Autonomous Dynamic Control of Crown Ether Cargo Release from [2]Rotaxane Carriers in a Piperidine Oscillator

Abstract

Chemical oscillations play a fundamental role in biological systems, yet their synthetic counterparts remain challenging to implement with functional outputs. Here, we report a piperidine-based chemical oscillator that autonomously drives periodic cleavage of a [2]rotaxane carrier, leading to controlled cargo release. The system operates through self-sustained oscillations, triggering rotaxane cleavage and the release of a crown ether cargo. Crown ethers were selected for their reactivity distinct from piperidine, while Fmoc-protected benzylamine rotaxane structures allowed for straightforward carrier modification. For all tested carriers, a piperidine pulse is present and occurs simultaneously with carrier cleavage, yielding up to 95% cargo release. Under flow conditions, periodic cargo release was sustained without extensive reoptimization, demonstrating the robustness of the system. Additionally, by adjusting space velocity, trigger concentration, and inhibitor levels, the oscillation period was varied by up to 2.5 h, with cargo release amplitude changing more than 3-fold. This work demonstrates the potential of catalytic oscillators to regulate downstream processes, paving the way toward construction of complex dynamic chemical systems.

1

(a) Role of natural oscillations observed in biological systems. (b) Overview of the synthetic piperidine oscillator. (c) Autonomous release of cargo by the piperidine oscillator.

2

(a) Piperidine oscillator components and their interactions. (b) Variation of piperidine concentration over time when the system is initiated in batch and flow conditions. The piperidine pulse obtained in batch conditions can be split into three phases: I–lag phase, II–autocatalytic phase, and III–decay phase. (c) Outline of the designed cargo release system, where the Fmoc-protected benzylamine [2]­rotaxane carrier is cleaved by piperidine, resulting in the release of a crown ether cargo molecule. (d) Variation of piperidine (blue trace) and cargo (red trace) concentration over time when the cargo release system is initiated under batch and flow conditions.

3

Synthesis and structure of three carrier molecules. Reaction conditions: in toluene 0.22 M benzylamine, crown ether (1 equiv), Fmoc-X (1 equiv), Et₃N (2 equiv) at 0 °C for 16 h.

4

Reaction scheme and results of cargo release experiments under batch conditions. Data points are reported as averages of two runs. Reaction conditions: 50 mM Fmoc-pip, carriers 1–3 (0.0–3.0 equiv), trigger (5 mol %), fast inhibitor (5 mol %), slow inhibitor (10 equiv) in DMSO-d ₆ at 60 °C for 100 min. Monitored by ¹H NMR spectroscopy with an internal standard from the moment of trigger addition (t = 0 min). (a) Reaction network initiated under batch conditions with carrier 1. (b) Concentration of piperidine (blue), 24C8 (red), and piperidine acetate (Pip-Ac, yellow) over time in a batch experiment with no carrier (blank) and 1.0 equiv of carrier 1. (c) Piperidine concentration over time for different carrier 1 loadings (0.0–3.0 equiv). (d) Cargo release over time for different carrier 1 loadings (0.0–3.0 equiv). (e) Cargo release over time for carriers 1–3 (0.5 equiv).

5

Reaction scheme and the results of cargo release in flow experiments. Reaction conditions: 100 mM Fmoc-pip, carrier 1 (0.50 equiv), trigger (4.0–5.0 mol %), fast inhibitor (0.30–0.40 equiv), slow inhibitor (18 equiv) in DMSO at 68 °C with space velocity: v = 10^–4 s^–1 or 1.25 × 10^–4 s^–1. Monitored by sampling, quenching with 4-nitrophenyl propionate, and analysis via GC-FID with an internal standard. (a) Reaction network initiated under flow conditions with carriers 1. (b) Damped oscillations with carrier 1 for: v = 10^–4 s^–1, trigger (5.0 mol %), and fast inhibitor (0.30 equiv). (c) Sustained oscillations with carrier 1 for: v = 10^–4 s^–1, trigger (4.5 mol %), and fast inhibitor (0.35 equiv). Only the first 19 h are shown, as then the system switched to a new limit cycle (Supporting Information Figure S13). (d) Sustained oscillations with carrier 1 for: v = 10^–4 s^–1, trigger (4.5 mol %), and fast inhibitor (0.40 equiv). (e) Sustained oscillations with carrier 1 for v = 1.25 × 10^–4 s^–1, trigger (4.5 mol %), and fast inhibitor (0.30 equiv).

6

Reaction scheme and the results of cargo release in flow experiments for carriers 2 and 3. Reaction conditions: 100 mM Fmoc-pip, carriers 2–3 (0.50 equiv), trigger (4.5 mol %), fast inhibitor (0.35 equiv), slow inhibitor (18 equiv) in DMSO at 68 °C with space velocity: v = 10^–4 s^–1. Monitored by sampling, quenching with 4-nitrophenyl propionate, and analysis via GC-FID with an internal standard. (a) Reaction network initiated under flow conditions with carriers 2–3. (b) Sustained oscillations with carrier 2. (c) Sustained oscillations with carrier 3.