Structural Study of Host-Guest Assembly Using Ion Mobility Spectrometry-Mass Spectrometry

Abstract

Host–guest chemistry defines the formation of complexes involving two or more molecules or ions held together in unique structural relationships by non-covalent bonds. This versatility extends its applicability across diverse fields, including biomedical and catalysis. Complexes formed through the interactions between host and guest molecules can manifest varied structures, a crucial aspect for studying the foundations of host-guest chemistry. Mass spectrometry coupled with electrospray ionization and ion mobility spectrometry (ESI-IMS-MS) offers a highly suitable analytical approach capable of observing the structure and behavior of complexes from solution to the gas phase. Within this thesis, the focus centers on exploring structures and mechanistic properties derived from host-guest complexes, employing IMS-MS, with a particular emphasis on cucurbituril and cyclodextrin. In Chapter 1, the focus is on providing an overview of host-guest chemistry, centered around host molecules such as cucurbituril and cyclodextrin. The chapter delves into the properties of host-guest chemistry and explores various examples of host-guest complex structures depending on the guest molecule using various methods. In addition to conventional analytical methods, the chapter describes the analysis of complex structures derived from the gas or solution phase using IMS-MS, highlighting the advantages of this analytical approach. In Chapter 2, the investigation of protonation sites in small molecules within host molecules using IMS-MS is elaborated. It is known that small molecules with multiple proton-accessible sites play a significant role in biological systems and host-guest chemistry. The protonation states of these molecules influence specific host-guest interactions, but determining the protonation site is challenging. To address this, we employ electrospray ionization IMS-MS to investigate imipramine, a molecule with two protonation sites, in the presence of cucurbit[7]uril as a host molecule. This approach distinguishes the two protomers of protonated imipramine as host-guest complex ions, offering insight into the energetically less preferable protomer. In Chapter 3, the observation of the unique host-guest chemistry between alkali metal halides and cucurbit[7]uril (CB[7]) during the electrospray process is described. Investigating how guest molecules are trapped in the nano-sized cavity is crucial for exploring new derivatives and applications in host-guest chemistry involving cavity-containing host molecules. In the present work, we observed CB[7] complexed with various alkali chloride cluster cations or anions generated during the electrospray ionization. Interestingly, trends in the collision cross section (CCS) values indicate that the small clusters smaller than a specific critical size are readily trapped inside the CB[7] cavity in the gas phase, although the trapping alkali halide clusters in the solution at the given concentration are supposed to be unfavorable. The critical size shows a strong dependence on the ionic size of alkali metal species. The density functional theory calculations predicted several stable inclusion complexes. Molecular dynamics simulations were also performed to gain insights into the driving force for forming and trapping alkali halide clusters inside the CB[7] cavity. We suggest that the rapid solvent evaporation, which leads to the abrupt increase of ion concentrations and subsequent formation of alkali-chloride contact ion pair, may provide the specific molecular environment enabling the formation of the inclusion complexes. In Chapter 4, the exploration of unique cyclodextrin aggregation arising from the interaction with alkali metal halide clusters is detailed. Cyclodextrins (CDs) exhibit versatile self-assembly properties due to their hydrophilic and hydrophobic components. While extensive research has focused on CD self-assembly, limited studies have explored their aggregation behavior, particularly in interaction with small molecule guests due to their complex structures. In this study, we investigated the tetramer structure of CDs formed in the presence of alkali metal chloride clusters (MCl). Compact isomers, defined as a tetrahedral structure, emerged only when a specific number (n) of alkali halide clusters were included. Furthermore, the specific value of n varied depending on the size of the alkali metal, leading to the determination of the critical volume condition for creating the tetrahedral isomer. The present work demonstrates that alkali metal clusters serve as a template for the formation of a new tetramer, unlike cases where alkali metals standalone to construct complexes.