Chiral macrocyclic terpyridine complexes

Interlinking of two terpyridine ligands results in mononuclear chiral metal complexes (Fe and Ru) which were separated into their enantiomers.


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were performed on a Bruker microflex™ mass spectrometer, calibrated with CsI3, and α-cyano-4-hydroxycinnamic acid (unless stated differently) was used as matrix Column chromatography was performed with SiliaFlash® P60 from SILICYCLE with a particle size of 40-63 μm (230-400 mesh) and for TLC Silica gel 60 F254 glass plates with a thickness of 0.25 mm from Merck were used. The detection was observed with a UV-lamp at 254 or 366 nm. Gel Permeation Chromatography (GPC) was performed on a Shimadzu Prominence System with PSS SDV preparative columns from PSS (2 columns in series: 600 mm x 20.0 mm, 5 μm particles, linear porosity "S", operating ranges: 100 -100 000 g.mol -1 ) using chloroform as eluent. For HPLC a Shimadzu LC-20AD and a LC-20AT HPLC, respectively, was used equipped with a diodearray UV/Vis detector (SPD-M10A VP from Shimadzu, = 200-600 nm) and a column oven Shimadzu CTO-20AC. The used column for reverse phase was a Reprosil 100 C18, 5 m, 250 x 16 mm; Dr. Maisch GmbH and for chiral separation a Chiralpak IB, 5 m, 4.6 x 250 mm; Daicel Chemical Industries Ltd. CD measurements were performed with a Chirascan CD Spectrometer in acetonitrile at room temperature in 1 cm quartz glass cuvettes.

UV-Vis spectroscopy:
The UV-Vis spectra were recorded on a Shimadzu UV spectrometer UV-1800. λmax was measured in nm. All solutions were prepared and measured under air saturated conditions in acetonitrile.
UV/Vis spectra were recorded on a Shimadzu UV spectrometer UV-1800 using optical 1115F-QS Hellma cuvettes (10 mm light path). The wavelength of maxima absorption maxima (λmax) are reported in nm.  Table SI 1.

Computational Methodology:
All density functional theory (DFT) calculations were carried out by using the GAUSSIAN 09 suite.
Geometries for all complexes were optimized computationally using Becke's threeparameter exchange functional (B3) 2 in conjunction with the Lee, Yang, and Parr (LYP) 3 nonlocal functional.
No geometry restrictions were used during the optimization and the LANL2DZ basis set was employed for all molecules. 4 Additional calculations on the Fe complexes were performed with the 6-31G(d) basis set. 5

Racemization experiments and determination of the inversion barrier of Fe(L1)2-c:
The complexes were irradiated with a blue LED at 450 nm (3 Watt) for 12 hours. Therefore one enantiomer of the complexes was dissolved in acetonitrile and placed in a thin test tube. The glass was placed in a shaker to move the solution and the LED was placed in close proximity (2 cm). Even after irradiating for 12 hours no racemization of the enantiomer was observed. For the next racemization experiment a "Polychrome V monochromator" from Till Photonics monochromator equipped with a 150 W Xenon high stability lamp and an optical fiber was used. The output power is specified as >10 mW at 470 nm. Irradiation in solution at 560 nm with a spectral transmission band of 2 nm of one enantiomer in acetonitrile for 12 hours did not result in racemization as monitored by HPLC.
Racemization experiments by oxidation and successive reduction were performed on a Versastat3-200 potentiostat from Princeton Applied Research using a glassy carbon disk as working electrode, a silver wire as pseudo reference electrode, and a silver wire as counter electrode, 0.1 M solution of TBAPF6 in dichloromethane served as supporting electrolyte. Even applying an oxidation potential of 1.5 V for 30 minutes and successive reductive potential of 0 V for 30 minutes did not lead to racemization.
The racemization experiments were performed in a high boiling solvent. Therefore several solvents like ethylene glycol, o-xylene, DMSO, 1-hexanol and p-cymene were tested. Unfortunately none of these solvents dissolved the Fe(L1)2-c complex. Suitable solvents that dissolves the complex like EtOH, acetonitrile, acetone, dichloromethane or 1,2-dichloroethane have a too low boiling point. The only possible solvents found were 1,1,2,2-tetrachlorethane and DMF. Due to possible side-reaction that sometimes arise in DMF close to refluxing temperatures, 1,1,2,2-tetrachlorethane was used for the racemization experiment. In order to be consistent in the experiment, always the first obtained enantiomer from the chiral HPLC was used.
The rate of racemization between the two enantiomers of Fe(L1)2-c can be described as a first order process with

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The decay of the enantiomeric excess was determined by HPLC. Each temperature was measured three times and each sample was injected three times to HPLC in order to take the average enantiomeric excess values: ) gives a linear relation with the slope that corresponds to krac directly: The k values can be used to determine the free Gibbs energy of racemization ∆ ≠ by the rearranged Eyring equation:
And substituting ∆ ≠ by S44 which can be brought in a linear form:

Crystal data for Ru(L1)2-c and Fe(L1)2-c:
Compound For both structures the diffraction data were collected on a Stoe StadiVari diffractometer attached to a Ga Metaljet X-ray source at low temperature.
Compound Ru(L1)2-c: Using Olex2 6 , the structure was solved with the ShelXS 7 structure solution program using Direct Methods and refined with the ShelXL 8 refinement package using Least Squares minimization. Non-hydrogen atoms were refined anisotropically (atoms of the disordered solvent molecule were refined isotropically); hydrogen atoms were modeled on idealized positions. Molecular drawings were generated using Diamond3.2 9 .
Compound Fe(L1)2-c: The structure was solved with the program Superflip 10 using the charge flipping method and refined with CRYSTALS 11 using Least Squares minimization. Non-hydrogen atoms were refined anisotropically. About 37% of the volume of the structure is occupied by disordered solvent molecules. As interpretation of the electron density map in terms of molecules was not possible SQUEEZE 12 has been used in order to complete the refinement.

High dilution macrocyclization experiment of the free ligand L1:
An interesting aspect is the importance of the templating in a M(II) complex for the success of the macrocyclization. In order to shine light on this issue, high dilution macrocyclization experiments were performed with the ligand L1. Based on the experience we have in the lab with high dilution experiments, the active concentration of L1 was further reduced by adding it with a syringe pump. In spite of several approaches, the closed macrocycle (L1)2 could neither be detected in reasonable yields nor be isolated. Particular challenging for the high dilution reaction is that the copper ions required for the oxidative coupling form complexes with the pyridiyl-subunits of L1 as well. Furthermore is seems that metal free oligomers of L1 have only limited solubility. However, in the most successful attempt traces of the dimers of L1 have been observed by MALDI-ToF mass spectrometry. In this attempt CuCl (4.71 mg, 46.1 mol, 10 eq.) and TMEDA (6.99 L, 46.1 mol, 10 eq.) were dissolved in DCM (50 mL). The reaction mixture was saturated with oxygen before the ligand L1 (2.00 mg, 4.61 mol, 1.0 eq) dissolved in DCM (20 mL) was added over a period of 4 hours. The procedure results in a maximum concentrations of the ligand L1 of 6.6 ·10 -8 mol/L. The reaction was monitored by MALDI-ToF mass spectrometry (see figure SI 15). The most prominent signals in the MS are the ones of the ligand L1 and its copper adducts. But there are also signals that can be assigned to the copper adducts of the singly closed dimer of L1 and even a weak signal that can be assigned to the copper complex of the doubly closed dimer of L1, which is the desired macrocycle (L1)2 (red arrow in Fig. SI 15). Interestingly, also the signal of the copper adduct of the next higher oligomer L13 can be detected. However, all attempts to isolate the macrocycle (L1)2 failed. After work up and extraction of the copper ions, exclusively the monomer L1 was detected by analyzing the reaction mixture by HPLC. Whether the traces of S55 the macrocycle were too little for the detection threshold of the HPLC-MS device or its detection was hampered by its solubility features we are not able to distinguish.
Closer inspection of the MALDI-ToF MS signal of the Cu-L12 adducts (Fig. SI 16) suggest that the signal corresponds to about a 4:5 mixture of the copper adducts of the doubly closed macrocycle and the single closed open dimer. It seems that in spite of the intramolecular nature of the second oxidative acetylene coupling, the macrocyclization is not particularly favored. The working hypothesis is that the copper complex of the one-fold closed dimer does not arrange the remaining terminal acetylenes in a favorable position for the second ring closing reaction.
All together the unsuccessful template-free macrocyclization attempts contrast the high yields in the macrocyclization reactions of the M(II) complexes and thus underscore the importance of the template approach.