Exploring the Conformational Landscape of Poly(l-lysine) Dendrimers Using Ion Mobility Mass Spectrometry.

Ion mobility mass spectrometry (IM-MS) measures the mass, size, and shape of ions in the same experiment, and structural information is provided via collision cross-section (CCS) values. The majority of commercially available IM-MS instrumentation relies on the use of CCS calibrants, and here, we present data from a family of poly(l-lysine) dendrimers and explore their suitability for this purpose. In order to test these compounds, we employed three different IM-MS platforms (Agilent 6560 IM-QToF, Waters Synapt G2, and a home-built variable temperature drift tube IM-MS) and used them to investigate six different generations of dendrimers in two buffer gases (helium and nitrogen). Each molecule gives a highly discrete CCS distribution suggestive of single conformers for each m/z value. The DTCCSN2 values of this series of molecules (molecular weight: 330-16,214 Da) range from 182 to 2941 Å2, which spans the CCS range that would be found by many synthetic molecules including supramolecular compounds and many biopolymers. The CCS values for each charge state were highly reproducible in day-to-day analysis on each instrument, although we found small variations in the absolute CCS values between instruments. The rigidity of each dendrimer was probed using collisionally activated and high-temperature IM-MS experiments, where no evidence for a significant CCS change ensued. Taken together, this data indicates that these polymers are candidates for CCS calibration and could also help to reconcile differences found in CCS measurements on different instrument geometries.

Studying Cation Exchange in {Cr7Co} Pseudorotaxanes: Preparatory Studies for Making Hybrid Molecular Machines.

In the design of dynamic supramolecular systems used in molecular machines, it is important to understand the binding preferences between the macrocycle and stations along the thread. Here, we apply 1H NMR spectroscopy to investigate the relative stabilities of a series of linear alkylammonium templated pseudorotaxanes with the general formula [H2NRR'][Cr7CoF8(O2CCH2 tBu)16] by exchanging the cation in solution. Our results show that the pseudorotaxanes are able to exchange threads via a dissociative mechanism. The position of equilibrium is dependent upon the ammonium cation and solvent used. Short chain primary ammonium cations are shown to be far less favourable macrocycle stations than secondary ammonium cations. Collision-induced dissociation mass spectrometry (CID-MS) has been used to look at disassembly of the pseudorotaxanes in a solvent-free environment and stability trends compared to those in acetone-d6. The energy needed to induce 50 % of the precursor ion loss (E50) is used and shows a similar trend to the equilibria measured by NMR. The relative stabilities of these hybrid inorganic-organic pseudo-rotaxanes are different to those of host-guest compounds involving crown ethers and this may be valuable for the design of molecular machines.

Modern Electrospray Ionization Mass Spectrometry Techniques for the Characterization of Supramolecules and Coordination Compounds.

Mass spectrometry is routinely used for myriad applications in clinical, industrial, and research laboratories worldwide. Developments in the areas of ionization sources, high-resolution mass analyzers, tandem mass spectrometry, and ion mobility have significantly extended the repertoire of mass spectrometrists; however, for coordination compounds and supramolecules, mass spectrometry remains underexplored and arguably underappreciated. Here, the reader is guided through different tools of modern electrospray ionization mass spectrometry that are suitable for larger inorganic complexes. All steps, from sample preparation and technical details to data analysis and interpretation are discussed. The main target audience of this tutorial is synthetic chemists as well as technicians/mass spectrometrists with little experience in characterizing labile inorganic compounds.

Ion Mobility Mass Spectrometry for Large Synthetic Molecules: Expanding the Analytical Toolbox.

Understanding the composition, structure and stability of larger synthetic molecules is crucial for their design, yet currently the analytical tools commonly used do not always provide this information. In this perspective, we show how ion mobility mass spectrometry (IM-MS), in combination with tandem mass spectrometry, complementary techniques and computational methods, can be used to structurally characterize synthetic molecules, make and predict new complexes, monitor disassembly processes and determine stability. Using IM-MS, we present an experimental and computational framework for the analysis and design of complex molecular architectures such as (metallo)supramolecular cages, nanoclusters, interlocked molecules, rotaxanes, dendrimers, polymers and host-guest complexes.

Hexanuclear Ln6 L6 Complex Formation by Using an Unsymmetric Ligand.

Multinuclear, self-assembled lanthanide complexes present clear opportunities as sensors and imaging agents. Despite the widely acknowledged potential of this class of supramolecule, synthetic and characterization challenges continue to limit systematic studies into their self-assembly restricting the number and variety of lanthanide architectures reported relative to their transition metal counterparts. Here we present the first study evaluating the effect of ligand backbone symmetry on multinuclear lanthanide complex self-assembly. Replacement of a symmetric ethylene linker with an unsymmetric amide at the center of a homoditopic ligand governs formation of an unusual Ln6 L6 complex with coordinatively unsaturated metal centers. The choice of triflate as a counterion, and the effect of ionic radii are shown to be critical for formation of the Ln6 L6 complex. The atypical Ln6 L6 architecture is characterized using a combination of mass spectrometry, luminescence, DOSY NMR and EPR spectroscopy measurements. Luminescence experiments support clear differences between comparable Eu6 L6 and Eu2 L3 complexes, with relatively short luminescent lifetimes and low quantum yields observed for the Eu6 L6 structure indicative of non-radiative decay processes. Synthesis of the Gd6 L6 analogue allows three distinct Gd⋯Gd distance measurements to be extracted using homo-RIDME EPR experiments.

Influence of ß-Cyclodextrin Methylation on Host-Guest Complex Stability: A Theoretical Study of Intra- and Intermolecular Interactions as Well as Host Dimer Formation.

Understanding the non-covalent interactions in host-guest complexes is crucial to their stability, design and applications. Here, we use density functional theory to compare the ability of ß-cyclodextrin (ß-CD) and heptakis(2,6-di-O-methyl)-ß-cyclodextrin (DM-ß-CD) to encapsulate the model guest phenol. For both macrocycles, we quantify the intramolecular interactions before and after the formation of the complex, as well as the intermolecular host-guest and host-host dimer interactions. These are individually classified as van der Waals interactions or hydrogen bonds, respectively. The results show a stronger intramolecular binding energy of ß-CD, with the absolute difference being -5.53 kcal/mol relative to DM-ß-CD. Consequently, the intermolecular interactions of both cyclodextrins with phenol are affected, such that the free binding energy calculated for the DM-ß-CD/phenol complex (-5.23 kcal/mol) is ≈50% more negative than for the complex with ß-CD (-2.62 kcal/mol). The latter is in excellent agreement with the experimental data (-2.69 kcal/mol), which validates the level of theory (B97-3c) used. Taken together, the methylation of ß-CD increases the stability of the host-guest complex with the here studied guest phenol through stronger van der Waals interactions and hydrogen bonds. We attribute this to the disruption of the hydrogen bond network in the primary face of ß-CD upon methylation, which influences the flexibility of the host toward the guest as well as the strength of the intermolecular interactions. Our work provides fundamental insights into the impact of different non-covalent interactions on host-guest stability, and we suggest that this theoretical framework can be adapted to other host-guest complexes to evaluate and quantify their non-covalent interactions.

Adduct Ions as Diagnostic Probes of Metallosupramolecular Complexes Using Ion Mobility Mass Spectrometry.

Following electrospray ionization, it is common for analytes to enter the gas phase accompanied by a charge-carrying ion, and in most cases, this addition is required to enable detection in the mass spectrometer. These small charge carriers may not be influential in solution but can markedly tune the analyte properties in the gas phase. Therefore, measuring their relative influence on the target molecule can assist our understanding of the structure and stability of the analyte. As the formed adducts are usually distinguishable by their mass, differences in the behavior of the analyte resulting from these added species (e.g., structure, stability, and conformational dynamics) can be easily extracted. Here, we use ion mobility mass spectrometry, supported by density functional theory, to investigate how charge carriers (H+, Na+, K+, and Cs+) as well as water influence the disassembly, stability, and conformational landscape of the homometallic ring [Cr8F8(O2CtBu)16] and the heterometallic rotaxanes [NH2RR'][Cr7MF8(O2CtBu)16], where M = MnII, FeII, CoII, NiII, CuII, ZnII, and CdII. The results yield new insights on their disassembly mechanisms and support previously reported trends in cavity size and transition metal properties, demonstrating the potential of adduct ion studies for characterizing metallosupramolecular complexes in general.

Disassembly Mechanisms and Energetics of Polymetallic Rings and Rotaxanes.

Understanding the fundamental reactivity of polymetallic complexes is challenging due to the complexity of their structures with many possible bond breaking and forming processes. Here, we apply ion mobility mass spectrometry coupled with density functional theory to investigate the disassembly mechanisms and energetics of a family of heterometallic rings and rotaxanes with the general formula [NH2RR'][Cr7MF8(O2CtBu)16] with M = MnII, FeII, CoII, NiII, CuII, ZnII, CdII. Our results show that their stability can be tuned both by altering the d-metal composition in the macrocycle and by the end groups of the secondary ammonium cation [NH2RR']+. Ion mobility probes the conformational landscape of the disassembly process from intact complex to structurally distinct isobaric fragments, providing unique insights to how a given divalent metal tunes the structural dynamics.

Structural characterisation methods for supramolecular chemistry that go beyond crystallography.

Supramolecular chemistry has grown rapidly over the past three decades, yet synthetic supramolecular chemists still face several challenges when it comes to characterising their compounds. In this review, we present an introduction to structural characterisation techniques commonly used for non-crystalline supramolecular molecules, e.g. nuclear magnetic and electron paramagnetic resonance spectroscopy (NMR and EPR), mass spectrometry (MS), ion mobility mass spectrometry (IM-MS), small-angle neutron and X-ray scattering (SANS and SAXS) as well as cryogenic transmission electron microscopy (cryo-TEM). We provide an overview of their fundamental concepts based on case studies from different fields of supramolecular chemistry, e.g. interlocked structures, molecular self-assembly and host-guest chemistry, while focussing on particular strengths and weaknesses of the discussed methods. Additionally, three multi-technique case studies are examined in detail to illustrate the benefits of using complementary techniques simultaneously.

Supramolecular Control of Reactivity toward Hydrolysis of 7-Diethylaminocoumarin Schiff Bases by Cucurbit[7]uril Encapsulation.

A series of aromatic Schiff bases, featuring 7-diethylamino-coumarin and with five different substituents at an adjacent phenyl ring, were synthesized and characterized. With the aim of assessing the stability of these dyes in acidic medium, their hydrolysis reactions were kinetically studied in the absence and presence of the macrocycle cucurbit[7]uril (CB[7]). Our results are consistent with a model containing three different forms of substrates (un-, mono-, and diprotonated) and three parallel reaction pathways. The pK a values and the rate constants were estimated and discussed in terms of the presence of a hydroxyl group at the ortho position and electron-releasing groups on the phenyl ring of the dyes. The kinetic study in the presence of CB[7] led to two different behaviors. Promotion of the reaction by CB[7] was observed for the hydrolysis of the Schiff bases containing only one coordination site toward the macrocycle. Conversely, an inhibitor effect was observed for the hydrolysis of a Schiff base with two coordination sites toward CB[7]. The latter effect could be explained with a model as a function of a prototropic tautomeric equilibrium and the formation of a 2:1 host/guest complex, which prevents the attack of water. Therefore, the kinetic results demonstrated a supramolecular control of the macrocycle toward the reactivity and stability of 7-diethylaminocoumarin Schiff bases in acidic medium.

Thermodynamic Control over Molecular Aggregate Assembly Enables Tunable Excitonic Properties across the Visible and Near-Infrared.

Specific molecular arrangements within H-/J-aggregates of cyanine dyes enable extraordinary photophysical properties, including long-range exciton delocalization, extreme blue/red shifts, and excitonic superradiance. Despite extensive literature on cyanine aggregates, design principles that drive the self-assembly to a preferred H- or J-aggregated state are unknown. We tune the thermodynamics of self-assembly via independent control of the solvent/nonsolvent ratio, ionic strength, or dye concentration, obtaining a broad range of conditions that predictably stabilize the monomer (H-/J-aggregate). Diffusion-ordered spectroscopy, cryo-electron microscopy, and atomic force microscopy together reveal a dynamic equilibrium between monomers, H-aggregated dimers, and extended J-aggregated 2D monolayers. We construct a model that predicts the equilibrium composition for a range of standard Gibbs free energies, providing a vast aggregation space which we access using the aforementioned solvation factors. We demonstrate the universality of this approach among several sheet-forming cyanine dyes with tunable absorptions spanning visible, near, and shortwave infrared wavelengths.