Multiple‐Frequency and Variable‐Temperature EPR Study of Gadolinium(III) Complexes with Polyaminocarboxylates: Analysis and Comparison of the Magnetically Dilute Powder and the Frozen‐Solution Spectra

An electron paramagnetic resonance (EPR) study of glasses and magnetically dilute powders of [Gd(DTPA)(H₂O)]^2?, [Gd(DOTA)(H₂O)]^?, and macromolecular gadolinate(1?) complexes P792 was carried out at the X‐ and Q‐bands and at 240 GHz (DTPA=diethylenetriaminepentaacetato; DOTA=1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetato). The results show that the zero‐field splitting (ZFS) parameters for these complexes are quite different in a powder as compared to the frozen aqueous solution. In several complexes, an inversion of the sign of the axial component D of the zero field splitting is observed, indicating a significant structural change. In contrary to what was expected, powder samples obtained by lyophilization do not allow a more precise determination of the static ZFS parameters. The results obtained in glasses are more relevant to the problem of electron spin relaxation in aqueous solution than those obtained from powders.     

Target Visualization by MRI Using the Avidin/Biotin Amplification Route: Synthesis and Testing of a Biotin–Gd‐DOTA Monoamide Trimer

To design efficient targeting strategies in magnetic resonance (MR) molecular imaging applications, the formation of supramolecular adducts between (strept)avidin ((S)Av) and tribiotinylated Gd‐DOTA‐monoamide complexes (DOTA=1,4,7,10‐tetraazacyclododecane‐N,N′,N′′,N′′′‐tetraacetic acid) was explored. Two compounds based on the trivalent core of tris(2‐aminoethyl)amine each containing three biotin molecules and one ( L1 ) or three ( L2 ) DOTA‐monoamide (DOTAMA) ligands were synthesized. In these tribiotinylated derivatives the biotins are spaced far enough apart to allow the formation of the supramolecular adduct with the protein and to host the chelating units in between the (S)Av layers. Size exclusion HPLC analyses indicated complete formation of very high molecular weight polymers (>2 MDa) with (S)Av in solution. A ¹H NMR spectroscopy relaxometric study on the obtained polymeric adducts showed a marked increase of the relaxivity at 35–40 MHz as a consequence of the lengthening of the tumbling time due to the formation of Gd‐chelates/(S)Av polymers. The most efficient Gd₃ L2 /(S)Av polymeric system was used for a test in cell cultures. The target is represented by a neural cell adhesion molecule (NCAM), which is overexpressed in Kaposi’s sarcoma cells and tumor endothelial cells (TEC) and that is efficiently recognized by a biotinylated tetrameric peptide (C3d‐Bio). In vitro experiments showed that only cells incubated with both C3d‐Bio and Gd₃ L2 /SAv polymer were hyperintense with respect to the control. Relaxation rates of cell pellets incubated with Gd₃ L2 /SAv alone were not significantly different from the untreated cells demonstrating the absence of a specific binding.     

Optical Activity in the Near‐IR Region: The λ=980 nm Multiplet of Chiral Yb3+ Complexes

We used a very simplified electrostatic model based on charge and polarizability of atoms and groups on an organic ligand around a lanthanide ion to predict the near‐infrared electronic circular dichroism (NIR ECD) spectra of Yb³⁺ (a monoelectronic ion). We tuned our method by using two widely different complexes. The first was the heterobimetallic species CsYb(hfbc)₄ [hfbc=(?)‐3‐heptafluorobutyrylcamphorate], in which the ligand is a diketonate and, as such, is endowed with a chromophore with strong UV absorption (π–π^*). Its oxygen atoms define a square antiprism, which provides a symmetric coordination polyhedron. The second system was Yb DOTMA [DOTMA=(1R,4R,7R,10R)‐α,α′,α′′,α′′′‐tetramethyl‐1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid], a chiral Yb analogue of Gd DOTA (DOTA=1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid), in which the ligand lacks relevant electronic transitions and provides a dissymmetric cage. The relative weights of dynamic (ligand polarization) and static contributions to Yb NIR ECD were evaluated, and the spectra appear to have been well predicted by theory through the introduction of a heuristic weight factor. To validate the approach and to confirm the value of the weight factor, we applied it to two other compounds, namely, Na₃Yb(BINOLate)₃ and Yb(BINOLAM)₃ [BINOLate=2,2′‐dihydroxy‐1,1′‐binaphthyl; BINOLAM=3,3′‐bis(diethylaminomethyl)‐1‐1′‐bi‐2‐naphthol].     

Synthesis and Characterization of α-Hexadecyl-DOTA and its Gd（Ⅲ） Chelate

Synthesis and characterization of the ligand, 10-(α-hexadecylcarboxymethyl)- 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (H4L), and its Gd(Ⅲ) chelate are described. Protonation constants for H4L ( lg Ki^H = 10.52, 9.45,4.74, 4.10) and the stability constant for GdL^-(lg KGdL^-=24.50) were determined by potentiometric titrations.The results obtained show that the ligand still maintains the strong chelating properties of the parent DOTA(1,4,7,10-tetraazacyclododecane-N,N‘,N“N′“-tetraacetic acid) after introduction of a linear chain hexadecyl group at the acetic side chain of DOTA, and its basicity is not significantly altered.     

Acetate and acetamide complexes of [Ni(Me4[12]aneN4)]PF6: a tale of two ligands

Although there are many examples of acetate complexes, acetamide complexes are virtually unknown. A side‐by‐side comparison in (acetato‐κ²O,O′)(1,4,7,10‐tetramethyl‐1,4,7,10‐tetraazacyclododecane‐κ⁴N)nickel(II) hexafluoridophosphate, [Ni(C₂H₃O₂)(C₁₂H₂₈N₄)]PF₆, (1), and (acetamidato‐κ²O,O′)(1,4,7,10‐tetramethyl‐1,4,7,10‐tetraazacyclododecane‐κ⁴N)nickel(II) hexafluoridophosphate, [Ni(C₂H₄NO)(C₁₂H₂₈N₄)]PF₆, (2), shows the steric equivalence between these two ligands, suggesting that acetamide could be considered as a viable acetate replacement for electronic tuning.     

Near‐Infrared‐Emitting BODIPY‐trisDOTA111In as a Monomolecular Multifunctional Imaging Probe: From Synthesis to In Vivo Investigations

A new generation of monomolecular imaging probes (MOMIP) based on a distyryl‐BODIPY (BODIPY=boron‐dipyrromethene) coupled with three DOTA macrocycles has been prepared (DOTA=1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid). The MOMIP presents good fluorescence properties and is very stable in serum. The bimodal probe was conjugated to trastuzumab, and an optical in vivo study showed high accumulation of the imaging agent at the tumor site. ¹¹¹In radiometallation of the bioconjugate was performed in high radiochemical yield, highlighting the potential of this new BODIPY‐chelators derivative as a bimodal imaging probe.     

Synthesis and Characterization of a Hypoxia‐Sensitive MRI Probe

Tissue hypoxia occurs in pathologic conditions, such as cancer, ischemic heart disease and stroke when oxygen demand is greater than oxygen supply. An imaging method that can differentiate hypoxic versus normoxic tissue could have an immediate impact on therapy choices. In this work, the gadolinium(III) complex of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) with a 2‐nitroimidazole attached to one carboxyl group via an amide linkage was prepared, characterized and tested as a hypoxia‐sensitive MRI agent. A control complex, Gd(DO3A‐monobutylamide), was also prepared in order to test whether the nitroimidazole side‐chain alters either the water proton T₁ relaxivity or the thermodynamic stability of the complex. The stabilities of these complexes were lower than that of Gd(DOTA)^? as expected for mono‐amide derivatives. The water proton T₁ relaxivity (r₁), bound water residence lifetime (τ_M) and rotational correlation time (τ_R) of both complexes was determined by relaxivity measurements, variable temperature ¹⁷O NMR spectroscopy and proton nuclear magnetic relaxation dispersion (NMRD) studies. The resulting parameters (r₁=6.38 mM ^?1 s^?1 at 20 MHz , τ_M=0.71 μs, τ_R=141 ps) determined for the nitroimidazole derivative closely parallel to those of other Gd(DO3A‐monoamide) complexes of similar molecular size. In vitro MR imaging experiments with 9L rat glioma cells maintained under nitrogen (hypoxic) versus oxygen (normoxic) gas showed that both agents enter cells but only the nitroimidazole derivative was trapped in cells maintained under N₂ as evidenced by an approximately twofold decrease in T₁ measured for hypoxic cells versus normoxic cells exposed to this agent. These results suggest that the nitroimidazole derivative might serve as a molecular reporter for discriminating hypoxic versus normoxic tissues by MRI.     

Oxidative Conversion of a Europium(II)‐Based T1 Agent into a Europium(III)‐Based paraCEST Agent that can be Detected In Vivo by Magnetic Resonance Imaging

The Eu^II complex of 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) tetra(glycinate) has a higher reduction potential than most Eu^II chelates reported to date. The reduced Eu^II form acts as an efficient water proton T₁ relaxation reagent, while the Eu^III form acts as a water‐based chemical exchange saturation transfer (CEST) agent. The complex has extremely fast water exchange rate. Oxidation to the corresponding Eu^III complex yields a well‐defined signal from the paraCEST agent. The time course of oxidation was studied in vitro and in vivo by T₁‐weighted and CEST imaging.     

Dissociation Kinetics of Open‐Chain and Macrocyclic Gadolinium(III)‐Aminopolycarboxylate Complexes Related to Magnetic Resonance Imaging: Catalytic Effect of Endogenous Ligands

The kinetics of the metal exchange reactions between open‐chain Gd(DTPA)^2? and Gd(DTPA‐BMA), macrocyclic Gd(DOTA)^? and Gd(HP‐DO3A) complexes, and Cu²⁺ ions were investigated in the presence of endogenous citrate, phosphate, carbonate and histidinate ligands in the pH range 6–8 in NaCl (0.15 M ) at 25 °C. The rates of the exchange reactions of Gd(DTPA)^2? and Gd(DTPA‐BMA) are independent of the Cu²⁺ concentration in the presence of citrate and the reactions occur via the dissociation of Gd³⁺ complexes catalyzed by the citrate ions. The HCO₃^?/CO₃^2? and H₂PO₄^? ions also catalyze the dissociation of complexes. The rates of the dissociation of Gd(DTPA‐BMA), catalyzed by the endogenous ligands, are about two orders of magnitude higher than those of the Gd(DTPA)^2?. In fact near to physiological conditions the bicarbonate and carbonate ions show the largest catalytic effect, that significantly increase the dissociation rate of Gd(DTPA‐BMA) and make the higher pH values (when the carbonate ion concentration is higher) a risk‐factor for the dissociation of complexes in body fluids. The exchange reactions of Gd(DOTA)^? and Gd(HP‐DO3A) with Cu²⁺ occur through the proton assisted dissociation of complexes in the pH range 3.5–5 and the endogenous ligands do not affect the dissociation rates of complexes. More insights into the interaction scheme between Gd(DTPA‐BMA) and Gd(DTPA)^2? and endogenous ligands have been obtained by acquiring the ¹³C NMR spectra of the corresponding diamagnetic Y(III)‐complexes, indicating the increase of the rates of the intramolecular rearrangements in the presence of carbonate and citrate ions. The herein reported results may have implications in the understanding of the etiology of nephrogenic systemic fibrosis, a rare disease that has been associated to the administration of Gd‐containing agents to patients with impaired renal function.     

A Carborane‐Derivative “Click” Reaction under Heterogeneous Conditions for the Synthesis of a Promising Lipophilic MRI/GdBNCT Agent

In this study, the Huisgen reaction has been used to functionalise a carborane cage with a lipophilic moiety and a 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) ligand to obtain a new Gd boron neutron‐capture therapy (BNCT)/magnetic resonance imaging (MRI) agent. The introduction of the triazole units has been accomplished under both heterogeneous conditions, by the use of a Cu‐supported ionic‐liquid catalyst, and homogeneous conditions. The ability of the Gd complex of the synthesised ligand to form stable adducts with low‐density lipoproteins (LDLs) has been evaluated and then MRI has been performed on tumour melanoma cells incubated in the presence of a Gd‐complex/LDL imaging probe. It has been concluded that the high amount of intracellular boron necessary to perform BNCT can be reached even in the presence of a relatively low‐boron‐containing LDL concentration.     

DOTP versus DOTA as Ligands for Lanthanide Cations: Novel Structurally Characterized CeIV and CeIII Cyclen-Based Complexes and Clusters in Aqueous Solutions

The coordination and redox chemistry of aqueous Ce^IV/III macrocyclic compounds were studied by using the ligands DOTA and DOTP (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetrayl)tetraacetic acid and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra(methylene phosphonic acid), respectively). The hydrolysis tendency of the tetravalent cation in the presence of DOTA is shown to result in the formation of a highly ordered, fluorite-like [Ce^IV₆(O)₄(OH)₄(H₂O)₈(DOTAH)₄] oxo-hydroxo structure both in solution and in the solid state. The lifetime of the analogous species formed in the presence of DOTP was found to be much shorter. Spectroscopic measurements of the latter suggest its similarity to the former. Its gradual decomposition in solution leads to the accumulation of the in-cage complexes [Ce^IVDOTP] and [Ce^IIIDOTP(H₂O)], which were crystallographically characterized in this study. The redox energetics and spectroscopic characteristics for the transition between these two in-cage complexes in aqueous solutions were studied as well. Together with the crystallographic structures of the above-mentioned species, the in-cage [Ce^IVDOTA(H₂O)] complex structure is presented herein for the first time. An elaborative analysis of the X-ray crystallographic structural data obtained for the in-cage complexes studied herein and similar structures published previously suggests that hard-bonding cyclen-derived ligands are, counter-intuitively, better suited for encapsulating, and perhaps kinetically stabilize softer cations than harder ones with DOTP, marked as a possible adequate chelator for the study of the aqueous properties of Ln^II and Ac^III cations.     

Serum Albumin Targeted,pH‐Dependent Magnetic Resonance Relaxation Agents

The objective of this work was the synthesis of serum albumin targeted, Gd^III‐based magnetic resonance imaging (MRI) contrast agents exhibiting a strong pH‐dependent relaxivity. Two new complexes ( Gd‐glu and Gd‐bbu ) were synthesized based on the DO3A macrocycle modified with three carboxyalkyl substituents α to the three ring nitrogen atoms, and a biphenylsulfonamide arm. The sulfonamide nitrogen coordinates the Gd in a pH‐dependent fashion, resulting in a decrease in the hydration state, q, as pH is increased and a resultant decrease in relaxivity (r₁). In the absence of human serum albumin (HSA), r₁ increases from 2.0 to 6.0 mM ^?1 s^?1 for Gd‐glu and from 2.4 to 9.0 mM ^?1 s^?1 for Gd‐bbu from pH 5 to 8.5 at 37 °C, 0.47 T, respectively. These complexes (0.2 mM ) are bound (>98.9 %) to HSA (0.69 mM ) over the pH range 5–8.5. Binding to albumin increases the rotational correlation time and results in higher relaxivity. The r₁ increased 120 % (pH 5) and 550 % (pH 8.5) for Gd‐glu and 42 % (pH 5) and 260 % (pH 8.5) for Gd‐bbu . The increases in r₁ at pH 5 were unexpectedly low for a putative slow tumbling q=2 complex. The Gd‐bbu system was investigated further. At pH 5, it binds in a stepwise fashion to HSA with dissociation constants K_d1=0.65, K_d2=18, K_d3=1360 μM . The relaxivity at each binding site was constant. Luminescence lifetime titration experiments with the Eu^III analogue revealed that the inner‐sphere water ligands are displaced when the complex binds to HSA resulting in lower than expected r₁ at pH 5. Variable pH and temperature nuclear magnetic relaxation dispersion (NMRD) studies showed that the increased r₁ of the albumin‐bound q=0 complexes is due to the presence of a nearby water molecule with a long residency time (1–2 ns). The distance between this water molecule and the Gd ion changes with pH resulting in albumin‐bound pH‐dependent relaxivity.     

Copolymerization of propylene and 1,5‐hexadiene with stereospecific metallocene/Al(i‐Bu)3/[Ph3C][B(C6F5)4]

Copolymerizations of propylene (P) with 1,5‐hexadiene (1,5‐HD) were carried out with isospecific rac‐1,2‐ethylenebis(1‐indenyl)Zr(NMe₂)₂ [rac‐(EBI)Zr(NMe₂)₂, 1] and syndiospecific isopropylidene(cyclopentadienyl)(9‐fluorenyl)ZrMe₂ [i‐Pr(Cp)(Flu)ZrMe₂, 2] compounds combined with Al(i‐Bu)₃/[Ph₃C][B(C₆F₅)₄] as a cocatalyst system. Microstructures of poly(propylene‐co‐1,5‐HD) were determined by ¹H NMR, ¹³C NMR, Raman spectroscopies and X‐ray powder diffraction. The isospecific 1/Al(i‐Bu)₃/[Ph₃C][B(C₆F₆)₄] catalyst showed much higher polymerization rate than 2/Al(i‐Bu)₃/[Ph₃C][B(C₆F₆)₄] system, however, the latter system showed higher incorporation of 1,5‐HD (r_P = 8.85, r_1,5‐HD = 0.274) than the former system (r_P = 16.25, r_1,5‐HD = 0.34). The high value of r_P × r_1,5‐HD far above 1 demonstrated that the copolymers obtained by both catalysts are somewhat blocky. The insertion of 1,5‐HD proceeded by enantiomorphic site control; however, the diastereoselectivity of the intramolecular cyclization reaction of 1,2‐inserted 1,5‐HD was independent of the stereospecificity of metallocene compounds, but dependent on the concentration of 1,5‐HD in the feed. The insertion of the monomers by enantiomorphic site control could also be realized by Raman spectroscopy and X‐ray powder diffraction of the polymers. © 2000 John Wiley & Sons, Inc. J Polym Sci A: Polym Chem 38: 1590–1598, 2000     

Thermodynamic and Kinetic Study of Scandium(III) Complexes of DTPA and DOTA: A Step Toward Scandium Radiopharmaceuticals

Diethylenetriamine‐N,N,N′,N′′,N′′‐pentaacetic acid (DTPA) and 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA) scandium(III) complexes were investigated in the solution and solid state. Three ⁴⁵Sc NMR spectroscopic references suitable for aqueous solutions were suggested: 0.1 M Sc(ClO₄)₃ in 1 M aq. HClO₄ (δ_Sc=0.0 ppm), 0.1 M ScCl₃ in 1 M aq. HCl (δ_Sc=1.75 ppm) and 0.01 M [Sc(ox)₄]^5? (ox^2?=oxalato) in 1 M aq. K₂C₂O₄ (δ_Sc=8.31 ppm). In solution, [Sc(dtpa)]^2? complex (δ_Sc=83 ppm, ?ν=770 Hz) has a rather symmetric ligand field unlike highly unsymmetrical donor atom arrangement in [Sc(dota)]^? anion (δ_Sc=100 ppm, ?ν=4300 Hz). The solid‐state structure of K₈[Sc₂(ox)₇] ? 13 H₂O contains two [Sc(ox)₃]^3? units bridged by twice “side‐on” coordinated oxalate anion with Sc³⁺ ion in a dodecahedral O₈ arrangement. Structures of [Sc(dtpa)]^2? and [Sc(dota)]^? in [(Hguanidine)]₂[Sc(dtpa)] ? 3 H₂O and K[Sc(dota)][H₆dota]Cl₂ ? 4 H₂O, respectively, are analogous to those of trivalent lanthanide complexes with the same ligands. The [Sc(dota)]^? unit exhibits twisted square‐antiprismatic arrangement without an axial ligand (TSA′ isomer) and [Sc(dota)]^? and (H₆dota)²⁺ units are bridged by a K⁺ cation. A surprisingly high value of the last DOTA dissociation constant (pK_a=12.9) was determined by potentiometry and confirmed by using NMR spectroscopy. Stability constants of scandium(III) complexes (log K_ScL 27.43 and 30.79 for DTPA and DOTA, respectively) were determined from potentiometric and ⁴⁵Sc NMR spectroscopic data. Both complexes are fully formed even below pH 2. Complexation of DOTA with the Sc³⁺ ion is much faster than with trivalent lanthanides. Proton‐assisted decomplexation of the [Sc(dota)]^? complex (τ_1/2=45 h; 1 M aq. HCl, 25 °C) is much slower than that for [Ln(dota)]^? complexes. Therefore, DOTA and its derivatives seem to be very suitable ligands for scandium radioisotopes.     

Synthesis and Characterization of New 3‐(3‐Hydroxyphenyl)‐4‐ alkyl‐3,4‐dihydrobenzo[e][1,3]oxazepine‐1,5‐dione Compounds

A series of 3‐(3‐hydroxyphenyl)‐4‐alkyl‐3,4‐dihydrobenzo[e][1,3]oxazepine‐1,5‐dione compounds with general formula C_nH_2n+1CNO(CO)₂C₆H₄(C₆H₄OH) in which n are even parity numbers from 2 to 18. The structure determinations on these compounds were performed by FT‐IR spectroscopy which indicated that the terminal alkyl chain attached to the oxazepine ring was fully extended. Conformational analysis in DMSO at ambient temperature was carried out for the first time via high resolution ¹H NMR and ¹³C NMR spectroscopy.     

A Cyclen‐Based Tetraphosphinate Chelator for the Preparation of Radiolabeled Tetrameric Bioconjugates

The cyclen‐based tetraphosphinate chelator 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetrakis[methylene(2‐carboxyethyl)phosphinic acid] (DOTPI) comprises four additional carboxylic acid moieties for bioconjugation. The thermodynamic stability constants (logK_ML) of metal complexes, as determined by potentiometry, were 23.11 for Cu^II, 20.0 for Lu^III, 19.6 for Y^III, and 21.0 for Gd^III. DOTPI was functionalized with four cyclo(Arg‐Gly‐Asp‐D ‐Phe‐Lys) (RGD) peptides through polyethylene glycol (PEG₄) linkers. The resulting tetrameric conjugate DOTPI(RGD)₄ was radiolabeled with ¹⁷⁷Lu and ⁶⁴Cu and showed improved labeling efficiency compared with 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid (DOTA). The labeled compounds were fully stable in transchelation challenges against trisodium diethylenetriaminepentaacetate (DTPA) and disodium ethylenediaminetetraacetic acid (ETDA), in phosphate buffered saline (PBS), and human plasma. Integrin α_vβ₃ affinities of the non‐radioactive Lu^III and Cu^II complexes of DOTPI(RGD)₄ were 18 times higher (both IC₅₀ about 70 picomolar) than that of the c(RGDfK) peptide (IC₅₀=1.3 nanomolar). Facile access to tetrameric conjugates and the possibility of radiolabeling with therapeutic and diagnostic radionuclides render DOTPI suitable for application in peptide receptor radionuclide imaging (PRRI) and therapy (PRRT).     

Estimation of peptide N–Cα bond cleavage efficiency during MALDI‐ISD using a cyclic peptide

Matrix‐assisted laser desorption/ionization in‐source decay (MALDI‐ISD) induces N–C_α bond cleavage via hydrogen transfer from the matrix to the peptide backbone, which produces a c′/z? fragment pair. Subsequently, the z? generates z′ and [z + matrix] fragments via further radical reactions because of the low stability of the z?. In the present study, we investigated MALDI‐ISD of a cyclic peptide. The N–C_α bond cleavage in the cyclic peptide by MALDI‐ISD produced the hydrogen‐abundant peptide radical [M + 2H]⁺? with a radical site on the α‐carbon atom, which then reacted with the matrix to give [M + 3H]⁺ and [M + H + matrix]⁺. For 1,5‐diaminonaphthalene (1,5‐DAN) adducts with z fragments, post‐source decay of [M + H + 1,5‐DAN]⁺ generated from the cyclic peptide showed predominant loss of an amino acid with 1,5‐DAN. Additionally, MALDI‐ISD with Fourier transform‐ion cyclotron resonance mass spectrometry allowed for the detection of both [M + 3H]⁺ and [M + H]⁺ with two ¹³C atoms. These results strongly suggested that [M + 3H]⁺ and [M + H + 1,5‐DAN]⁺ were formed by N–C_α bond cleavage with further radical reactions. As a consequence, the cleavage efficiency of the N–C_α bond during MALDI‐ISD could be estimated by the ratio of the intensity of [M + H]⁺ and [M + 3H]⁺ in the Fourier transform‐ion cyclotron resonance spectrum. Because the reduction efficiency of a matrix for the cyclic peptide cyclo(Arg‐Gly‐Asp‐D‐Phe‐Val) was correlated to its tendency to cleave the N–C_α bond in linear peptides, the present method could allow the evaluation of the efficiency of N–C_α bond cleavage for MALDI matrix development. Copyright © 2016 John Wiley & Sons, Ltd.     

Synthesis and structural characterization of iridium(I) complexes of 20‐membered macrocyclic rings bearing chelating bis(N‐heterocyclic carbene) ligands

The reactivities of two 20‐membered macrocyclic ligands, each containing two N‐heterocyclic carbene (NHC) and two amine groups, towards [IrCl(COD)]₂ (COD is cycloocta‐1,5‐diene) were investigated. Macrocycles containing imidazolin‐2‐ylidene groups formed the monometallic complex [(1,2,5,6‐η)‐cycloocta‐1,5‐diene](5,16‐dibenzyl‐1,5,9,12,16,20‐hexaazatricyclo[18.2.1.1^9,12]tetracosa‐10,21‐dien‐21,22‐diylidene)iridium(I) bromide dichloromethane monosolvate, [Ir(C₈H₁₂)(C₃₂H₄₂N₆)]Br·CH₂Cl₂, 2a . The structure of iridium complex 2a at 100 K has triclinic P symmetry. The ligand in 2a coordinates to the Ir center through the NHC moieties in a cis fashion. Additionally, the ligand adopts an umbrella‐like structure that appears to envelope the Ir center. The structure displays C—H…Br interactions. Macrocycles containing benzimidazolin‐2‐ylidene groups formed the bimetallic complex [μ‐5,20‐dibenzyl‐1,5,9,16,20,24‐hexaazapentacyclo[22.6.1.1^9,16.0^10,15.0^25,30]dotriaconta‐10(15),11,13,25(30),26,28‐hexaene‐31,32‐diylidene]bis{bromido[(1,2,5,6‐η)‐cycloocta‐1,5‐diene]iridium(I)}, [Ir₂Br₂(C₈H₁₂)₂(C₄₀H₄₆N₆)], 2b . The structure of complex 2b at 100 K has orthorhombic Pbca symmetry. Each NHC moiety in 2b coordinates in a monodentate fashion to an Ir(COD) fragment. The structure exhibits disorder of the main molecule. This disorder is found in the portion of the macrocycle containing an amine group. This structure also displays C—H…Br interactions. Finally, the structure of the hexafluorophosphate salt of the imidazolin‐2‐ylidene‐containing macrocycle, namely 5,16‐dibenzyl‐1λ⁵,5,9,12λ⁵,16,20‐hexaazatricyclo[18.2.1.1^9,12]tetracosa‐1(23),10,12(24),21‐tetraene‐1,12‐diium bis(hexafluorophosphate), C₃₂H₄₄N₆²⁺·2PF₆^?, 1c , was determined. The structure of macrocycle 1c at 100 K has triclinic P symmetry and was found to contain C—H…F interactions.     

The Role of Ligand Topology in the Decomplexation of Luminescent Lanthanide Complexes by Dipicolinic Acid

In this study, we present the aqueous solution behavior of two luminescent lanthanide antenna complexes (Eu³⁺? 1 , Dy³⁺? 9 ) with different ligand topologies in the presence of dipicolinic acid (DPA, pyridine‐2,6‐dicarboxylic acid). Macrocyclic (1,4,7,10‐tetraazacyclododecane‐1,4,7‐triacetic acid, DO3A, 9 ) and acyclic (1,4,7‐triazaheptane‐1,1,7,7‐tetraacetic acid, DTTA, 1 ) ligands have been selected to form a ratiometric pair in which Dy³⁺? 9 acts as a reference and Eu³⁺? 1 acts as a probe for the recognition of DPA. The pair of luminescent complexes in water reveals the capability to work as a DPA luminescent sensor. The change of emission intensity of Eu³⁺ indicates the occurrence of a new sensitization path for the lanthanide cation through excitation of DPA. NMR evidence implies the presence of free 1 and mass spectrometry shows the formation of emitting [EuDPA₂]^? as a result of a ligand exchange reaction.