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Mon Mar 29, 2021, 04:49 PM

Calix[4]trap: A Bioinspired Host Equipped with Dual Selection Mechanisms

The paper I'll discuss in this post is this one: Calix (4) trap A Bioinspired Host Equipped with Dual Selection Mechanisms (Zhenchuang Xu, Nie Fang, and Yanchuan Zhao, Journal of the American Chemical Society 2021 143 (8), 3162-3168)

(The HTML codes here did not allow for me to write the title in the link as written in the actual title of the paper: Calix[4]trap: A Bioinspired Host Equipped with Dual Selection Mechanisms)

I am always interested in the separation of group I and group II elements in the periodic table. Group I consists of the elements lithium (Li), sodium (Na), potassium (K), rubidium (Rb) and cesium (Cs). (Let's forget about francium, a laboratory curiosity.) Group II consists of the elements beryllium (Be), magnesium (Mg), calcium (Ca), strontium (Sr), barium (Ba) and radium (Ra).

These separations, particularly for the heavier members, play an important role, among many other places, in the recovery of important valuable materials from used nuclear fuels, and in the clean up of historical sites contaminated with fission products.

A post I wrote yesterday in this space inspired some thinking about group II separations (although it was actually about the electrochemically driven "combustion in reverse," the reduction of carbon dioxide to elemental carbon). It seems to me that this particular technology is a path to addressing some problematic environmental problems connected with the production of aluminum metal, including, but not limited to carbon emissions from the "green" anodes.

Today I stumbled on the paper cited at the outset of this post, and thought I'd just point out some very wonderful scientific thinking.

From the introduction to the paper:

Molecular recognitions ubiquitously occur in life activities. Metal ions are vital to various physiological processes, ranging from heartbeat and muscle contraction to signal transduction.(1−3) Through evolution, living organisms have mastered the skill of selective binding and transporting ions by creating task-oriented functional units.(4,5) Prominent examples include valinomycin and K+ channels, both of which allow for ion trafficking across the cell membrane.(6) Valinomycin possesses a rigid scaffold and utilizes six carbonyl oxygens to form an ion binding cavity (Figure 1A).(7) The preorganized structure along with the optimal cavity size account for its much stronger affinity to K+ than Na+. In contrast, kinetic factors dominate in the selection mechanism of K+ channels, in which ions are conducted at vastly different rates. The successive binding sites within the channels selectivity filter constitute an ion transporting highway, where strict permeation of K+ is not only dictated by the ions charge and radius but also by the ease for the ion to undergo desolvation (Figure 1A).(8−11) These two examples demonstrate cases in which nature achieves guest discrimination through manipulating either binding affinities or rates. Although bionic designs are mostly directed to mimic one specific biological structure and function,(12−21) we asked what if we combine the selection strategies of valinomycin and K+ channels and realize them in a single host?...


A little while later they take on the task of answering their scientific question.


Inspired by the unique structure and properties of valinomycin and K+ channels, we sought to create a biomimetic ion host that discriminates ions through both thermodynamic and kinetic selection mechanisms. Given the fact many ion hosts display excellent thermodynamic ion selectivity,(22,23) our effort is directed to confer established ion hosts with a tunnel-like ion transport path that is essential for kinetically varied ion binding. We see the 1,3-alternate calix[4]arenecrown-5 (1) as a great candidate on which to perform the structural reengineering because it functionally resembles valinomycin and displays recording-setting K+/Na+ selectivity.(24,25) Unlike the orderly ion transport occurring within ion channels, metal ions approach 1s central cavity from diverse directions, resulting in rapid and poorly controlled binding processes. Despite the exceptional K+/Na+ selectivity, 1 fails to effectively discriminate K+ from metal ions of comparable sizes, such as Rb+ and Ba2+. We thus wonder whether the not-yet-owned discrimination ability could be conferred by a confined binding tunnel biomimetic to K+ channel, where ions are uptaken with distinct rates. To test the feasibility of this idea, we first attempted to encapsulate 1s ligating etheric oxygens within a confined tunnel to block the original ion binding path.


A few pictures from the paper show the experimental path and the results:



The caption:

Figure 1. Design and synthesis of calix[4]traps. (A) Valinomycin and the selectivity filter of K+ channel of streptomyces A (KcsA) (Protein Data Bank, 1K4C). (B) Image of a pitcher plant, the structure of 1,3-alternate calix[4]crown-5 (1), and X-ray single-crystal structure of calix[4]trap 3a. The picture of the pitcher plant was crafted by Ms. Suzhen Zhu. (C) The flip and lock strategy used to synthesize the designed ion hosts. Hydrogenation of double bond of 3aK+ affords 4aK+.




The caption:

Figure 2. Ion recognition behaviors and ions separation experiments. (A) 1H NMR titration of calix[4]trap 3a with K+ in d6-acetone. Two sets of NMR signals corresponding to 3a and 3aK+ were observed, suggesting that the exchange between free and bound K+ is slow on the NMR time scale. (B) Measured log K (binding affinity, in d6-acetone/CDCl3 = 4:1 (v/v)) and log kin (associating rate constant, in d6-acetone/CDCl3 or acetone/CHCl3 = 4:1 (v/v)) of 3a at 25 C. (C) Separation of K+, Rb+, and Cs+ based on the distinct complexation rates. Ion compositions were measured at different times using ICP-MS. (D) Selective cation extraction using 3a in the presence of various cations. Hyphens indicate that the concentration of the measured cation was lower than the limit of detection.




The caption:

Figure 3. Kinetic and thermodynamic data for the association between K+, Rb+, and Cs+ and various ion hosts. (A) Chemical and X-ray single-crystal structures of calix[4]traps 3b and 4c. (B) Measured logK for complexation of various metal cations with calix[4]traps 3a, 3b, 4a, and 4c in d6-acetone/CDCl3 = 4:1 (v/v) at 25 C. (C) Measured log kin for complexation of various metal cations with calix[4]traps 3a, 3b, 4a, and 4c in d6-acetone/CDCl3 = 4:1 (v/v) at 25 C.




The caption:

Figure 4. Investigation of the ion recognition pathway. (A) 1H NMR titration of calix[4]trap 3b with Cs+ before the inclusion of Cs+ into the buried cavity. (B) Proposed ion recognition path for the uptake of Cs+ with calix[4]trap 3b. For detailed assignments, see Figures S26.


From the conclusion to the paper:

By mimicking the preorganized binding sites of valinomycin and the consecutive ligating sites of K+ channels, we synthesized a series of novel ion hosts, which simultaneously possess a deeply buried binding cavity and a confined ion translocation tunnel. Mechanistic studies verify that the hosts portal could discriminate metal cations by their size, enabling varied ion uptake rates. The confined tunnel bearing consecutive binding sites promotes complete desolvation of ions during their inclusion into the buried cavity, mimicking the ion translocation within biological ion channels. The merging of selection strategies learned from valinomycin and K+ channels proved useful to further boost the record-setting selectivity and make possible the modulation of successive recognition events evolving in space and time...


It is very unlikely that these interesting reagents will prove to be of industrial importance, other than perhaps inspiring nanostructural templating, nor are they likely to be radiation stable, but this said, they are cool nonetheless.

People of course, find different things inspiring. Musicians and composers and musicologists will find Benjamin Britten's Requiem on a deeper level to which I could ever aspire, for example, and literary types can find deeper meanings in John Ashbery's "Self Portrait in a Convex Mirror" than I could ever dream of understanding.

But as a chemist, I find this paper beautiful, very beautiful.

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