Atomic-level understanding on conformational flexibility of neochlorogenic and chlorogenic acids and their inclusion complexation with β-cyclodextrin

Neochlorogenic acid (NCA) and chlorogenic acid (CGA) are positional isomers, abundant in plums and prunes. Their limited bioavailability due to instability under ambient conditions can be overcome by cyclodexrin (CD) encapsulation. Here, single-crystal X-ray diffraction combined with density functional theory (DFT) calculation has been carried out on NCA in free form (1) and in complex with β-CD (2), providing atomic-level insights into the structural flexibility and the inclusion complexation with β-CD of CGA isomers. X-ray analysis revealed that the two symmetry-independent s-cis-NCA and 0.3 water molecules form elaborated H-bond networks (1). Upon β-CD encapsulation, complex H-bond patterns are disrupted and the converted s-trans-NCA is almost entirely enclosed in the asymmetric capsular β-CD dimer (2). On the contrary, the twofold symmetry-related β-CD–s-cis-CGA dimer forms a rare [4]pseudorotaxane reported previously. DFT full-geometry optimization disclosed that both the 2:1 and 1:1 trimodal β-CD–s-trans-NCA inclusion complexes are energetically stable, as the reported s-cis-CGA complex. Furthermore, the three-dimension potential energy surface (3D PES) profiles and all the DFT-fully optimized NCA and CGA structures existing in different lattice environments showed that both the s-cis and s-trans conformers are thermodynamically stable. This study not only presents crystallographic evidence for the distinct NCA and CGA conformers, unequivocally differentiating and resolving the long-time confusing CGA nomenclature for the first time, but also highlights the prime role of CGA conformational flexibility in their pharmacological functions.