Abstract

Carboxylic acid/carboxylate mixtures in ionic liquids are frequently proposed to form oligomeric anionic species stabilized by hydrogen bonding, although the protonation state within these aggregates—ranging from localized to dynamically exchanging or symmetrically shared protons—often remains difficult to determine experimentally. One prominent example is choline–geranic acid at a 1:2 ratio (CAGE12), which has attracted considerable attention due to its outstanding therapeutic performance in drug delivery and drug activation, particularly in transdermal and anticancer applications [1,2]. In this system, NMR observations [3] indicating proton mobility have led to suggestions that oligomeric anionic motifs may be present; however, whether these correspond to long-lived complex anions or to dynamically fluctuating acid–carboxylate pairs remains unresolved.

Here we combine ATR–FTIR spectroscopy with ab initio and machine-learned force-field molecular dynamics simulations to elucidate the structure and proton dynamics of CAGE12. The simulations reveal a highly fluctuating hydrogen-bond network and provide key dynamical insight: although geranic acid (AGE) and geranate (GE) frequently form hydrogen-bonded contacts, these associations are short-lived and do not stabilize persistent oligomeric anions. Proton transfer between AGE and GE occurs intermittently, consistent with available NMR observations, and requires comparatively sustained hydrogen-bond configurations that are only occasionally achieved.

The proton is thus not symmetrically shared but shuttles between distinct molecular species while preserving carboxylic and carboxylate chemical identities. In agreement with this picture, experimental and theoretical vibrational spectra display coexisting carboxylate and carboxylic acid signatures, with no spectral features characteristic of proton-shared oligomeric anions.

These results reconcile apparently conflicting spectroscopic interpretations and demonstrate that CAGE12 is governed by transient carboxylic/carboxylate pairing rather than long-lived complex anions. More broadly, this work shows how combining vibrational spectroscopy with machine-learned molecular dynamics enables direct resolution of proton dynamics and ion-pairing motifs in complex ionic liquids relevant to functional and biomedical applications.

References

[1] Y. Shi, Z. Zhao, K. Peng, Y. Gao, D. Wu, J. Kim, S. Mitragotri Adv. Healthcare Mater. 10, 2001455 (2021) and references therein

[2] M. C. Verdugo, E. Rezabal et al. Chemical Communications, 61, 12167-12170 (2025).

[3] J. Takeda et al. ACS Biomaterials Science & Engineering, 7, 595-604 (2021).