Dynamic multi-component covalent assembly for the reversible binding of secondary alcohols and chirality sensing

Abstract

Reversible covalent bonding is often used for the creation of novel supramolecular structures, multi-component assemblies and sensing ensembles. Despite the remarkable success of dynamic covalent systems, the reversible binding of a mono-alcohol with high strength is challenging. Here, we show that a strategy of carbonyl activation and hemiaminal ether stabilization can be embodied in a four-component reversible assembly that creates a tetradentate ligand and incorporates secondary alcohols with exceptionally high affinity. Evidence is presented that the intermediate leading to binding and exchange of alcohols is an iminium ion. To demonstrate the use of this assembly process we also explored chirality sensing and enantiomeric excess determinations. An induced twist in the ligand by a chiral mono-ol results in large Cotton effects in the circular dichroism spectra indicative of the handedness of the alcohol. The strategy revealed in this study should prove broadly applicable for the incorporation of alcohols into supramolecular architecture construction.

Figure 1. Proposed solution to the challenge of the binding of secondary alcohols

a, Lewis acid activation of carbonyls via chelation control, and the reversible binding of secondary alcohols to give hemiacetals. b, Zinc-templated three-component dynamic assembly to create a hemiaminal 2. c, Proposed tris(pyridine) based iminium 3 for alcohol binding and metal complex formation. d, Our four-component reversible covalent assembly for secondary alcohol binding, likely through iminum ion 3 as an intermediate. OTf = trifluoromethanesulfonate (triflate).

Figure 2. Component exchange within the multi-component assembly

a, Exchange of IPA derived assembly 4 (bottom panel) with 3-methyl-2-butanol (middle panel) and with 3,3-dimethyl-2-butanol (top panel). Only the methine portion of the ¹H NMR spectra is shown. b, The structures of the alcohols and their respective equilibrium constants for exchange. K_eq = [4(R²OH)][R¹OH]/{[4(R¹OH)][R²OH]}. c, Exchange of thiazole-2-carboxaldehyde derived assembly (bottom panel) with 2-PA (top panel). Resonance from thiazole-2-carboxaldehyde at 10 ppm increased. d, The structures of the aldehydes and their respective equilibrium constants for exchange. K_eq = [4(A²)][A¹]/{[4(A¹)][A²]}. X is the counterion for zinc (chloride or triflate).

Figure 3. Experimental evidence, and proposed mechanism for the multi-component assembly

a, Proposed mechanism for formation of 4 that also explains the reversible exchange of alcohols and aldehydes. b, A three-component assembly of 2-PA, DPA, and Zn(OTf)₂ to form 2 with molecular sieves (bottom panel) upon addition of IPA and CEM-HCl led to the same complex 4 (top panel) as a four-component reaction. The arrows indicate that these peaks belong to the structures shown. c, ESI mass spectrum of IPA derived assembly. Peaks of 2, 3, and 4 were all observed with chloride as counter anion for 2 and 4.

Figure 4. Exploration of four-component assembly for chirality sensing and ee determination

a, dr values for assemblies with chiral mono-ols (R or S) obtained from ¹H NMR. b, CD spectra of assembly derived from three alcohols (0.175 mM 2-PA, 0.525 mM mono-ol). c, CD spectra of 1-phenylethanol derived assembly with different ee of alcohol (from top to bottom: ee −100, −80, −60, −40, −20, 0, 20, 40, 60, 80, 100 %, 0.175 mM 2-PA, 0.525 mM 1-phenylethanol). d, Linear ee calibration line at 251 nm and 269 nm (For all experiments, 35 mM of 2-PA was used for assembly reaction).