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Molecular scaffolds that enable the combinatorial synthesis of new supramolecular building blocks are promising targets for the construction of functional molecular systems. Here, we report a supramolecular scaffold based on boroxine that enables the formation of chiral and ordered 1D supramolecular polymers, which can be easily functionalized for circularly polarized luminescence. The boroxine monomers are quantitatively synthesized in situ, both in bulk and in solution, from boronic acid precursors and cooperatively polymerize into 1D helical aggregates stabilized by threefold hydrogen-bonding and π-π stacking. We then demonstrate amplification of asymmetry in the co-assembly of chiral/achiral monomers and the co-condensation of chiral/achiral precursors in classical and in situ sergeant-and-soldiers experiments, respectively, showing fast boronic acid exchange reactions occurring in the system. Remarkably, co-condensation of pyrene boronic acid with a hydrogen-bonding chiral boronic acid results in chiral pyrene aggregation with circularly polarized excimer emission and g-values in the order of 10-3. Yet, the electron deficiency of boron in boroxine makes them chemically addressable by nucleophiles, but also sensitive to hydrolysis. With this sensitivity in mind, we provide first insights into the prospects offered by boroxine-based supramolecular polymers to make chemically addressable, functional, and adaptive systems.
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Amplification of asymmetry in complex molecular systems results from a delicate interplay of chiral supramolecular structures and their chemical reactivity. In this work, we show how the helicity of supramolecular assemblies can be controlled by performing a non-stereoselective methylation reaction on comonomers. By methylating chiral glutamic acid side chains in benzene-1,3,5-tricarboxamide (BTA) derivatives to form methyl esters, the assembly properties are modulated. As reacted comonomers, the methyl ester-BTAs induce a stronger bias in the screw-sense of helical fibers predominantly composed of stacked achiral alkyl-BTA monomers. Hence, applying the in situ methylation in a system with the glutamic acid-BTA comonomer induces asymmetry amplification. Moreover, mixing small quantities of enantiomers of glutamic acid-BTA and glutamate methyl ester-BTA in the presence of the achiral alkyl-BTAs leads to deracemization and inversion of the helical structures in solution via the in situ reaction toward a thermodynamic equilibrium. Theoretical modeling suggests that the observed effects are caused by enhanced comonomer interactions after the chemical modification. Our presented methodology enables on-demand control over asymmetry in ordered functional supramolecular materials.
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Supramolecular copolymers have typically been studied in the extreme cases, such as self-sorting or highly mixed copolymer systems, while the intermediate systems have been less understood. We have reported the temperature-dependent microstructure in copolymers of triazine- and benzene-derivatives based on charge-transfer interactions with a highly alternating microstructure at low temperatures. Here, we investigate the temperature-dependent copolymerization further and increase the complexity by combining triazine- and benzene-derivatives with opposite preferred helicities. In this case, intercalation of the benzene-derivative into the triazine-derivative assemblies causes a helical inversion. The inversion of the net helicity was rationalized by comparing the mismatch penalties of the individual monomers, which indicated that the benzene-derivative dictates the helical screw-sense of the supramolecular copolymers. Surprisingly, this was not reflected in further investigations of slightly modified triazine- and benzene-derivatives, thus highlighting that the outcome is a subtle balance between structural features, where small differences can be amplified due to the competitive nature of the interactions. Overall, these findings suggest that the temperature-dependent microstructure of triazine- and benzene-based supramolecular copolymers determines the copolymer helicity of the presented system in a similar way as the mixed majority-rules phenomenon.
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Crystal structures of N-acetylated proline and homologs with four- and six-membered rings (azetidine carboxylic acid and piperidine carboxylic acid) were obtained and compared. The distinctly different conformations of the four-, five-, and six-membered rings reflect Bayer strain, n â π* interaction, and allylic strain, and result in crystal lattices with a zigzag structure.
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Ácido Azetidinocarboxílico , Prolina , Prolina/química , Conformación Molecular , Ácido Azetidinocarboxílico/química , Ácidos CarboxílicosRESUMEN
New N-heterocyclic fluorophores are sought-after compounds for organic electronic devices. Here, we report on a straightforward synthesis to access meta/para-dipyrrolobenzenes and para-dipyrrolopyrazines in high yields using a bidirectional gold-catalyzed cyclization strategy. The versatility of our reaction protocol was showcased by preparing dipyrroloarenes with different substituents, various functional groups, and in a multitude of substitution patterns. Furthermore, we showed that the dipyrroloarenes can be post-modified by N-alkylation to improve the solubility or bromination to yield precursors for further derivatization via cross-coupling. Investigation of the photophysical properties of theâmostly unprecedentedâdipyrroloarenes identified strong blue emitters such as the diphenyl meta-dipyrrolobenzene with a quantum yield of 98%. Moreover, we showed that changes in the solvent polarity or interactions with Lewis acids such as borane can be used to fine-tune the photophysical properties of the fluorophores.
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Colorantes Fluorescentes , Oro , Alquilación , Catálisis , CiclizaciónRESUMEN
The combination of covalent and non-covalent synthesis is omnipresent in nature and potentially enables access to new materials. Yet, the fundamental principles that govern such a synthesis are barely understood. Here, we demonstrate how even simple reaction mixtures behave surprisingly complex when covalent reactions are coupled to self-assembly processes. Specifically, we study the reaction behavior of a system in which the in situ formation of discotic benzene-1,3,5-tricarboxamide (BTA) monomers is linked to an intertwined non-covalent reaction network including self-assembly into helical BTA polymers. This system shows an unexpected phase-separation behavior in which an interplay of reactant/product concentrations, side-products and solvent purity determines the system composition. We envision that these insights can bring us one step closer to how to design the synthesis of systems in a combined covalent/non-covalent fashion.
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The desire to construct complex molecular systems is driven by the need for technological (r)evolution and our intrinsic curiosity to comprehend the origin of life. Supramolecular chemists tackle this challenge by combining covalent and noncovalent reactions leading to multicomponent systems with emerging complexity. However, this synthetic strategy often coincides with difficult preparation protocols and a narrow window of suitable conditions. Here, we report on unsuspected observations of our group that highlight the impact of subtle "irregularities" on supramolecular systems. Based on the effects of pathway complexity, minute amounts of water in organic solvents or small impurities in the supramolecular building block, we discuss potential pitfalls in the study of complex systems. This article is intended to draw attention to often overlooked details and to initiate an open discussion on the importance of reporting experimental details to increase reproducibility in supramolecular chemistry.
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Solventes , Agua , Reproducibilidad de los Resultados , Solventes/química , Agua/químicaRESUMEN
Despite impressive advances in the construction of metal-organic frameworks (MOFs), the formation of networks from peptidic ligands is difficult, though they are sought after for their modularity and biocompatibility. Herein we present a peptide-metal framework that consists of helical oligoproline ligands and Zn/K (or Zn/Rb). The crystalline network contains pleated nanosheets with the metal ions aligned in strings. This unprecedented architecture derives from under-appreciated London dispersion interactions between the oligoproline ligands that play in concert with the metal coordination to create the network. Hence, the secondary structure of the peptidic ligand represents an additional control element for the creation of new MOF architectures. We anticipate that our results will instruct the design of further peptidic MOFs and enable the generation of versatile biocompatible materials.
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Supramolecular copolymers formed by the noncovalent synthesis of multiple components expand the complexity of functional molecular systems. However, varying the composition and microstructure of copolymers through tuning the interactions between building blocks remains a challenge. Here, we report a remarkable discovery of the temperature-dependent supramolecular copolymerization of the two chiral monomers 4,4',4â³-(1,3,5-triazine-2,4,6-triyl)tribenzamide (S-T) and 4,4',4â³-(benzene-1,3,5-triyl)tribenzamide (S-B). We first demonstrate in the homopolymerization of the two individual monomers that a subtle change from the central triazine to benzene in the chemical structure of the monomers significantly affects the properties of the resulting homopolymers in solution. Homopolymers formed by S-T exhibit enhanced stability in comparison to S-B. More importantly, through a combination of spectroscopic analysis and theoretical simulation, we reveal the complex process of copolymerization: S-T aggregates into homopolymers at elevated temperature, and upon slow cooling S-B gradually intercalates into the copolymers, to finally give copolymers with almost 80% alternating bonds at 10 °C. The formation of the predominantly alternating copolymers is plausibly contributed by preferred heterointeractions between triazine and benzene cores in S-T and S-B, respectively, at lower temperatures. Overall, this work unravels the complexity of a supramolecular copolymerization process where an intermediate heterointeraction (higher than one homointeraction and lower than the other homointeraction) presents and proposes a general method to elucidate the microstructures of copolymers responsive to temperature changes.
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Discrete block co-oligomers (BCOs) assemble into highly ordered nanostructures, which adopt a variety of morphologies depending on their environment. Here, we present a series of discrete oligodimethylsiloxane-oligoproline (oDMS-oPro) BCOs with varying oligomer lengths and proline end-groups, and study the nanostructures formed in both bulk and solution. The conjugation of oligoprolines to apolar siloxanes permits a study of the aggregation behavior of oligoproline moieties in a variety of solvents, including a highly apolar solvent like methylcyclohexane. The apolar solvent is more reminiscent of the polarity of the siloxane bulk, which gives insights into the supramolecular interactions that govern both bulk and solution assembly processes of the oligoproline. This extensive structural characterization allows the bridging of the gap between solution and bulk assembly. The interplay between the aggregation of the oligoproline block and the phase segregation induced by the siloxane drives the assembly. This gives rise to disordered, micellar microstructures in apolar solution and crystallization-driven lamellar nanostructures in the bulk. While most di- and triblock co-oligomers adopt predictable morphological features, one of them, oDMS15-oPro6-NH2, exhibits pathway complexity leading to gel formation. The pathway selection in the complex interplay between aggregation and phase segregation gives rise to interesting material properties.
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Oligopéptidos/química , Polímeros/química , Prolina/química , Siloxanos/química , Soluciones/química , Dicroismo Circular , Cristalización , Nanoestructuras/química , Oligopéptidos/metabolismo , Polímeros/metabolismoRESUMEN
The conformational analysis of a 2,4-bis(4-dialkylamino-2-amido)phenyl squaraine dye revealed the presence of two rotational isomers at room temperature. Combination of spectroscopic and computational techniques showed that the rotational barrier is influenced by hydrogen bonds between the amido substituents and the oxygen atoms at the quadratic core. Even small amounts of trifluoroacetic acid interfered with the intramolecular hydrogen bond formation and accelerated the interconversion of the conformers.
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Stereoselective organocatalytic C-C bond formations that tolerate N-heterocycles are valuable since these moieties are common motifs in numerous chiral bioactive compounds. Such transformations are, however, challenging since N-heterocyclic moieties can interfere with the catalytic reaction. Here, we present a peptide that catalyzes conjugate addition reactions between aldehydes and nitroolefins bearing a broad range of different N-heterocyclic moieties with basic and/or H-bonding sites in excellent yields and stereoselectivities. Tuning of the pyramidalization direction of the enamine intermediate enabled the high stereoselectivity.
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Despite intense interest in amine-catalyzed stereoselective reactions, high catalyst loadings of ≥10 mol % are still common and either due to low reactivity or catalyst deactivation. Yet, few deactivation pathways are well understood. Here, we unraveled the deactivation of secondary amines by undesired aldol reaction. Mechanistic studies with peptide and prolinol silyl ether catalysts showed the generality of this so-far underappreciated catalyst deactivation pathway. The insights enabled conjugate addition reactions between aldehydes and nitroolefins on a multigram scale in the absence of solvent-conditions that are attractive as environmentally benign processes-with excellent product yields and stereoselectivities in the presence of as little as 0.1 mol % of a chemoselective peptidic catalyst.
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Trans/cis isomerization of Xaa-Pro bonds is key for the structure and function of several enzymes. In recent years, numerous versatile peptidic catalysts have been developed that bear Xaa-Pro amide bonds. Due to the many degrees of freedom within even short peptides, the design and optimization of peptidic catalysts by rational structural modifications is difficult. We envisioned that control over the trans/cis amide bond ratio may provide a tool to optimize the catalytic performance of peptidic catalysts. Here, we investigated the influence of the amide bond conformation on the stereoselectivity of H-Pro-Pro-Xaa-NH2-type peptidic catalysts in conjugate addition reactions. The middle Pro residue within the tripeptides was replaced with analogues of varying ring sizes (azetidine carboxylic acid, Aze, and piperidine carboxylic acid, Pip) to produce different trans/cis ratios in different solvents. The studies revealed a direct correlation between the trans/cis amide bond ratio and the enantio- and diastereoselectivity of structurally related peptidic catalysts. These insights led to the identification of H-d-Pro-Pip-Glu-NH2 as a highly reactive and stereoselective amine-based catalyst that allows C-C bond formations to be performed in the presence of as little as 0.05 mol %, which is the lowest catalyst loading yet achieved for organocatalyzed reactions that rely on an enamine-based mechanism.
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Péptidos/química , Amidas/química , Catálisis , Conformación Proteica , Estereoisomerismo , Especificidad por SustratoRESUMEN
From an enzymatic perspective, there is a general notion that the bigger and more complex a catalytically active peptide is the more enzyme-like and the better it should become. But is this really true? We have tackled this question firstly by screening split-and-mix-libraries of tri- and tetrapeptides for members that catalyze aldol reactions. Then, the catalytic performance of all possible diastereoisomers of related tri- and tetrapeptidic catalysts of the type H-Pro-Pro-Glu/Asp-NH2 and H-Pro-Pro-Glu/Asp-Pro-NH2 in aldol and conjugate addition reactions was compared.
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Oligopéptidos/química , Catálisis , Estructura MolecularRESUMEN
Peptides have been established as modular catalysts for various transformations. Still, the vast number of potential amino acid building blocks renders the identification of peptides with desired catalytic activity challenging. Here, we develop a machine-learning workflow for the optimization of peptide catalysts. First-in a hypothetical competition-we challenged our workflow to identify peptide catalysts for the conjugate addition reaction of aldehydes to nitroolefins and compared the performance of the predicted structures with those optimized in our laboratory. On the basis of the positive results, we established a universal training set (UTS) containing 161 catalysts to sample an in silico library of â¼30,000 tripeptide members. Finally, we challenged our machine learning strategy to identify a member of the library as a stereoselective catalyst for an annulation reaction that has not been catalyzed by a peptide thus far. We conclude with a comparison of data-driven versus expert-knowledge-guided peptide catalyst optimization.
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Enantioselective iridium-catalyzed allylic substitutions were used to prepare N-allyl hydroxamic acid derivatives that were suitable for ring-closing metathesis, giving N-methoxylactams. Reactions of these derivatives with Grignard or organolithium compounds gave hemiaminals, which could be reduced diastereoselectively via acyliminium intermediates to give cis-piperidines or cis-pyrrolidines with substituents in the 2,6- or 2,5-positions, respectively. In addition, compounds with a quaternary carbon center could be synthesized by corresponding reactions with potassium cyanide/AcOH. The procedures were applied in the syntheses of alkaloids (-)-209D and (+)-prosophylline.
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In dynamic polyamide networks, 1,2,4,5-benzene tetraamide (B4A) units act simultaneously as a dynamic covalent cross-linker and as supramolecular stacking motif. This results in materials with a rubbery plateau modulus that is about 20 times higher than that of a corresponding reference network in which the supramolecular interaction is suppressed. In branched polyamides with the same B4A dynamic motif, hydrogen bonding and stacking lead to strong and reversible supramolecular networks, whereas a branched polyamide with the nonstacking reference linker is a viscous liquid under the same conditions. Wide-angle X-ray scattering and variable-temperature infrared experiments confirm that covalent cross-linking and stacking cooperatively contribute to the dynamics of the network. Stress relaxation in the reference network is dominated by a single mode related to the dynamic covalent chemistry, whereas relaxation in the B4A network has additional modes assigned to the stacking dynamics.
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Many stereoselective peptide catalysts have been established. They consist, like nature's catalysts, of amino acids but have significantly lower molecular weights than enzymes. Whereas enzymes operate with exquisite chemoselectivity in complex biological environments, peptide catalysts are used in pure organic solvents and at higher concentrations. Can a peptide catalyst exhibit chemoselectivity reminiscent of enzymes? Here, we investigated the properties of tripeptide catalysts in complex mixtures in hydrophobic and aqueous solvents. We challenged the catalysts with biomolecules bearing functional groups that could interfere by coordination or reaction with the peptide, the substrates, or intermediates. H-dPro-αMePro-Glu-NHC12H15 emerged through tailoring of the trans/cis ratio of the tertiary amide as a conformationally well-defined tripeptide that catalyzes C-C bond formations with high reactivity and stereoselectivity - regardless of the solvent and compound composition. The chemoselectivity of the tripeptide is so high that it even catalyzes reactions in cell lysates. The findings provoke the question of the potential role of peptide catalysis in nature and during the evolution of enzymes.
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Machine learning has greatly facilitated the analysis of medical data, while the internal operations usually remain intransparent. To better comprehend these opaque procedures, a convolutional neural network for optical coherence tomography image segmentation was enhanced with a Traceable Relevance Explainability (T-REX) technique. The proposed application was based on three components: ground truth generation by multiple graders, calculation of Hamming distances among graders and the machine learning algorithm, as well as a smart data visualization ('neural recording'). An overall average variability of 1.75% between the human graders and the algorithm was found, slightly minor to 2.02% among human graders. The ambiguity in ground truth had noteworthy impact on machine learning results, which could be visualized. The convolutional neural network balanced between graders and allowed for modifiable predictions dependent on the compartment. Using the proposed T-REX setup, machine learning processes could be rendered more transparent and understandable, possibly leading to optimized applications.