ACS Publications最新文献

A nonheme iron complex bearing the tris(6-phenylamino-pyridyl)methylamine (TPA^NHPh) ligand with appended hydrogen bond (H-bond) groups displays facile O₂ reactivity to form a monomeric Fe(III)OH complex, which can release •OH via rebound to a carbon radical. An analogous compound without H-bonds, based on tris(6-methylpyridyl)methylamine (TPA^Me), exhibits minimal O₂ reactivity, forming a Fe(III)₂(μ-O)(μ-OH) dimer, which also reacts with carbon-based radicals. The H-bonding system enables O₂ binding and activation at weakly reducing nonheme iron complexes, highlighting a cooperative role of secondary sphere units to facilitate reactions at atypical redox environments.

Validating the performance of exchange-correlation functionals is vital to ensure the reliability of density functional theory (DFT) calculations. Typically, these validations involve benchmarking data sets. Currently, such data sets are usually assembled in an unprincipled manner, suffering from uncontrolled chemical bias, and limiting the transferability of benchmarking results to a broader chemical space. In this work, a data-efficient solution based on active learning is explored to address this issue. Focusing─as a proof of principle─on pericyclic reactions, we start from the BH9 benchmarking data set and design a chemical reaction space around this initial data set by combinatorially combining reaction templates and substituents. Next, a surrogate model is trained to predict the standard deviation of the activation energies computed across a selection of 20 distinct DFT functionals. With this model, the designed chemical reaction space is explored, enabling the identification of challenging regions, i.e., regions with large DFT functional divergence, for which representative reactions are subsequently acquired as additional training points. Remarkably, it turns out that the function mapping the molecular structure to functional divergence is readily learnable; convergence is reached upon the acquisition of fewer than 100 reactions. With our final updated model, a more challenging─and arguably more representative─pericyclic benchmarking data set is curated, and we demonstrate that the functional performance has changed significantly compared to the original BH9 subset.

Metal hydrides play a significant role in a variety of reactions, including chemical, electrochemical, and photochemical CO₂ reduction. Molecular metal hydrides have the distinct advantage of allowing tunability of their hydricities by rational ligand modifications, with more electron-rich metal hydrides being in general more hydridic. We report here a new approach to generate highly hydridic metal hydrides of the type [Ru(tpy)(LL)(H)]ⁿ⁺ by introducing electron-withdrawing substituents into the backbone of the bidentate LL ligand. This strategy enables the generation of the metal hydride [Ru(tpy)(LL)(H)]⁺ at mild negative potentials and further one-electron reduction to the more hydridic [Ru(tpy)(LL)(H)]⁰ at a potential window that is redox silent for the more electron-rich metal hydride analogue [Ru(tpy)(bpy)(H)]⁺. In addition, formate release takes place from the hydride transfer adducts [Ru---HCOO)(tpy)(LL)]⁰ rather than from the corresponding formato complexes [Ru(tpy)(LL)(OCHO)]⁰, which would require further reduction to [Ru(tpy)(LL)(OCHO)]^- as demonstrated by IR spectroelectrochemistry. The parent [Ru(tpy)(LL)(CH₃CN)]ⁿ⁺ solvento complexes were then tested as catalysts for the reduction of CO₂ to formate in a four-component homogeneous photochemical approach driven by a Ru(II) sensitizer. The results showed selective (>88%) formate production with a record turnover number of ∼50,000 and record turnover frequency of 4.4 s^-1 when compared to other molecular catalysts.

In this work, we study the possibility to extend electronic structure simulations for electrocatalysis by explicit solvation models. In previous work, we proposed a simulation scheme that explicitly includes the effects of pH and electrochemical potential in density functional theory (DFT) simulations with implicit solvation. Based on calculations of protonation and oxidation reactions, the pH and electrochemical potential can be included given appropriate reference values. In this work, we compute the pK_a values and oxidation potentials for a series of transition metal aquo complexes and compare the results including implicit, explicit static and explicit dynamic (AIMD) models for the aqueous solvent and compare vs experimental pK_a and redox potential data. This allows the construction of a pK_a/redox potential scale that can in principle be extrapolated to the simulation of other transition metal-based materials. An explicit dynamic solvent model is then proposed and applied to a model system for iridium oxide-based catalysts for the oxygen evolution reaction. We outline the advantages and disadvantages of the different approaches and demonstrate that, at the expense of a larger computational effort, the microsolvation environment of a given model can be described in a robust way using a limited amount of solvent molecules and AIMD. Especially for reactions in which water is solvent and reactant like the oxygen evolution reaction (OER) or oxygen reduction reaction (ORR), this model provides a more detailed and complete description that can be exploited in mechanistic studies.

A novel family of antibiotics, MDN-0057 to MDN-0060 (1-4), was isolated from liquid cultures of the fungus Ophiosphaerella korrae. These compounds incorporate two isocyanide groups in their complex structures that were elucidated by extensive spectroscopic analyses, including HRESIMS, and 1D and 2D NMR experiments. The relative configurations were determined by using J-based configuration analyses and the interpretation of key NOESY correlations consistent with the existence of a major conformation in solution. Mosher ester derivatization analysis allowed the establishment of their absolute configurations. All four compounds displayed in vitro antibacterial activity with a broad spectrum against Gram-negative pathogens.

Cross-link containing products from ribosomally synthesized and post-translationally modified peptides (RiPPs) are generated by radical SAM enzymes (rSAM). Here, we bioinformatically expanded rSAM enzymes based on the known families StrB, NxxcB, WgkB, RrrB, TqqB and GggB. Through in vivo functional studies in E. coli, the newly identified enzyme WprB from Xenorhabdus sp. psl was found to catalyze formation of a cross-link between Trp-C5 and Arg-Cγ at three WPR motifs on the precursor peptide WprA. This represents the first report of this type of cross-link by rSAM enzymes.

The treatment of critically ill patients has made great strides in the past few decades due to the rapid development of indwelling medical devices. Despite immense advancements in the design of these devices, indwelling medical device-associated infections and thrombosis are two major clinical problems that may lead to device failure and compromise clinical outcomes. Antibiotics are the current treatment choice for these infections; however, the global emergence of antibiotic-resistance and their biofilm formation abilities complicate the management of such infections. Moreover, systemic administration of anticoagulants has been used to counter medical device-induced thrombosis, but a range of serious adverse effects associated with all types of available anticoagulants entails exploring alternative options to counter device-associated thrombosis. In this study, bacteriophages (phages) were covalently immobilized on polydimethylsiloxane (PDMS) surface containing the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine (SNAP) via SNAP impregnation method. This dual strategy combines the targeted antibacterial activity of phages against bacterial pathogens with the antibacterial-antithrombotic activity of NO released from the polymeric surface. The PDMS, SNAP-PDMS, phage-immobilized PDMS (PDMS-Phage), and phage-immobilized SNAP-PDMS (SNAP-PDMS-Phage) surfaces were characterized for their surface topology, elemental composition, contact angle, SNAP loading, NO release and phage distribution. SNAP-PDMS and SNAP-PDMS-Phage surfaces showed similar and consistent NO release profiles over 24 h of incubation. Immobilization of whole phages on PDMS and SNAP-PDMS was achieved with densities of 2.4 ± 0.54 and 2.1 ± 0.33 phages μm^-2, respectively. Immobilized phages were found to retain their activity, and SNAP-PDMS-Phage surfaces showed a significant reduction in planktonic (99.99 ± 0.08%) as well as adhered (99.80 ± 0.05%) Escherichia coli as compared to controls in log killing assays. The SNAP-PDMS-Phage surfaces also exhibited significantly reduced platelet adhesion by 64.65 ± 2.95% as compared to control PDMS surfaces. All fabricated surfaces were found to be nonhemolytic and do not exhibit any significant cytotoxic effects toward mammalian fibroblast cells. This study is the first of its kind to demonstrate the combinatorial pertinence of phages and NO to prevent antibiotic-resistant/sensitive bacterial infections and thrombosis associated with indwelling medical devices.

The purpose of this study was to investigate the effect of the pH and buffer capacity (β) of physiological bicarbonate buffer solutions (BCB) on drug precipitation. The precipitation profiles of poorly soluble drugs in BCB were evaluated by using a pH-shift precipitation test. Phosphate buffer solutions (PPB) were used for comparison. Two weakly acidic drugs (pK_a: 4.9 and 7.0) and two weakly basic drugs (pK_a: 6.1 and 8.3) were used as model drugs. The bulk phase pH value (pH_bulk) and β values were set to cover the physiological range in the small intestines (pH: 5.5 to 7.5, β: 2.2 to 17.6 mM/ΔpH). A floating lid was used to maintain the pH_bulk of BCB to avoid CO₂ loss. It was also applied to PPB to align the experimental conditions. Each drug was completely dissolved in HCl (pH 3.0, for weakly basic drugs) or NaOH (pH 11.0, for weakly acidic drugs) solutions (450 mL, 50 rpm, 37 °C). The pH_bulk value was then shifted to the neutral pH region by adding a 10-fold concentrated buffer solution (50 mL, final volume of 500 mL). The initial total drug concentration (neutral + ionized species) was set so that the concentration and supersaturation ratio of the neutral species were the same under all pH_bulk conditions. The solid forms of the precipitates were determined by powder X-ray diffraction and differential scanning calorimetry. In BCB, as pH_bulk was increased above (for weakly acidic drugs) or decreased below (for weakly basic drugs) the drug pK_a value, the precipitation of the free form solid became slower. As β was increased, drug precipitation in BCB became faster. Drug precipitation in PPB was faster than that in BCB and less affected by pH_bulk and β. In BCB, at pH_bulk at which a drug is ionizable, the surface pH of the precipitating particles can differ from pH_bulk because of the slow hydration process of CO₂. In conclusion, pH_bulk and β affected the precipitation of weakly acidic and basic drugs in BCB. As BCB is a physiological buffer in the small intestine, it should be used for precipitation studies of weakly acidic and basic drugs.

ConspectusDuring the past few years, the interest among organic synthesis practitioners in the use of sulfonium salts has exponentially growth. This can arguably be attributed to a series of specific factors: (a) The recent development of more direct and efficient protocols for the synthesis of these species, which make sulfonium reagents of a wide structural variety easily available in multigram scale. (b) The recognition that the reactivity of these salts resembles that of hypervalent iodine compounds, and therefore, they can be used as effective replacement of such species in most of their applications. (c) Their intrinsic thermal stability and tolerance to air and moisture, which clearly surpass that of I(III)-reagents of analogue reactivity, and facilitate their purification, isolation as well-defined species, storage, and safely handling on larger scale. (d) Finally, the possibility to further functionalize sulfonium salts once the sulfur-containing platform has been incorporated. Specifically, this last synthetic approach is not trivial when working with hypervalent I(III)-species and facilitates the access to sulfonium salts with no counterpart in the I(III) realm.This renewed interest in sulfonium salts has led to the improvement of already existing transformations as well as to the discovery of unprecedented ones; in particular, by the development of protocols that incorporate sulfonium salts as partners in traditional cross-coupling and C-H activation steps or combine them with more modern technologies such as photocatalysis or electrosynthesis. In this Account, the reactivity of a series of sulfonium salts originally prepared in our laboratory will be outlined and compared to their I(III)-counterparts. Some of these reagents are now commercially available, and their use has started to spread widely across the synthetic chemistry community, helping to speed the process of identification of potentially bioactive products or new functionaliced materials. However, challenges still remain. The development of sulfonium reagents characterized by an optimal balance between reactivity and site-selectivity, or showing broader compatibility toward sensitive functional groups is still a need. In addition, the intrinsic stability of sulfonium salts often makes necessary the use of (sophisticated) catalysts that activate the latent reactivity hidden in their structures. Although a priori one can see this fact as a disadvantage, it might actually be decisive to harvest the full synthetic potential of sulfonium salts because their thermal stability will surely facilitate the preparation of operational reagents with no counterpart in the context of I(III)-chemistry. If this becomes true, sulfonium salts may contribute to the expediting of retrosynthetic disconnections that, to date, are impossible.