My MSCA postdoctoral tenure was a highly rewarding experience that allowed me to work across multiple disciplines including supramolecular polymers, flow chemistry, and chiral recognition and separation. During this time, I also acquired hands-on expertise in a range of analytical techniques such as chiral HPLC, SEM, and DLS. The project began with the fabrication of H-type and Y-type microfluidic channels for flow experiments (Figure 1A). I systematically explored various flow parameters within these channels and investigated the diffusion behavior of small dye molecules, such as Rhodamine B and dansyl chloride, under different flow rates (Figure 1B). COMSOL simulations were employed to model the flow profiles under laminar conditions, and experimental results confirmed the expected diffusion trends (Figure 1C).
Following this, I synthesized several benzenetricarboxamide (BTA)-based helical supramolecular polymers (HSPs) and studied their polymerization behavior and enantioselectivity toward chiral guest molecules. A significant challenge encountered during this phase was that BTA derivatives bearing terminal hydroxyl or amino groups failed to form well-defined HSPs, instead aggregating randomly due to strong interactions with the BTA core’s carboxamide groups. The first successful HSP-forming molecule was ethyl 3-(3,5-bis(((S)-2-octyl)carbamoyl)benzamido)benzoate (BTAOCE) (Figure 2). Its synthesis and polymerization was confirmed via circular dichroism (CD), UV-Vis spectroscopy, and DLS. Flow experiments using BTAOCE in both H- and Y-type channels showed significantly reduced diffusion compared to small molecules, indicating its potential for chiral separation. However, when chiral guest molecules were introduced into the BTAOCE solution in methylcyclohexane (MCH), the polymerization was disrupted. This was likely due to the interference of guest molecules with the intermolecular hydrogen bonding of the carboxamide groups.
To address this, I designed and synthesized three new BTA-based monomers with enhanced binding sites while minimizing interference with carboxamide hydrogen bonding: (3-((3,5-dimethylphenyl)carbamoyl)phenyl)-S,S-dioctyl BTA (BTAAMI), (3-((3-chloro-5-methylphenyl)carbamoyl)phenyl)-S,S-dioctyl BTA (BTAAMICl) (4-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)-S,S-dioctyl BTA (BTAPEG). All three monomers formed supramolecular polymers in non-polar MCH solvent. NMR studies showed that chiral guest molecules interacted with these polymers, and CD spectra confirmed that polymerization remained intact after guest addition. Subsequently, I tested the enantioseparation capabilities of these polymers with chiral amino alcohols, diamines, and diols using microfluidic channels, with the flow outputs analyzed by chiral HPLC. Unfortunately, no significant enantioseparation was observed. However, reduced diffusion was noted for certain chiral molecules, suggesting some interaction with the supramolecular polymers during flow, albeit non-enantioselective.
To introduce enantioselectivity, I next focused on incorporating a known chiral selector, β-cyclodextrin (β-CD), into the BTA framework to create a supramolecular polymer. β-CD is well-documented for its enantioselective encapsulation abilities and its incorporation also imparts water solubility, thereby broadening the range of compatible chiral substrates. Before proceeding with polymer synthesis, I conducted preliminary separation experiments using β-CD alone with mandelic acid and tryptophan as guest molecules. The binding affinities of β-CD for R- and S-mandelic acid were 811 M-1 and 178 M-1, respectively; for D- and L-tryptophan, 447 ± 83 M-1 and 88 ± 17 M-1. Flow experiments with β-CD at 100 µL/min in water yielded enantiomeric excess (ee) values of 3% for mandelic acid and 1.8% for tryptophan. Encouraged by these results, I am currently synthesizing a β-CD-incorporated BTA-based supramolecular polymer (BTACD), which is expected to yield significantly higher enantioseparation due to the lower diffusion coefficient of the polymer compared to β-CD alone.
