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Redox Allosteric Control – New communication in JACS

The Weak Link Approach (WLA) is a successful strategy for allosterically controlling the formation of cavities¹ and the access to them² through the action of reversible hemilabile-bond formation around an organometallic center. Thus far, the WLA has been used to mimic biological cavities whose access is controlled chemically as in the scheme shown below which belongs to a previous WLA work published in 2014, my first time involved in the calculation of bond energies for hemilabile groups.

Screenshot from 2018-10-29 22:57:15

Mendez-Arroyo et al. JACS (2014) 136, 10340-10348

Chiefly developed by the Chad Mirkin group at Northwestern, the WLA has now reached a new milestone in which the allosteric control is further coupled to a redox equilibrium which alters the strength of the hemilabile bonds. These findings are reported in JACS as a communication (DOI: 10.1021/jacs.8b09321). Previous efforts were unsuccessful due to the instability of the oxidized species, which makes regulation challenging. A ferrocenyl (Fc) group was attached to the hemilabile ligand to provide the redox center which can further assist and control the ring opening via an increment in the electrostatic repulsion of the two metallic centers. Thus, the weak-link is displaced by exogenous ligands only after the Fc group was oxidized.


Bond strengths for the hemilabile bonds were calculated at the ω-B97XD/lanl2dz level of theory upon optimized structures. Relative energies were calculated through the thermochemistry analysis (freq=noraman) made by Gaussian09 and the bond strengths were calculated with the NBODel procedure included in NBO3.1. In the open configurations we found that upon oxidation of Fc the exogenous ligand bond to Pt(II) strengthens by a few kcal/mol (2 – 10), however the Fe(III)-P distance increases and that can be observed via ³¹P NMR spectroscopy.

For the non-oxidized complexes, the HOMO’s are largely composed of the ferrocene highest energy orbitals, which is susceptible of being oxidized, whereas the LUMO’s are located throughout the organometallic fragment. When Ferrocene is oxidized to Ferrocenium, the situation is reversed and now HOMO’s are found spread over the organometallic fragment and the LUMO’s over ferrocenium; all of which is coherent with the idea of Fc now being able to be reduced. Plots for the HOMO LUMO orbitals for compound (6) in the Reduced (Fe2) and Oxidized (Fe3) states are shown (alpha and beta density are shown separately in the latter case).


Thanks to Prof. Chad Mirkin, Dr. Andrea d’Aquino, and Edmund Cheng for letting me be a part of this project.

[1] D’Aquino, A. I., Cheng, H. F., Barroso-Flores, J., Kean, Z. S., Mendez-Arroyo, J., McGuirk, C. M., & Mirkin, C. A. (2018). An Allosterically Regulated, Four-State Macrocycle. Inorganic Chemistry, 57(7), 3568–3578.
[2] Mendez-Arroyo, J., Barroso-Flores, J., Lifschitz, A. M., Sarjeant, A. a., Stern, C. L., & Mirkin, C. a. (2014). A multi-state, allosterically-regulated molecular receptor with switchable selectivity. Journal of the American Chemical Society, 136(29), 10340–10348.


A new paper on the Weak Link Approach

Chemically actuating a molecule is a very cool thing to do and the Weak Link Approach (WLA) allows us to do precisely that through the reversible coordination of one or various organometallic centers to a longer ligand that opens or closes a macrocyclic cavity. All this leads to an allosteric effect so important in biological instances available in inorganic molecules. Once again, the Mirkin group at Nortwestern University in Evanston, Illinois, has given me the opportunity to contribute with the calculations to the energetic properties of these actuators as well as their electronic properties for their use as molecular scavengers or selective capsules for various purposes such as drug delivery agents.

As in the previous WLA work (full paper), the NBODel procedure was used at the B97D/LANL2DZ level of theory, only this time the macrocycle consisted of two organometallic centers and for the first time the asymmetric opening of the cavity was achieved, as observed by NMR. With the given fragments, all possibilities shown in scheme 1 were obtained. The calculated bond energies for the Pt – S bonds are around 60 – 70 kcal/mol whereas for the Pt – Cl bonds the values are closer to 90 kcal/mol. This allows for a selective opening of the cavity which can then be closed by removing the chlorine atoms with the help of silver salts.


For the case of complex mixture 4a, 4b, and 4c, the thermochemistry calculations show they are all basically isoenergetic with differences in the thousandths of kcal/mol. The possibilities for the groups in the weakly bonded ligands are enormous; currently, there is work being done about substituting those phenyl rings for calix[4]arenes in order to have a macrucyclic capsule made by macrocylic capusules.

Thanks to Andrea D’Aquino for taking me into her project, for all the stimulating discussions and her great ideas for expanding WLA into new avenues; I’m sure she’ll succeed in surprising us with more possibilities for these allosteric macrocycles.

The full paper is published in Inorganic Chemistry from the ACS (DOI: 10.1021/acs.inorgchem.7b02745). Thanks for reading and -if you made it this far into the post- happy new year!

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