Tandem mass spectrometry has found widespread application as a powerful tool for the characterization of linear and branched oligosaccharides. Though the technique has been applied to the analysis of cyclic oligosaccharides as well, the underlying fragmentation mechanisms have hardly been investigated. This study focuses on the mechanistic aspects of the gas-phase dissociation of protonated β-cyclodextrins. Elucidation of the dissociation mechanisms is supported by tandem mass spectrometric experiments and by experiments on di- and trimethylated cyclodextrin derivatives. The fragmentation pathway comprises the linearization of the macrocyclic structure as the initial step of the decomposition, followed by the elimination of glucose subunits and the subsequent release of water and formaldehyde moieties from the glucose monomer and dimer fragment ions. Linearization of the macrocycle occurs due to proton-driven scission of the glycosidic bond adjacent to carbon atom C1 in conjunction with the formation of a new hydroxy group. The resulting ring-opened structure further decomposes in charge-independent processes forming either zwitterionic fragments, a 1,4-anhydroglucose moiety, or a new macrocyclic structure, that is lost as a neutral, and an oxonium ion. Since the hydroxy group formed at the ring-opening site can be regarded as the non-reducing end of the linearized structure, the fragment ion nomenclature commonly used for linear and branched oligosaccharides, which relies on the designation of a reducing and a non-reducing end, can also be applied to the description of fragment ions derived from cyclic structures.

Bent metallocene dichlorides (Cp₂MCl₂, M = Ti, Mo, Nb, …) have found interest as anti-cancer drugs in order to overcome the drawbacks associated with platinum-based therapeutics. However, they suffer from poor hydrolytic stability at physiological pH. A promising approach to improve their hydrolytic stability is the formation of host-guest complexes with macrocyclic structures, such as cyclodextrins. In this work, we utilized nanoelectrospray ionization tandem mass spectrometry to probe the interaction of titanocene dichloride with β-cyclodextrin. Unlike the non-covalent binding of phenylalanine and oxaliplatin to β-cyclodextrin, the mixture of titanocene and β-cyclodextrin led to signals assigned as [βCD + Cp₂Ti–H]⁺, indicating a covalent character of the interaction. This finding is supported by titanated cyclodextrin fragment ions occurring from collisional activation. Employing di- and trimethylated β-cyclodextrins as hosts enabled the elucidation of the influence of the cyclodextrin hydroxy groups on the interaction with guest structures. Masking of the hydroxy groups was found to impair the covalent interaction and enabling the encapsulation of the guest structure within the hydrophobic cavity of the cyclodextrin. Findings are further supported by breakdown curves obtained by gas-phase dissociation of the various complexes.