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Reports: UR352779-UR3: Triazole-Containing Tridentate Anionic Chelators for Lanthanide and Group VIII Organometallic Complexes

James T. Fletcher, PhD, Creighton University

Ligand motifs containing 1,2,3-triazole subunits have become increasingly prevalent due to their ease of preparation as allowed by Sharpless-Meldal click methods.  A common example is the 2,6-bis(1-substituted-1,2,3-triazol-4-yl)pyridine ligand (1), which has been shown to coordinate a variety of transition metals in a neutral tridentate manner.  1,2,3-Triazole containing compounds able to coordinate metals as anionic chelators are much less prevalent.  Metal complexes comprised of anionic ligands can display properties unique to analogous neutral ligands, as well as preclude the requirement of outer sphere counter ions.  The overall goal of this study is to develop two previously unreported 1,2,3-triazole ligand motifs displaying the ability to coordinate transition metals in an anionic tridentate manner: 6-(1-substituted-1,2,3-triazol-4-yl)-2-carboxypyridine (2) and 2-(1H-tetrazol-5-yl)-6-(1-substituted-1,2,3-triazol-4-yl)pyridine (3).  Using a click chemistry approach to install the 1,2,3-triazole ring enables the target chelators to be prepared modularly and in high yield, while also allowing a diverse range of functionality to be incorporated onto the periphery of the chelator at the 1-triazolyl position.  Functional groups allowing the tuning of electronic properties and solubility are of particular interest, as is exploring the ability of such compounds to form stable 2:1 coordination compounds with Ru(II) and Fe(II) ions and stable 3:1 coordination compounds with trivalent lanthanide ions.

Figure 1.  Identity of the tridentate 1,2,3-triazole-containing chelators described in this report: 2,6-bis(1-substituted-1,2,3-triazol-4-yl)pyridine (1), 6-(1-substituted-1,2,3-triazol-4-yl)-2-carboxypyridine (2) and 2-(1H-tetrazol-5-yl)-6-(1-substituted-1,2,3-triazol-4-yl)pyridine (3).

In the first year of this grant, successful preparation of each of the two proposed chelators was realized for a range of peripheral substituents.  Preparation of 2 was achieved using a three step synthetic approach starting from commercially available 6-bromopyridine-2-carboxyethyl ester (Figure 2).  A sequence of Sonogashira coupling with trimethylsilylacetylene, followed by a tandem TMS-deprotection/click transformation with a variety of organic azides was used to install the 1,2,3-triazole ring.  Saponification of this ester to give the carboxylic acid resulted in the three step preparation of desired chelator 2 in an overall three-step yield ranging from 39-67%.

Figure 2.  Preparation of target compound Ru(2)2.

This chelator was successfully shown to chelate Ru(II) in a 2:1 manner following a traditional approach used to prepare 2:1 coordination compounds with neutral tridentate chelators such as terpyridine.  This procedure involves heating the chelators in an ethanol/water mixture using Ru(III) chloride as the metal source.  Importantly, the addition of base to these conditions (triethylamine was used successfully) was necessary to deprotonate the chelator and push the reactions forward. 

The tetrazole-containing chelator 3 was prepared in a largely analogous manner as that used to prepare 2.  As summarized in Figure 3, this was achieved using a three step synthetic approach starting from commercially available 2-bromo-6-cyanopyridine.  A sequence of Sonogashira coupling followed by a tandem TMS-deprotection/click transformation was used to install the 1,2,3-triazole ring.  The cyano functionality was then transformed into the desired tetrazole ring via Zn(II) mediated cycloaddition with sodium azide, with an overall three-step yield ranging from 50-66%.  It was demonstrated that the order of these three steps was important.  Installation of the tetrazole ring needs to follow the cross coupling step, as the Sonogashira coupling is incompatible with 6-bromo-2-(1H-tetrazol-5-yl)pyridine, and the TMS-protected alkyne is not stable towards the conditions required to install the tetrazole ring.  Stable 2:1 Ru(II) complexes were successfully prepared using identical conditions as described for 2.

Figure 3.  Preparation of target compound Ru(3)2.

Each approach was demonstrated feasible for a range of benzyl and aryl substituents, as summarized in Figure 4.  The intent of these substituents was to explore the degree to which peripheral changes to the chelators impact both the electronic properties and solubility of the Ru(II) coordination compounds.  The 2:1 ligand:metal product identity for each analog was confirmed by NMR spectroscopy and mass spectrometry.  It is notable that the lack of counter ion was reflected in MS analysis (MALDI-TOF MS), and significantly less fragmentation of ligand from metal was observed relative to analogous Ru(tpy)2Cl2 or Ru(1)2Cl2 complexes possessing outer sphere counter ions. 

Figure 4.  Summary of analogs prepared for 2 and 3 in year one.

These coordination compounds were sufficiently soluble to allow characterization by UV-Visible spectroscopy.  The absorption spectra showed a slight shifting of high energy bands and an emergence of a new low energy band upon formation of the metal complex relative to the chelator itself (Figure 5).  None of the coordination compounds displayed measurable fluorescence emission at room temperature.  Electrochemical measurements were planned in order to help discern the influence that electron-rich and electron-poor substituents have on the redox properties of the coordination compounds.  Unfortunately, these compound analogs were insufficiently soluble to allow completion of reliable cyclic voltammetry measurements.

Figure 5.  UV-Visible absorbance spectra of chelators 1 (left), 2, (center) and 3 (right) (shown as dotted lines) compared to their 2:1 divalent ruthenium complexes (shown as solid lines).  For each, the analog is R = phenyl.  Spectra are normalized to l(max) = 1.

With a modular synthetic approach to prepare analogs of chelators 2 and 3 established in year one, work during the second year of this grant will focus on two major areas.  One goal is to prepare analogs of 2 and 3 that display significantly improved solubility, so that reliable electrochemical characterization can be performed.  A second goal is to prepare stable 2:1 coordination compounds with Fe(II) and stable 3:1 coordination compounds with trivalent lanthanide ions using analogs of 2 and 3.  Such products will be characterized analogously to the Ru(II) compounds.  Efforts will continue to grow crystals of representative coordination compounds suitable for analysis by X-ray diffraction.  In addition, new iterations of tridentate triazolylpyridine ligand motifs will be explored.

In year one, this project has directly supported three different undergraduate research students who have conducted research during both the summer months and academic semesters.  A presentation made at the 2014 ACS Fall National Meeting included one of these students as a coauthor.