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1.D.215.  The Chalcoen Bond Donor Trimer (CBDT) Family

Most synthetic anion channels use hydrogen bonds with acidic donors (O–H, N–H) to bind anions. Other interactions such as C–H⋯A, anion–π and halogen bonds have been used in channel design. Chalcogen bonds have been used to make transmembrane anion carriers. Lee et al. 2019 extended that concept to include rod-like molecules that form supramolecular pores spanning the membrane (see figure below). Chalcogen bonds arise from electron donation to σ* orbitals of chalcogens (S, Se), and bond strength increases as the Lewis acid becomes more electron-deficient. Matile and colleagues synthesised dithienothiophene (DTT) trimers designed to provide a chalcogen bond path for anion hopping. Trimer 66a (dubbed acceptor–acceptor–acceptor, AAA) aligns 3 electron-deficient DTTs to give a chain with σ holes located for shuttling anions. Trimer 66b, a donor–donor–acceptor (DDA) analogue with the same length as 66a, has two electron-rich DTT units and is expected to be a weaker Lewis acid than AAA 66a.

Chalcogen bond donor, trimer 66a, with three Lewis acid sulfones (AAA) and a less acidic analogue 66b (DDA) and a schematic (bottom) showing how anions hop along the chalcogen path afforded by trimer 66a. Copyright 2018, Wiley.

Trimer 66a was a potent ion transporter in EYPC LUVs, with a submicromolar EC50 = 0.28 ± 0.05 μM and complete transport (Ymax = 1), uncommon for any transporter. In comparison, the weaker Lewis acid DDA trimer 66b was not as effective as 66a, with EC50 = 3.5 ± 0.3 μM and Ymax of ∼0.5. The authors concluded that the 3σ* holes located along 66a drive anion transport. In addition, trimer 66a, which can span the bilayer, was a better transporter than monomeric DTT sulfone (EC50 = 1.9 μM), which presumably must act as a carrier. Trimer 66a transported NO3 and ClO4 better than the halides. The authors suggested that this selectivity for oxyanions might be due to the formation of bundles of 66a in the membrane, which could provide more chalcogen bond contacts for non-spherical oxyanions.

Consistent with the proposal that AAA trimer 66a forms bundles in the membrane it was active in, voltage-clamp experiments supported numerous conductance values ranging from 0.16 nS to 1.40 nS (corresponding to pores of d = 2.3–7.0 Å). This heterogeneous channel activity indicated that trimer 66a self-assembles into different sized bundles, rather than a well-defined structure. Matile's study shows that chalcogen bonds, like anion–π and halogen bonds, can be used to make functional ion channels. The authors noted that chalcogen bond cascades may lead to design and synthesis of more complex systems, including mechanosensitive channels, active transport pumps and catalytic pores.

References associated with 1.D.215 family:

Lee, L.M., M. Tsemperouli, A.I. Poblador-Bahamonde, S. Benz, N. Sakai, K. Sugihara, and S. Matile. (2019). Anion Transport with Pnictogen Bonds in Direct Comparison with Chalcogen and Halogen Bonds. J. Am. Chem. Soc. 141: 810-814. 30618243