1H and (17)O NMR detection of a lanthanide-bound water molecule at ambient temperatures in pure water as solvent

Lanthanide complexes of a tetra-amide derivative of DOTA (structure 4 in text) with four extended carboxymethyl esters have been characterized by X-ray crystallography and multinuclear NMR spectroscopy. [Eu(4)(H(2)O)](triflate)(3) crystallized from water in the monoclinic, P(21/)(c) space group (a = 10.366 A, b = 22.504 A, c = 23.975 A, and beta = 97.05 degrees ). The Eu(3+) cation is bound to four macrocyclic nitrogen atoms (mean Eu-N = 2.627 A) and four amide oxygen atoms (mean Eu-O(amide) = 2.335 A) in a square antiprismatic geometry with a twist angle of 38.5 degrees between the N4 and O4 planes. A single bound water molecule (Eu-O(W) = 2.414 A) occupies a typical monocapped position on the O4 surface. In pure water, resonances corresponding to a single Eu(3+)-bound water molecule were observed in the (1)H (53 ppm) and (17)O (-897 ppm) NMR spectra of [Eu(4)(H(2)O)](triflate)(3) at 25 degrees C. A fit of the temperature-dependent Eu(3+)-bound (1)H and (17)O water resonance line widths in acetonitrile-d(3) (containing 4% v/v (17)O enriched water) gave identical lifetimes (tau(m)(298)) of 789 +/- 50 micros (in water as solvent; a line shape analysis of the Eu(3+)-bound water resonance gave a tau(m)(298) = 382 +/- 5 micros). Slow water exchange was also evidenced by the water proton relaxivity of Gd(4) (R(1) = 2.2 mM(-1) s(-1), a value characteristic of pure outer-sphere relaxation at 25 degrees C). With increasing temperature, the inner-sphere contribution gradually increased due to accelerated chemical exchange between bound water and bulk water protons. A fitting of the relaxation data (T(1)) to standard SBM theory gave a water proton lifetime (tau(m)(298)) of 159 micros, somewhat shorter than the value determined by high-resolution (1)H and (17)O NMR of Eu(4). Exchange of the bound water protons in Gd(4) with bulk water protons was catalyzed by addition of exogenous phosphate at 25 degrees C (R(1) increased to 10.0 mM(-1) s(-1) in the presence of 1500-fold excess HPO(4)(2-)).     

Europium(III) macrocyclic complexes with alcohol pendant groups as chemical exchange saturation transfer agents

Paramagnetic lanthanide(III) complexes that contain hyperfine-shifted exchangeable protons offer considerable advantages over diamagnetic molecules as chemical exchange saturation transfer (CEST) agents for MRI. As part of a program to investigate avenues to improve the sensitivity of such agents, the CEST characteristics of europium(III) macrocyclic complexes having appended hydroxyethyl groups were investigated. The CEST spectrum of the asymmetrical complex, EuCNPHC3+, shows five distinct peaks for each magnetically nonequivalent exchangeable proton in the molecule. The CEST spectra of this complex were fitted to NMR Bloch theory to yield exchange rates between each of six exchanging proton pools (five on the agent plus bulk water). Exchange between the Eu3+-bound hydroxyl protons and bulk water protons was slow in dry acetonitrile but accelerated incrementally upon stepwise addition of water. In pure water, exchange was too fast to observe a CEST effect. The utility of this class of europium(III) complex for CEST imaging applications is ultimately limited by the small chemical shifts induced by the hydroxyl-appended ligands of this type and the resulting small Deltaomega values for the exchangeable hydroxyl protons.     

Luminescence properties and quenching mechanisms of Ln(Tf2N)3 complexes in the ionic liquid bmpyr Tf2N

The emission properties, including luminescence lifetimes, of the lanthanide complexes Ln(Tf(2)N)(3) (Tf(2)N = bis(trifluoromethanesulfonyl)amide); Ln(3+) = Eu(3+), Tm(3+), Dy(3+), Sm(3+), Pr(3+), Nd(3+), Er(3+)) in the ionic liquid bmpyr Tf(2)N (bmpyr = 1-n-butyl-1-methylpyrrolidinium) are presented. The luminescence quantum efficiencies, η, and radiative lifetimes, τ(R), are determined for Eu(3+)((5)D(0)), Tm(3+)((1)D(2)), Dy(3+)((4)F(9/2)), Sm(3+)((4)G(5/2)), and Pr(3+)((3)P(0)) emission. The luminescence lifetimes in these systems are remarkably long compared to values typically reported for Ln(3+) complexes in solution, reflecting weak vibrational quenching. The 1.5 μm emission corresponding to the Er(3+) ((4)I(13/2)→(4)I(15/2)) transition, for example, exhibits a lifetime of 77 μs. The multiphonon relaxation rate constants are determined for 10 different Ln(3+) emitting states, and the trend in multiphonon relaxation is analyzed in terms of the energy gap law. The energy gap law does describe the general trend in multiphonon relaxation, but deviations from the trend are much larger than those normally observed for crystal systems. The parameters determined from the energy gap law analysis are consistent with those reported for crystalline hosts. Because Ln(3+) emission is known to be particularly sensitive to quenching by water in bmpyr Tf(2)N, the binding properties of water to Eu(3+) in solutions of Eu(Tf(2)N)(3) in bmpyr Tf(2)N have been quantified. It is observed that water introduced into these systems binds quantitatively to Ln(3+). It is demonstrated that Eu(Tf(2)N)(3) can be used as a reasonable internal standard, both for monitoring the dryness of the solutions and for estimating the quantum efficiencies and radiative lifetimes for visible-emitting [Ln(Tf(2)N)(x)](3-x) complexes in bmpyr Tf(2)N.     

Iron(II) PARACEST MRI contrast agents

The first examples of Fe(II) PARACEST magnetic resonance contrast agents are reported (PARACEST = paramagnetic chemical exchange saturation transfer). The iron(II) complexes contain a macrocyclic ligand, either 1,4,7-tris(carbamoylmethyl)-1,4,7-triazacyclononane (L1) or 1,4,7-tris[(5-amino-6-methyl-2-pyridyl)methyl]-1,4,7-triazacyclononane (L2). The macrocycles bind Fe(II) in aqueous solution with formation constants of log K = 13.5 and 19.2, respectively, and maintain the Fe(II) state in the presence of air. These complexes each contain six exchangeable protons for CEST which are amide protons in [Fe(L1)](2+) or amino protons in [Fe(L2)](2+). The CEST peak for the [Fe(L1)](2+) amide protons is at 69 ppm downfield of the bulk water resonance whereas the CEST peak for the [Fe(L2)](2+) amine protons is at 6 ppm downfield of bulk water. CEST imaging using a MRI scanner shows that the CEST effect can be observed in solutions containing low millimolar concentrations of complex at neutral pH, 100 mM NaCl, 20 mM buffer at 25 °C or 37 °C.     

Iron(II) complexes containing octadentate tetraazamacrocycles as paraCEST magnetic resonance imaging contrast agents

Iron(II) complexes of the macrocyclic ligands 1,4,7,10-tetrakis(carbamoylmethyl)-1,4,7,10-tetraazacyclododecane (TCMC) and (1S,4S,7S,10S)-1,4,7,10-tetrakis(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane (STHP) contain a highly stabilized Fe(II) center in the high-spin state, which is encapsulated by an octadentate macrocycle. The complexes are resistant to acid, metal cations, phosphate, carbonate, and oxygen in aqueous solution. [Fe(TCMC)](2+) contains exchangeable amide protons, and [Fe(STHP)](2+) contains exchangeable protons attributed to alcohol OH donors, which give chemical exchange saturation transfer (CEST) peaks at physiological pH and 37 °C at 50 and 54 ppm from bulk water, respectively. The distinct pH dependence of the CEST peak of the two complexes over the range of pH 6-8 shows that these two groups may be useful in the development of ratiometric pH sensors based on iron(II).     

Modulation of water exchange in europium(III) DOTA-tetraamide complexes via electronic substituent effects

The chemical exchange saturation transfer (CEST) efficiency for a series Eu3+-based tetraamide complexes bearing p-substituents on a single coordinating pendant arm is highly sensitive to water exchange rates. The CEST effect increases in the order Me < MeO < F approximately CO2tBu < CN < H. These results show that CEST contrast can be modulated by changes in electron density at a single ligating atom, and this forms the basis of creating imaging agents that respond to chemical oxidation and reduction.     

DOTA-bis(amide)]lanthanide complexes: NMR evidence for differences in water-molecule exchange rates for coordination isomers

Two derivatives of 1,4,7,10-tetraazacyclododecane with trans-acetate and trans-amide side-chain ligating groups have been prepared and their complexes with lanthanide cations examined by multinuclear NMR spectroscopy. These lanthanide complexes exist in aqueous solution as a mixture of slowly interconverting coordination isomers with 1H chemical shifts similar to those reported previously for the major (M) and minor (m) forms of the tetraacetate ([Ln(dota)]-) and tetraamide ([Ln(dtma)]3+) complexes. As in the [Ln(dota)]- and [Ln(dtma)]3+ complexes, the m/M ratio proved to be a sensitive function of lanthanide size and temperature. An analysis of 1H hyperfine shifts in spectra of the Yb3+ complexes revealed significant differences between the axial (D1) and non-axial (D2) components of the magnetic susceptibility tensor anisotropy in the m and M coordination isomers and the energetics of ring inversion and m <==> M isomerization as determined by two-dimensional exchange spectroscopy (EXSY). (17)O shift data for the Dy3+ complexes showed that both have one inner-sphere water molecule. A temperature-dependent (17)O NMR study of bulk water linewidths for solutions of the Gd3+ complexes provided direct evidence for differences in water exchange rates for the two coordination isomers. The bound-water lifetimes (tauM298) in the M and m isomers of the Gd3+ complexes ranged from 1.4-2.4 micros and 3-14 ns, respectively. This indicates that 1) the inner-sphere water lifetimes for the complexes with a single positive charge reported here are considerably shorter for both coordination isomers than the corresponding values for the [Gd(dtma)]3+ complex with three positive charges, and 2) the difference in water lifetimes for M and m isomers in these two series is magnified in the [Gd[dota-bis(amide)]] complexes. This feature highlights the remarkable role of both charge and molecular geometry in determining the exchange rate of the coordinated water.     

A paramagnetic CEST agent for imaging glucose by MRI

The europium(III) complex of a DOTA-tetraamide ligand (DOTA = 1,4,7,10-tetraazacyclododecane-N,N',N' ',N' '-tetraacetic acids) containing two phenyl boronate pendent arms binds glucose reversibly with an association constant of 383 M-1 at pH 7. Glucose binding results in slowing of water exchange between a single Eu(III)-bound water molecule and bulk water, and this can be imaged by MRI using chemical exchange saturation transfer (CEST) imaging sequence. This metabolite-responsive paramagnetic CEST agent responds to changes in glucose over the physiologically important range (0-20 mM), and thus it offers the possibility of high-sensitivity MR imaging glucose in tissues using bulk water protons as antenna.     

Modulation of the Lifetime of Water Bound to Lanthanide Metal Ions in Complexes with Ligands Derived from 1,4,7,10‐Tetraazacyclododecane Tetraacetate (DOTA)

A series of di‐ and tetraamide derivatives of DOTA were synthesized, and their lanthanide(III) complexes were examined by multinuclear ¹H‐, ¹³C‐, and ¹⁷O‐NMR spectroscopy, and compared with literature data of similar, known complexes (Table). All ligands formed structures similar to the parent [Ln^III(DOTA)]^? complexes, with four N‐atoms and four O‐atoms from DOTA and one O‐atom from the inner‐sphere water molecules. Interestingly, the lifetimes τ_M of the inner‐sphere, metal‐bound water molecules vary widely, ranging from nano‐ to milliseconds, depending on the identity of the pendent amide side chains. In general, positively charged [Ln^III(DOTA‐tetraamide)]³⁺ complexes display the longest residence times (high τ_M values), while complexes with additional charged functional groups on the extended amides display much smaller τ_M values, even when the side groups are not directly coordinated to the central Ln³⁺ ions. The design of novel [Ln^III(DOTA‐tetraamide)]³⁺ complexes with a wide, tunable range of τ_M values is of prime importance for the application of fast‐responding, paramagnetic chemical‐exchange‐saturation‐transfer (PARACEST) imaging agents used for the study of physiological and metabolic processes.     

A Cl- anion-responsive luminescent Eu3+ complex with a chiral tripod: ligand substituent effects on ternary complex stoichiometry and anion sensing selectivity

A new series of N3,O-mixed donor tripods was prepared for luminescent Eu3+ complexes, in which the soft quinoline nitrogen, tertiary amine nitrogen, and hard amide oxygen donors were cooperatively involved. The mixed donor tripods formed more stable 1 : 1 complexes with Eu(NO3)3, La(NO3)3 and Tb(NO3)3 than the corresponding N4 donor tripods, and their Eu3+ complexes particularly exhibited anion-responsive luminescence properties. NMR, UV, and luminescence spectroscopic characterizations revealed that -CH3 substitution on the tripod skeleton remarkably altered the preferred stoichiometry of the "tripod-Eu3+-anion" ternary complex and gave anion-dependent europium luminescence. Although the disubstituted tripod preferred to form non-luminescent 2 : 1 (tripod : Eu3+) complexes with Eu(NO3)3 and other salts, it formed a luminescent 1 : 1 complex with EuCl3. Thus, this type of tripod offered Cl- anion-selective luminescence enhancement that was easily observed by the naked eye.     

Six,Seven or Eight Coordinate FeII,CoII or NiII Complexes of Amide‐Appended Tetraazamacrocycles for ParaCEST Thermometry

Fe^II, Co^II and Ni^II complexes of two tetraazamacrocycles (1,4,8,11‐tetrakis(carbamoylmethyl)‐1,4,8,11‐tetraazacyclotetradecane ( L1 ) and 1,4,7,10‐tetrakis(carbamoylmethyl)‐1,4,7,10‐tetraazacyclododecane ( L2 ) show promise as paraCEST agents for registration of temperature (paraCEST=paramagnetic chemical exchange saturation transfer). The Fe^II, Co^II and Ni^II complexes of L1 show up to four CEST peaks shifted ≤112 ppm, whereas analogous complexes of L2 show only a single CEST peak at ≤69 ppm. Comparison of the temperature coefficients (C_T) of the CEST peaks of [Co( L2 )]²⁺, [Fe( L2 )]²⁺, [Ni( L1 )]²⁺ and [Co( L1 )]²⁺ showed that a CEST peak of [Co( L1 )]²⁺ gave the largest C_T (?0.66 ppm ^oC^?1 at 4.7 T). NMR spectral and CEST properties of these complexes correspond to coordination complex symmetry as shown by structural data. The [Ni( L1 )]²⁺ and [Co( L1 )]²⁺ complexes have a six‐coordinate metal ion bound to the 1‐, 4‐amide oxygen atoms and four nitrogen atoms of the tetraazamacrocycle. The [Fe( L2 )]²⁺ complex has an unusual eight‐coordinate Fe^II bound to four amide oxygen atoms and four macrocyclic nitrogen atoms. For [Co( L2 )]²⁺, one structure has seven‐coordinate Co^II with three bound amide pendents and a second structure has a six‐coordinate Co^II with two bound amide pendents.     

Luminescence and structural properties of lanthanide complexes of Schiff bases derived from pyridoxal and amino acids

Lanthanide complexes of Schiff bases (SBs) with 1:1 and 1:2 (M:Lig) stoichiometric ratios were prepared by condensation of pyridoxal (PL) and aspartic acid (Asp) or l-histidine (His), respectively, in the presence of the appropriate metal chloride as a templating agent. These complexes were studied by optical spectroscopy and single crystal X-ray diffraction techniques. Crystallographic studies of 1:1 ([Eu(PL-Asp)(H(2)O)(4)](H(2)O)) and 1:2 ([Eu(PL-His)(2)(H(2)O)(2)]Cl(H(2)O)(4)) complexes show that Eu(III) is eight-coordinate in both structures, in a distorted square antiprism environment formed by the phenolic oxygen of PL, the nitrogen atom of carbon-nitrogen double bond, oxygen atoms of the carboxylate groups of His or Asp, and oxygen atoms of the water molecules. The main species formed in aqueous solutions containing these SBs have been determined by analysis of the luminescence spectra, lifetimes of Eu(III) excited states and vibronic interaction as well as structural features of the Eu(III) coordination sphere. Possible tetradentate coordination function of SBs in aqueous solutions with relatively high concentrations as well as the potential application of the lanthanide SB complexes as new luminescence materials are discussed.     

A Frequency-Selective pH-Responsive paraCEST Agent

Paramagnetic chemical exchange saturation transfer (paraCEST) agents are well-suited for imaging tissue pH because the basis of CEST, chemical exchange, is inherently sensitive to pH. Several previous pH-sensitive paraCEST agents were based on an exchanging Ln³⁺-bound water molecule as the CEST antenna but this design often added additional line-broadening to the bulk water signal due to T₂ exchange. We report herein a pH-sensitive paraCEST agent that lacks an inner-sphere water molecule but contains one Ln-bound −OH group for CEST activation. The Yb³⁺ complex, Yb( 1 ), displayed a single, highly shifted CEST peak originating from the exchangeable Yb-OH proton, the frequency of which changed over the biologically relevant pH range. CEST images of phantoms ranging in pH from 6 to 8 demonstrate the potential of this agent for imaging pH. Initial rodent imaging studies showed that Gd( 1 ) remains in the vascular system much longer than anticipated but is cleared slowly via renal filtration.     

Synthesis, crystal structure, and luminescent properties of 2-(2,2,2-trifluoroethyl)-1-indone lanthanide complexes

A new β-diketone, 2-(2,2,2-trifluoroethyl)-1-indone (TFI), which contains a trifluorinated alkyl group and a rigid indone group, has been designed and employed for the synthesis of two series of new TFI lanthanide complexes with a general formula [Ln(TFI)(3)L] [Ln = Eu, L = (H(2)O)(2) (1), bpy (2), and phen (3); Ln = Sm, L = (H(2)O)(2) (4), bpy (5), and phen (6); bpy = 2,2'-bipyridine, phen = 1,10-phenanthroline]. X-ray crystallographic analysis reveals that complexes 1-6 are mononuclear, with the central Ln(3+) ion eight-coordinated by six oxygen atoms furnished by three TFI ligands and two O/N atoms from ancillary ligand(s). The room-temperature photoluminescence (PL) spectra of complexes 1-6 show strong characteristic emissions of the corresponding Eu(3+) and Sm(3+) ions, and the substitution of the solvent molecules by bidentate nitrogen ligands essentially enhances the luminescence quantum yields and lifetimes of the complexes.     

Triethylenetetramine penta- and hexa-acetamide ligands and their ytterbium complexes as paraCEST contrast agents for MRI

The ligand triethylenetetramine-N,N,N',N',N',N'-hexaacetamide (ttham) was synthesized with the aim of forming lanthanide complexes suitable as contrast agents for magnetic resonance imaging applications utilizing the chemical exchange-dependent saturation transfer (CEST) effect. It was designed to exclude water molecules from the first coordination sphere and provide a high number of CEST active amide protons per lanthanide ion. The ligand was characterized by its protonation behavior and its complexation properties with ytterbium ions in aqueous solution. The basicity of the ttham backbone amine protons decreases in the order N(central(1)) > N(terminal(1)) > N(terminal(2)) > N(central(2)), as deduced from NMR titration experiments and from a comparison of its protonation constants with those of two ttham derivatives, in which either a terminal (N-benzyl-triethylenetetramine-N,N',N',N',N'-pentaacetamide, 1bttpam) or a central acetamide group (N'-benzyl-triethylenetetramine-N,N,N',N',N'-pentaacetamide, 4bttpam) is substituted with a benzyl group. This protonation sequence results from the combined influence of inductive effects, the intramolecular hydrogen bonding network, and the Coulomb repulsion between protonated ammonium groups. The ytterbium complex of ttham, [Yb(ttham)]Cl(3), is coordinatively frustrated. Due to steric constraints, in addition to the four backbone nitrogen atoms, only three of the four symmetry-equivalent terminal acetamide donors can coordinate simultaneously to the ytterbium ion, and the dangling fourth one exchanges quickly with the other three. The ytterbium complexes of a total of five ligands (ttham, 1bttpam, 4bttpam, 2,2',2'-triaminotriethylaminehexaacetamide (ttaham), and diethylenetriamine-N,N,N',N',N'-pentaacetamide (dtpam)) were studied with respect to their CEST properties. In solution, all of these complexes have a low symmetry. The presence of multiple magnetically different amide groups in each complex prevents the realization of very high CEST effects. These results nevertheless form an excellent basis for a further optimization of this class of ligands.     

Paramagnetic lanthanide complexes as PARACEST agents for medical imaging

This tutorial review examines the fundamental aspects of a new class of contrast media for MRI based upon the chemical shift saturation transfer (CEST) mechanism. Several paramagnetic versions called PARACEST agents have shown utility as responsive agents for reporting physiological or metabolic information by MRI. It is shown that basic NMR exchange theory can be used to predict how parameters such as chemical shift, bound water lifetimes, and relaxation rates can be optimized to maximize the sensitivity of PARACEST agents.     

Experimental and theoretical approaches toward anion-responsive tripod-lanthanide complexes: mixed-donor ligand effects on lanthanide complexation and luminescence sensing profiles

A new series of tripods were designed to form anion-responsive, luminescent lanthanide complexes. These tripods contain pyridine, thiazole, pyrazine, or quinoline chromophores combined with amide carbonyl oxygen and tertiary nitrogen atoms. Crystallographic and EXAFS studies of the 10-coordinated tripod-La(NO(3))(3) complexes revealed that each La(3+) cation was cooperatively coordinated by one tetradentate tripod and three bidentate NO(3)(-) anions in the crystal and in CH(3)CN. Quantum chemical calculations indicated that the aromatic nitrogen plays a significant role in lanthanide complexation. The experimentally determined stability constants of complexes of the tripod with La(NO(3))(3), Eu(NO(3))(3), and Tb(NO(3))(3) were in good agreement with the theoretically calculated interaction energies. Complexation of each tripod with lanthanide triflate gave a mixture of several lanthanide complex species. Interestingly, the addition of a coordinative NO(3)(-) or Cl(-) anion to the mixture significantly influenced the lanthanide complexation profiles. The particular combination of tripod and a luminescent Eu(3+) center gave anion-selective luminescence enhancements. Pyridine-containing tripods exhibited the highest NO(3)(-) anion-selective luminescence and thus permit naked-eye detection of the NO(3)(-) anion.     

Study of pH-dependent zinc(II)-carboxamide interactions by zinc(II)-carboxamide-appended cyclen complexes (cyclen = 1,4,7,10-tetraazacyclododecane)

To elucidate intrinsic recognition of carboxamides by zinc(II) in carbonic anhydrase (CA) (as inhibitors) and carboxypeptidase A (CPA) (as substrates), a new series of Zn(2+)-carboxamide-appended cyclen complexes have been synthesized and characterized (cyclen = 1,4,7,10-tetraazacyclododecane). Two types of Zn(2+)-carboxamide interactions have been found. In the first case represented by a zinc(II) complex of carbamoylmethyl-1,4,7,10-tetraazacyclododecane (L(1)), the amide oxygen binds to zinc(II) at slightly acidic pH (to form ZnL(1)), and the deprotonated amide N(-) binds to zinc(II) at alkaline pH (to form ZnH(-1)L(1)) with pK(a) = 8.59 at 25 degrees C and I = 0.1 (NaNO(3)), as determined by potentiometric pH titrations, infrared spectral changes, and (13)C and (1)H NMR titrations. The X-ray crystal structure of ZnH(-1)L(3) (where L(3) = N-(4-nitrophenyl)carbamoylmethyl cyclen, pK(a) = 7.01 for ZnL(3) <==> ZnH(-1)L(3)) proved that the zinc(II) binds to the amidate N(-) (Zn-N(-) distance of 1.974(3) A) along with the four nitrogen atoms of cyclen (average Zn-N distance 2.136 A). Crystal data: monoclinic, space group P2(1)/n (No. 14) with a = 10.838(1) A, b = 17.210(2) A, c = 12.113(2) A, b = 107.38(1) degrees, V = 2156.2(5) A(3), Z = 4, R = 0.042, and R(w) = 0.038. These model studies provide the first chemical support that carboxamides are CA(-) inhibitors by occupying the active Zn(2+) site both in acidic and alkaline pH to prevent the occurrence of the catalytically active Zn(2+)-OH(-) species. In the second case represented by a zinc(II) complex of 1-(N-acetyl)aminoethylcyclen, ZnL(6), the pendant amide oxygen had little interaction with zinc(II) at acidic pH. At alkaline pH, the monodeprotonation yielded a zinc(II)-bound hydroxide species ZnL(6)(OH(-)) (pK(a) = 7.64) with the amide pendant remaining intact. The ZnL(6)(OH(-)) species showed the same nucleophilic activity as Zn(2+)-cyclen-OH(-). The second case may mimic the Zn(2+)-OH(-) mechanism of CPA, where the nucleophilic Zn(2+)-OH(-) species does not act as a base to deprotonate a proximate amide.     

Exceptionally Inert Lanthanide(III) PARACEST MRI Contrast Agents Based on an 18‐Membered Macrocyclic Platform

We report a macrocyclic ligand based on a 3,6,10,13‐tetraaza‐1,8(2,6)‐dipyridinacyclotetradecaphane platform containing four hydroxyethyl pendant arms (L¹) that forms extraordinary inert complexes with Ln³⁺ ions. The [EuL¹]³⁺ complex does not undergo dissociation in 1 M HCl over a period of months at room temperature. Furthermore, high concentrations of phosphate and Zn²⁺ ions at room temperature do not provoke metal‐complex dissociation. The X‐ray crystal structures of six Ln³⁺ complexes reveal ten coordination of the ligand to the metal ions through the six nitrogen atoms of the macrocycle and the four oxygen atoms of the hydroxyethyl pendant arms. The analysis of the Yb³⁺‐ and Pr³⁺‐induced paramagnetic ¹H NMR shifts show that the solid‐state structures are retained in aqueous solution. The intensity of the ¹H NMR signal of bulk water can be modulated by saturation of the signals of the hydroxy protons of Pr³⁺, Eu³⁺, and Yb³⁺ complexes following chemical‐exchange saturation transfer (CEST). The ability of these complexes to provide large CEST effects at 25 and 37 °C and pH 7.4 was confirmed by using CEST magnetic resonance imaging experiments.     

Surface speciation of Eu3+ adsorbed on kaolinite by time-resolved laser fluorescence spectroscopy (TRLFS) and parallel factor analysis (PARAFAC)

Time-resolved laser fluorescence spectroscopy (TRLFS) is an effective speciation technique for fluorescent metal ions and can be further extended by the parallel factor analysis (PARAFAC). The adsorption of Eu(3+) on kaolinite as well as gibbsite as a reference mineral was investigated by TRLFS together with batch adsorption measurements. The PAFAFAC modeling provided the fluorescence spectra, decay lifetimes, and relative intensity profiles of three Eu(3+) surface complexes with kaolinite; an outer-sphere (factor A) complex and two inner-sphere (factors B and C) complexes. Their intensity profiles qualitatively explained the measured adsorption of Eu(3+). Based on the TRLFS results in varied H(2)O/D(2)O media, it was shown that the outer-sphere complex exhibited more rapid fluorescence decay than Eu(3+) aquo ion, because of the energy transfer to the surface. Factor B was an inner-sphere complex, which became dominant at relatively high pH, high salt concentration and low Eu(3+) concentration. Its spectrum and lifetime were similar to those of Eu(3+) adsorbed on gibbsite, suggesting its occurrence on the edge face of the gibbsite layer of kaolinite. From the comparison with the spectra and lifetimes of crystalline or aqueous Eu(OH)(3), factor C was considered as a poly-nuclear surface complex of Eu(3+) formed at relatively high Eu(3+) concentration.