7) x 10(-5) mol x kg(-1), deltaHo = -15.65 +/- 0.8 kJ x mol(-1), deltaSo = -130.2 +/- 3 J x mol(-1) x K(-1) and deltaVo(256 K)= -160 +/- 12 cm3 x mol(-1). The reaction volume calculated according to Connolly's method indicates that the calculated structure of [Ag4L1(4)]4+ is plausible. Both the signs and large magnitudes of deltaSo and deltaVo are counterintuitive, yet can be understood by modelling methods.

Towards rational design of fast water-exchanging Gd(dota-like) contrast agents? Importance of the M/m ratio.

1H NMR line-shape analysis and magnetisation-transfer experiments at variable temperature and pressure have been used to elucidate the solution dynamics of both M and m isomers of three [Eu(dota-tetraamide)(H2O)]3+ complexes. The direct 1H NMR observation of the bound water signal allows the water-exchange rates on each isomer to be measured individually. They are definitely independent of the ligand for both M and m isomers (M: k298(ex)=9.4+/-0.2 x 10(3) s(-1) for [Eu(dotam)(H2O)]3+, 8.2+/-0.2 x 10(3) s(-1) for [Eu(dtma)(H2O)]3+ and 11.2+/-1.4 x 10(3) s(-1) for [Eu(dotmam)-(H2O)]3+; m: k298(ex)=474+/-130 x 10(3) s(-1) for [Eu(dotam)(H2O)3+, 357+/-92 x 10(3) s(-1) for [Eu(dtma)(H2O)3+), and proceed through a dissociative mechanism (M isomers: deltaV++ = +4.9 cm3 mol(-1) for [Eu(dotam)(H2O)]3+ and + 6.9 cm3 mol(-1) for [Eu(dtma)(H2O)]3+). The overall water exchange only depends on the M/m isomeric ratio. The m isomer, which exchanges more quickly, is favoured by a-substitution of the ring nitrogen. Therefore the synthesis of DOTA-like ligands, which predominantly form complexes in the m form, should be a sufficient condition to ensure faster water exchange on potential Gd(III)-based contrast agents. Furthermore the activation parameters for the water-exchange and isomerisation processes are both compatible with a nonhydrated complex as intermediate.

Solution and solid-state characterization of Eu(II) chelates: a possible route towards redox responsive MRI contrast agents.

We report the first solid state X-ray crystal structure for a Eu(II) chelate, [C(NH2)3]3[Eu(II)(DTPA)(H2O)].8H2O, in comparison with those for the corresponding Sr analogue, [C(NH2)3]3[Sr(DTPA)(H2O).8H2O and for [Sr(ODDA)].8H2O (DTPA5 = diethylenetriamine-N,N,N',N",N"-pentaacetate, ODDA2- =1,4,10,13-tetraoxa-7,16-diazacyclooctadecane-7,16-diacetate ). The two DTPA complexes are isostructural due to the similar ionic size and charge of Sr(2+) and Eu(2+). The redox stability of [Eu(II)(ODDA)(H2O)] and [Eu(II)(ODDM)]2- complexes has been investigated by cyclovoltammetry and UV/Vis spectrophotometry (ODDM4- =1,4,10,13-tetraoxa-7,16-diaza-cyclooctadecane-7,16-++ +dimalonate). The macrocyclic complexes are much more stable against oxidation than [Eu(II)(DTPA)(H2O)]3- (the redox potentials are E1/2 =-0.82 V, -0.92 V, and -1.35 V versus Ag/AgCl electrode for [Eu(III/II)(ODDA)(H2O)],[Eu(III/II)(ODDM)], and [Eu(III/II)(DTPA)(H2O)], respectively, compared with -0.63 V for Eu(III/II) aqua). The thermodynamic stability constants of [Eu(II)(ODDA)(H2O)], [Eu(II)(ODDM)]2-, [Sr(ODDA)(H2O)], and [Sr(ODDM)]2- were also determined by pH potentiometry. They are slightly higher for the EuII complexes than those for the corresponding Sr analogues (logK(ML)=9.85, 13.07, 8.66, and 11.34 for [Eu(II)(ODDA)(H2O)], [Eu(II)(ODDM)]2-, [Sr(ODDA)(H2O)], and [Sr(ODDM)]2-, respectively, 0.1M (CH3)4NCl). The increased thermodynamic and redox stability of the Eu(II) complex formed with ODDA as compared with the traditional ligand DTPA can be of importance when biomedical application is concerned. A variable-temperature 17O-NMR and 1H-nuclear magnetic relaxation dispersion (NMRD) study has been performed on [Eu(II)(ODDA)(H2O)] and [Eu(II)(ODDM)]2- in aqueous solution. [Eu(II)(ODDM)]2- has no inner-sphere water molecule which allowed us to use it as an outer-sphere model for [Eu(II)(ODDA)(H2O)]. The water exchange rate (k298(ex)= 0.43 x 10(9)s(-1)) is one third of that obtained for [Eu(II)(DTPA)(H2O)]3-. The variable pressure 17O-NMR study yielded a negative activation volume, deltaV (not=) = -3.9cm3mol(-1); this indicates associatively activated water exchange. This water exchange rate is in the optimal range to attain maximum proton relaxivities, which are, however, strongly limited by the fast rotation of the small molecular weight complex.

Denaturant-induced movement of the transition state of protein folding revealed by high-pressure stopped-flow measurements.

The small all-beta protein tendamistat folds and unfolds with two-state kinetics. We determined the volume changes associated with the folding process by performing kinetic and equilibrium measurements at variable pressure between 0.1 and 100 MPa (1 to 1, 000 bar). GdmCl-induced equilibrium unfolding transitions reveal that the volume of the native state is increased by 41.4 +/- 2.0 cm(3)/mol relative to the unfolded state. This value is virtually independent of denaturant concentration. The use of a high-pressure stopped-flow instrument enabled us to measure the activation volumes for the refolding (DeltaVo/f) and unfolding reaction (DeltaVo/u) over a broad range of GdmCl concentrations. The volume of the transition state is 60% native-like (DeltaVo/f) = 25.0 +/- 1.2 cm(3)/mol) in the absence of denaturant, indicating partial solvent accessibility of the core residues. The volume of the transition state increases linearly with denaturant concentration and exceeds the volume of the native state above 6 M GdmCl. This result argues for a largely desolvated transition state with packing deficiencies at high denaturant concentrations and shows that the structure of the transition state depends strongly on the experimental conditions.

Can octahedral t2g6 complexes substitute associatively? The case of the isoelectronic ruthenium(II) and rhodium(III) hexaaquaions.

For the low-spin t2g6 Ru(OH2)6(2+) (delta V++ = -0.4 cm3 mol-1) and Rh(OH2)6(3+) (delta V++ = -4.2 cm3 mol-1) hexaaquaions, the respective Id and Ia water exchange mechanisms had been assigned, mainly on the basis of activation volumes delta V++ and entering ligands effects for water substitution. For Ru(II) the near-zero delta V++ was supposed to be due to the compensation between a positive contribution (the loss of a water molecule) and a negative one (the contraction of the bonds of the five spectator ligands at the transition state). Recently, it has been suggested that Rh(III), because of its higher positive charge, could promote further spectator ligands bond contraction sufficient to change the sign of delta V++ to a negative value. If true, this would be an example of limitation in the use of delta V++ for a direct diagnosis of the mechanism. Quantum chemical calculations including hydration effects show that the activation energies for the water exchange on Rh(OH2)6(3+) via the Ia (114.8 kJ mol-1) and the D pathways is 21.8 kJ mol-1 in favor of the former. In the case of Ru(OH2)6(2+) all attemps to compute a transition state for an interchange mechanism failed, but the calculated delta E++ for the D mechanism (71.9 kJ mol-1) is close to both experimental delta G298++ and delta H298++ values. The calculated delta sigma d(M-O) values of -0.53 A for rhodium(III) and +1.25 A for ruthenium(II) agree with the experimented delta V++ values and suggest Ia and D (or Id) mechanisms, respectively. In the case of Ru(OH2)6(2+) the shortening of the bonds of the five spectator ligands to reach the transition states corresponds to a volume change of -1.7 cm3 mol-1. For Rh(OH2)6(3+) these spectator ligands' volume decrease is much smaller (maximum of -0.8 cm3 mol-1) and the bond lengths of the two exchanging ligands at the transition state are characteristic of an interchange pathway with a small "a" character. Because of the strong RhIII-O bonds, water exchange on Rh(OH2)6(3+) proceeds via the Ia pathway with retention of the configuration, whereas the same reaction of Ru(OH2)6(2+), which has considerably weaker RuII-O bonds, follows the Id or the D mechanism.

Structure and reactivity of aquacarbonylruthenium(II) complexes. An X-ray and oxygen-17 NMR study.

The water exchange on [Ru(CO)(H2O-eq)4(H2O-ax)](tos)2 (1), [Ru(CO)2(H2O-eq)2(H2O-ax)2](tos)2 (2), and [Ru(CO)3(H2O)3](ClO4)2 (3), the 17O exchange between the bulk water and the carbonyl oxygens have been studied by 17O NMR spectroscopy, and the X-ray crystallographic structures of 1 and 2 have been determined. The water exchange of equatorially and axially coordinated water molecules on 1 and 2 follow an Id mechanism and are characterized by keq298 (s-1), delta H++ (kJ/mol), and delta S++ (J/(mol K)) of (2.54 +/- 0.05) x 10(-6), 111.6 +/- 0.4, and 22.4 +/- 1 (1-eq); (3.54 +/- 0.02) x 10(-2) and 81 (1-ax); (1.58 +/- 0.14) x 10(-7), 120.3 +/- 2, and 28.4 +/- 4 (2-eq); and (4.53 +/- 0.08) x 10(-4), 97.9 +/- 1, and 19.3 +/- 3 (2-ax). The observed reactivities correlate with the strength of the Ru-OH2 bonds, as expressed by their length obtained by X-ray studies: 2.079 (1-eq), 2.140 (1-ax), 2.073 (2-eq), and 2.110 (2-ax) A. 3 is strongly acidic witha pKa of -0.14 at 262 K. Therefore, the acid-dependent water exchange can take place through 3 or Ru(CO)3(H2O)3OH+ with an estimated keq298 of 10(-4)/10(-3) s-1 and kOH262 of 0.053 +/- 0.006 s-1. The 17O exchange rate between the bulk water and the carbonyl oxygens increases from 1 to 2 to 3. For 1 an upper limit of 10(-8) s-1 was estimated. For 2, no acid dependence of kRuCO between 0.1 and 1 m Htos was observed. At 312.6 K, in 0.1 and 1 m Htos, kRuCO = (1.18 +/- 0.03) x 10(-4). For the tricarbonyl complex, the exchange can proceed through 3 or Ru(CO)3(H2O)2OH+ with kRuCO and kRuOHCO of, respectively, 0.003 +/- 0.002 and 0.024 +/- 0.003 s-1, with a ruthenacarboxylic acid intermediate.

Speciation and kinetics related to catalytic carbonylation in the presence of cis-[Ir(CO)2I2]P(C6H5)4 under CO and H2 pressures.

The differences in the reactivities of the square-planar complexes cis-[Rh(CO)2I2]- (1) and cis-[Ir(CO)2I2]- (2), involved in the catalytic carbonylation of olefins, are investigated, with P(C6H5)4+ as the counterion, by ambient- and high-pressure NMR and IR spectroscopy. Under an elevated pressure of CO, 1 and 2 form the [M(CO)3I] complexes with the equilibrium constants KIr approximately 1.8 x 10(-3) and KRh approximately 4 x 10(-5). The ratio KIr/KRh close to 50 shows that, under catalytic conditions (a few megapascals), only complex 1 remains in the anionic form, while a major amount of the iridium analogue 2 is converted to a neutral species. The oxidative addition reactions of HI with 1 and 2 give two monohydrides of different geometries, mer,trans-[HRh(CO)2I3]- (3) and fac,cis-[HIr(CO)2I3]- (4), respectively. Both hydrides are unstable at ambient temperature and form, within minutes for Rh and within hours for Ir, the corresponding cis-[M(CO)2I2]- (1 or 2) and [M(CO)2I4]- (5 or 6) species and H2. When an H2 pressure of 5.5 MPa is applied to a nitromethane solution of complex 2, ca. 50% of 2 is transformed to cis-dihydride complexes. The formation of cis,cis,cis-[IrH2(CO)2I2]- (8a) is followed by intermolecular rearrangements to form cis,trans,cis-[IrH2(CO)2I2]- (8b) and cis,cis,trans-[IrH2(CO)2I2]- (8c). A small amount of a dinuclear species, [Ir2H(CO)4I4]x- (9), is also observed. The formation rate constants for 8a and 8b at 262 K are k1(262) = (4.42 +/- 0.18) x 10(-4) M-1 s-1, k-1(262) = (1.49 +/- 0.07) x 10(-4) s-1, k2(262) = (2.81 +/- 0.04) x 10(-5) s-1, and k-2(262) = (5.47 +/- 0.16) x 10(-6) s-1. The two equilibrium constants K1(262) = [8a]/([2][H2]) = 2.97 +/- 0.03 M-1 and K2(262) = [8b]/[8a] = 5.13 +/- 0.10 show that complex 8b is the thermodynamically stable addition product. However, no similar H2 addition products of the rhodium analogue 1 are observed. The pressurization with H2 of a solution containing 2 and 6 give the monohydride 4, the dihydrides 8a and 8b, the dinuclear complex 9, and the two new complexes [Ir(CO)2I3] (10) and [HIr(CO)2I2] (11). The reactions of the iridium complexes with H2 and HI are summarized in a single scheme.

Mechanism of CO exchange on cis-[M(CO)2X2]- complexes (M=Rh,Ir;X=Cl, Br, or I).

The CO exchange on cis-[M(CO)2X2]- with M = Ir (X = Cl, la; X = Br, 1b; X = I, 1c) and M = Rh (X = Cl, 2a; X = Br, 2b; X = I, 2c) was studied in dichloromethane. The exchange reaction [cis-[M(CO)2X2]- + 2*CO is in equilibrium cis-[M(*CO)2X2]- + 2CO (exchange rate constant: kobs)] was followed as a function of temperature and carbon monoxide concentration (up to 6 MPa) using homemade high gas pressure NMR sapphire tubes. The reaction is first order for both CO and cis-[M(CO)2X2]- concentrations. The second-order rate constant, k2(298) (=kobs)[CO]), the enthalpy, deltaH*, and the entropy of activation, deltaS*, obtained for the six complexes are respectively as follows: la, (1.08 +/- 0.01) x 10(3) L mol(-1) s(-1), 15.37 +/- 0.3 kJ mol(-1), -135.3 +/- 1 J mol(-1) K(-1); 1b, (12.7 +/- 0.2) x 10(3) L mol(-1) s(-1), 13.26 +/- 0.5 kJ mol(-1), -121.9 +/- 2 J mol(-1) K(-1); 1c, (98.9 +/- 1.4) x 10(3) L mol(-1) s(-1), 12.50 +/- 0.6 kJ mol(-1), -107.4 +/- 2 J mol(-1) K(-1); 2a, (1.62 +/- 0.02) x 10(3) L mol(-1) s(-1), 17.47 +/- 0.4 kJ mol(-1), -124.9 +/- 1 J mol(-1) K(-1); 2b, (24.8 +/- 0.2) x 10(3) L mol(-1) s(-1), 11.35 +/- 0.4 kJ mol(-1), -122.7 +/- 1 J mol(-1) K(-1); 2c, (850 +/- 120) x 10(3) L mol(-1), s(-1), 9.87 +/- 0.8 kJ mol(-1), -98.3 +/- 4 J mol(-1) K(-1). For complexes la and 2a, the volumes of activation were measured and are -20.9 +/- 1.2 cm3 mol(-1) (332.0 K) and -17.2 +/- 1.0 cm3 mol(-1) (330.8 K), respectively. The second-order kinetics and the large negative values of the entropies and volumes of activation point to a limiting associative, A, exchange mechanism. The reactivity of CO exchange follows the increasing trans effect of the halogens (Cl < Br << I), and this is observed on both metal centers. For the same halogen, the rhodium complex is more reactive than the iridium complex. This reactivity difference between rhodium and iridium is less marked for chloride (1.5: 1) than for iodide (8.6:1) at 298 K.

Kinetics and mechanism of complex formation of nickel(II) with tetra-N-alkylated cyclam in N,N-dimethylformamide (DMF): comparative study on the reactivity and solvent exchange of the species Ni(DMF)6(2+) and Ni(DMF)5Cl+.

13C NMR was used to study the rate of DMF exchange in the nickel(II) cation Ni(DMF)6(2+) and in the monochloro species Ni(DMF)5Cl+ with 13C-labeled DMF in the temperature range of 193-395 K in DMF (DMF = N,N-dimethylformamide). The kinetic parameters for solvent exchange are kex = (3.7 +/- 0.4) x 10(3) s-1, delta H++ = 59.3 +/- 5 kJ mol-1, and delta S++ = +22.3 +/- 14 J mol-1 K-1 for Ni(DMF)6(2+) and kex = (5.3 +/- 1) x 10(5) s-1, delta H++ = 42.4 +/- 4 kJ mol-1, and delta S++ = +6.7 +/- 15 J mol-1 K-1 for Ni(DMF)5Cl+. Multiwavelength stopped-flow spectrophotometry was used to study the kinetics of complex formation of the cation Ni(DMF)6(2+) and of the 100-fold more labile cation Ni(DMF)5Cl+ with TMC (1,4,8,11-tetramethyl-1,4,8,11-tetraazacyclotetradecane) and TEC (1,4,8,11-tetraethyl-1,4,8,11-tetraazacyclotetradecane) in DMF at 298 K and I = 0.6 M (tetra-n-butylammoniumperchlorate). Equilibrium constants K for the addition of the nucleophiles DMF, Cl-, and Br- to the complexes Ni(TMC)2+ and Ni(TEC)2+ were determined by spectrophotometric titration. Formation of the complexes Ni(TMC)2+ and Ni(TEC)2+ was found to occur in two stages. In the initial stage, fast, second-order nickel incorporation with rate constants k1(TMC) = 99 +/- 5 M-1 s-1 and k1 (TEC) = 235 +/- 12 M-1 s-1 leads to the intermediates Ni(TMC)int2+ and Ni(TEC)int2+, which have N4-coordinated nickel. In the second stage, these intermediates rearrange slowly to form the stereochemically most stable configuration. First-order rate constants for the one-step rearrangement of Ni(TMC)int2+ and the two-step rearrangment of Ni(TEC)int2+ are presented. Because of the rapid formation of Ni(DMF)5Cl+, the reactions of Ni(DMF)6(2+) with TMC and TEC are accelerated upon the addition of tetra-n-butylammoniumchloride (TBACl) and lead to the complexes Ni(TMC)Cl+ and Ni(TEC)Cl+, respectively. For initial concentrations such that [TBACl]o/[nickel]o > or = 20, intermediate formation is 230 times (TMC) and 47 times (TEC) faster than in the absence of chloride. The mechanism of complex formation is discussed.

1H-NMRD and 17O-NMR assessment of water exchange and rotational dynamics of two potential MRI agents: MP-1177 (an extracellular agent) and MP-2269 (a blood pool agent).

The parameters that govern water proton magnetic relaxation (e.g. water exchange rates, and rotational and electronic correlation times) of representatives of two classes of Gd(III) complexes have been estimated, using two different approaches and the results compared with those derived for known analogs. The complexes studied are: (i) the non-ionic GdDTPA-bis(-methoxyethyl-amide) [Gd(DTPA-BMEA)], a typical small-molecule extracellular MR agent, and (ii) the ionic Gd(III) complex of 4-pentylbicyclo[2.2.2]octane-1-carboxyl-di-L-aspartyl-lysine-deriv ed-DTPA [GdL]4-, a prototype MR blood pool agent, which binds to serum albumin in vivo through non-covalent hydrophobic interactions. An 17O-NMR study of [Gd(DTPA-BMEA)] gives a water exchange rate constant of k(ex)298 = (0.39 +/- 0.02) x 10(6) s(-1), identical to that for the bismethylamide analog [Gd(DTPA-BMA)]. Both approaches yield longer rotational correlation times for [Gd(DTPA-BMEA)], consistent with its higher molecular weight. An 17O-NMR study of [GdL]4- gives a water exchange rate constant of k(ex)298 = (4.2 +/- 0.1) x 10(6) s(-1), identical to that for [Gd(DTPA)]2-. The water exchange rate on [GdL]4- did not decrease considerably when bound to albumin, the lowest limit is k(ex,GdL-BSA) = k(ex,GdL)/2. Both approaches yield identical rotational correlation times for [GdL]4-, however, it was difficult to derive a consistent rotational constant for the albumin-bound [GdL]4- using the different approaches (values ranged between 1.0 and 23.0 ns).

High-pressure stopped-flow spectrometer for kinetic studies of fast reactions by absorbance and fluorescence detection.

The development of a stopped-flow instrument that operates over a temperature range of -40 to +100 °C and up to 200 MPa is described. The system has been designed so that measurements can be performed in absorbance and fluorescence modes simultaneously, without dismantling the unit. It can easily be combined with an optical system of a conventional ambient pressure setup by using light guides. Optimum optical performance and a wide operating wavelength range (220-850 nm) are achieved as the light is not passing through the pressurizing fluid. A special design for the pistons has been developed; thus, the apparatus has proven to be leak-free, even under extreme conditions (high pressure, low temperature, various solvents). The dead time of the system is found to be less than 2 ms at 298 K and is pressure independent up to 200 MPa. We examined the kinetics for the formation of the Mg(2+)-8-hydroxyquinoline chelate in aqueous solutions at pH 8.0 in order to develop a convenient alternative test method for high-pressure stopped-flow spectrometers with absorption and fluorescence detection.