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Acid–base reactions that are exceedingly unfavorable under standard conditions can be catalytically important at enzyme active sites. For example, in triose phosphate isomerase, a glutamate side chain (nominal pK (a) ≈ 4 in solution) can in fact deprotonate a CH group that is vicinal to a carbonyl (pK (a) ≈ 18 in solution). This is true because of three distinct interactions: (a) ground state pK (a) shifts due to environment polarity and electrostatics; (b) dramatic increases in effective molarity due to optimization of proximity and orientation; and (c) transition state pK (a) shifts due to binding interactions and the formation of strong low barrier hydrogen bonds. In this report, we review the literature showing that the sum of these three effects supplies more than enough free energy to push forward proton transfer reactions that under standard conditions are exceedingly nonspontaneous and slow.

A new separation-based analytical method was developed to evaluate the multivalency and cooperativity of supramolecular host-guest complexation in porous materials. The method is based on inverse mixed-mode chromatography in which a porous material with a multivalent functional group is packed into a column and bound with a complementary guest molecule to form a multivalent complex. The bound guest molecules are eluted in the mobile phase and detected by appropriate methods such as UV absorption. The retention factor of the guest molecule is determined and broken down into the contributions of noncovalent interactions between binding sites (e.g., hydrophobic and ionic components), thereby calculating the effective molarity and cooperativity factor of the complexation. Two model systems denoted as RP/SCX and RP/SAX were analyzed by the established method. On average, the RP/SCX system has an effective molarity (EM) of 0.14 M and a cooperativity factor (β) of 0.86, while the RP/SAX system has an EM value of 0.18 M and a β value of 2.3. Interestingly, experiments have shown that these values do not change with changes in the intrinsic binding strength of the constituent sites. In summary, the developed method allows for quantitative assessment of multivalency and cooperativity effects in porous materials, providing a valuable complement to the analytical toolbox for supramolecular chemists and materials scientists.

Computational and cyclic voltammetry studies have been used to explore electrochemical reductions of three helically chiral homologues, 22+, 32+, and 42+, of methyl viologen. Thermochemical-electrochemical cycles are used as frameworks to describe the reversible redox properties of these helically chiral viologens as novel reversible four-sided ECEC (Electron-transfer Chemical-reaction Electron-transfer Chemical-reaction) processes.

Nature uses multivalency as one of the most important governing principles to control selective molecular recognition and assembly. By combining a large number of weak interactions, it is possible to obtain high affinity, selective and reversible non-covalent binding processes. Multivalency has also become an important tool in the design of synthetic molecular systems. The result of multiple binding events is not just a simple sum of individual contributions due to cooperative interactions between binding sites. The main part of this thesis deals with the study of chelate cooperativity in multivalent supramolecular systems. Firstly, a well-known H-bonded rosette system was revisited and the effective molarity was determined experimentally by 1H NMR titrations to be around 2 M, which is a high chelate cooperativity compared to other supramolecular systems. Moreover, the concept of peripheral crowding in solution was revisited, since rosettes based on less bulky pyrimidines showed higher stabilities and effective molarities than the rosettes based on bulky pyrimidines. The following two chapters deal with efforts towards a supramolecular system inside a porphyrin nanoring. The porphyrin nanoring shows the highest value of effective molarity reported in the literature and is, therefore, a great system to study the cooperative behaviour when a covalent ligand is replaced with a supramolecular system. The first studied system was based on small molecules containing simple hydrogen-bond acceptors and donors. Unfortunately, solubility issues led to the termination of the project. The second system used the hydrogen-bonded rosette motif. A number of different pyridine-pyrimidine and pyridinebarbiturate ligands were synthesised and their assembly inside the porphyrin nanoring was studied in detail by UV-vis-NIR experiments. The effective molarities for the sequential binding of the rosette systems to 6-ring were determined to range from 0.23 to 3.7 M, which is significantly lower compared to the system that utilised a covalent hexadentate ligand (126 M). The final part of the thesis introduces a new class of hybrid hydrogen-bonded/metalcoordinated cages based on the rosette motif. These complexes are a rare example of architectures where both hydrogen-bonding and metal-coordination form the crucial part of the topology of the complex since if either is removed, the architecture changes drastically., This project has received funding from the European Union���s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 642793. The author would also like to thank Cambridge Philosophical Society for Research studentship that partially funded the work on Chapter VI.

Chemical communication between macromolecules was studied by observing the controlled single chain collapse that ensues the exchange of a metal cross-linker between two polymer chains. The rhodium (I) organometallic cross-linker transfer from a low molecular weight collapsed polybutadiene to a larger polymer was followed using size exclusion chromatography. The increased effective molarity in the larger polymer seems to be the driving force for the metal migration. Thus, we demonstrate here a strategy for transferring a molecular signal that induces chain collapse of a polymer chain based on non-covalent interactions, mimicking biological behaviors reminiscent of signal transductions in proteins.

Easy-to-use platforms for rapid antibody detection are likely to improve molecular diagnostics and immunotherapy monitoring. However, current technologies require multi-step, time-consuming procedures that limit their applicability in these fields. Herein, we demonstrate effective molarity-driven electrochemical DNA-based detection of target antibodies. We show a highly selective, signal-on DNA-based sensor that takes advantage of antibody-binding-induced increase of local concentration to detect clinically relevant antibodies in blood serum. The sensing platform is modular, rapid, and versatile and allows the detection of both IgG and IgE antibodies. We also demonstrate the possible use of this strategy for the monitoring of therapeutic monoclonal antibodies in body fluids. Our approach highlights the potential of harnessing effective molarity for the design of electrochemical sensing strategies.

Protein-protein interactions (PPIs) are at the core of molecular control over cellular function. Multivalency in PPI formation, such as via proteins with multiple binding sites and different valencies, requires fundamental understanding to address correlated challenges in pathologies and drug development. Thermodynamic binding models are needed to provide frameworks for describing multivalent PPIs. We established a model based on ditopic host-guest systems featuring the effective molarity, a hallmark property of multivalency, as a prime parameter governing the intramolecular binding in divalent interactions. By way of illustration, we study the interaction of the bivalent 14-3-3 protein scaffold with both the nonavalent CFTR and the hexavalent LRRK2 proteins, determining the underlying thermodynamics and providing insights into the role of individual sites in the context of the multivalent platform. Fitting of binding data reveals enthalpy-entropy correlation in both systems. Simulations of speciations for the entire phosphorylated protein domains reveal that the CFTR protein preferably binds to 14-3-3 by combinations including the strongest binding site pS768, but that other binding sites take over when this site is eliminated, leading to only a minor decrease in total affinity for 14-3-3. For LRRK2, two binding sites dominate the complex formation with 14-3-3, but the distantly located pS1444 site also plays a role in complex formation. Thermodynamic modeling of these multivalent PPIs allowed analyzing and predicting the effects of individual sites regarding their modulation via, for example, (de)phosphorylation or small-molecule targeting. The results specifically bring forward the potential of PPI stabilization, as an entry for drug discovery for multivalent PPIs.

Understanding self-assembly in confined spaces is essential to fully understand molecular processes in confined cell compartments and will offer clues on the behaviour of simple confined systems, such as protocells and lipid-vesicle based devices. Using a model system composed of lipid vesicles, a membrane impermeable receptor and a membrane-permeable ligand, we have studied in detail how compartmentalization modulates the interaction between the confined receptor and its ligand. We demonstrate that confinement of one of the building blocks stabilizes complex self-assembled structures to the extent that dilution leads, counterintuitively, to the formation of long range assemblies. The behaviour of the system can be explained by considering a confinement factor that is analogous, although not identical, to the effective molarity for intramolecular binding events. The confinement effect renders complex self-assembled species robust and persistent under conditions where they do not form in bulk solution. Moreover, we show that the formation of stable complex assemblies in systems compartmentalized by semi-permeable membranes does not require the prior confinement of all components, but only that of key membrane impermeable building blocks. To use a macroscopic analogy, lipid vesicles are like ship-in-a bottle constructs that are capable of directing the assembly of the confined ship following the confinement of a few key wooden planks. Therefore, we believe that the confinement effect described here would have played an important role in shaping the increase of chemical complexity within protocells during the first stages of abiogenesis. Additionally, we argue that this effect can be exploited to design increasingly efficient functional devices based on comparatively simple vesicles for applications in biosensing, nanoreactors and drug delivery vehicles.

Scaffold proteins are thought to accelerate protein phosphorylation reactions by tethering kinases and substrates together, but there is little quantitative data on their functional effects. To assess the contribution of tethering to kinase reactivity, we compared intramolecular and intermolecular kinase reactions in a minimal model system. We find that tethering can enhance reaction rates in a flexible tethered kinase system, and the magnitude of the effect is sensitive to the structure of the tether. The largest effective molarity we obtained was ∼0.08 µM, which is much lower than the effects observed in small molecule model systems and tethered protein-ligand interactions. We further demonstrate that the tethered, intramolecular reaction only makes a significant contribution to observed rates when the scaffolded complex assembles at concentrations below the effective molarity. These findings provide a quantitative framework that can be applied to understand endogenous protein scaffolds and to engineer synthetic networks.

The self-assembly of triaminopyrimidines with barbiturates and with cyanates was investigated in chloroform solution. Equimolar mixtures of two complementary components form stable macrocyclic 3 : 3 complexes (rosettes). The thermodynamics of self-assembly were quantified by using 1H NMR titrations to measure the strength of pairwise H-bonding interactions between two rosette components (K), allosteric cooperativity associated with formation of a second H-bonding interaction with each component, and the effective molarity for cyclisation of the rosette motif (EM). Pyrimidine-cyanurate interactions are an order of magnitude more favourable than pyrimidine-barbiturate interactions, so the cyanurate rosettes are significantly more stable than barbiturate rosettes. There is no allosteric cooperativity associated with rosette formation, but the chelate cooperativity quantified by the product K EM is exceptionally high (102-104), indicating that there are no other species present that compete with rosette assembly. The values of EM for rosette formation are approximately 2 M for all four rosettes studied and are not affected by differences in peripheral substituents or intrinsic H-bond strength.

In the present study, we apply a computational approach, based on DFT calculations and molecular dynamics simulations, to investigate the catalytic behavior of four supramolecular catalysts active in the cleavage of phosphodiesters. The QM data indicate the operation of a synchronous associative mechanism with limited differences in the structures and energies of the transition states. The comparison with the experimental data, expressed in terms of effective molarity (EM), suggests that the difference in catalytic performance are not ascribable to a difference in the enthalpy of activation. On the other hand, the analysis of the Molecular Dynamics trajectories clearly indicates the conformational mobility, and therefore the conformational entropy, to be at the origin of the superior catalytic efficiency of the catalysts based on a more preorganized structure. Essentially, the combined method presented here provides, at a limited computational cost, a tool that is simple, general, and potentially suited for a large variety of catalytic systems to rationalize their performances and to predict those of enzyme mimics to be synthesized in a rational design process.

Biology utilizes multiple strategies, including sequestration in lipid vesicles, to raise the rate and specificity of chemical reactions through increases in effective molarity of reactants. We show that micelle-assisted reaction can facilitate native chemical ligations (NCLs) between a peptide-thioester – in which the thioester leaving group contains a lipid-like alkyl chain – and a Cys-peptide modified by a lipid-like moiety. Hydrophobic lipid modification of each peptide segment promotes the formation of mixed micelles, bringing the reacting peptides into close proximity and increasing the reaction rate. The approach enables the rapid synthesis of polypeptides using low concentrations of reactants without the need for thiol catalysts. After NCL, the lipid moiety is removed to yield an unmodified ligation product. This micelle-based methodology facilitates the generation of natural peptides, like Magainin 2, and the derivatization of the protein Ubiquitin. Formation of mixed micelles from lipid-modified reactants shows promise for accelerating chemical reactions in a traceless manner., Sequestration of reactants in lipid vesicles is a strategy prevalent in biological systems to raise the rate and specificity of chemical reactions. Here, the authors show that micelle-assisted reactions facilitate native chemical ligation between a peptide-thioester and a Cys-peptide modified by a lipid-like moiety.

A new family of recognition-encoded oligomers that form stable duplexes in chloroform have been prepared. Monomer building blocks composed of dialdehydes functionalised with either a trifluoromethylphenol or phosphine oxide H-bond recognition unit were prepared. The dialdehydes were coupled with diamines by imine formation and then reduction to give homo-oligomers between one and three recognition units in length. Duplex formation was characterised by 19F and 1H NMR titration experiments in toluene and in chloroform. For duplexes formed between length complementary H-bond donor and acceptor homo-oligomers, an order of magnitude increase in stability was observed for every base-pair added to the duplex in chloroform. The effective molarity for the intramolecular H-bonds responsible for zipping up the duplex is 30 mM, which results in the fully assembled duplex in all cases. The uniform increase in duplex stability with oligomer length suggests that the backbone structure and geometry is likely to be compatible with the formation of extended duplexes in longer oligomers.

Most macrocycles are made from a simple repeat unit, resulting in high symmetry. Breaking this symmetry allows fine-tuning of the circumference, providing better control of the host–guest behavior and electronic structure. Here, we present the template-directed synthesis of two unsymmetrical cyclic porphyrin hexamers with both ethyne (C2) and butadiyne (C4) links, and we compare these nanorings with the symmetrical analogues with six ethyne or six butadiyne links. Inserting two extra carbon atoms into the smaller nanoring causes a spectacular change in binding behavior: the template affinity increases by a factor of 3 × 109, to a value of ca. 1038M–1, and the mean effective molarity is ca. 830 M. In contrast, removing two carbon atoms from the largest nanoring results in almost no change in its template-affinity. The strain in these nanorings is 90–130 kJ mol–1, as estimated both from DFT calculation of homodesmotic reactions and from comparing template affinities of linear and cyclic oligomers. Breaking the symmetry has little effect on the absorption and fluorescence behavior of the nanorings: the low radiative rates that are characteristic of a circular delocalized S1excited state are preserved in the low-symmetry macrocycles.

Two homochiral building blocks featuring a protected thiol, an alkene and a H-bond recognition unit (phenol or phosphine oxide) have been prepared. Iterative photochemical thiol-ene coupling reactions were used to synthesize oligomers containing 1-4 phosphine oxide and 1-4 phenol recognition sites. Length-complementary H-bond donor and H-bond acceptor oligomers were found to form stable duplexes in toluene. NMR titrations and thermal denaturation experiments show that the association constant and the enthalpy of duplex formation increase significantly for every additional H-bonding unit added to the chain. There is an order of magnitude increase in stability for each additional H-bonding interaction at room temperature indicating that all of the H-bonding sites are fully bound to their complements in the duplexes. The backbone of the thiol-ene duplexes is a highly flexible alkane chain, but this conformational flexibility does not have a negative impact on binding affinity. The average effective molarity for the intramolecular H-bonding interactions that zip up the duplexes is 18 mM. This value is somewhat higher than the EM of 14 mM found for a related family of duplexes, which have the same recognition units but a more rigid backbone prepared using reductive amination chemistry. The flexible thiol-ene AAAA·DDDD duplex is an order of magnitude more stable than the rigid reductive amination AAAA·DDDD duplex. The backbone of the thiol-ene system retains much of its conformational flexibility in the duplex, and these results show that highly flexible molecules can make very stable complexes, provided there is no significant restriction of degrees of freedom on complexation.

The thermodynamic equilibrium of the aminotransferase reaction from l -alanine and 2-oxoglutarate to l -glutamate and pyruvate in aqueous solution was investigated in a temperature range between 25 and 37 °C and pH between at 5 and 9. Prior to considering the reaction equilibria, measurements were carried out to ensure the enzyme activity in the aqueous reaction media. After that, equilibrium concentrations of reacting agents were measured by HPLC-analysis. At constant temperature and pH, reaction equilibrium was shown to depend on the absolute molalities (0.005–0.130 mol kg−1) as well as on the ratio of initial molalities of the reactants. It could be concluded that reaction equilibrium was shifted towards the product site upon increasing reactant molalities, increasing temperature, and increasing pH. Further, yields of pyruvate were increased upon excess initial molality of l -alanine compared to 2-oxoglutarate. The thermodynamic equilibrium constant K a ∗ was determined by extrapolating the ratio of product equilibrium molalites and reactant equilibrium molalites to infinite dilution of all reacting agents. The activity-coefficient ratio of products and reactants in the reaction media was predicted with ePC-SAFT. Combining K a ∗ and the activity-coefficient ratio allowed quantitatively predicting the influence of temperature, pH, and reacting-agent molalities on the reaction equilibrium.

Proton transfer reactions are ubiquitous in enzymes and utilize active site residues as general acids and bases. Crystal structures and site-directed mutagenesis are routinely used to identify these residues, but assessment of their catalytic contribution remains a major challenge. In principle, effective molarity measurements, in which exogenous acids/bases rescue the reaction in mutants lacking these residues, can estimate these catalytic contributions. However, these exogenous moieties can be restricted in reactivity by steric hindrance or enhanced by binding interactions with nearby residues, thereby resulting in over- or underestimation of the catalytic contribution, respectively. With these challenges in mind, we investigated the catalytic contribution of an aspartate general base in ketosteroid isomerase (KSI) by exogenous rescue. In addition to removing the general base, we systematically mutated nearby residues and probed each mutant with a series of carboxylate bases of similar pKa but varying size. Our results underscore the need for extensive and multifaceted variation to assess and minimize steric and positioning effects and determine effective molarities that estimate catalytic contributions. We obtained consensus effective molarities of ∼5 × 10(4) M for KSI from Comamonas testosteroni (tKSI) and ∼10(3) M for KSI from Pseudomonas putida (pKSI). An X-ray crystal structure of a tKSI general base mutant showed no additional structural rearrangements, and double mutant cycles revealed similar contributions from an oxyanion hole mutation in the wild-type and base-rescued reactions, providing no indication of mutational effects extending beyond the general base site. Thus, the high effective molarities suggest a large catalytic contribution associated with the general base. A significant portion of this effect presumably arises from positioning of the base, but its large magnitude suggests the involvement of additional catalytic mechanisms as well.

Phosphoimidazole-containing compounds are versatile players in biological and chemical processes. We explore catalytic and mechanistic criteria for the efficient formation of cyclic aryl phosphoimidazoles in aqueous solution, viewed as a template reaction for the in situ synthesis of related compounds. To provide a detailed analysis for this reaction a series of o-(2′-imidazolyl)naphthyl (4-nitrophenyl) phosphate isomers were examined to provide a basis for analysis of both mechanism and the influence of structural factors affecting the nucleophilic attack of the imidazolyl group on the phosphorus center of the substrate. Formation of the cyclic aryl phosphoimidazoles was probed by NMR and ESI-MS techniques. Kinetic experiments show that cyclization is faster under alkaline conditions, with an effective molarity up to 2900 M for the imidazolyl group, ruling out competition from external nucleophiles. Heavy atom isotope effect and computational studies show that the reaction occurs through a SN2(P)-type me...

Conspectus The biotechnological revolution has made it possible to create enzymes for many reactions by directed evolution. However, because of the immense number of possibilities, the availability of enzymes that possess a basal level of the desired catalytic activity is a prerequisite for success. For new-to-nature reactions, artificial metalloenzymes (ARMs), which are rationally designed hybrids of proteins and catalytically active transition-metal complexes, can be such a starting point. This Account details our efforts toward the creation of ARMs for the catalysis of new-to-nature reactions. Key to our approach is the notion that the binding of substrates, that is, effective molarity, is a key component to achieving large accelerations in catalysis. For this reason, our designs are based on the multidrug resistance regulator LmrR, a dimeric transcription factor with a large, hydrophobic binding pocket at its dimer interface. In this pocket, there are two tryptophan moieties, which are important for promiscuous binding of planar hydrophobic conjugated compounds by π-stacking. The catalytic machinery is introduced either by the covalent linkage of a catalytically active metal complex or via the ligand or supramolecular assembly, taking advantage of the two central tryptophan moieties for noncovalent binding of transition-metal complexes. Designs based on the chemical modification of LmrR were successful in catalysis, but this approach proved too laborious to be practical. Therefore, expanded genetic code methodologies were used to introduce metal binding unnatural amino acids during LmrR biosynthesis in vivo. These ARMs have been successfully applied in Cu(II) catalyzed Friedel–Crafts alkylation of indoles. The extension to MDRs from the TetR family resulted in ARMs capable of providing the opposite enantiomer of the Friedel–Crafts product. We have employed a computationally assisted redesign of these ARMs to create a more active and selective artificial hydratase, introducing a glutamate as a general base at a judicious position so it can activate and direct the incoming water nucleophile. A supramolecularly assembled ARM from LmrR and copper(II)–phenanthroline was successful in Friedel–Crafts alkylation reactions, giving rise to up to 94% ee. Also, hemin was bound, resulting in an artificial heme enzyme for enantioselective cyclopropanation reactions. The importance of structural dynamics of LmrR was suggested by computational studies, which showed that the pore can open up to allow access of substrates to the catalytic iron center, which, according to the crystal structure, is deeply buried inside the protein. Finally, the assembly approaches were combined to introduce both a catalytic and a regulatory domain, resulting in an ARM that was specifically activated in the presence of Fe(II) salts but not Zn(II) salts. Our work demonstrates that LmrR is a privileged scaffold for ARM design: It allows for multiple assembly methods and even combinations of these, it can be applied in a variety of different catalytic reactions, and it shows significant structural dynamics that contribute to achieving the desired catalytic activity. Moreover, both the creation via expanded genetic code methods as well as the supramolecular assembly make LmrR-based ARMs highly suitable for achieving the ultimate goal of the integration of ARMs in biosynthetic pathways in vivo to create a hybrid metabolism.

Competition from intramolecular folding is a major challenge in the design of synthetic oligomers that form intermolecular duplexes in a sequence-selective manner. One strategy is to use very rigid backbones that prevent folding, but this design can prejudice duplex formation if the geometry is not exactly right. The alternative approach found in nucleic acids is to use bases (or recognition units) that have different dimensions. A long-short base-pairing scheme makes folding geometrically difficult and is compatible with the flexible backbones that are required to guarantee duplex formation. A monomer building block equipped with a long hydrogen bond donor (phenol, D) recognition unit and a monomer building block equipped with a short hydrogen bond acceptor (phosphine oxide, A) recognition unit were prepared with differentially protected alcohol and carboxylic acid groups. These compounds were used to synthesise the homo and hetero-sequence 2-mers AA, DD and AD. 19F and 31P NMR experiments were used to characterize the assembly properties of these compounds in toluene solution. AA and DD form a stable doubly-hydrogen-bonded duplex with an effective molarity of 20 mM for formation of the second intramolecular hydrogen bond. AD forms a duplex of similar stability. There is no evidence of intramolecular folding in the monomeric state of this compound, which shows that the long-short base-pairing scheme is effective. The ester coupling chemistry used here is an attractive method for the synthesis of long oligomers, and the properties of the 2-mers indicate that this molecular architecture should give longer mixed sequence oligomers that show high fidelity sequence-selective duplex formation.

This review article is concerned with the measurement, significance and applications of the concept of effective molarity (EM) in a large variety of cyclization reactions ranging from the formation of giant macromolecules in polymeric equilibrates to the self-assembly of cyclic supermolecules and supramolecular aggregates. Based on a dissection of EM into enthalpic and entropic components (EM = EMH× EMS), a careful examination of a large number of often overlooked quantitative studies of reversible cyclizations led to the definition of a set of "canonical" values of the entropic component EMS, expressed in graphical form by the plot of EMS* vs. n, where the asterisk denotes statistically corrected quantities, and n is the number of single bonds in the ring product. It is proposed that, to a useful approximation, all cyclization reactions comply with the "canonical" EMS* values, independent of the chemical nature of end groups and of the intervening chain, but solely dependent on the number n of rotatable bonds. The entropic component EMS* is approximately the same for cyclizations carried out under kinetic or thermodynamic control, and does not appear to be altered to a very significant extent by replacement of covalent with noncovalent bonds.

A calix[4]arene scaffold, blocked in the cone conformation and decorated at the upper rim with two acylguanidine units, effectively catalyzes the cleavage of phosphodiester bonds of HPNP and BNPP under neutral pH conditions. The catalyst performance is discussed in terms of acceleration over background hydrolysis and effective molarity (EM). The combination of potentiometric acid-base titrations with pH-rate profiles for HPNP and BNPP cleavage in the presence of 2-2HCl additives points to a marked synergic action of an acylguanidine/acylguanidinium catalytic dyad in 2H(+), via general base-electrophilic bifunctional catalysis. Acceleration factors over background larger than 3 orders of magnitude are obtained. The connection of the guanidine/guanidinium dyad to the calixarene scaffold by means of carbonyl joints has a double advantage: (i) the acidity of the guanidinium moiety is enhanced by the electron-withdrawing carbonyl group and maximum conversion into the catalytically active form 2H(+) occurs at almost neutral pH, lower than the pH needed for the monoprotonated form 1H(+) devoid of carbonyl groups; (ii) the EM value for HPNP cleavage with 2H(+) is definitely higher than that with 1H(+), suggesting a highly preorganized catalyst that perfectly fits in a strainless ring-shaped transition state in the catalyzed process. DFT calculations also provide useful insights into the reaction mechanisms and transition states.

This paper describes the use of the copper(I)-catalysed azide–alkyne cycloaddition reaction in an active metal template methodology for the synthesis of [2]rotaxanes both in solution and on polymer resins. The use of TentaGel resin beads has allowed the rotaxane functionalised solid supports to be characterized by 1H HR MAS NMR. Whereas previous research in the assembly of interlocked architectures on surfaces are complicated by the concurrent attachment of large proportions of non-interlocked byproducts, in this example over 80% of the functionalization is the desired interlocked rotaxane. The inclusion of zinc metalloporphyrins in the structure of the [2]rotaxane thread allowed the position of the macrocycle to be ‘switched’ upon the addition of competing base, removal of the metal or appropriate choice of solvent. Investigations into the pseudocooperative effect the mechanical bond has on the metalloporphyrin-macrocycle coordination equilibrium were performed and the associated effective molarity in this [2]rotaxane was calculated to be 120 mM.

Oligomeric molecules equipped with complementary H-bond recognition sites form stable duplexes in non-polar solvents. The use of a single H-bond between a good H-bond donor and a good H-bond acceptor as the recognition motif appended to a non-polar backbone leads to an architecture with interchangeable recognition alphabets. The interactions of three different families of H-bond acceptor oligomers (pyridine, pyridine N-oxide or phosphine oxide recognition module) with a family of H-bond donor oligomers (phenol recognition module) are compared. All three donor-acceptor combinations form stable duplexes, where the stability of the 1 : 1 complex increases with increasing numbers of recognition modules. The effective molarity for formation of intramolecular H-bonds that lead to zipping up of the duplex (EM) increases with decreasing flexibility of the recognition modules: 14 mM for the phosphine oxides which are connected to the backbone via a flexible linker; 40 mM for the pyridine N-oxides which have three fewer degrees of torsional freedom, and 80 mM for the pyridines where the geometry of the H-bond is more directional. However, the pyridine-phenol H-bond is an order of magnitude weaker than the other two types of H-bond, so overall the pyridine N-oxides form the most stable duplexes with the highest degree of cooperativity. The results show that it is possible to use different recognition motifs with the same duplex architecture, and this makes it possible to tune overall stabilities of the complexes by varying the components., We thank the EPSRC and ERC for funding

The intermolecular interaction between 2-phenoxypropionic acid and β-bromo-cyclodextrin affixed on the stationary phase surface in a chiral HPLC system was studied by the moment analysis method. At first, pulse response and peak parking experiments were conducted to measure some parameters concerning the column geometry, adsorption equilibrium, and mass-transfer kinetics. Then, the first absolute moment (μ1) and second central moment (μ2') of the elution peaks were analyzed by the moment equations, which were developed by assuming that the reaction kinetics between the solute molecules and the functional ligands can be represented by the Langmuir-type rate equation. Finally, the flow-rate dependence of HETP calculated from μ1 and μ2' was analyzed by using the values of the parameters to determine the association and dissociation rate constants of the intermolecular interaction. It was demonstrated that the combination of the chromatographic experiments and moment analysis is one of the effective strategies for the kinetic study of intermolecular interactions.

Examples of guanidinium-based artificial phosphodiesterases are illustrated in this review article. A wide set of collected catalytic systems are presented, from the early examples to the most recent developments of the use of this unit in the design of supramolecular catalysts. Special attention is dedicated to illustrate the operating catalytic mechanism and the role of guanidine/ium units in the catalysis. One or more of these units can act by themselves or in conjunction with other active units. The analogy with the mechanism of enzymatic systems is presented and discussed. In the last part of this overview, recent examples of guanidinophosphodiesterases based on nanostructured supports are reported, namely gold-monolayer-protected clusters and polymer brushes grafted to silica nanoparticles. The issue of the dependence of the catalytic performance on the preorganization of the spacer is tackled and discussed in terms of effective molarity, a parameter that can be taken as a quantitative measurement of this preorganization for both conventional molecular linker and nanosized supports.

In chemistry, synthesis is the process in which a target compound is produced in a step-wise manner from given base compounds. A recent, promising approach for carrying out these reactions is DNA-templated synthesis, since, as opposed to more traditional methods, this approach leads to a much higher effective molarity and makes much desired (sequential) one-pot synthesis possible. With this method, compounds are tagged with DNA sequences and reactions can be controlled by bringing two compounds together via their tags. This leads to new cost optimization problems of minimizing the number of different tags or strands to be used under various conditions. We identify relevant optimization criteria, provide the first computational approach to automatically inferring DNA-templated programs, and obtain efficient optimal and near-optimal results, and also provide a brute-force integer linear programming approach for complete solutions to smaller instances.