Time-Dependent Pulses of Lithium Ions in Cascaded Signaling and Out-of-Equilibrium (Supra)molecular Logic Amit Ghosh, Indrajit Paul, and Michael Schmittel* Center of Micro- and Nanochemistry and Engineering, Organische Chemie I, Adolf-Reichwein-Str. 2, D-57068 Siegen, Germany * S Supporting Information ABSTRACT: The present paper adds the time domain to chemical ion translocation and (supra)molecular logic. When the self-sorted system of [Zn(1)] 2+ + [Li(2)] + + 3 (composed of hexacyclen 1, nanoswitch 2, luminophore 3) was treated with 2-cyano-2-phenylpropanoic acid (4) as a chemical fuel, protonation of 1 entailed a cascade translocation of first Zn 2+ , then Li + , resulting in the system [H(1)] + + [Zn(2)] 2+ + [Li(3)] + that slowly reversed back to the initial state. The kinetic evolution of the lithium pulses was followed by changes in color and luminescence using the lithium-sensitive probe 3. The utility of fueling in combination with lithium pulses was exemplified among others by generating time-encoded SOS morse signals and implementing the time domain in two distinct AND gates. I n multicellular organisms, transfer, processing and storage of information is vital. 1,2 To increase information density and security in communication, biological signaling relies not only on fail-safe intra- and intercellular transmission cascades 3 but also on the use of the time domain. 4 For instance, the use of oscillating calcium ion signals is an important way to encode communication in cells for various purposes. 4 Up to now, programing the time domain of ion signals did not play a role in artificial molecular communication and information handling. 5 Thus, in logic circuits the input signals are usually converted via intramolecular energy transfer, PET (photoinduced electron transfer), and so forth into “static outputs” that are decoded by truth tables. 6 Adding the time domain to signals and enabling information exchange between distinct gates, so far limited due to the lack of reliable strategies for exchanging chemical signals between independent molec- ular components, 5c,7 would constitute an enormous advance- ment. Herein, we demonstrate a fully reversible and cascaded signaling system (i) allowing the generation of time-dependent lithium(I) pulses that are monitored by a lithium-sensitive optical probe, (ii) allowing its use as a supramolecular three- input AND gate, and (iii) implementing the time domain in molecular logic using chemical fuel in the operation of the AND gate. The last topic establishes a chemical analogy to combinational logic with pulsed waveforms. 8 Using pulses of fuel, an unambiguous time pattern will be imprinted that increases information security. Cascaded information transfer requires at least two consecutive transfers. Notably, interference-free and unambig- uous signaling is best realized with equimolar amounts of chemical signals and receptors/senders, whereas large excess of input signals is counter-productive. Due to our expertise in stoichiometric metal-ligand self-sorting, 9 we have designed a two-step cascade signaling based on five components: hexacyclen (1), nanoswitch 2, luminophore 3, zinc(II) ions, and lithium(I) ions (Figure 2). In this small network, the initial networked state (NetState I) is defined by a clean self-sorting 10 of Zn 2+ on hexacyclen (1) while Li + is tightly captured within the cavity of the triangular nanoswitch 2. The lithium-sensitive luminophore 3 is unloaded (Figure 2). The idea was as follows: Addition of protic acid was expected to protonate the complex [Zn(1)] 2+ , liberating Zn 2+ that should displace Li + from nanoswitch [Li(2)] + . Eventually, the release of Li + should be visualized by its complex to luminophore 3, thus generating NetState II composed of [H(1)] + , [Zn(2)] 2+ , and [Li(3)] + . The constituents 1-3 were selected based on the following considerations: (a) The first state (NetState I) should involve a 3-fold incomplete self-sorting 11 of three ligands and two metal ions, i.e., 1-3, Zn 2+ , and Li + in a 1:1:1:1:1 ratio. Formation of [Zn(1)] 2+ was expected due to the known strong preference of zinc(II) toward hexacyclen. 12 An unknown was whether the lithium(I) ion would selectively bind to either switch 2 or Received: October 7, 2019 Figure 1. Frequency modulated Ca 2+ oscillations in (a) neuro- blastoma and (b) cardiac cells. Adapted from ref 4 (CC BY). Figure 2. Reversible cascaded communication, monitored by distinct fluorescence colors. Communication pubs.acs.org/JACS Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX-XXX © XXXX American Chemical Society A DOI: 10.1021/jacs.9b10763 J. Am. Chem. Soc. XXXX, XXX, XXX-XXX Downloaded via UNIV OF BIRMINGHAM on November 19, 2019 at 02:14:41 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.