Chiral Resolution of Lanthanoid Cryptates with Extreme

Jul 12, 2017 - Chirality is one of the most fundamental aspects of chemistry. In this context, enantiopure metal complexes have long been recognized t...
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Chiral Resolution of Lanthanoid Cryptates with Extreme Configurational Stability Elisabeth Kreidt,† Carolin Dee,† and Michael Seitz*,† †

Institute of Inorganic Chemistry, University of Tübingen, Auf der Morgenstelle 18, 72076 Tübingen, Germany S Supporting Information *

Scheme 1. Chiral Resolution of the Racemic Cryptates 1-Ln

ABSTRACT: Chiral resolution is achieved for racemic tris(2,2′-bipyridine)-based lanthanoid cryptates by chiral HPLC. The resolved complexes exhibit very rare configurational stability under extreme conditions.

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hirality is one of the most fundamental aspects of chemistry. In this context, enantiopure metal complexes have long been recognized to play a crucial role in a wide variety of areas, most prominently in the recent past as catalysts in asymmetric catalysis. The archetypes of this class of compounds are octahedral tris(bidentate) complexes such as [Ru(bpy)3]n+, which in many instances can be chirally resolved and often show remarkable configurational stability in enantiopure form.1 In contrast, lanthanoid complexes, due to their inherent kinetic lability and generally rather fluxional coordination sphere, rarely show similarly advantageous properties and usually only form configurationally stable complexes with enantiopure ligands.2 For example, the chiral europium complex anion [Eu(dpa) 3 ] 3− (with dpa  dipicolinate) shows very fast exchange between its Δ and Λ enantiomers with a half-life on the order of a few tens of milliseconds in aqueous solution at ambient temperature.3 Despite the great potential that enantiopure lanthanoid complexes have for unique applications such as paramagnetic NMR shift reagents4 or circularly polarized luminescence (CPL) probes,5 there is currently only one practically useful ligand platform based on 1,4,7-triazacyclononane that provides lanthanoid complexes which can be chirally resolved and which show sufficient configurational stability after resolution.6 It has so far proven very difficult to develop other ligands for lanthanoid chelation with the same advantageous properties. Here, we report the chiral resolution of tris(2,2′-bipyridine)based lanthanoid cryptates as a different class of universally applicable rare earth chelators and their remarkable chemical and configurational stability under rather harsh conditions. Rigidified bipyridine cryptands such as (±)-1-Ln (Scheme 1, left) have proven to be excellent ligands for lanthanoids, providing kinetically inert complexes with outstanding photophysical and interesting magnetic properties.7 Due to the helical arrangement of the overall cryptate architecture and the axial chirality of the 2,2′-bipyridine-N,N′-dioxide units, these cryptates are chiral but have so far almost exclusively been synthesized and used as racemates. Cryptates of this type are also accessible as single enantiomers using enantiomerically pure cryptands,8 but the much more desirable and practically straightforward chiral © 2017 American Chemical Society

resolution to obtain both enantiomers of the corresponding cryptates with racemic or achiral cryptands has not been achieved so far. In order to test the latter possibility, we subjected a series of previously realized cryptates (±)-1-Ln (with Ln = Pr, Nd, Sm, Er, Lu)7c,d to chiral HPLC. Under optimized HPLC conditions (stationary phase, CHIRALPAK IE; eluent, isocratic CH3OH + 0.5 vol % CF3COOH), the racemates could be sufficiently resolved for all lanthanoids investigated along the series. As a representative example, Figure 1 shows the HPLC traces for the racemate (±)-1-Lu, as well as the isolated enantiomers 1-Lu-ent1 (first fraction) and 1-Lu-ent2 (second fraction) after the preparative resolution (see Figure S1 in the Supporting Information for the HPLC traces for all other lanthanoids). The HPLC trace of the racemate shows the two peaks assigned to the enantiomers in the expected 50:50 ratio. The recovery of the pure enantiomers from the racemate was quite good with 72% for 1-Lu-ent1 and 88% for 1-Lu-ent2 (see the Supporting Information for details). Both of these resolved fractions showed no sign of the other enantiomer in the HPLC traces, identical 1H NMR spectra (Figure S1 in the Supporting Information) in CD3OD, and perfect mirror-image CD spectra in CH3OH (Figure 2). Taken together, this constitutes conclusive evidence that the two fractions contain the corresponding enantiomers and that the enantiopurity of each form is very high. At the moment, we cannot assign the absolute configurations of the two enantiomers, but efforts in this direction are underway. In order to test the configurational stability of the resolved enantiomers, 1-Lu-ent1 was subjected to two rather harsh environments, and the progress over time was monitored by chiral HPLC (Figure 3). On the one hand, we evaluated Received: June 7, 2017 Published: July 12, 2017 8752

DOI: 10.1021/acs.inorgchem.7b01407 Inorg. Chem. 2017, 56, 8752−8754

Communication

Inorganic Chemistry

Figure 1. HPLC traces (CHIRALPAK IE, CH3OH + 0.5 vol % CF3COOH, UV detection: 300 nm). (A) Preparative separation of racemic (±)-1-Lu. (B and C) Analytical HPLC of the purified enantiomers 1-Lu-ent1 (B) and 1-Lu-ent2 (C) from the preparative run in A.

Figure 3. Configurational stability tests by chiral HPLC of 1-Lu-ent1 under the following conditions: Left, neat CF3COOH, room temperature; Right, 10 equiv LuCl3·6H2O in CH3CN, reflux.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.inorgchem.7b01407. Experimental details for chiral HPLC measurements, the configurational stability studies, and CD spectroscopy; chiral HPLC traces of the racemates (±)-1-Ln (Ln = Pr, Nd, Sm, Er); and NMR spectra of 1-Lu-ent1 and 1-Luent2 (PDF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

Figure 2. CD spectra of both enantiomers: 1-Lu-ent1 (black) and 1Lu-ent2 (red) in CH3OH (c ≈ 0.4 mM).

ORCID

Michael Seitz: 0000-0002-9313-2779 Notes

potential racemization reactions in solutions of this enantiomer in neat CF3COOH at room temperature, conditions which usually favor rapid decomplexation and/or configurational instability in most other lanthanoid chelates. Second, we also heated 1-Lu-ent1 in CH3CN under reflux with 10 equiv of externally added LuCl3·6H2O and monitored the potential selfexchange of the lutetium cations which would lead to the appearance of the second enantiomer 1-Lu-ent2. In neither of these experiments could we detect any chemical instability or any sign of the other enantiomer after 5 days. In conclusion, we could show that the lanthanoid cryptates (±)-1-Ln can be separated into pure enantiomers by chiral HPLC and that the resolved, enantiopure complexes show very high configurational stability. This extraordinary and very rare ability to preserve the absolute stereochemical information under extremely challenging conditions makes these enantiopure cryptates very interesting lanthanoid chelates. We expect that this will open up entirely new prospects for applications where enantiopurity is a key requirement, for example for the development of new CPL probes in the near-IR wavelength range, a spectral region where we have already shown the great worth of these cryptates.7b−d

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge financial support from the German Research Foundation (DFG, research grant SE 1448/6-1) and the German National Academic Foundation (predoctoral fellowship for E.K.). We thank Mrs. Joana Tavares Macedo (Interfaculty Institute for Biochemistry, University of Tübingen) for help with the CD measurements.

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REFERENCES

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DOI: 10.1021/acs.inorgchem.7b01407 Inorg. Chem. 2017, 56, 8752−8754

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DOI: 10.1021/acs.inorgchem.7b01407 Inorg. Chem. 2017, 56, 8752−8754