title: Synthesis, dynamic NMR characterization and XRD studies of novelN,N'-substituted piperazines for bioorthogonal labeling.
abstract: Novel, functionalized piperazine derivatives were successfully synthesized and fully characterized by1H/13C/19F NMR, MS, elemental analysis and lipophilicity. All piperazine compounds occur as conformers resulting from the partial amide double bond. Furthermore, a second conformational shape was observed for all nitro derivatives due to the limited change of the piperazine chair conformation. Therefore, two coalescence points were determined and their resulting activation energy barriers were calculated using1H NMR. To support this result, single crystals of 1-(4-nitrobenzoyl)piperazine (3a, monoclinic, space groupC2/c,a= 24.587(2),b= 7.0726(6),c= 14.171(1) Å, β = 119.257(8)°,V= 2149.9(4) Å3,Z= 4,Dobs= 1.454 g/cm3) and the alkyne derivative 4-(but-3-yn-1-yl)-1-(4-fluorobenzoyl)piperazine (4b, monoclinic, space groupP21/n,a= 10.5982(2),b= 8.4705(1),c= 14.8929(3) Å, β = 97.430(1)°,V= 1325.74(4) Å3,Z= 4,Dobs= 1.304 g/cm3) were obtained from a saturated ethyl acetate solution. The rotational conformation of these compounds was also verified by XRD. As proof of concept for future labeling purposes, both nitropiperazines were reacted with [18F]F-. To test the applicability of these compounds as possible18F-building blocks, two biomolecules were modified and chosen for conjugation either using the Huisgen-click reaction or the traceless Staudinger ligation.
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Bautzner Landstraße 400, D-01328 Dresden, Germany; Technische Universität Dresden, Fachrichtung Chemie und Lebensmittelchemie, D-01062 Dresden, Germany.
authors.forename: Constantin
authors.initials: C
authors.lastname: Mamat
authors.affiliation: Medizinische Fakultät Mannheim der Universität Heidelberg, Institut für Klinische Radiologie und Nuklearmedizin, Theodor-Kutzner-Ufer 1-3, D-68167 Mannheim, Germany.
authors.forename: Marc
authors.initials: M
authors.lastname: Pretze
authors.affiliation: Helmholtz-Zentrum Dresden-Rossendorf, Institut für Radiopharmazeutische Krebsforschung, Bautzner Landstraße 400, D-01328 Dresden, Germany.
authors.forename: Matthew
authors.initials: M
authors.lastname: Gott
authors.affiliation: Universität Rostock, Institut für Chemie - Festkörperchemie, Albert-Einstein-Straße 3a, D-18059 Rostock, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Köckerling
keywords: Staudinger ligation; building blocks; coalescence; dynamic NMR; labeling