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Imination reactions in water represent a challenge not only because of the high propensity of imines to be hydrolysed but also as a result of the competing hydrate formation through H2O addition to the aldehyde. In the present work we report a successful approach that allows for favouring imitation reactions while silencing hydrate formation. Such remarkable reactivity and selectivity can be attained by fine-tuning the electronic and steric structural features of the ortho-substituents of the carbonyl groups. It resulted from studying the structure-reactivity relationships in a series of condensation reactions between different amines and aldehydes, comparing the results to the ones obtained in the presence of the biologically-relevant pyridoxal phosphate (PLP). The key role of negatively-charged and sterically-crowding units (i.e., sulfonate groups) in disfavouring hydrate formation was corroborated by DFT and steric-hindrance calculations. Furthermore, the best-performing aldehyde leads to higher imine yields, selectivity and stability than those of PLP itself, allowing for the inhibition of a PLP-dependent enzyme (transaminase) through dynamic aldimine exchange. These results will increase the applicability of imine-based dynamic covalent chemistry (DCvC) under physiological conditions and will pave the way for the design of new carbonyl derivatives that might be used in the dynamic modification of biomolecules.

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The mechanisms through which environmental conditions affect the expression of interconnected species is a key step to comprehending the principles underlying complex chemical processes. In Nature, chemical modifications triggered by the environment have a major impact on the structure and function of biomolecules and regulate different reaction pathways. Yet, minimalistic artificial systems implementing related adaptation behaviours remain barely explored. The hydrolysis of amino acid methyl esters to their corresponding amino acids leads to a drastic change in pKa (ca. 7 and 9, respectively) that protonates the free amino group at physiological conditions. Dynamic covalent libraries (DCvLs) based on amino acid methyl esters and aldehydes respond to such hydrolysis and lead to constitutional adaptation. Each of the libraries studied experiences a DCvL conversion allowing for constituent selection due to the silencing of the zwitterionic amino acids towards imine formation. The selective action of different enzymes on the DCvLs results in states with simplified constitutional distributions and transient chirality. When additional components (i.e., scavengers) that are not affected by hydrolysis are introduced into the dynamic libraries, the amino acid methyl ester hydrolysis induces the up-regulation of the constituents made of these scavenging components. In these systems, the constituent distribution is resolved from a scrambled mixture of imines to a state characterized by the predominance of a single aldimine. Remarkably, although the final libraries display higher "simplexity", the different transient states present an increased complexity that allows for the emergence of organized structures [micelle formation] and distributions [up-regulation of two antagonistic constituents]. This reactive site inhibition by a remote chemical modification resembles the scenario found in some enzymes for the regulation of their activity through proximal post-translational modifications.

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Dynamic noncovalent and covalent chemistries have enabled the constitutional modulation of chemical entities within chemical dynamic systems. The switching between order and disorder, i.e., self-sorted and unsorted states of constitutional dynamic libraries, remains challenging. Herein, we study the adaptive behaviors of a dynamic library of imine macrocycles generated from dialdehydes and diamines, seeking ways to exert control over sorting and unsorting processes. The distribution of constituents in the present library of dynamic macrocycles is modulated in response to internal and external effectors (e.g., time, metal cations, and chemical fuels), resulting in the transient amplification of self-sorted constituents in out-of-equilibrium states. The present study showcases higher complexity in systems subject to multiple adaptation through the dynamic interconversion between singularity/order and diversity/disorder.

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Imine formation under physiological conditions represents a challenging reaction due to the strong propensity of aldimines to be hydrolyzed. Herein we disclose the remarkable effect of supramolecular multivalency on increasing imine stability. A family of reactive aldehydes was synthesized bearing supramolecularly-active sites within their structure. The imine formation activity for such aldehydes was evaluated and compared with model aldehydes. The reaction of the best-performing species - containing two carboxylate groups-with a set of amines showed a significant decrease in imine yields as the degree of supramolecular multivalency between sidechains decreased. The reversible conjugation of amino acid derivatives and small peptides was also assayed, with excellent selectivities for the imine formation at the Nα position even in substrates containing competing sites. Preliminary results on protein bioconjugation revealed that a model enzyme could be dynamically inhibited upon reaction with the aldehyde, with its native activity being recovered by displacing the imine bonds with a suitable chemical effector (i.e., acylhydrazide).

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Investigating the self-assembly and self-sorting behaviour of dynamic covalent organic architectures makes possible the parallel generation of multiple discrete products in a single one pot procedure. We here report the self-assembly of covalent organic macrocycles and macrobicyclic cages from dialdehyde and polyamine components via multiple [2 + 2] and [3 + 2] polyimine condensations. Furthermore, component self-sorting processes have been monitored within the dynamic covalent libraries formed by these macrocycles and macrobicyclic cages. The progressive assembly of the final structures involves intermediates which undergo component selection and self-correction to generate the final thermodynamic constituents. The homo-self-sorting observed seems to involve entropic factors, as the homoleptic species present a higher symmetry than the competing heteroleptic ones. This study not only emphasizes the importance of an adequate design of the components of complex self-sorting systems, but also verifies the conjecture that systems of higher complexity may generate simpler outputs through the operation of competitive self-sorting.

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The reaction mechanism for the cycloaddition of CO2 to styrene oxide in the presence of macrocyclic pseudopeptides has been studied using DFT methods. Computational calculations indicate that the unprecedented catalytic behaviour previously observed experimentally, in which the most reactive species was not the most nucleophilic but the most basic one, can be associated to the tight cooperativity between several supramolecular interactions promoted by simple peptidomimetics able to display a synzymatic behaviour. This bizarre catalytic performance afforded remarkable conversions of a sluggish substrate like styrene oxide into the desired cyclic carbonate, even under relatively mild reaction conditions, opening the way for the practical use of CO2 as a raw material in the preparation of valuable chemicals. Furthermore, the remote modification of essential structural features of the macrocycle (synzyme engineering) permitted the driving forces of the synzymatic system to be analyzed, stressing the crucial synergic effect between an elegantly preorganized oxyanion hole and additional aromatic interactions.

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A new family of C2-symmetric pseudopeptides with a high functional density for supramolecular interactions has been synthetized through the attachment of four amino acid subunits to a diamino aliphatic spacer. The resulting open-chain compounds present remarkable properties as low-molecular-weight hydrogelators. The self-assembled 3D networks were characterized by SEM analyses, observing regular nanofibres with 80-100 nm diameters. Spectroscopic and molecular modelling experiments revealed the presence of strong synergic effects between the H-bonding and π-π interactions, with the best results obtained for the homoleptic tetra-pseudopeptide derived from l-Phe. In addition, these bioinspired hydrogels possessed pH- and CO2-responsive sol-gel transitions. The formation of ammonium carbamate derivatives in the presence of carbon dioxide led to a detrimental change in its adequate self-assembly. CO2 desorption temperatures of ca. 70 °C were assigned to the thermodynamically favoured recovery of the supramolecular gel.

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Herein we report our efforts to develop a continuous flow methodology for the efficient preparation of pseudopeptidic macrocyclic compounds containing the hexahydropyrrolo-[3,4-f]-isoindolocyclophane scaffold and involving four coupled substitution reactions in the macrocyclization process. Appropriate design of a supported base permitted the continuous production of the macrocycles even at large scales, taking advantage of the positive template effect promoted by the bromide anions. In addition, the use of flow protocols allowed a ca. 20-fold increase in productivity as well as reducing the environmental impact almost 2 orders of magnitude, in comparison with the related batch macrocyclization process.

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The most common approaches for classification rely on the inference of a specific class. However, every category could be naturally organized within a taxonomic tree, from the most general concept to the specific element, and that is how human knowledge works. This representation avoids the necessity of learning roughly the same features for a range of very similar categories, and it is easier to understand and work with and provides a classification for each abstraction level. In this paper, we carry out an exhaustive study of different methods to perform multilevel classification applied to the task of classifying wild animals and plant species. Different convolutional backbones, data setups, and ensembling techniques are explored to find the model which provides the best performance. As our experimentation remarks, in order to achieve the best performance on the datasets that are arranged in a tree-like structure, the classifier must feature an EfficientNetB5 backbone with an input size of 300 × 300 px, followed by a multilevel classifier. In addition, a Multiscale Crop data augmentation process must be carried out. Finally, the accuracy of this setup is a 62% top-1 accuracy and 88% top-5 accuracy. The architecture could benefit for an accuracy boost if it is involved in an ensemble of cascade classifiers, but the computational demand is unbearable for any real application.

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Herein, we report the synthesis of a novel family of constrained pseudopeptidic macrocyclic compounds containing the hexahydropyrrolo[3,4-f]isoindolocyclophane scaffold and involving four coupled substitution reactions in the macrocyclization process. Although the increase in the number of steps involved in the macrocyclization could lead to a larger number of possible side products, the optimization of the methodology and the study of the driving forces have made it possible to obtain the desired macrocycles in excellent yields. A thorough computational study has been carried out to understand the macrocyclization process, and the results obtained nicely agree with experimental data. Moreover, the bromide anion had a clear catalytic template effect in the macrocyclization reaction, and surprisingly, the chloride anion had a negative template effect in opposition to the results obtained for analogous macrocycles. The parameters responsible for the specific kinetic template effect observed have been studied in detail.

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El accidente laboral más frecuente entre el personal de enfermería es el pinchazo accidental de la piel mediante una aguja. Su efecto puede ser considerado como muy grave cuando la aguja ha estado directamente en contacto con un acceso vascular, especialmente cuando ha sido utilizada para extraer muestras de sangre. Por otra parte, la manipulación de los catéteres intravasculares se asocia a un elevado número de infecciones, y que el riesgo se incrementa en función del número de manipulaciones. El uso de llaves de tres pasos permite reducir el riesgo de accidente laboral por punción, dado que a través de ellas es posible introducir líquidos o medicamentos en el lecho vascular, o realizar extracciones del mismo, sin emplear aguja. No obstante, su uso no ha reducido la incidencia de infecciones en el catéter. Los sistemas de conexión a accesos vasculares sin agujas con luer desinfectable, además de permitir la manipulación sin aguja del catéter, consiguen, por su especial diseño, reducir notablemente el riesgo de infección nosocomial. En el presente artículo se describen las características, funcionamiento y ventajas de este tipo de conectores (AU)

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The most frequent on the job accident for nursing personnel is accidentally stabbing oneself in the skin with a syringe. The effect of this accident can be considered to be very serious whenever the syringe has been in direct contact with a blood vessel, especially if it has been used to draw blood samples. On the other hand, the handling of intravenous catheters is associated with a high number of infections and the risk of an accident increases in terms of the number of times one handles them. The use of a three-way valve lowers the risk of an on the job accident due to pricking since by means of a three-way valve, it is possible to introduce liquids or medicines into a blood vessel, or to carry out extractions from a vessel, without having to use a needle. However, its use has not reduced the possibility of infections in catheters. Besides allowing one to handle a catheter without a needle, non-needle connection systems using Luer disinfectant, due to their design, make it possible to noticeably reduce the risk of nosocomial infections. In this article, the author describes the characteristics, working methods, and advantages of this kind of connectors.

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