Lanthanide(III) Complexes with a Reinforced Cyclam Ligand Show Unprecedented Kinetic Inertness Aurora Rodríguez-Rodríguez, † David Esteban-Gó mez, † Raphaë l Tripier,* ,‡ Gyula Tircsó ,* ,§ Zolta ́ n Garda, § Imre Tó th, § Andre ́ s de Blas, † Teresa Rodríguez-Blas, † and Carlos Platas-Iglesias* ,† † Departamento de Química Fundamental, Universidade da Coruñ a, Campus da Zapateira-Rú a da Fraga 10, 15008 A Coruñ a, Spain ‡ UMR-CNRS 6521, UFR des Sciences et Techniques, Universite ́ de Bretagne Occidentale, 6 avenue Victor le Gorgeu, C.S. 93837, 29238 Brest Cedex 3, France § Department of Inorganic and Analytical Chemistry, Faculty of Science and Technology, University of Debrecen, Egyetem té r 1, H-4032 Debrecen, Hungary * S Supporting Information ABSTRACT: Lanthanide(III) complexes of a cross- bridged cyclam derivative containing two picolinate pendant arms are kinetically inert in very harsh conditions such as 2 M HCl, with no dissociation being observed for at least 5 months. Importantly, the [Ln(dota)] - complexes, which are recognized to be extremely inert, dissociate under these conditions with lifetimes in the range ca. 1 min to 12 h depending upon the Ln 3+ ion. X- ray diffraction studies reveal octadentate binding of the ligand to the metal ion in the [Eu(cb-tedpa)] + complex, while 1 H and 13 C NMR experiments in D 2 O point to the presence of a single diastereoisomer in solution with a very rigid structure. The structure of the complexes in the solid state is retained in solution, as demonstrated by the analysis of the Yb 3+ -induced paramagnetic shifts. L anthanide(III) coordination chemistry in aqueous sol- utions is currently receiving a great deal of attention due to the important biomedical and bioanalytical applications of the complexes of these metal ions. Indeed, stable Gd 3+ complexes with polyaminocarboxylate ligands are commonly used as contrast agents in magnetic resonance imaging (MRI), 1 while luminescent complexes of Eu 3+ and Tb 3+ have found applications in fluoroimmunoassays and as luminescent probes for optical imaging. 2 These applications require a very robust complexation of the metal ion in highly competitive biological media. For instance, macrobicyclic structures such as the famous cryptates reported by Lehn have found application in homogeneous fluoroimmunoassays thanks to their very low dissociation rates in biological media. 3 However, stable Ln 3+ complexation is normally achieved with the use of macrocyclic ligands based on 1,4,7,10-tetraazacyclododecane (cyclen) such as dota (H 4 dota = 1,4,7,10-tetraazacyclododecane-1,4,7,10- tetraacetic acid, Chart 1), which forms lanthanide complexes of exceptionally high thermodynamic stability and kinetic inertness. 4 In spite of the intense research efforts carried out in the past 20 years to develop stable Ln 3+ chelates for medical or biochemical applications, none of the systems reported to date can rival with dota derivatives in terms of combined thermodynamic stability and kinetic inertness. Some Ln 3+ complexes of dota-tetraamides and cyclen-based polyazaphos- phinic acids were shown to be somewhat more inert than the parent dota complexes, but their thermodynamic stability is considerably lower. 5 Kinetic inertness of Ln 3+ complexes with functionalized tetraazamacrocyclic ligands decreases by several orders of magnitude from the 12-membered dota to the 13-membered trita and the 14-membered teta, which is based on a cyclam platform (Chart 1). 6 An interesting approach to develop kinetically inert complexes of transition metal complexes is the use of cross-bridged cyclam derivatives, which commonly contain a 1,8-ethylene unit bridging two nitrogen atoms of the tetraazamacrocycle in trans positions. 7 However, to the best of our knowledge cross-bridged cyclam derivatives have never been used for Ln 3+ complexation. In this contribution we report the cross-bridged cyclam derivative cb-tedpa (Scheme 1), which forms Ln 3+ complexes endowed with a very high kinetic inertness. Received: November 4, 2014 Published: December 12, 2014 Chart 1. Ligands Discussed in the Present Work Communication pubs.acs.org/JACS © 2014 American Chemical Society 17954 dx.doi.org/10.1021/ja511331n | J. Am. Chem. Soc. 2014, 136, 17954-17957