Heterotrimetallic Double Cavity Cages: Syntheses and Selective Guest Binding

Abstract A strategy for the generation of heterotrimetallic double cavity (DC) cages [Pd n Pt m L4]6+ (DC1: n=1, m=2; and DC2: n=2, m=1) is reported. The DC cages were generated by combining an inert platinum(II) tetrapyridylaldehyde complex with a suitably substituted pyridylamine and PdII ions. 1H and DOSY nuclear magnetic resonance spectroscopy (NMR) and electrospray ionization mass spectrometry (ESIMS) data were consistent with the formation of the DC architectures. DC1 and DC2 were shown to interact with several different guest molecules. The structure of DC1, which features two identical cavities, binding two 2,6‐diaminoanthraquinone (DAQ) guest molecules was determined by single‐crystal X‐ray crystallography. In addition, DC1 was shown to bind two molecules of 5‐fluorouracil (5‐FU) in a statistical (non‐cooperative) manner. In contrast, DC2, which features two different cage cavities, was found to interact with two different guests, 5‐FU and cisplatin, selectively.


5-Fluorouracil (5-FU) binding to DC1 and DC2
N H NH O O F 5-Fluorouracil guest binding studies were carried out in CD3CN using tetrakis(trimethylsilyl)silane as a standard (0.10 µmol). Stock solutions of DC1 (1.48 mg, 1 mL) or DC2 (0.57 mg, 1 mL) (including the by-products) were prepared in CD3CN and the undissolved impurities were removed by centrifugation. Half of the cage stock solution (0.5 mL) was taken and combined with solid 5-fluorouracil (50 eq) to give the guest stock solution.
The remaining host stock solution was added to an NMR tube to which varying aliquots of the guest stock were added (5 -50 µL). The resulting solutions with different host-guest stoichiometries were examined using 1 H NMR spectroscopy and the final concentrations of host/guest were determined by integration of peaks and comparison to the standard used. Using this procedure, the concentration of the host remained the same throughout the titration experiment. Association constants were obtained using Bindfit (supramolecular.org) by curve fitting the shifts of proton signals against mole ratio of guest relative to host. [6] The titration experiments were repeated in triplicates and an average binding constant is reported. Data for 5-fluorouracil binding within DC1 was fitted to 1:2 host/guest binding models. The model presenting the lowest errors, root mean square and covariances were assumed to be the most accurate. The binding constants for the statistical model provided binding constants with the least error and was therefore the model used to determine the binding constants of 5fluorouracil binding within DC1 (K1 = 1260 ± 20 M -1 , K2 = 315 ± 5 M -1 ). The binding of 5-S22 fluorouracil in DC2 was fitted to a 1:1 host-guest mixture to give an average binding constant of 210 ± 3 M -1 .

Segregated Host-Guest Chemistry
Segregated guest binding studies within DC2 were tested using 5-fluorouracil and cisplatin.  Figure S47 Stacked partial 1 H NMR spectra (CD3CN, 400 MHz, 298 K) of DC2 followed by the addition of 5-FU and then the addition of CP.

Figure S48
Stacked partial 1 H NMR spectra (CD3CN, 400 MHz, 298 K) of DC2 followed by the addition of CP and then the addition of 5-FU.

Molecular Modelling/ Computations
All MMFF models were obtained using SPARTAN 16®. The structures were energy minimized to give the optimized models. The MMFF molecular models initially generated in SPARTAN 16® [8] were then optimised at the GFN2-xtb level of theory using the XTB program. [9] Standard settings were used, with a DMSO implicit solvent field, at 298 K. The .xyz files for the different models are available as supporting information.

X-ray crystallography
X-ray data were collected at 100 K on an Agilent Technologies Supernova system using Mo Kα or Cu Kα radiation with exposures over 1.0°, and data were treated using CrysAlisPro software. [10] The structures were solved using SHELXT and weighted full-matrix refinement on F2 was carried out using SHELXL-97 [11] both running within the OLEX2-v1.2.9 package. [12] All non-hydrogen atoms were refined anisotropically. Hydrogen atoms attached to carbons were placed in calculated positions and refined using a riding model. Ellipsoids are shown at 50% probability level. The structure was solved in the monoclinic space group I2/m and refined to an R1 value of 8.38%. The asymmetric unit contains one ligand, a quarter palladium, a half platinum and half a DAQ guest with two half carbonyl groups. The rest of the cage was generated through rotation and inversion across the palladium and a reflection across a mirror plane passing through the platinum and palladium. The rest of the DAQ molecule was generated through a reflection across a mirror plane passing through the carbonyl groups. There was disorder in the 2-fold rotation axis perpendicular to the carbonyl groups of the DAQ molecule which solved to have two amine groups with half occupancy. The FLAT command was used on the pyridine ring coordinated to the platinum centre. Crystal packing effects presented one DAQ molecule in each cavity of DC1. A "solvent mask" (with the OLEX2-v1.2.9 package) was applied to resolve diffused electron density, where a void consisting of 609.9 electrons was measured which was attributed to six BF4counteranions and eight DMSO solvent molecules. Ellipsoids are shown at the 50% probability level. Color scheme: carbon = grey, hydrogen = white, nitrogen = blue, oxygen = red, palladium = purple, platinum = pink.