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.     

Unexpected aggregation of neutral, xylene-cored dinuclear GdIII chelates in aqueous solution

We have synthesized ditopic ligands L(1), L(2), and L(3) that contain two DO3A(3-) metal-chelating units with a xylene core as a noncoordinating linker (DO3A(3-) = 1,4,7,10-tetraazacyclododecane-1,4,7-triacetate; L(1) = 1,4-bis{[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]methyl}benzene; L(2) = 1,3-bis{[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]methyl}benzene; L(3) = 3,5-bis{[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]methyl}benzoic acid). Aqueous solutions of the dinuclear Gd(III) complexes formed with the three ligands have been investigated in a variable-temperature, multiple-field (17)O NMR and (1)H relaxivity study. The (17)O longitudinal relaxation rates measured for the [Gd(2)L(1-3)(H2O)(2)] complexes show strong field dependence (2.35-9.4 T), which unambiguously proves the presence of slowly tumbling entities in solution. The proton relaxivities of the complexes, which are unexpectedly high for their molecular weight, and in particular the relaxivity peaks observed at 40-50 MHz also constitute experimental evidences of slow rotational motion. This was explained in terms of self-aggregation related to hydrophobic interactions, pi stacking between the aromatic linkers, or possible hydrogen bonding between the chelates. The longitudinal (17)O relaxation rates of the [Gd(2)L(1-3)(H2O)(2)] complexes have been analysed with the Lipari-Szabo approach, leading to local rotational correlation times tau(1)(298) of 150-250 ps and global rotational correlation times tau(g)(298) of 1.6-3.4 ns (c(Gd): 20-50 mM), where tau(1)(298) is attributed to local motions of the Gd segments, while tau(g)(298) describes the overall motion of the aggregates. The aggregates can be partially disrupted by phosphate addition; however, at high concentrations phosphate interferes in the first coordination sphere by replacing the coordinated water. In contrast to the parent [Gd(DO3A)(H2O)(1.9)], which presents a hydration equilibrium between mono- and dihydrated species, a hydration number of q = 1 was established for the [Ln(2)L(1-3)(H2O)(2)] chelates by (17)O chemical shift measurements on Ln = Gd and UV/Vis spectrophotometry for Ln = Eu. The exchange rate of the coordinated water is higher for [Gd(2)L(1-3)(H2O)(2)] complexes k(ex)(298) = 7.5-12.0 x 10(6) s(-1)) than for [Gd(DOTA)(H2O)](-). The proton relaxivity of the [Gd(2)L(1-3)(H2O)(2)] complexes strongly decreases with increasing pH. This is related to the deprotonation of the inner-sphere water, which has also been characterized by pH potentiometry. The protonation constants determined for this process are logK(OH) = 9.50 and 10.37 for [Gd(2)L(1)(H2O)(2)] and [Gd(2)L(3)(H2O)(2)], respectively.     

Fine-tuning water exchange on Gd(III) poly(amino carboxylates) by modulation of steric crowding

In the objective of optimizing water exchange rate on stable, nine-coordinate, monohydrated Gd(III) poly(amino carboxylate) complexes, we have prepared monopropionate derivatives of DOTA4- (DO3A-Nprop4-) and DTPA5- (DTTA-Nprop5-). A novel ligand, EPTPA-BAA(3-), the bisamylamide derivative of ethylenepropylenetriamine-pentaacetate (EPTPA5-) was also synthesized. A variable temperature 17O NMR study has been performed on their Gd(III) complexes, which, for [Gd(DTTA-Nprop)(H2O)]2- and [Gd(EPTPA-BAA)(H2O)] has been combined with multiple field EPR and NMRD measurements. The water exchange rates, k(ex)(298), are 8.0 x 10(7) s(-1), 6.1 x 10(7) s(-1) and 5.7 x 10(7) s(-1) for [Gd(DTTA-Nprop)(H2O)]2-, [Gd(DO3A-Nprop)(H2O)]- and [Gd(EPTPA-BAA)(H2O)], respectively, all in the narrow optimal range to attain maximum proton relaxivities, provided the other parameters (electronic relaxation and rotation) are also optimized. The substitution of an acetate with a propionate arm in DTPA5- or DOTA4- induces increased steric compression around the water binding site and thus leads to an accelerated water exchange on the Gd(III) complex. The k(ex) values on the propionate complexes are, however, lower than those obtained for [Gd(EPTPA)(H2O)]2- and [Gd(TRITA)(H2O)]- which contain one additional CH(2) unit in the amine backbone as compared to the parent [Gd(DTPA)(H2O)]2- and [Gd(DOTA)(H2O)]-. In addition to their optimal water exchange rate, [Gd(DTTA-Nprop)(H2O)]2- has, and [Gd(DO3A-Nprop)(H2O)]- is expected to have sufficient thermodynamic stability. These properties together make them prime candidates for the development of high relaxivity, macromolecular MRI contrast agents.     

GdIII complexes with fast water exchange and high thermodynamic stability: potential building blocks for high-relaxivity MRI contrast agents

On the basis of structural considerations in the inner sphere of nine-coordinate, monohydrated Gd(III) poly(aminocarboxylate) complexes, we succeeded in accelerating the water exchange by inducing steric compression around the water binding site. We modified the common DTPA(5-) ligand (DTPA=(diethylenetriamine-N,N,N',N",N"-pentaacetic acid) by replacing one (EPTPA(5-)) or two (DPTPA(5-)) ethylene bridges of the backbone by propylene bridges, or one coordinating acetate by a propionate arm (DTTA-prop(5-)). The ligand EPTPA(5-) was additionally functionalized with a nitrobenzyl linker group (EPTPA-bz-NO(2) (5-)) to allow for coupling of the chelate to macromolecules. The water exchange rate, determined from a combined variable-temperature (17)O NMR and EPR study, is two orders of magnitude higher on [Gd(eptpa-bz-NO(2))(H(2)O)](2-) and [Gd(eptpa)(H(2)O)](2-) than on [Gd(dtpa)(H(2)O)](2-) (k(ex)298=150x10(6), 330x10(6), and 3.3x10(6) s(-1), respectively). This is optimal for attaining maximum proton relaxivities for Gd(III)-based, macrocyclic MRI contrast agents. The activation volume of the water exchange, measured by variable-pressure (17)O NMR spectroscopy, evidences a dissociative interchange mechanism for [Gd(eptpa)(H(2)O)](2-) (DeltaV(not equal sign)=(+6.6+/-1.0) cm(3) mol(-1)). In contrast to [Gd(eptpa)(H(2)O)](2-), an interchange mechanism is proved for the macrocyclic [Gd(trita)(H(2)O)](-) (DeltaV (not equal sign)=(-1.5+/-1.0) cm(3) mol(-1)), which has one more CH(2) group in the macrocycle than the commercial MRI contrast agent [Gd(dota)(H(2)O)](-), and for which the elongation of the amine backbone also resulted in a remarkably fast water exchange. When one acetate of DTPA(5-) is substituted by a propionate, the water exchange rate on the Gd(III) complex increases by a factor of 10 (k(ex)298=31x10(6) s(-1)). The [Gd(dptpa)](2-) chelate has no inner-sphere water molecule. The protonation constants of the EPTPA-bz-NO(2) (5-) and DPTPA(5-) ligands and the stability constants of their complexes with Gd(III), Zn(II), Cu(II) and Ca(II) were determined by pH potentiometry. Although the thermodynamic stability of [Gd(eptpa-bz-NO(2))(H(2)O)](2-) is reduced to a slight extent in comparison with [Gd(dtpa)(H(2)O)](2-), it is stable enough to be used in medical diagnostics as an MRI contrast agent. Therefore both this chelate and [Gd(trita)(H(2)O)](-) are potential building blocks for the development of high-relaxivity macromolecular agents.     

Dinuclear complexes formed with the triazacyclononane derivative ENOTA4-: high-pressure 17O NMR evidence of an associative water exchange on [MnII2(ENOTA)(H2O)2

Mn2+ has five unpaired d-electrons, a long electronic relaxation time, and labile water exchange, all of which make it an attractive candidate for contrast agent application in medical magnetic resonance imaging. In the quest for stable and nonlabile Mn2+ complexes, we explored a novel dimeric triazacyclononane-based ligand bearing carboxylate functional groups, H4ENOTA. The protonation constants of the ligand and the stability constants of the complexes formed with some endogenously important metals (Ca2+, Cu2+, Zn2+), as well as with Mn2+ and Ce3+, have been assessed by NMR methods, potentiometry, and UV-vis spectrophotometry. Overall, the thermodynamic stability of the complexes is lower as compared to that of the corresponding NOTA analogues (H3NOTA, 1,4,7-triaazacyclononane-1,4,7-triacetic acid). The crystal structure of Mn2(ENOTA)(H2O) x 5H2O contains two six-coordinated Mn2+, in addition to the three amine nitrogens and the two oxygens from the pendent monodentate carboxylate groups, and one water (Mn2) or one bridging carboxylate oxygen (Mn1) completes the coordination sphere of the metal ion. In an aqueous solution, this bridging carboxylate is replaced by a water molecule, as evidenced by the 17O chemical shifts and proton relaxivity data that point to monohydration for both metal ions in the dinuclear complex. A variable-temperature and -pressure 17O NMR study has been performed on [Mn2(ENOTA)(H2O)2] to assess the rate and, for the first time on a Mn2+ chelate, also the mechanism of the water exchange. The inner sphere water is slightly more labile in [Mn2(ENOTA)(H2O)2] (k298ex = 5.5 x 107 s-1) than in the aqua ion (2.1 x 107 s-1, Merbach, A. E.; et al. Inorg. Chem. 1980, 19, 3696). The water exchange proceeds via an almost limiting associative mechanism, as evidenced by the large negative activation volume (deltaV = -10.7 cm3 mol-1). The proton relaxivities measured on [Mn2(ENOTA)(H2O)2] show a low-field dispersion at approximately 0.1 MHz arising from a contact interaction between the MnII electron spin and the water proton nuclear spins.     

Positively charged GdIII cryptates: slow, associative water exchange

A combined variable-temperature and multiple field 17O NMR, EPR and NMRD study has been performed for the first time on gadolinium(III) complexes of cryptand ligands, L1 and L2, where L1 contains three 2,2'-bipyridine units ([bpy.bpy.bpy]) and L2 is the disubstituted methyl ester derivative of L1. The experimental data have been analysed in a simultaneous fit in order to determine parameters for water exchange, rotational dynamics and electronic relaxation for both complexes. The cryptates have three water molecules in the inner sphere which exchange with a rate of k(ex)298 = 1.8 x 10(6) s(-1) and 0.97 x 10(6) s(-1) for [GdL1(H2O)3]3+ and [GdL2(H2O)3)]3+, respectively. The k(ex)298 values obtained for these positively charged cryptates are smaller than those of the negatively charged Gd-poly(amino carboxylate) complexes. The water exchange mechanism was assessed for [GdL2(H2O)3]3+ by variable-pressure 17O NMR relaxation measurements. Based on the activation volume, DeltaV++ = -2.5 cm3 mol(-1), the water exchange is an associative interchange process. The proton relaxivities, r1, of the cryptate complexes are 9.79 mM(-1) s(-1) for [GdL1(H2O)3]3+ and 11.18 mM(-1) s(-1) for [GdL2(H2O)3]3+ (298 K, 20 MHz), which, due to the presence of three inner sphere water molecules, represent much higher values than those obtained for Gd3+ poly(amino carboxylate) complexes of similar molecular weight.     

Facile synthesis and relaxation properties of novel bispolyazamacrocyclic Gd3+ complexes: an attempt towards calcium-sensitive MRI contrast agents

Three novel GdDO3A-type bismacrocyclic complexes, conjugated to Ca (2+) chelating moieties like ethylenediaminetetraacetic acid and diethylenetriamine pentaacetic acid bisamides, were synthesized as potential "smart" magnetic resonance imaging contrast agents. Their sensitivity toward Ca (2+) was studied by relaxometric titrations. A maximum relaxivity increase of 15, 6, and 32% was observed upon Ca (2+) binding for Gd 2L (1), Gd 2L (2), and Gd 2L (3), respectively (L (1) = N, N-bis{1-[{[({1-[1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-10-yl]eth-2-yl}amino)carbonyl]methyl}-(carboxymethyl)amino]eth-2-yl}aminoacetic acid; L (2) = N, N-bis[1-({[({alpha-[1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-10-yl]- p-tolylamino}carbonyl)methyl]-(carboxymethyl)}amino)eth-2-yl]aminoacetic acid; L (3) = 1,2-bis[{[({1-[1,4,7-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-10-yl]eth-2-yl}amino)carbonyl]methyl}(carboxymethyl)amino]ethane). The apparent association constants are log K A = 3.6 +/- 0.1 for Gd 2L (1) and log K A = 3.4 +/- 0.1 for Gd 2L (3). For the interaction between Mg (2+) and Gd 2L (1), log K A = 2.7 +/- 0.1 has been determined, while no relaxivity change was detected with Gd 2L (3). Luminescence lifetime measurements on the Eu (3+) complexes in the absence of Ca (2+) gave hydration numbers of q = 0.9 (Eu 2L (1)), 0.7 (Eu 2L (2)), and 1.3 (Eu 2L (3)). The parameters influencing proton relaxivity of the Gd (3+) complexes were assessed by a combined nuclear magnetic relaxation dispersion (NMRD) and (17)O NMR study. Water exchange is relatively slow on Gd 2L (1) and Gd 2L (2) ( k ex (298) = 0.5 and 0.8 x 10 (6) s (-1)), while it is faster on Gd 2L (3) (k ex (298) = 80 x 10 (6) s (-1)); in any case, it is not sensitive to the presence of Ca (2+). The rotational correlation time, tau R (298), differs for the three complexes and reflects their rigidity. Due to the benzene linker, the Gd 2L (2) complex is remarkably rigid, with a correspondingly high relaxivity despite the low hydration number ( r 1 = 10.2 mM (-1)s (-1) at 60 MHz, 298 K). On the basis of all available experimental data from luminescence, (17)O NMR, and NMRD studies on the Eu (3+) and Gd (3+) complexes of L (1) and L (3) in the absence and in the presence of Ca (2+), we conclude that the relaxivity increase observed upon Ca (2+) addition can be mainly ascribed to the increase in the hydration number, and, to a smaller extent, to the Ca (2+)-induced rigidification of the complex.     

Steric control of lanthanide hydration state: fast water exchange at gadolinium in a mono-amide 'DOTA' complex

Detailed analyses of the solution structure and exchange dynamics of two sets of homologous mono-amide triacetate lanthanide complexes (Ln = Eu, Gd) of cyclen have been undertaken. The complex [LnL1], bearing an N-linked CH2CH2NHCO-pyridyl moiety, forms mono-aqua (q = 1) species in solution and the Gd complex undergoes rapid water exchange (k(ex)= 11 x 10(7) s(-1), 298 K) as a result of the steric destabilisation of the Ln-water binding interaction. The homologous complex with a C-3 spacing chain, [LnL2], forms a q = 0 species.     

Dinuclear, bishydrated Gd(III) polyaminocarboxylates with a rigid xylene core display remarkable proton relaxivities

Two novel dinuclear Gd(III) complexes have been synthesized, based on a xylene core substituted with diethylenetriamine-N,N,N',N'-tetraacetate (DTTA) chelators in para or meta position. The complexes [Gd2(pX(DTTA)2)(H2O)4]2- and [Gd2(mX(DTTA)2)(H2O)4]2- both exhibit high complex stability (log K(GdL) = 19.1 and 17.0, respectively), and a good selectivity for Gd(III) against Zn(II), the most abundant endogenous metal ion (log K(ZnL) = 17.94 and 16.19). The water exchange rate is identical within experimental error for the two isomers: k(ex)298 = (9.0 +/- 0.4) x 10(6) s(-1) for [Gd2(pX(DTTA)2)(H2O)4]2- and (8.9 +/- 0.5) x 10(6) s(-1) for [Gd2(mX(DTTA)2)(H2O)4]2-. It is very similar to the k(ex)298 of the structural analogue, bishydrated [Gd(TTAHA)(H2O)2]3-, and about twice as high as that of the monohydrated [Gd(DTPA)(H2O)]2- (TTAHA(6-) = N-tris(2-aminoethyl)amine-N',N',N',N',N',N'-hexaacetate; DTPA(5-) = diethylenetriamine-N,N,N',N',N'-pentaacetate). This relatively fast water exchange can be related to the presence of two inner sphere water molecules which decrease the stereorigidity of the inner sphere thus facilitating the water exchange process. At all frequencies, the water proton relaxivities (r1 = 16.79 and 15.84 mM(-1) s(-1) for the para and meta isomers, respectively; 25 degrees C and 20 MHz) are remarkably higher for the two dinuclear chelates than those of mononuclear commercial contrast agents or previously reported dinuclear Gd(III) complexes. This is mainly the consequence of the two inner-sphere water molecules. In addition, the increased molecular size as compared to monomeric compounds associated with the rigid xylene linker between the two Gd(III) chelating subunits also contributes to an increased relaxivity. However, proton relaxivity is still limited by fast molecular motions which also hinder any beneficial effect of the increased water exchange rate.     

Phosphinic derivative of DTPA conjugated to a G5 PAMAM dendrimer: an 17O and 1H relaxation study of its Gd(III) complex

A DTPA-based chelate containing one phosphinate group was conjugated to a generation 5 polyamidoamine (PAMAM) dendrimer via a benzylthiourea linkage. The Gd(III) complex of this novel conjugate has potential as a contrast agent for magnetic resonance imaging (MRI). The chelates bind Gd3+via three nitrogen atoms, four carboxylates and one phosphinate oxygen, and one water molecule completes the inner coordination sphere. The monomer Gd(III) chelates bearing nitrobenzyl and aminobenzyl groups ([Gd(DTTAP-bz-NO2)(H2O)]2- and [Gd(DTTAP-bz-NH2)(H2O)]2-) as well as the dendrimeric Gd(III) complex G5-(Gd(DTTAP))63) were studied by multiple-field, variable temperature 17O and 1H NMR. The rate of water exchange is faster than that of [Gd(DTPA)(H2O)]2- and very similar on the two monomeric complexes (8.9 and 8.3 x 10(6) s-1 for [Gd(DTTAP-bz-NO2)(H2O)]2- and [Gd(DTTAP-bz-NH2)(H2O)]2-, respectively), while it is decreased on the dendrimeric conjugate (5.0 x 10(6) s-1). The Gd(III) complex of the dendrimer conjugate has a relaxivity of 26.8 mM-1 s-1 at 37 degrees C and 0.47 T (corresponding to 1H Larmor frequency of 20 MHz). Given the contribution of the second sphere water molecules to the overall relaxivity, this value is slightly higher than those reported for similar size dendrimers. The experimental 17O and 1H NMR data were fitted to the Solomon-Bloembergen-Morgan equations extended with a contribution from second coordination sphere water molecules. The rotational dynamics of the dendrimeric conjugate was described in terms of global and local motions with the Lipari-Szabo approach.     

The highest water exchange rate ever measured for a Gd(III) chelate

The complex [Gd(L)(H2O)]3- (H(6)L =N,N'-bis(6-carboxy-2-pyridylmethyl)ethylenediamine-N,N'-methylenephosphonic acid) displays the highest water exchange rate ever measured for a Gd(III) chelate (k(298)(ex)= 8.8 x 10(8) s(-1)), which is attributed to the flexibility of the metal coordination environment.     

A benzene-core trinuclear GdIII complex: towards the optimization of relaxivity for MRI contrast agent applications at high magnetic field

A novel ligand, H(12)L, based on a trimethylbenzene core bearing three methylenediethylenetriamine-N,N,N',N'-tetraacetate moieties (-CH(2)DTTA(4-)) for Gd(3+) chelation has been synthesized, and its trinuclear Gd(3+) complex [Gd(3)L(H(2)O)(6)](3-) investigated with respect to MRI contrast agent applications. A multiple-field, variable-temperature (17)O NMR and proton relaxivity study on [Gd(3)L(H(2)O)(6)](3-) yielded the parameters characterizing water exchange and rotational dynamics. On the basis of the (17)O chemical shifts, bishydration of Gd(3+) could be evidenced. The water exchange rate, k(ex)(298)=9.0+/-3.0 s(-1) is around twice as high as k(ex)(298) of the commercial [Gd(DTPA)(H(2)O)](2-) and comparable to those on analogous Gd(3+)-DTTA chelates. Despite the relatively small size of the complex, the rotational dynamics had to be described with the Lipari-Szabo approach, by separating global and local motions. The difference between the local and global rotational correlation times, tau(lO)(298)=170+/-10 ps and tau(gO)(298)=540+/-100 ps respectively, shows that [Gd(3)L(H(2)O)(6)](3-) is not fully rigid; its flexibility originates from the CH(2) linker between the benzene core and the poly(amino carboxylate) moiety. As a consequence of the two inner-sphere water molecules per Gd(3+), their close to optimal exchange rate and the appropriate size and limited flexibility of the molecule, [Gd(3)L(H(2)O)(6)](3-) has remarkable proton relaxivities when compared with commercial contrast agents, particularly at high magnetic fields (r(1)=21.6, 17.0 and 10.7 mM(-1)s(-1) at 60, 200 and 400 MHz respectively, at 25 degrees C; r(1) is the paramagnetic enhancement of the longitudinal water proton relaxation rate, referred to 1 mM concentration of Gd(3+)).     

A starburst-shaped heterometallic compound incorporating six densely packed gd(3+) ions

The heterotritopic ligand [bpy(DTTA)2]8- has two diethylenediamine-tetraacetate units for selective lanthanide(III) coordination and one bipyridine function for selective Fe(II) coordination. In aqueous solution and in the presence of these metals, the ligand is capable of self-assembly to form a rigid supramolecular metallostar structure, [Fe[Gd2bpy(DTTA)2(H2O)4]3]4-. We report here the physicochemical characterization of the dinuclear complex [Gd2bpy(DTTA)2(H2O)4]2- and the metallostar [Fe[Gd2bpy(DTTA)2(H2O)4]3]4- with regard to potential MRI contrast agent applications. A combination of pH potentiometry and 1H NMR spectroscopy has been used to determine protonation constants for the ligand [bpy(DTTA)2]8- and for the complexes [Fe[bpy(DTTA)2]3]22- and [Y2bpy(DTTA)2]2-. In addition, stability constants have been measured for the dinuclear chelates [M2bpy(DTTA)2]n- formed with M = Gd3+ and Zn2+ (log K(GdL) = 18.2; log K(ZnL) = 18.0; log K(ZnHL) = 3.4). A multiple field, variable-temperature 17O NMR and proton relaxivity study on [Gd2bpy(DTTA)2(H2O)4]2- and [Fe[Gd2bpy(DTTA)2(H2O)4]3](4-) yielded the parameters for water exchange and the rotational dynamics. The 17O chemical shifts are indicative of bishydration of the lanthanide ion. The exchange rates of the two inner-sphere water molecules are very similar in the dinuclear [Gd2bpy(DTTA)2(H2O)(4)]2- and in the metallostar (k(ex)298 = 8.1 +/- 0.3 x 10(6) and 7.4 +/- 0.2 x 10(6) s(-1), respectively), and are comparable to k(ex)298 for similar Gd(III) poly(amino carboxylates). The rotational dynamics of the metallostar has been described by means of the Lipari-Szabo approach, which involves separating global and local motions. The difference between the local and global rotational correlation times, tau(lO)298 = 190 +/- 15 ps and tau(gO)298 = 930 +/- 50 ps, respectively, shows that the metallostar is not completely rigid. However, the relatively high value of S2 = 0.60 +/- 0.04, describing the restriction of the local motions with regard to the global one, points to a limited flexibility compared with previously reported macromolecules such as dendrimers. As a result of the two inner-sphere water molecules, with their near-optimal exchange rate, and the limited flexibility, the metallostar has a remarkable molar proton relaxivity, particularly at high magnetic fields (r1 = 33.2 and 16.4 mM(-1) s(-1) at 60 and 200 MHz, respectively, at 25 degrees C). It packs six efficiently relaxing Gd(III) ions into a small molecular space, which leads, to the best of our knowledge, to the highest relaxivity per molecular mass ever reported for a Gd(III) complex. The [bpy(DTTA)2]8- ligand is also a prime candidate as a terminal ligand for constructing larger sized, Fe(II) (or Ru(II))-based metallostars or metallodendrimers loaded with Gd(III) on the surface.     

Supramolecular assembly of an amphiphilic Gd(III) chelate: tuning the reorientational correlation time and the water exchange rate

We report the synthesis and characterization of the novel ligand H(5)EPTPA-C(16) ((hydroxymethylhexadecanoyl ester)ethylenepropylenetriaminepentaacetic acid). This ligand was designed to chelate the Gd(III) ion in a kinetically and thermodynamically stable way while ensuring an increased water exchange rate (kappa(ex)) on the Gd(III) complex owing to steric compression around the water-binding site. The attachment of a palmitic ester unit to the pendant hydroxymethyl group on the ethylenediamine bridge yields an amphiphilic conjugate that forms micelles with a long tumbling time (tau(R)) in aqueous solution. The critical micelle concentration (cmc = 0.34 mM) of the amphiphilic [Gd(eptpa-C(16))(H(2)O)](2-) chelate was determined by variable-concentration proton relaxivity measurements. A global analysis of the data obtained in variable-temperature and multiple-field (17)O NMR and (1)H NMRD measurements allowed for the determination of parameters governing relaxivity for [Gd(eptpa-C(16))(H(2)O)](2-); this is the first time that paramagnetic micelles with optimized water exchange have been investigated. The water exchange rate was found to be kappa(298)(ex) = 1.7 x 10(8) s(-1), very similar to that previously reported for the nitrobenzyl derivative [Gd(eptpa-bz-NO(2))(H(2)O)](2-) kappa(298)(ex) = 1.5 x 10(8) s(-1)). The rotational dynamics of the micelles were analysed by using the Lipari-Szabo approach. The micelles formed in aqueous solution show considerable flexibility, with a local rotational correlation time of tau(298)(l0) = 330 ps for the Gd(III) segments, which is much shorter than the global rotational correlation time of the supramolecular aggregates, tau(298)(g0) = 2100 ps. This internal flexibility of the micelles is responsible for the limited increase of the proton relaxivity observed on micelle formation (r(1) = 22.59 mM(-1) s(-1) for the micelles versus 9.11 mM(-1) s(-1) for the monomer chelate (20 MHz; 25 degrees C)).     

Relaxivity and water exchange studies of a cationic macrocyclic gadolinium(III) complex

We conducted relaxometric and water exchange studies of the cationic [Gd((S,S,S,S)-THP)(H2O)]3+ complex (THP 1,4,7,10-tetrakis(2-hydroxy-propyl)-1,4,7,10-tetraazacyclododecane). While the NMRD profiles obtained are typical for DOTA-like complexes (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), variable-temperature 7O NMR investigations revealed a relatively high water exchange rate (k(298)(ex) = 1.89 x 10(7) s(-1)). These results differ from those reported for other cationic tetraamide macrocyclic Gd(III) complexes, which exhibit characteristically low exchange rates. Since the low exchange rates are attributed partially to the geometry of the M isomer (square antiprismatic) in the tetraamide derivatives, the atypical water exchange rate observed in [Gd((S,S,S,S)-THP-(H2O)]3+ may result from a twisted square antiprismatic structure in this complex and from the relatively high steric strain at the water coordination site as a result of the presence of methyl groups at the alpha-position with respect to the Gd(III)-bound O atoms of THP.     

Structural and magnetic properties of layered copper(II) coordination polymers intercalating s and f metal ions

The nanoporous coordination polymer [Cu(pyrimidin-2-olate-N1,N3)2]n (1C) of the sodalite zeotype sorbs a variety of metal nitrates [M(NO3)m, M = Na+, K+, Rb+, Tl+, Ca2+, Sr2+, Ba2+, Pb2+, La3+, Nd3+, Gd3+, Er3+] from H2O/MeOH solutions, with a concomitant structural change to a layered [Cu(pyrimidin-2-olate-N1,N3)2]n.[M(NO3)m]n/2 (MNO3@1L) coordination framework. Single-crystal X-ray diffraction analyses revealed that the layers are based on Cu4(pyrimidin-2-olate-N1,N3)4 square grids of copper(II) ions bridged by N1,N3 exobidentate ligands, displaying a structural motif of the metallacalix[4]arene type in pinched cone conformation. The interlayer space is occupied by the guest metal nitrates, each metal being coordinated by (at least) the four oxygen atoms of a metallacalix[4]arene. Magnetic measurements on the MNO3@1L series denoted a weak ferromagnetic ordering taking place below the Néel temperatures (typically close to 35 K), arising from spin-canting phenomena of the antiferromagnetically coupled copper centers. When M = Nd3+, Gd3+, or Er3+, additional magnetic ordering is observed at lower temperatures, which, on the basis of static and dynamic magnetic susceptibility measurements, can be attributed to copper- lanthanide interactions.     

1H and 17O NMR relaxometric study in aqueous solution of Gd(III) complexes of EGTA-like derivatives bearing methylenephosphonic groups

The Gd(III) complexes of three new octadentate chelators, prepared by substitution of four, two, and one carboxylate groups of EGTA with phosphonate groups, have been investigated by 1H and 17O NMR relaxometric techniques in aqueous solutions. The analysis of the solvent proton relaxivity data as a function of pH, temperature, and magnetic field strength (nuclear magnetic relaxation dispersion (NMRD) profiles) in combination with the 17O transverse relaxation rate data at variable temperature allowed assessing the hydration state of the complexes, the occurrence of pH-dependent oligomerization processes for the tetraphosphonate derivative, the presence of a well-defined second sphere of hydration that markedly contributes to the relaxivity, and the values of the structural and dynamic relaxation parameters. In addition, in the case of the monophosphonate derivative the presence of a coordinated water molecule has allowed evaluation of the kinetic parameters of the exchange process, highly relevant for the possible use of this Gd(III) complex as an MRI probe. The rate of exchange of the water molecule, (298)k(ex) = 4.2 x 10(8)s(-1), is one of the highest measured so far for a nonacoordinate Gd(III) chelate and optimal for developing contrast-enhancing probes of high efficacy at high magnetic fields.     

On the structure and dynamics of the hydrated sulfite ion in aqueous solution--an ab initio QMCF MD simulation and large angle X-ray scattering study

Theoretical ab initio quantum mechanical charge field molecular dynamics (QMCF MD) formalism has been applied in conjunction to experimental large angle X-ray scattering to study the structure and dynamics of the hydrated sulfite ion in aqueous solution. The results show that there is a considerable effect of the lone electron-pair on sulfur concerning structure and dynamics in comparison with the sulfate ion with higher oxidation number and symmetry of the hydration shell. The S-O bond distance in the hydrated sulfite ion has been determined to 1.53(1) ? by both methods. The hydrogen bonds between the three water molecules bound to each sulfite oxygen are only slightly stronger than those in bulk water. The sulfite ion can therefore be regarded as a weak structure maker. The water exchange rate is somewhat slower for the sulfite ion than for the sulfate ion, τ(0.5) = 3.2 and 2.6 ps, respectively. An even more striking observation in the angular radial distribution (ARD) functions is that the for sulfite ion the water exchange takes place in close vicinity of the lone electron-pair directed at its sides, while in principle no water exchange did take place of the water molecules hydrogen bound to sulfite oxygens during the simulation time. This is also confirmed when detailed pathway analysis is conducted. The simulation showed that the water molecules hydrogen bound to the sulfite oxygens can move inside the hydration shell to the area outside the lone electron-pair and there be exchanged. On the other hand, for the hydrated sulfate ion in aqueous solution one can clearly see from the ARD that the distribution of exchange events is symmetrical around the entire hydration sphere.     

Synthesis and structure of two tetranuclear osmium carbonyl isotopomers: a crystallographic isotope effect

A synthetic route to [Os4(mu-H)(mu-OH)(mu-CO)(CO)12] ( 1) has been devised through the activation of [Os4(CO)14] with Me3NO. The pyrolysis and photolysis of the reactant in the presence of a trace amount of water produces 1 in low yield. The solid-state structure of [Os4(mu-H)(mu-OH)(mu-CO)(CO)12 x H2O] (1 x H2O) reveals a butterfly Os4 skeleton with bridging H, OH and CO ligands as well as hydrogen-bonded molecules of water in the crystal lattice. A low-temperature 13C{1H} NMR spectroscopic study revealed a merry-go-round exchange of CO ligands around the Os3 plane containing the asymmetric bridging CO. The exposure of 1 x H2O to D2O yielded [Os4(mu-H)(mu-OD)(mu-CO)(CO)12]2. Although the solid-state, intramolecular structure of 2 closely matched that of 1 x H2O, the intermolecular structure did not: its crystal lattice contained no water of crystallization, a previously unreported crystallographic isotope effect.     

Synthesis of a bifunctional monophosphinic acid DOTA analogue ligand and its lanthanide(III) complexes. A gadolinium(III) complex endowed with an optimal water exchange rate for MRI applications

A new bifunctional octa-coordinating ligand containing an aminobenzyl moiety, DO3APABn (H4DO3APABn = 1,4,7,10-tetraazacyclododecane-4,7,10-triacetic-1-{methyl[(4-aminophenyl)methyl]phosphinic acid}), has been synthesized. Its lanthanide(III) complexes contain one water molecule in the first coordination sphere. The high-resolution 1H and 31P spectra of [Eu(H2O) (DO3APABn)]- show that the twisted square-antiprismatic form of the complexes is more abundant in respect to the corresponding Eu(III)-DOTA complex. The 1H NMRD and variable-temperature 17O relaxation measurements of [Gd(H2O)(DO3APABn)]- show that the water residence time is short (298tauM = 16 ns) and falls into the optimal range predicted by theory for the attainment of high relaxivities once this complex would be endowed by a slow tumbling rate. The relaxivity (298r1 = 6.7 mM(-1) s(-1) at 10 MHz) is higher than expected as a consequence of a significant contribution from the second hydration sphere. These results prompt the use of [Gd(H2O)(DO3APABn)]- as a building block for the set-up of highly efficient macromolecular MRI contrast agents.