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α,ω-Stoppered perfluorous domains act as rigid and chiral linear helical elements in rotaxane constructs. Dynamic NMR shows modified ring dynamics over 4–orders of magnitude compared to hydrocarbon analogues, while vibrational-CD shows stopper-induced preferential axle chirality.

The periodic table allows students to easily understand the chemical elements and predict the behavior of theoretical yet undiscovered new elements. Many memorization techniques have been used for learning the periodic table, yet serious games (i.e., designed for a primary purpose other than pure entertainment) have been underexplored to complement or even replace such memorization techniques. Since CHEMMEND, an existing physical card game, was found to assist with learning the periodic table, we explore the potential of E-CHEMMEND, a digital version of the game as an aid to memorize the group and period numbers of the elements. E-CHEMMEND is a single-player serious game to explore the effect of four different game conditions involving two experimental factors that account for different educational scenarios. The first factor investigates the role of playing through levels of increasing difficulty versus playing with all elements from the very beginning. The second factor investigates the role of displaying the group and period numbers of the chemical element along with its symbol versus only displaying the element symbol. Preliminary results show that E-CHEMMEND is perceived as more enjoyable when the group and period numbers are displayed. In contrast, the game is found to better assist learning when this information is hidden and levels are shown. Taken together, our results suggest that a variety of educational purposes can be accommodated with a range of game settings. Ultimately, the design rationale and the lessons learned while testing E-CHEMMEND will be valuable for chemistry instructors and education researchers. A desktop-based Windows executable version of the game is available at http://www.chemmend.uji.es/game

High-symmetry metallosupramolecular architectures (MSAs) have been exploited for a range of applications including molecular recognition, catalysis, and drug delivery. Recently, there have been increasing efforts to enhance those applications by generating reduced-symmetry MSAs. Here we report our attempts to use supramolecular (dispersion and hydrogen-bonding) forces and solvophobic effects to generate isomerically pure [Pd2(L)4]4+ cage architectures from a family of new reduced-symmetry ditopic tripyridyl ligands. The reduced-symmetry tripyridyl ligands featured either solvophilic polyether chains, solvophobic alkyl chains, or amino substituents. We show using NMR spectroscopy, high-performance liquid chromatography, X-ray diffraction data, and density functional theory calculations that the combination of dispersion forces and solvophobic effects does not provide any control of the [Pd2(L)4]4+ isomer distribution with mixtures of all four cage isomers (HHHH, HHHT, cis-HHTT, or trans-HTHT, where H = head and T = tail) obtained in each case. More control was obtained by exploiting hydrogen-bonding interactions between amino units. While the cage assembly with a 3-amino-substituted tripyridyl ligand leads to a mixture of all four possible isomers, the related 2-amino-substituted tripyridyl ligand generated a cis-HHTT cage architecture. Formation of the cis-HHTT [Pd2(L)4]4+ cage was confirmed using NMR studies and X-ray crystallography.

High-symmetry metallosupramolecular architectures (MSAs) have been exploited for a range of applications including molecular recognition, catalysis, and drug delivery. Recently, there have been increasing efforts to enhance those applications by generating reduced-symmetry MSAs. Here we report our attempts to use supramolecular (dispersion and hydrogen-bonding) forces and solvophobic effects to generate isomerically pure [Pd

[EN] Macrocyclic and cage structures preorganize functional groups around a central cavity providing unique properties in the field of supramolecular chemistry. Their synthesis requires an appropriate design of the building blocks that will form a macrocycle through a macrocyclization reaction or a cage through a cage formation reaction. Besides the importance of the appropriate geometry of the building blocks, it is necessary to design a suitable synthetic route with special attention to the final macrocyclization or cage formation reaction pathway. The kinetic and thermodynamic aspects are crucial factors to consider for a successful reaction that will be analyzed in this digest. (c) 2022 Elsevier Ltd. All rights reserved., V.M.-C. acknowledges the financial support from Project CIDEGENT/2020/031 funded by Generalitat Valenciana and Project PID2020-113256RA-I00 funded by MCIN/AEI/10.13039/501100011033.

[EN] Self-assembled metallo-organic cages have emerged as promising biomimetic platforms that can encapsulate whole substrates akin to an enzyme active site. Extensive experimental work has enabled access to a variety of structures, with a few notable examples showing catalytic behavior. However, computational investigations of metallo-organic cages are scarce, not least due to the challenges associated with their modeling and the lack of accurate and efficient protocols to evaluate these systems. In this review, we discuss key molecular principles governing the design of functional metallo-organic cages, from the assembly of building blocks through binding and catalysis. For each of these processes, computational protocols will be reviewed, considering their inherent strengths and weaknesses. We will demonstrate that while each approach may have its own specific pitfalls, they can be a powerful tool for rationalizing experimental observables and to guide synthetic efforts. To illustrate this point, we present several examples where modeling has helped to elucidate fundamental principles behind molecular recognition and reactivity. We highlight the importance of combining computational and experimental efforts to speed up supramolecular catalyst design while reducing time and resources., T.K.P., P.J.L., and F.D. acknowledge the financial support from EPSRC (EP/W010666/1 and EP/W009803/1). T.K.P. and F.D. acknowledge the financial support from the John Fell Fund (ref 0006752). V.M.-C. acknowledges the financial support from Generalitat Valenciana (CIDEGENT/2020/031). T.A.Y. acknowledges the impact acceleration account (IAA) grant (EP/R511742/1).

[EN] Cage compounds offer unique binding pockets similar to enzyme-binding sites, which can be customized in terms of size, shape, and functional groups to point toward the cavity and many other parameters. Different synthetic strategies have been developed to create a toolkit of methods that allow preparing tailor-made organic cages for a number of distinct applications, such as gas separation, molecular recognition, molecular encapsulation, hosts for catalysis, etc. These examples show the versatility and high selectivity that can be achieved using cages, which is impossible by employing other molecular systems. This review explores the progress made in the field of fully organic molecular cages and containers by focusing on the properties of the cavity and their application to encapsulate guests., V.M.-C. acknowledges the financial support from project CIDEGENT/2020/031 funded by the Generalitat Valenciana and project PID2020-113256RA-I00 funded by MCIN/AEI/10.13039/501100011033. R.M.-M. and F.S. acknowledge the financial support from project PROMETEO 2018/024 from the Generalitat Valenciana and project RTI2018-100910-B-C41 funded by MCIN/AEI/10.13039/501100011033/and FEDER A way to make Europe. Funding for open access charge: CRUE-Universitat Politecnica de Valencia.

Allosteric regulation is an essential biological process that allows enzymes to modulate their active site properties by binding a control molecule at the protein exterior. Here we show the first example of capsule catalysis in which activity is changed by exotopic binding. This study utilizes a simple Pd2L4 capsule that can partition substrates and external effectors with high fidelity. We also present a detailed, quantitative understanding of how effector interactions alter both substrate and transition state binding. Unlike other allosteric host systems, perturbations are not a consequence of large mechanical changes, rather subtle electronic effects resulting from weak, non-covalent binding to the exterior surface. This investigation paves the way to more sophisticated allosteric systems., External effector binding allosterically regulates the catalytic properties of a simple Pd2L4 capsule.

Kinetic control of molecular self-assembly remains difficult because of insufficient understanding of molecular self-assembly mechanisms. Here we report the formation of a metastable [Pd2L4]4+ cage structure composed of naphthalene-based ditopic ligands (L) and Pd(II) ions in very high yield (99%) under kinetic control by modulating the energy landscape. When self-assembly occurs with anionic guests in weakly cooordinating solvent then suitable intermedites and the metastable cage is formed. These conditions also prevent further transformation into the thermodynamically decomposed state. The cage formation pathways under kinetic control and the effect of the anions encapsulated on the self-assembly processes were investigated by QASAP (quantitative analysis of self-assembly process) and NASAP (numerical analysis of self-assembly process). It was found that the self-assembly with a preferred guest (BF4 -) proceeds through intermediates composed of no more components than the cage ([PdaLbXc]2a+ (a ≤ 2, b ≤ 4, X indicates a leaving ligand)) and that the final intramolecular cage-closure step is the rate-determining step. In contrast, a weaker guest (OTf-) causes the transient formation of intermediates composed of more components than the cage ([PdaLbXc]2a+ (a > 2, b > 4)), which are finally converted into the cage.

New hemi-cage compounds with the formula Pd2(L1)2(L2)2 (L1 = ditopic pyridine ligand, L2 = bpy or TMEDA) have been synthesized and characterized by spectroscopic methods, X-ray crystallography and electronic structure methods. The host–guest chemistry of these new structures, with naphthoquinone as a guest, reveals the key role of the host shape and flexibility on competitive binding processes. The influence of counteranions, solvent and non-covalent interactions to binding were quantified by Density Functional Theory calculations. Together, this study provides new insights into the concept of pre-organized guest binding when applied to charged, coordination-assembled hosts.

Bidirectional electronic energy shuttling is shown to occur between the molecular ring and axle components of a rotaxane. The engineered energetic and kinetic parameters give rise to long-lived, delayed luminescence. Perturbation of the quasi-isoenergetic ring and stopper chromophore excited-state energy levels upon cation binding influences the energy shuttling process, and hence luminescence read-out, representing a new potential mechanism in luminescent molecular chemosensor development

We demonstrate the first example of bidirectional reversible electronic energy transfer (REET) between the mechanically bonded components of a rotaxane. Our prototypical system was designed such that photoexcitation of a chromophore in the axle results in temporary storage of electronic energy in a quasi-isoenergetic “reservoir” chromophore in the macrocycle. Over time, the emissive state of the axle is repopulated from this reservoir, resulting in long-lived, delayed luminescence. Importantly, we show that cation binding in the cavity formed by the mechanical bond perturbs the axle chromophore energy levels, modulating the REET process, and ultimately providing a luminescence read-out of cation binding. Modulation of REET processes represents an unexplored mechanism in luminescent molecular sensor development., Delayed emission due to reversible electronic energy transfer (REET) between chromophores in the axle and macrocycle components of a rotaxane is demonstrated. The REET process can be modulated by metal ion binding in the cavity of the rotaxane.

[EN] Prolinamides are well-known organocatalysts for the HSiCl3 reduction of imines; however, custom design of catalysts is based on trial-and-error experiments. In this work, we have used a combination of computational calculations and experimental work, including kinetic analyses, to properly understand this process and to design optimized catalysts for the benchmark (E)-N-(1-phenylethylidene)aniline. The best results have been obtained with the amide derived from 4-methoxyaniline and the N-pivaloyl protected proline, for which the catalyzed process is almost 600 times faster than the uncatalyzed one. Mechanistic studies reveal that the formation of the component supramolecular complex catalyst-HSiCl3-substrate, involving hydrogen bonding breaking and costly conformational changes in the prolinamide, is an important step in the overall process., This research was funded by Generalitat Valenciana, grant number PROMETEO/2016/071 and AICO/2021/139, Pla de Promocio de la Investigacio de la Universitat Jaume I, grant number UJI-B2019-40 and Ministerio de Ciencia, Innovacion y Universidades, grant number RTI2018098233-B-C22. V.M.-C. acknowledges the financial support from Generalitat Valenciana (CIDEGENT/2020/031).

The templated clipping of a ferrocene-grafted isophthalic acid derivative to encircle a hydrogen-bonding axle through the reaction with 1,4-bis(aminomethyl)benzene is described. The constituent electroactive macrocycle of the resultant [2]rotaxane is a homologue of the versatile benchmark tetraamide variant developed by Leigh and co-workers. The relative templating effect of different hydrogen-bonding motifs in rotaxane and pseudorotaxane generation is compared, with yields varying from 0 to 41%. The electrochemical properties and single crystal X-ray structure of a doubly ferrocene-decorated [2]rotaxane are further reported.

A homologous series of two-station [2]rotaxanes incorporating amino-acid units in the molecular thread has been developed. The degenerate [2]rotaxanes exhibit amino-acid specific shuttling rates between two fumaric stations related to the steric factor associated to the amino-acid side chain, as demonstrated by variable-temperature 1H NMR spectroscopy and exchange spectroscopy (EXSY). This allows tuning of the macrocycle shuttling rate over 4 orders of magnitude, which further has a relatively small solvent dependency., Comment: 7 figures; supplementary information appended

Self-assembled cages have emerged as novel platforms to explore bio-inspired catalysis. While many different size and shape supramolecular structures are now readily accessible, only a few are known to accelerate chemical reactions under sub-stoichiometric conditions. These limited examples point to a poor understanding of cage catalysis in general, limiting the ability to design new systems. Here we show that a simple and efficient density functional theory-based methodology, in-formed by explicitly solvated molecular dynamics and coupled-cluster calculations is sufficient to accurately reproduce experimental guest binding affinities (MAD = 1.9 kcal mol-1) and identify the catalytic Diels-Alder proficiencies (>80 % accuracy) of two homologous Pd2L4 metallocages with a variety of substrates. This analysis reveals how subtle structural differences in the cage framework affect binding and catalysis. These effects manifest in a smaller distortion and more favorable interaction energy for the catalytic cage compared to the inactive structure. This study gives a detailed insight that would otherwise be difficult to obtain from experiments, providing new opportunities in the design catalytically active supramolecular cages.

Kinetic control of molecular self-assembly remains difficult because of insufficient understanding of molecular self-assembly mechanisms. Here we report the formation of a metastable [Pd

The Diels–Alder (DA) reaction is a cornerstone of synthesis, yet Nature does not use catalysts for intermolecular [4+2] cy-cloadditions. Attempts to create artificial “Diels–Alderases” have also met with limited success, plagued by product inhibi-tion. Using a simple Pd2L4 capsule we now show DA catalysis that combines efficient turnover alongside enzyme-like hall-marks. This includes excellent activity (kcat/kuncat > 103), selective transition-state (TS) stabilization comparable to the most proficient DA catalytic antibodies, and control over regio- and chemo-selectivity that would otherwise be difficult to achieve using small-molecule catalysts. Unlike other catalytic approaches that use synthetic capsules, this method is not defined by entropic effects; instead multiple H-bonding interactions modulate reactivity, reminiscent of enzymatic action.

The self-assembly process of a Pd2L4 cage complex consisting of rigid ditopic ligands, in which two 3-pyridyl groups are connected to a benzene ring through acetylene bonds, and Pd(II) ions was firstly revealed by a recently developed QASAP (quantitative analysis of self-assembly process), with which the self-assembly process of the coordination assemblies can be investigated by monitoring the time evolution of the average composition of all the intermediates. QASAP revealed that the rate-determining steps of the cage formation are the intramolecular ligand exchanges in the final stage of the self-assembly, [Pd2L4Py*2]4+ → [Pd2L4Py*1]4+ + Py* and [Pd2L4Py*1]4+ → [Pd2L4]4+ + Py* (Py*: 3-chloropyridine, which was used as a leaving ligand on the metal source). The energy barriers for the two reactions were determined to be 22.3 and 21.9 kcal mol-1, respectively. DFT calculation of the TS (transition state) structures for the two steps indicates that the distortion of the trigonal-bipyramidal Pd(II) center at the TS geometries increases the activation free energy of the two steps.

Two new C 2 -symmetric N , N ’ -benzylated bis(amino amides) have been synthesised and their interaction with di ff erent transition metals studied using a variety of techniques including UV-Vis and CD spec- troscopy or ESI-MS. The determination of the corresponding stability constants with Cu 2+ has been possi- ble, in H 2 O/CH 3 CN 7/3 v/v, for one of these ligands ( 4 ) using potentiometric titrations. The results obtained reveal that N -benzylation a ff ords signi fi cant changes to their properties and is accompanied by an appreciable decrease in the corresponding complexation stability constants. However, this, along with the low kinetics associated to Ni 2+ , facilitates the recognition of Cu 2+ by 4 that can be followed by the naked-eye up to the submillimolar range. Very interestingly, the chiral nature of this ligand provides an intense and well de fi ned CD curve for the corresponding Cu 2+ complex, very sensitive to the coordination geometry, facilitating the analysis of this interaction even at the μ M range. The formation by both ligands ( 3 and 4 ) of square planar complexes with Cu 2+ and Ni 2+ displaying a 1 : 1 stoichiometry was con fi rmed by their X-ray crystal structures Financial support from Spanish MINECO (CTQ2015-68429-R), Generalitat Valenciana (PROMETEO/2016/071) and PPI-UJI (P1-1B-2013-38) is gratefully acknowledged. L. G. thanks Generalitat Valenciana for a Grisolia fellowship (GRISOLIA 2012/015).

Self-assembled cages have emerged as novel platforms to explore bio-inspired catalysis. While many different size and shape supramolecular structures are now readily accessible, only a few are proficient catalysts. Here we show that a simple and efficient DFT-based methodology i is sufficient to accurately reproduce experimental binding affinities (MAD = 1.9 kcal mol-1) and identify the catalytic and non-catalytic Diels-Alder proficiencies (>90 % accuracy) of two homologous Pd2L4 metallocages with a variety of substrates. We demonstrate how subtle structural differences in the cage framework affect binding and catalysis, highlighting the critical role of structural dynamics and flexibility on catalytic activity. This flexibility manifests in a smaller transition state distortion energy for the catalytic cage compared to the inactive structure. To facilitate the computational exploration of novel Pd2L4 systems, we introduce an open-source Python module cgbind, which largely automates the screening of novel architectures.

The self-assembly patterns of a family of C2-symmetric pseudopeptidic compounds have been studied in the crystalline state, analysing the influence of both the nature of the central spacer and that of the side chain of the amino acid on the observed features. The nature of the side chain of the component amino acid is the most important structural element defining the conformational and self-assembly patterns. The presence of an aromatic side chain, in the case of Phe derivatives, seems to play a key role in defining folded conformations with the aromatic side chain located over the central spacer. The formation of β-sheet-like stacks in crystals is predominant in Val derivatives but not in Phe-derived compounds. Side chains are strongly involved in intermolecular contacts, with isopropyl groups defining preferentially knob-into-hole interactions and aromatic groups of Phe pseudopeptides defining preferentially edge-to-face arrangements. NMR and CD data suggest that the conformational differences observed in the crystalline structures are also present in solution, in particular in polar solvents.

A strong preference for the formation of tripodal systems over the related monotopic and ditopic compounds is observed for the reaction between tris(halomethyl)benzenes and imidazoles derived from amino acids and containing an amide fragment. This preference allows the formation of the tripodal derivative as the major product even when an equimolar mixture of the tris(halomethyl)benzene and the imidazole is reacted (1 : 1 ratio instead of the stoichiometric 1 : 3 ratio). The reactions were monitored using 1 H NMR spectroscopy and ESI mass spectrometry and kinetically characterized. Computational studies were also performed in order to rationalize the observed preference of the tri-substituted product. The results reveal the existence of well-defined supramolecular interactions between the imidazolium groups and the reacting imidazoles that facilitate the formation of the multitopic systems once the first imidazolium group is formed. Analysis of the different structural components shows that the presence of the amide group from the amino acid moiety is the key structural requirement for such supramolecular assistance to take place. The preorganization of the supramolecular intermediates formed through hydrogen bonding interactions involving amide-NH fragments in imidazoles and bromide anions in imidazolium groups seems to be also present at the corresponding TSs, decreasing the associated energy barriers.

A new family of pseudopeptidic macrocyclic compounds has been prepared involving an anion-templated amide bond formation reaction at the macrocyclization step. Chloride anion was found to be the most efficient template in the macrocyclization process, producing improved macrocyclization yields with regard to the nontemplated reaction. The data suggest a kinetic effect of the chloride template, providing an appropriate folded conformation of the openchain precursor and reducing the energy barrier for the formation of the macrocyclic product. This work was supported by the Spanish Ministry of Science and Innovation (CTQ2012-38543-C03) and Generalitat Valenciana (PROMETEO/2012/020). V.M.-C. thanks Generalitat Valenciana for a postdoctoral fellowship (APOSTD/ 2013/041).

The synthesis of a novel [2]rotaxane host system containing a bis(triazolium)acridine-based axle component is reported. (1)H NMR anion-binding titrations reveal that the rotaxane is able to recognise selectively the NO3(-) anion over a range of more basic oxoanions (AcO(-), HCO3(-) and H2PO4(-)) in a competitive organic-aqueous solvent mixture.

The self-assembly process of a Pd

Two new C

The deeply knowledge of the periodic table is one of the most important keys to understand the basic principles of Chemistry. Memorizing the elements of the groups and periods is one of the most commonly used strategies to learn the position of each element in the periodic table; nevertheless it is a hard task for most students. The use of card games can represent a useful alternative to teach some chemical aspects. Here, we present ChemMend, a new Chemical card game which will allow chemistry students to obtain a good ability in the periodic table. This game attracts the attention of the students, and it allows them to review mentally the period and group while playing; being the learning a consequence of the game. The ChemMend game will introduce and explore the periodic table in the classroom.

Pseudopeptidic receptors containing ferrocene fragments have been prepared and their response to a series of anions was measured by a voltammetry of microparticles methodology. Such water-insoluble compounds yield anion-assisted reversible solid-state oxidations differing in their open-circuit potential and their midpeak potential recorded in cyclic voltammetric measurements. The difference between those potentials provides the individual thermodynamic contributions of electron and proton transfer, revealing that the mechanism of an ion-sensitive electrode can differ in potentiometry and voltammetry. The studied receptors are potentially interesting for potentiometric sensing, showing relatively high selectivity for H2PO4− and HPO42− anions. Financial support by the Spanish MINECO and FEDER (Projects and Consolider-Ingenio, Projects CSD2010-000652010, CTQ2013-48917-C3-1-P and CTQ2014-53736-C3-2-P) and Unidad de Excelencia MDM 2015-0038, and Generalitat Valenciana (PROMETEOII 2015/002) is gratefully acknowledged. V. M.-C. and M. D. P. thank the Spanish Ministry of Science and Education for predoctoral (FPU AP2007-02562) and postdoctoral (SB2010-0088) fellowships. MDP also thankful to UGC India for startup grant. The support of the SCIC of the UJI for instrumental techniques is acknowledged.

Two new tetradentate C2-symmetric pseudopeptidic ligands derived from Val and Phe containing two amino and two amido groups and a central o-substituted aromatic spacer have been prepared. Their complexes with Cu2+, Zn2+, and Ni2+ have been studied by potentiometry, UV−vis spectrophotometry, FT-IR, and ESI-MS. The presence of the aromatic spacer provides Cu2+ complexes with stability constants several orders of magnitude higher than those observed for related ligands containing aliphatic central spacers. Besides, the formation of [MH−2L] complex species is favored. Crystal structures for the corresponding Cu2+ and Ni2+ have been obtained, revealing the metal atom in an essentially square-planar geometry, although, in several instances, the oxygen atom of an amide carbonyl of a second complex species can act as a fifth coordination site. In the case of Zn2+, the only crystal structure obtained displays a square-pyramidal arrangement of the metal center. Finally, preliminary experiments show the catalytic activity of some of these complexes, in particular, Zn2+ complexes, for epoxide ring-opening with using aniline as the nucleophile in a ligand accelerated process. Spanish MINECO CTQ2015-68429-R Generalitat Valenciana PROMETEO/2012/020 GRISOLIA 2012/015 PPI-UJI P1-1B-2013-38

Several kinetic models for the macrocyclization of aC2pseudopeptide with a dihalide through aSN2reaction have been developed. These models not only focus on the kinetic analysis of the main macrocyclization reaction, but also consider the competitive oligomerization/polymerization processes yielding undesired oligomeric/polymeric byproducts. The effect of anions has also been included in the kinetic models, as they can act as catalytic templates in the transition state reducing and stabilizing the transition state. The corresponding differential equation systems for each kinetic model can be solved numerically. Through a comprehensive analysis of these results, it is possible to obtain a better understanding of the different parameters that are involved in the macrocyclization reaction mechanism and to develop strategies for the optimization of the desired processes.

Financial support of the Spanish Ministry of Science and Innovation (CTQ2012-38543-C03) and Generalitat Valenciana (PROMETEO/2012/020) is acknowledged. V.M.-C. thanks the Spanish Ministry of Science and Education for a predoctoral fellowship (FPU AP2007-02562) and Generalitat Valenciana for a VALi+d postdoctoral fellowship (APOSTD/2013/041). M.D.P. thanks the Spanish Ministry of Education for a postdoctoral fellowship and UGC India for a Startup Grant.

The reaction of N-Boc triprotected cyclam with bis(chloromethyl)biphenyl followed by the corresponding deprotection of the nitrogen atoms allows the preparation of receptor 3 containing an azonia spiro subunit. This receptor shows slightly increased basicity than cyclam, in particular for the formation of the appropriate triply charged species as a consequence of the reduced capacity of the structure present in 3 to stabilize the species with lower protonation degrees through the formation of intramolecular hydrogen bonds. The properties of 3 as a receptor for Cu2+ and Zn2+ and the anions derived from PO 4 3 − ( Pi ) , P 2 O 7 4 − ( PPi ) , P 3 O 10 5 − ( TPP ) and ATP have been studied by pH-metric titrations carried out in aqueous solution. While Cu2+ forms a CuL2+ complex and two hydroxylated species of moderate stability, Zn2+ forms only hydroxylated complexes. The association constants obtained for the 1:1 A:L anion complexes denote significant stability for Pi, PPi and ATP; the stability of the H5LA complex found in the case of TPP being lower. 1H NMR spectra for the ATP:L carried out at pD=5.8 show features attributable to the occurrence of intermolecular π–π stacking between the biphenyl unit of 3 and the adenine ring of the nucleotide. DFT calculations have been carried out to rationalize some of the results found, in particular the remarkable different basicity between receptor 3 and cyclam.

The success of a given macrocyclization reaction involves a very delicate balance of many different factors. First, a proper understanding of the basic thermodynamic and kinetic concepts underlying these processes is essential in defining the strategies to obtain the targeted cyclic structures and the experimental elements to be optimized. essential element for achieving high yields in a macrocyclization process is the appropriate selection of the disconnection site. This defines the reaction used for the key step, which will clearly affect the overall process, but also delineates the nature and structure of the immediate linear precursor. The presence of structural elements, including configurational elements, able to induce a favorable folding of this linear precursor in such a way that both reactive ends approach with the proper orientation provides significant enhancements in macrocyclizations. The use of templates of very different natures is a versatile strategy to overcome the limitations of the other macrocyclization strategies. The use of templates has allowed the preparation of a variety of macrocyclic structures in better yields and usually in shorter reaction times, and often allows easier purification protocols. Financial support of the Spanish Ministry of Science and Innovation (CTQ2012-38543-C03) and Generalitat Valenciana (PROMETEO/2012/020) is acknowledged. V.M.-C. thanks the Spanish Ministry of Science and Education for a predoctoral fellowship (FPU AP2007-02562) and Generalitat Valenciana for a VALi+d postdoctoral fellowship (APOSTD/2013/041). M.D.P. thanks the Spanish Ministry of Education for a postdoctoral fellowship and UGC India for a Startup Grant.

The controlled radical polymerization of monomeric units containing chiral ionic liquids (CILs) allows the synthesis of intrinsically chiral polymers through a bottom-up design. These polymeric chiral ionic liquids (PCILs) show a well-defined three dimensional structure organized as the result of a complex non-covalent network of hydrogen-bonding contacts driven by the C2 hydrogen atoms of the imidazolium aromatic rings and the OH moieties present in the side functionalities of the main polymeric chain. The exchange of the chloride counter ion by the L-prolinate anion leads to new types of polymeric catalysts, which behave as efficient artificial aldolase biomimetic systems, being highly active and selective for the aldol reaction in water. These new polymeric catalysts are significantly more active than the corresponding monomeric counterpart when the reaction is performed either in water or in the presence of water. The increase in catalytic efficiency can be related to their 3D structure, displaying helical chirality in the polymeric chain as a function of their preparation methodology. Under suitable experimental conditions, these polymers are able to catalyse the consecutive aldol-dehydration process, behaving as synthetic mimics of the aldolase-dehydrogenase enzymatic system. Moderate enantioselectivities can be achieved under suitable conditions.

A family of pseudopeptidic macrocycles containing non-natural amino acids have been synthesized. The macrocyclization reaction has been studied experimentally and computationally, demonstrating the key role of both the amino acid side chain and the catalytic bromide anion. The bromide anion acts as an external template assisting the folding of the open-chain precursor in a proper conformation. Computations revealed that in the presence of the anion, the effect of the side chain on the energy barrier for the macrocyclization is very small. However, the effect on the conformational equilibria of the open-chain precursors is very important. Overall, the stabilization of those conformation(s) in which the two reactive ends of the open-chain intermediate are located at short distances from each other with the correct orientation is the critical parameter defining the success of the macrocyclization. The best yield was found for the compound containing cyclohexylalanine, for which the computationally-predicted most stable conformer in the presence of Br- has a proper preorganization for cyclization. The remarkable agreement obtained between experiments and theory reveals that the computational approach here considered can be of great utility for the prediction of the behavior of other related systems and for the design of appropriate synthetic routes to new macrocyclic compounds. © 2013 American Chemical Society., S.V.L. acknowledges GV (PROMETEO/2012/020) and MINECO (CTQ2012-38543-C03-01). C.C. acknowledges Ministerio de Ciencia e Innovación−FEDER (CTQ2010- 17436) and Gobierno de Aragón−FSE (Research Group E40). V.M.-C. thanks MICINN for personal financial support (FPU Fellowship AP2007-02562).