Reactions of heteroallenes with cyclam-based Zr(iv) complexes

Abstract

This work describes reactions of heteroallenes with diamido-diamine cyclam-based Zr(iv) complexes of the general formula (Bn2Cyclam)ZrX2 (X = O(t)Bu, , O(i)Pr, , SPh, , NH(t)Bu, ) as well as the di-orthometallated species ((C6H4CH2)2Cyclam)Zr, . The reactions of isocyanates or isothiocyanates with , or resulted in the formation of N-bonded ureate or thioureate cyclam complexes upon [2 + 2] cycloaddition of the Zr-Namido bonds of the cyclam to the heteroallene (). DFT calculations showed that κ(2)-N,N'-ureate bonding is favoured over κ(2)-N,O-ureates, which in turn may be formed in reactions with bulky isocyanates as 1-naphthyl isocyanate (NpN[double bond, length as m-dash]C[double bond, length as m-dash]O). The reactions of with N,N'-cyclohexylcarbodiimide (CyN[double bond, length as m-dash]C[double bond, length as m-dash]NCy) and carbon disulfide afforded guanidinate and dithiocarbamate fragments, respectively, appended to one of the nitrogen atoms of the cyclam ligand. These reactions represent a reliable method for the synthesis of asymmetrically N-functionalized cyclams giving rise to C1 symmetry Zr(iv) species by addition of one equivalent of heteroallenes. The reaction of (Bn2Cyclam)Zr(NH(t)Bu)2, , with one equivalent of mesityl isocyanate (MesN[double bond, length as m-dash]C[double bond, length as m-dash]O) also proceeds through insertion, involving one Zr-NH(t)Bu bond. However, it was observed that the reaction of (Bn2Cyclam)Zr(NH(t)Bu)2, , with MesN[double bond, length as m-dash]C[double bond, length as m-dash]O follows a different path if the reaction is carried out at 60 °C. In this case the reaction leads to [2 + 2] addition of the Zr-Ncyclam bond to the isocyanate, with a concomitant occurrence of orthometallation of the one benzyl pending group of the cyclam ring. The reaction of (t)BuN[double bond, length as m-dash]C[double bond, length as m-dash]O with the di-orthometallated complex ((C6H4CH2)2Cyclam)Zr, , also gave a κ(2)-N,N'-ureate fragment, by isocyanate addition to the macrocycle. DFT calculations on these systems were conducted in an attempt to rationalise the reactivity patterns observed.

Recent Advances in Zirconium-89 Chelator Development

“…It provided irrefutable proof of an octadentate coordination environment where all four macrocycle nitrogen atoms and acetate pendant arms participated in Zr 4+ ion coordination. Furthermore, the compressed, square anti-prismatic geometry and low-symmetry saddle-like ligand conformation displayed by Zr- 37 was consistent with the limited number of reports describing Zr-catalysts containing analogous ligands with a Zr(IV) metal center that lacks crystal-field stabilization [ 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 ].…”

Zirconium tetraazamacrocycle complexes display extraordinary stability and provide a new strategy for zirconium-89-based radiopharmaceutical development

“…This is not unusual, since Zr tetraazamacrocycle complexes exhibit varying geometries dictated by the additional ligands that occupy the coordination sites not occupied by the nitrogen atoms of the macrocycle. 25,26,28 The perpendicular distance from the metal center to the plane described by the 4 acetate-containing pendant arms of the macrocycle is 1.004(3) Å, and the perpendicular distance from the metal center to the plane described by the 4 nitrogens of the macrocycle is 1.310(4) Å. The DOTA ligand displays a low-symmetry saddle-like conformation similar to that of metal–dibenzotetramethytetraaza[14]annulene complexes described by De Angelis and co-workers.…”

“…29 The average Zr–ligand bond lengths and bond angles are comparable to those observed in structurally characterized Zr complexes containing hydroxamate, phenoxyamine, salophen, or cyclam ligands. 25,26,28,30–33 …”

“…Despite well-reasoned arguments to the contrary, 20,22–24 it seemed reasonable to posit that tetraazamacrocycles would be useful in 89 Zr-radiopharmaceutical applications, since several Zr–cyclam complexes have been described previously. 25,26 Additionally, we reasoned that their use would be advantageous since (1) they demonstrate enhanced stability over acyclic ligands due to the macrocyclic effect; (2) various functional groups can be introduced into the macrocycle's backbone or pendant arms to modulate the ligand's stereo- and coordination chemistry; (3) bifunctional chelators derived from these ligands allow them to be conjugated to various peptides, proteins, and antibodies; and (4) they have been used successfully in a number of radiopharmaceutical applications and clinical trials.…”

Synthesis and Characterization of New Cyclam-Based Zr(IV) Alkoxido Derivatives

“…The high polarity of M-OR bonds led to the application of several families of early transition metal complexes in the ring opening polymerization (ROP) of cyclic esters [3][4][5][6][7][8][9][10][11][12]. Our previous research on cyclam-based Zr(IV) alkoxido, phenoxido and thiophenoxido derivatives [13][14][15] also disclosed new catalytic systems for the ROP of rac-lactide strongly influenced by the nature of the OR ligands [13]. The characterization of the polymers obtained and DFT calculations clarified the important features that govern the catalytic activity and the role of OR ligands as initiators of the polymerization reactions or as supporting ligands that direct the insertion of the monomers into the Zr-N bonds of the cyclam ligand with concomitant formation of cyclam functionalized polylactide [13].…”