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A conceptual approach for the synthesis of quasi‐heteroleptic complexes with properly endo‐functionalized cages as ligands is presented. The cage ligand reported here is of a covalent organic nature, it has been synthesized via a dynamic combinatorial chemistry approach, making use of a masked amine. Inspired by enzymatic active sites, the described system bears one carboxylate and two imidazole moieties as independent ligating units through which it is able to coordinate to transition metals. Analysis of the iron(II) complex in solution and the solid state validates the structure and shows that no undesired but commonly observed dimerization process takes place. The solid‐state structure shows a five‐coordinate metal center with the carboxylate bidentately bound to iron, which makes Fe@2 an unprecedentedly detailed structural model complex for this kind of non‐heme iron oxygenases. As, as confirmed by the crystal structure, sufficient space for other organic ligands is available, the biologically relevant ligand α‐ketoglutarate is implemented. We observe biomimetic reaction behavior towards dioxygen that opens studies investigating Fe@2 as a functional model complex., A cage compound is synthesized that is endo‐functionalized with one carboxylic acid and two imidazole moieties. These groups can cooperate with each other to coordinate to Zn(II) and Fe(II) resulting in biomimetic quasi‐heteroleptic transition‐metal‐cage complexes. Coordination of α‐ketoglutarate to the iron complex leads to an increase of its reactivity towards dioxygen.

Nature segregates fundamental tasks such as information storage/transmission and catalysis between two different compound classes (e.g. polynucleotides for replication and folded polyamides for catalysis). This division of labor is likely a product of evolution, raising the question of how simpler systems in which replicators and folded macromolecules co‐exist may emerge in the transition from chemistry to biology. In synthetic systems, achieving co‐existence of replicators and foldamers in a single molecular network remains an unsolved problem. Previous work on dynamic molecular networks has given rise to either self‐replicating fibers or well‐defined foldamer structures (or completely un‐sorted complex systems). We report a system in which two cross‐reactive dithiol (nucleobase‐ and peptide‐based) building blocks self‐sort into a replicator fiber and foldamer that both emerge spontaneously and co‐exist. The self‐sorting behavior remains prevalent across different building block ratios as two phases of emergence occur: replicator growth followed by foldamer formation. This is attributed to the autocatalytic formation of the replicator fiber, followed by enrichment of the system in the remaining building block, which is subsequently incorporated into a foldamer., Two different dithiol building blocks interconvert through reversible covalent bonds to initially form a dynamic combinatorial library of macrocycles of various size. The self‐sorting process starts by the amplification of a single library member to form self‐replicating fibers. This step is followed by enrichment of the system in the remaining building block, which forms a large macrocyclic foldamer.

Here we report the simultaneous formation of doubly and triply dynamic libraries as a result of exchange reactions between functionalized organic building blocks. A combination of three different reversible covalent linkages involving a boronate ester transesterification along with an imine and disulfide exchange was employed to generate a new type of fully organic triply dynamic molecular assembly.

A bis-urea-functionalized ditopic subcomponent assembled with 2-formylpyridine and FeII , resulting in a dynamic library of metal-organic assemblies: an irregular FeII4 L6 structure and three FeII2 L3 stereoisomers: left- and right-handed helicates and a meso-structure. This library reconfigured in response to the addition of monosaccharide derivatives, which served as guests for specific library members, and the rate of saccharide mutarotation was also enhanced by the library. The (P) enantiomer of the FeII2 L3 helical structure bound β-D-glucose selectively over α-D-glucose. As a consequence, the library collapsed into the (P)-FeII2 L3 helicate following glucose addition. The α-D-glucose was likewise transformed into the β-D-anomer during equilibration and binding. Thus, β-D-glucose and (P)-3 amplified each other in the product mixture, as metal-organic and saccharide libraries geared together into a single equilibrating system.

The molecular components of biological systems self-sort via different mechanisms to act in a cooperative manner and to avoid interfering with each other. Herein we describe mechanistic insights and a versatile strategy for the synthesis of water-soluble, pseudopeptide molecular cages based on disulfide bonds. The use of trifunctional thiols led to a dynamic combinatorial library (DCL) of readily isolable, multi-component homo and hetero cage-like architectures showing a degree of self-sorting related to the symmetry and size of the trithiol. The work provided detailed kinetic studies and DFT molecular modeling giving original insights into the disulfide cages' properties. We also applied the selected cage system in the fluorometric detection of La3+ cations, which led to the generation of a strongly luminescent metal–organic assembly.

The idea of constitutional dynamic chemistry (CDC) and dynamic combinatorial chemistry (DCC) is widespread in the literature using the chemistry of disulfides. The synthesis of unsymmetrical diaryl disulfides is challenging due to the presence of a weak S–S bond. We report herein the synthesis of unsymmetrical diaryl disulfides from two symmetrical disulfides via a cross-metathesis reaction which was controlled by a weak sulfur⋯iodine (S⋯I) interaction. The unsymmetrical disulfides were stable in acetonitrile solution in the presence of N-iodosuccinimide (NIS), and found to be reversibly photoswitchable to the symmetrical disulfides under visible light irradiation.

We report the self-sorting of a dynamic combinatorial library (DCL) of metal–organic cages composed of a rotationally isomerisable ligand. Convergence of the DCL occurs upon crystallisation and leads to low-symmetry Cu4L2L′2 cages that display differing porosities based on their overall shape and ligand configuration.

A dynamic combinatorial library (DCL) is a set of molecular species existing in equilibrium in solution that can undergo self-assembly via reversible chemical bonds. Here, we report a unique DCL system that shows the independent crystallization of products from solvents with slightly different polarities. The reaction of a 1:1 mixture of [Au2(dppm)(dl-cys)2]2- and [Au2(dppm)(dl-pen)2]2- with Ni2+ in solution gave a DCL containing 10 cyclic AuI2NiII molecules of [Au2Ni(dppm)(dl-cys/dl-pen)2]. Upon crystallization, three kinds of enantiomeric pairs, homoleptic-heterochiral C/A-[Au2Ni(dppm)(d-cys)(l-cys)], homoleptic-homochiral [Au2Ni(dppm)(d-pen)2]/[Au2Ni(dppm)(l-pen)2], and heteroleptic-homochiral [Au2Ni(dppm)(d-cys)(d-pen)]/[Au2Ni(dppm)(l-cys)(l-pen)], were produced from the reaction solutions of MeOH, MeOH/H2O, and EtOH/H2O, respectively. The independent crystallization was explained by a combination of the different hydrogen-bonding interactions of the AuI2NiII molecules in the crystal and the different thermodynamic stabilities of the molecules in solution.

9 p.-8 fig.-2 tab., Protein-directed dynamic combinatorial chemistry (P-D DCC) is considered a powerful strategy to identify ligands to pharmacologically relevant protein targets. The protein selects its affinity ligands in situ through a thermodynamic templated effect in which the library composition shifts to the formation of specific library members at the expense of other (nonbinding) species. The increase in concentration of the selected species is known as amplification and leads to the discovery of new hit compounds for protein targets. This Mini-Review contains an updated overview of the protein-directed DCC applications and the fundamental aspects to take into account when designing a P-D DCC experiment such as the most biocompatible reversible reactions and the methodology used to analyze the experiments., This work was supported by the grant PID2019-108587RB-I00 from the Spanish Ministry of Science and Innovation (MCI).

We report a single‐molecule mechanistic investigation into 2‐cyanobenzothiazole (CBT) chemistry within a protein nanoreactor. When simple thiols reacted reversibly with CBT, the thioimidate monoadduct was approximately 80‐fold longer‐lived than the tetrahedral bisadduct, with important implications for the design of molecular walkers. Irreversible condensation between CBT derivatives and N‐terminal cysteine residues has been established as a biocompatible reaction for site‐selective biomolecular labeling and imaging. During the reaction between CBT and aminothiols, we resolved two transient intermediates, the thioimidate and the cyclic precursor of the thiazoline product, and determined the rate constants associated with the stepwise condensation, thereby providing critical information for a variety of applications, including the covalent inhibition of protein targets and dynamic combinatorial chemistry., Better off alone: A nanoreactor approach was used to investigate the chemistry of2‐cyanobenzothiazole (CBT), an important bioorthogonal reagent, at the single‐molecule level. Reactions with thiols and aminothiols revealed mechanistic and kinetic information with important implications for several essential applications of CBT reagents.

All key chemical transformations in biology are catalysed by linear oligomers. Catalytic properties could be programmed into synthetic oligomers in the same way as they are programmed into proteins, and an example of the discovery of emergent catalytic properties in a synthetic oligomer is reported. Dynamic combinatorial chemistry experiments designed to study the templating of a recognition-encoded oligomer by the complementary sequence have uncovered an unexpected imine polymerase activity. Libraries of equilibrating imines were formed by coupling diamine linkers with monomer building blocks composed of dialdehydes functionalised with either a trifluoromethyl phenol (D) or phosphine oxide (A) H-bond recognition unit. However, addition of the AAA trimer to a mixture of the phenol dialdehyde and the diamine linker did not template the formation of the DDD oligo-imine. Instead, AAA was found to be a catalyst, leading to rapid formation of long oligomers of D. AAA catalysed a number of different imine formation reactions, but a complementary phenol recognition group on the aldehyde reaction partner is an essential requirement. Competitive inhibition by an unreactive phenol confirmed the role of H-bonding in substrate recognition. AAA accelerates the rate of imine formation in toluene by a factor of 20. The kinetic parameters for this enzyme-like catalysis are estimated as 1 × 10−3 s−1 for kcat and the dissociation constant for substrate binding is 300 μM. The corresponding DDD trimer was found to catalyse oligomerisation the phosphine oxide dialdehyde with the diamine linker, suggesting an important role for the backbone in catalysis. This unexpected imine polymerase activity in a duplex-forming synthetic oligomer suggests that there are many interesting processes to be discovered in the chemistry of synthetic recognition-encoded oligomers that will parallel those found in natural biopolymers., Enzyme-like catalytic properties have been found in synthetic recognition-encoded oligomers.

[Image: see text] Protein–protein interactions (PPIs) play an important role in numerous biological processes such as cell-cycle regulation and multiple diseases. The family of 14-3-3 proteins is an attractive target as they serve as binding partner to various proteins and are therefore capable of regulating their biological activities. Discovering small-molecule modulators, in particular stabilizers, of such complexes via traditional screening approaches is a challenging task. Herein, we pioneered the first application of dynamic combinatorial chemistry (DCC) to a PPI target, to find modulators of 14-3-3 proteins. Evaluation of the amplified hits from the DCC experiments for their binding affinity via surface plasmon resonance (SPR), revealed that the low-micromolar (K(D) 15–16 μM) acylhydrazones are 14-3-3/synaptopodin PPI stabilizers. Thus, DCC appears to be ideally suited for the discovery of not only modulators but even the more elusive stabilizers of notoriously challenging PPIs.

Dynamic combinatorial chemistry is a method widely used for generating responsive libraries of compounds, with applications ranging from chemical biology to materials science. It relies on dynamic covalent bonds that are able to form in a reversible manner in mild conditions, and therefore requires the discovery of new types of these bonds in order to progress. Amides, due to their high stability, have been scarcely used in this field and typically require an external catalyst or harsh conditions for exchange. Compounds able to undergo uncatalysed transamidation at room temperature are still rare exceptions. In this work, we describe reversible amide formation and transamidation in a class of compounds known as maleamic acids. Due to the presence of a carboxylic acid in β-position, these compounds are in equilibrium with their anhydride and amine precursors in organic solvents at room temperature. First, we show that this equilibrium is responsive to external stimuli: by alternating the additions of a Brønsted acid and a base, we can switch between amide and anhydride several times without side-reactions. Next, we prove that this equilibrium provides a pathway for reversible transamidation without any added catalyst, leading to thermodynamic distributions of amides at room temperature. Lastly, we use different preparation conditions and concentrations of Brønsted acid to access different library distributions, easily controlling the transition between kinetic and thermodynamic regimes. Our results show that maleamic acids can undergo transamidation in mild conditions in a reversible and tunable way, establishing them as a new addition to the toolbox of dynamic combinatorial chemistry.

We here show for the first time that solid amines can act as catalysts for disulfide-based dynamic combinatorial chemistry by ball mill grinding. The mechanochemical equilibrium for the two disulfide reactions studied is reached within one to three hours using ten different amine catalysts. This contrasts with the weeks to months to achieve solution equilibrium for most solid amine catalysts at 2%M at 2mM concentration in a suitable solvent. The final mechanochemical equilibrium is independent of the catalyst used, but varies with other ball mill grinding factors such as the presence of traces of solvent. The different efficiencies of the amines tested are discussed.

The synthesis of mechanically interlocked molecules is valuable due to their unique topologies. With π-stacking intercomponent interaction, e.g., phenanthroline and anthracene, novel [2]rotaxanes have been synthesized by dynamic imine clipping reaction. Their X-ray crystal structures indicate the π-stackings between the anthracene moiety (stopper) on the thread and the (hetero)aromatic rings at the macrocycle of the rotaxanes. Moreover, the length of glycol chains affects the extra π-stacking intercomponent interactions between the phenyl groups and the dimethoxy phenyl groups on the thread. Dynamic combinatorial library has shown at best 84% distribution of anthracene-threaded phenanthroline-based rotaxane, coinciding with the crystallography in that the additional π-stacking intercomponent interactions could increase the thermodynamic stability and selectivity of the rotaxanes.

A reduction in CO2 emissions is required to mitigate global warming. Post-combustion carbon capture is one of the most developed technologies that has the potential to meet this goal, but its cost prevents its widespread use. A different approach would be to use CO2 directly as it is captured, before it is stored. Here we explore spontaneous CO2 fixation by industrial polyamines as a strategy to generate dynamic libraries of ligands for metal separation and recovery. We identify the CO2 loadings and solvents promoting the optimal precipitation of each metal from the dynamic libraries of complexes. We demonstrate the separation of lanthanum and nickel using the exhaust gas of an internal combustion engine vehicle, and show that the three metal constituents of the La2Ni9Co alloys used to manufacture the batteries of electric vehicles can be separated and recovered by successive CO2-induced selective precipitations. Beyond the concept of CO2-sourced multi-level dynamic coordination chemistry, this study provides a potential framework for integrated CO2 capture and use through sustainable processes.

This study establishes the applicability of imine-based dynamic combinatorial chemistry to discover non-covalent ligands for RNA targets. We elucidate properties underlying the reactivity of arylamines and demonstrate target-guided amplification of tight binders in an amiloride-based dynamic library.

Reversible covalent bonds play a significant role in achieving the high-yielding synthesis of mechanically interlocked molecules. Still, only a handful of such bonds have been successfully employed in synthetic procedures. Herein, we introduce a novel approach for the fast and simple preparation of interlocked molecules, combining the dynamic bond character of bis(acyloxy)iodate(I) anions with macrocyclic bambusuril anion receptors. The proof of principle was demonstrated on rotaxane synthesis, with near- quantitative yields observed in both the classical and “in situ” approach. The rotaxane formation was confirmed in the solid-state and solution by the X-ray and NMR studies. Our novel approach could be utilized in the fields of dynamic combinatorial chemistry, supramolecular polymers, or molecular machines, as well inspire further research on molecules that exhibit dynamic behavior, but owing to their high reactivity, have not been considered as constituents of more elaborate supramolecular structures.

Innovative and efficient hit‐identification techniques are required to accelerate drug discovery. Protein‐templated fragment ligations represent a promising strategy in early drug discovery, enabling the target to assemble and select its binders from a pool of building blocks. Development of new protein‐templated reactions to access a larger structural diversity and expansion of the variety of targets to demonstrate the scope of the technique are of prime interest for medicinal chemists. Herein, we present our attempts to use a protein‐templated reductive amination to target protein‐protein interactions (PPIs), a challenging class of drug targets. We address a flexible pocket, which is difficult to achieve by structure‐based drug design. After careful analysis we did not find one of the possible products in the kinetic target‐guided synthesis (KTGS) approach, however subsequent synthesis and biochemical evaluation of each library member demonstrated that all the obtained molecules inhibit MDM2. The most potent library member (K i=0.095 μm) identified is almost as active as Nutlin‐3, a potent inhibitor of the p53‐MDM2 PPI., Templated potential: Herein, we present our attempts to use a protein‐templated reductive amination to target protein–protein interactions (PPIs). After careful analysis, we did not find one of the possible products in the kinetic target‐guided synthesis (KTGS) approach. Subsequent synthesis and biochemical evaluation of each library member demonstrated that all the obtained molecules inhibit MDM2. The most potent library member (K i=0.095 μm) identified is almost as active as Nutlin‐3, a potent inhibitor of the p53‐MDM2 PPI.

The development of universal catalyst systems that enable efficient, selective, and straightforward chemical transformations is of immense scientific importance. Here we develop a domino process comprising three consecutive reaction steps based on the strategy of supramolecular substrate recognition. This approach provides valuable β-aryl aldehydes from readily accessible α-alkynoic acids and arenes under mild reaction conditions, employing a supramolecular Rh catalyst containing an acylguanidine-bearing phosphine ligand. Furthermore, the synthesis of a key intermediate of Avitriptan using this protocol is accomplished. The first step of the reaction sequence is proved to be the regioselective hydroformylation of α-alkynoic acids. Remarkably, molecular recognition of the ligand and the substrate via hydrogen bonding plays a key role in this step. Control experiments indicate that the reaction further proceeds via 1,4-addition of an arene nucleophile to the unsaturated aldehyde intermediate and subsequent decarboxylation., Supramolecular interactions may be responsible for higher degree of efficiency and selectivity in homogeneous catalysis. Here, the authors exploit the concept of supramolecular catalysis to develop a domino rhodium-catalyzed hydroformylation of α-alkynoic acids followed by Michael addition of nucleophiles.

13 p.-9 fig.-1 tab., Dynamic combinatorial chemistry (DCC) has proven its potential in drug discovery speedingthe identification of modulators of biological targets. However, the exchange chemistriestypically take place under specific reaction conditions, with limited tools capable of operatingunder physiological parameters. Here we report a catalyzed protein-directed DCC working atlow temperatures that allows the calcium sensor NCS-1 tofind the best ligands in situ.Ultrafast NMR identifies the reaction intermediates of the acylhydrazone exchange, tracingthe molecular assemblies and getting a real-time insight into the essence of DCC processesat physiological pH. Additionally, NMR, X-ray crystallography and computational methods areemployed to elucidate structural and mechanistic aspects of the molecular recognition event.The DCC approach leads us to the identification of a compound stabilizing the NCS-1/Ric8acomplex and whose therapeutic potential is proven in aDrosophilamodel of disease withsynaptic alterations., This work was supported by differentfunding agencies: the Spanish Ministry of Economy and Competitiveness (MINECO)with Grants CTQ2015-69643-R (R.P.F), SAF2015-74507-JIN (A. Mansilla) andBIO2017-89523-R (M.J.S.-B.), and European Cooperation in Science and Technology(COST) action CMI304 Emergence and evolution of complex chemical systems (R.P.-F.),and a 2017 Leonardo Grant for Researchers and Cultural Creators from the BBVAFoundation (M.J.S.-B) and a 2018 CaixaImpulse program from La Caixa Foundation(A.Mansilla). M.J.S.-B. was supported by a Ramón y Cajal Contract RYC-2008-03449from MINECO.

Dynamic combinatorial chemistry (DCC) is a powerful tool to identify bioactive compounds. This efficient technique allows the target to select its own binders and circumvents the need for synthesis and biochemical evaluation of all individual derivatives. An ever-increasing number of publications report the use of DCC on biologically relevant target proteins. This minireview complements previous reviews by focusing on the experimental protocol and giving detailed examples of essential steps and factors that need to be considered, such as protein stability, buffer composition and cosolvents.

Target-directed dynamic combinatorial chemistry (tdDCC) is a powerful method to screen ligands for pharmacologically relevant targets. Generating a dynamic library from reversibly reacting building blocks in the presence of a target protein leads to the amplification of the most potent library constituents. In previous studies on tdDCC, these compounds were identified in a qualitative “hit/no-hit”-manner. However, the precise relationship between the degree of amplification and the affinity of the library constituent has not yet been evaluated. To study the amplification–affinity relationship, we compared tdDCC experiments, employing reversible acylhydrazone formation and the bacterial adhesin FimH as a target, with affinities of the library constituents as determined by surface plasmon resonance.

The condensation reaction of 2,6-diformylpyridine with an equimolar mixture of opposite enantiomers of trans-1,2-diaminocyclopentane and trans-1,2-diaminocyclohexane using a dynamic combinatorial chemistry approach has been examined. In nonmetal-templated reactions, depending on reaction conditions, mixed 2 + 1 + 1 macrocyclic imine or bigger mixed 4 + 2 + 2 imine macrocycle are formed selectively. The 2 + 1 + 1 imine used as a precursor in the templated by CdII ions produces a library of enlarged chiral mixed imines coordinated with metal cations among which the hexanuclear CdII complex of 6 + 3 + 3 imine was isolated and characterized. All macrocyclic imine compounds have been reduced to the corresponding macrocyclic amines, which have been further transformed into their hydrochlorides. Each macrocyclic compound has been obtained as two enantiomers. For imine macrocycles and for the hydrochloride derivatives of macrocyclic amines, their X-ray crystal structures have been determined. In particular, the crystals of protonated 4 + 2 + 2 macrocyclic amine, which contains two types of diastereomeric cations differing in terms of inverted twists of pyridine moieties, and hexanuclear CdII complex of 6 + 3 + 3 imine, which gives a deeper insight into the expansion reaction, have been investigated. A heterochiral self-sorting of 2 + 2 and 2 + 1 + 1 macrocyclic imines has been confirmed by a competition reaction of 2,6-diformylpyridine, racemic trans-1,2-diaminocyclopentane, and racemic trans-1,2-diaminocyclohexane and theoretical calculations.

The methylation states of Lys and Arg represent a particularly challenging set of targets to distinguish selectively in water using synthetic receptors. To date, trimethyllysine (Kme3) is the only post translational modification (PTM) of the eight possible methylation states of Lys and Arg that can be recognized selectively. Here, we report the first synthetic receptor capable of selectively recognizing asymmetric dimethylarginine (Rme2a). This was achieved by using a biased dynamic combinatorial chemistry (DCC) library to generate a receptor mimicking the 5-sided box-like shape of Rme2 reader proteins, a feature that has been hypothesized to impart selectivity. Additionally, we synthesized a thioether-linked analogue of the resulting receptor to provide a novel scaffold with maintained selectivity but greater stability. This work introduces strategies that can be applied towards achieving selectivity based on subtle differences in hydrophilic guests in aqueous solutions.

Dynamic covalent chemistry is a new research area based on reversible covalent reactions. In such systems, the interconnected small molecules under dynamic equilibrium served as a responsive entirety, providing the possibility for constitutional selections and optimizations upon internal or external stimuli. When the stimulus is biocatalyst-enzyme, on one hand, the single reversible reaction enables fast racemization of substrates’ enantiomers, leading to highly increased product’s yield and enantiomeric excess (ee) through dynamic kinetic resolution; on the other hand, dynamic combinatorial chemistry can be used for screening of optimal enzyme substrates, with the increased versatility of the dynamic systems, the best fitted substrates can be efficiently obtained, to further achieve information on enzyme’s catalytic activity and active sites, holding broad applications in future biomedical developments.

Target-directed dynamic combinatorial chemistry (tdDCC) enables identification, as well as optimization of ligands for un(der)explored targets such as the anti-infective target 1-deoxy-d-xylulose-5-phosphate synthase (DXPS). We report the use of tdDCC to first identify and subsequently optimize binders/inhibitors of the anti-infective target DXPS. The initial hits were also optimized for their antibacterial activity against E. coli and M. tuberculosis during subsequent tdDCC runs. Using tdDCC, we were able to generate acylhydrazone-based inhibitors of DXPS. The tailored tdDCC runs also provided insights into the structure–activity relationship of this novel class of DXPS inhibitors. The competition tdDCC runs provided important information about the mode of inhibition of acylhydrazone-based inhibitors. This approach holds the potential to expedite the drug-discovery process and should be applicable to a range of biological targets., Target-directed dynamic combinatorial chemistry was used for hit-identification and subsequent hit-optimization for the anti-infective target 1-deoxy-d-xylulose-5-phosphate synthase resulting in novel inhibitors with low micromolar affinities.

We report herein the first all-donor aromatic [2]catenane formed through dynamic combinatorial chemistry, using single component libraries. The building block is a benzo[1,2-b:4,5-b′]dithiophene derivative, a π-donor molecule, with cysteine appendages that allow for disulfide exchange. The hydrophobic effect plays an essential role in the formation of the all-donor [2]catenane. The design of the building block allows the formation of a quasi-fused pentacyclic core, which enhances the stacking interactions between the cores. The [2]catenane has chiro-optical and fluorescent properties, being also the first known DCC-disulphide-based interlocked molecule to be fluorescent., An all-donor [2]catenane has been synthesised via dynamic combinatorial chemistry. It features stacked benzodithiophenes which are quasi-pentacyclic through hydrogen bonding.

Nature creates exquisite molecular assemblies, required for the molecular-level functions of life, via self-assembly. Understanding and harnessing these complex processes presents an immense opportunity for the design and fabrication of advanced functional materials. However, the significant industrial potential of self-assembly to fabricate highly functional materials is hampered by a lack of knowledge of critical reaction intermediates, mechanisms, and kinetics. As we move beyond the covalent synthetic regime, into the domain of non-covalent interactions occupied by self-assembly, harnessing and embracing complexity is a must, and non-targeted analyses of dynamic systems are becoming increasingly important. Coordination driven self-assembly is an important subtype of self-assembly that presents several wicked analytical challenges. These challenges are “wicked” due the very complexity desired confounding the analysis of products, intermediates, and pathways, therefore limiting reaction optimisation, tuning, and ultimately, utility. Ion Mobility-Mass Spectrometry solves many of the most challenging analytical problems in separating and analysing the structure of both simple and complex species formed via coordination driven self-assembly. Thus, due to the emerging importance of ion mobility mass spectrometry as an analytical technique tackling complex systems, this review highlights exciting recent applications. These include equilibrium monitoring, structural and dynamic analysis of previously analytically inaccessible complex interlinked structures and the process of self-sorting. The vast and largely untapped potential of ion mobility mass spectrometry to coordination driven self-assembly is yet to be fully realised. Therefore, we also propose where current analytical approaches can be built upon to allow for greater insight into the complexity and structural dynamics involved in self-assembly.