Nitro-sulfinate Reductive Coupling to Access (Hetero)aryl Sulfonamides.

A method to assemble (hetero)aryl sulfonamides via the reductive coupling of aryl sulfinates and nitroarenes is reported. Various reducing conditions with sodium bisulfite and with or without tin(II) chloride in DMSO were developed using an ultrasound bath to improve reaction homogeneity and mixing. A range of (hetero)aryl sulfonamides bearing a selection of functional groups were prepared, and the mechanism of the transformation was investigated. These investigations have led us to propose the formation of nitrosoarene intermediates, which were established via an independent molecular coupling strategy.

A direct link between active matter and sheared granular systems.

The similarity in mechanical properties of dense active matter and sheared amorphous solids has been noted in recent years without a rigorous examination of the underlying mechanism. We develop a mean-field model that predicts that their critical behavior-as measured by their avalanche statistics-should be equivalent in infinite dimensions up to a rescaling factor that depends on the correlation length of the applied field. We test these predictions in two dimensions using a numerical protocol, termed "athermal quasistatic random displacement," and find that these mean-field predictions are surprisingly accurate in low dimensions. We identify a general class of perturbations that smoothly interpolates between the uncorrelated localized forces that occur in the high-persistence limit of dense active matter and system-spanning correlated displacements that occur under applied shear. These results suggest a universal framework for predicting flow, deformation, and failure in active and sheared disordered materials.

SNP data reveals the complex and diverse evolutionary history of the blue-ringed octopus genus (Octopodidae: Hapalochlaena) in the Asia-Pacific.

The blue-ringed octopus species complex (Hapalochlaena spp.), known to occur from Southern Australia to Japan, currently contains four formally described species (Hapalochlaena maculosa, Hapalochlaena fasciata, Hapalochlaena lunulata and Hapalochlaena nierstraszi). These species are distinguished based on morphological characters (iridescent blue rings and/or lines) along with reproductive strategies. However, the observation of greater morphological diversity than previously captured by the current taxonomic framework indicates that a revision is required. To examine species boundaries within the genus we used mitochondrial (12S rRNA, 16S rRNA, cytochrome c oxidase subunit 1 [COI], cytochrome c oxidase subunit 3 [COIII] and cytochrome b [Cytb]) and genome-wide SNP data (DaRT seq) from specimens collected across its geographic range including variations in depth from 3 m to >100 m. This investigation indicates substantially greater species diversity present within the genus Hapalochlaena than is currently described. We identified 10,346 SNPs across all locations, which when analysed support a minimum of 11 distinct clades. Bayesian phylogenetic analysis of the mitochondrial COI gene on a more limited sample set dates the diversification of the genus to âˆ¼30 mya and corroborates eight of the lineages indicated by the SNP analyses. Furthermore, we demonstrate that the diagnostic lined patterning of H. fasciata found in North Pacific waters and NSW, Australia is polyphyletic and therefore likely the result of convergent evolution. Several "deep water" (>100 m) lineages were also identified in this study with genetic convergence likely to be driven by external selective pressures. Examination of morphological traits, currently being undertaken in a parallel morphological study, is required to describe additional species within the complex.

The dimensional evolution of structure and dynamics in hard sphere liquids.

The formulation of the mean-field infinite-dimensional solution of hard sphere glasses is a significant milestone for theoretical physics. How relevant this description might be for understanding low-dimensional glass-forming liquids, however, remains unclear. These liquids indeed exhibit a complex interplay between structure and dynamics, and the importance of this interplay might only slowly diminish as dimension d increases. A careful numerical assessment of the matter has long been hindered by the exponential increase in computational costs with d. By revisiting a once common simulation technique involving the use of periodic boundary conditions modeled on Dd lattices, we here partly sidestep this difficulty, thus allowing the study of hard sphere liquids up to d = 13. Parallel efforts by Mangeat and Zamponi [Phys. Rev. E 93, 012609 (2016)] have expanded the mean-field description of glasses to finite d by leveraging the standard liquid-state theory and, thus, help bridge the gap from the other direction. The relatively smooth evolution of both the structure and dynamics across the d gap allows us to relate the two approaches and to identify some of the missing features that a finite-d theory of glasses might hope to include to achieve near quantitative agreement.

Memory Formation in Jammed Hard Spheres.

Liquids equilibrated below an onset condition share similar inherent states, while those above that onset have inherent states that markedly differ. Although this type of materials memory was first reported in simulations over 20 years ago, its physical origin remains controversial. Its absence from mean-field descriptions, in particular, has long cast doubt on its thermodynamic relevance. Motivated by a recent theoretical proposal, we reassess the onset phenomenology in simulations using a fast hard sphere jamming algorithm and find it to be both thermodynamically and dimensionally robust. Remarkably, we also uncover a second type of memory associated with a Gardner-like regime of the jamming algorithm.

Photoredox-Catalyzed Dehydrogenative Csp3-Csp2 Cross-Coupling of Alkylarenes to Aldehydes in Flow.

Executing photoredox reactions in flow offers solutions to frequently encountered issues regarding reproducibility, reaction time, and scale-up. Here, we report the transfer of a photoredox-catalyzed benzylic coupling of alkylarenes to aldehydes to a flow chemistry setting leading to improvements in terms of higher concentration, shorter residence times, better yields, ease of catalyst preparation, and enhanced substrate scope. Its applicability has been demonstrated by a multi-gram-scale reaction using high-power light-emitting diodes (LEDs), late-stage functionalization of selected active pharmaceutical ingredients (APIs), and also a photocatalyst recycling method.

Thermodynamic stability of hard sphere crystals in dimensions 3 through 10.

Although much is known about the metastable liquid branch of hard spheres-from low dimension d up to [Formula: see text]-its crystal counterpart remains largely unexplored for [Formula: see text]. In particular, it is unclear whether the crystal phase is thermodynamically stable in high dimensions and thus whether a mean-field theory of crystals can ever be exact. In order to determine the stability range of hard sphere crystals, their equation of state is here estimated from numerical simulations, and fluid-crystal coexistence conditions are determined using a generalized Frenkel-Ladd scheme to compute absolute crystal free energies. The results show that the crystal phase is stable at least up to [Formula: see text], and the dimensional trends suggest that crystal stability likely persists well beyond that point.

Enantioselective counter-anions in photoredox catalysis: the asymmetric cation radical Diels-Alder reaction.

Control of absolute stereochemistry in radical and ion radical transformations is a major challenge in synthetic chemistry. Herein, we report the design of a photoredox catalyst system comprised of an oxidizing pyrilium salt bearing a chiral N-triflyl phosphoramide anion. This class of chiral organic photoredox catalysts is able to catalyze the formation of cation radical-mediated Diels-Alder transformations in up to 75:25 e.r. in both intramolecular and intermolecular examples.

Echoes of the Glass Transition in Athermal Soft Spheres.

Recent theoretical advances have led to the creation of a unified phase diagram for the thermal glass and athermal jamming transitions. This diagram makes clear that, while related, the mode-coupling-or dynamic-glass transition is distinct from the jamming transition, occurring at a finite temperature and significantly lower density than the jamming transition. Nonetheless, we demonstrate a prejamming transition in athermal frictionless spheres which occurs at the same density as the mode-coupling transition and is marked by percolating clusters of locally rigid particles. At this density in both the thermal and athermal systems, individual motions of an extensive number of particles become constrained, such that only collective motion is possible. This transition, which is well below jamming, exactly matches the definition of collective behavior at the dynamical transition of glasses. Thus, we reveal that the genesis of rigidity in both thermal and athermal systems is governed by the same underlying topological transition in their shared configuration space.

Towards More Efficient, Greener Syntheses through Flow Chemistry.

Technological advances have an important role in the design of greener synthetic processes. In this Personal Account, we describe a wide range of thermal, photochemical, catalytic, and biphasic chemical transformations examined by our group. Each of these demonstrate how the merits of a continuous flow synthesis platform can align with some of the goals put forth by the Twelve Principles of Green Chemistry. In particular, we illustrate the potential for improved reaction efficiency in terms of atom economy, product yield and reaction rates, the ability to design synthetic process with chemical and solvent waste reduction in mind as well as highlight the benefits of the real-time monitoring capabilities in flow for highly controlled synthetic output.

Synthesis and Utilization of Nitroalkyne Equivalents in Batch and Continuous Flow.

We report a method for overcoming the low stability of nitroalkynes through the development of nitrated vinyl silyltriflate equivalents. Because of their instability, nitroalkynes have only rarely been utilized in synthesis. The reactivity of these silyltriflates, which are prepared in situ, is exemplified by dipolar cycloaddition reactions with nitrones to give highly substituted 4-nitro-4-isoxazolines in high yields. This approach has proven general for several different alkyl and aryl substituted alkynes. In order to minimize the accumulation of potentially hazardous reaction intermediates, we have also developed a continuous flow variant of this method that is capable of carrying out the entire reaction sequence in a good yield and a short residence time.

Geometric order parameters derived from the Voronoi tessellation show signatures of the jamming transition.

A jammed packing of frictionless spheres at zero temperature is perfectly specified by the network of contact forces from which mechanical properties can be derived. However, we can alternatively consider a packing as a geometric structure, characterized by a Voronoi tessellation which encodes the local environment around each particle. We find that this local environment characterizes systems both above and below jamming and changes markedly at the transition. A variety of order parameters derived from this tessellation carry signatures of the jamming transition, complete with scaling exponents. Furthermore, we define a real space geometric correlation function which also displays a signature of jamming. Taken together, these results demonstrate the validity and usefulness of a purely geometric approach to jamming.

Geometric signatures of jamming in the mechanical vacuum.

Jamming has traditionally been studied as a mechanical phenomenon and characterized with mechanical order parameters. However, this approach is not meaningful in the "mechanical vacuum" of systems below jamming in which all mechanical properties are precisely zero. We find that the network of nearest neighbors and the geometric structure of the Voronoi cell contain well-defined and meaningful order parameters for jamming, which exist on both sides of the transition. We observe critical exponents in these order parameters and an upper critical dimension of 3. Further, we present evidence for a new incipient-jamming phase below the jamming transition marked by additional symmetry in the Voronoi tessellation.

Dynamics and fluctuations of minimally structured glass formers.

The mean-field theory (MFT) of simple structural glasses, which is exact in the limit of infinite spatial dimensions, d→∞, offers theoretical insight as well as quantitative predictions about certain features of d=3 systems. In order to more systematically relate the behavior of physical systems to MFT, however, various finite-d effects need to be accounted for. Although some efforts along this direction have already been undertaken, theoretical and technical challenges hinder progress. A general approach to sidestep many of these difficulties consists of simulating minimally structured models whose behavior smoothly converges to that described by the MFT as d increases, so as to permit a controlled dimensional extrapolation. Using this approach, we here extract the small fluctuations around the dynamical MFT captured by a standard liquid-state observable, the non-Gaussian parameter α_{2}. The results provide insight into the physical origin of these fluctuations as well as a quantitative reference with which to compare observations for more realistic glass formers.

Critical-like slowdown in thermal soft-sphere glasses via energy minimization.

Using hybrid molecular dynamics/SWAP Monte Carlo (MD/SMC) simulations, we show that while the terminal relaxation times τ(ϕ) for FIRE energy minimization of soft-sphere glasses can decrease by orders of magnitude as sample equilibration proceeds and the jamming density ϕ_{J} increases, they always scale as τ(ϕ)∼(ϕ_{J}-ϕ)^{-2}∼[Z_{iso}-Z_{ms}(τ)]^{-2}, where Z_{iso}=2d and Z_{ms}(τ) is the average coordination number of particles satisfying a minimal local mechanical stability criterion (Z≥d+1) at the top of the final potential-energy-landscape (PEL) sub-basin the system encounters. This scaling allows us to collapse τ datasets that look very different when plotted as a function of ϕ, and to address a closely related question: how does the character of the PEL basins that dense thermal glasses most typically occupy evolve as the glasses age at constant ϕ and T?

Jamming, relaxation, and memory in a minimally structured glass former.

Structural glasses form through various out-of-equilibrium processes, including temperature quenches, rapid compression (crunches), and shear. Although each of these processes should be formally understandable within the recently formulated dynamical mean-field theory (DMFT) of glasses, the numerical tools needed to solve the DMFT equations up to the relevant physical regime do not yet exist. In this context, numerical simulations of minimally structured (and therefore mean-field-like) model glass formers can aid the search for and understanding of such solutions, thanks to their ability to disentangle structural from dimensional effects. We study here the infinite-range Mari-Kurchan model under simple out-of-equilibrium processes, and we compare results with the random Lorentz gas [J. Phys. A 55, 334001 (2022)10.1088/1751-8121/ac7f06]. Because both models are mean-field-like and formally equivalent in the limit of infinite spatial dimensions, robust features are expected to appear in the DMFT as well. The comparison provides insight into temperature and density onsets, memory, as well as anomalous relaxation. This work also further enriches the algorithmic understanding of the jamming density.

Local stability of spheres via the convex hull and the radical Voronoi diagram.

Jamming is an emergent phenomenon wherein the local stability of individual particles percolates to form a globally rigid structure. However, the onset of rigidity does not imply that every particle becomes rigid, and indeed some remain locally unstable. These particles, if they become unmoored from their neighbors, are called rattlers, and their identification is critical to understanding the rigid backbone of a packing, as these particles cannot bear stress. The accurate identification of rattlers, however, can be a time-consuming process, and the currently accepted method lacks a simple geometric interpretation. In this manuscript, we propose two simpler classifications of rattlers in hard sphere systems based on the convex hull of contacting neighbors and the maximum inscribed sphere of the radical Voronoi cell, each of which provides geometric insight into the source of their instability. Furthermore, the convex hull formulation can be generalized to explore stability in hyperstatic soft sphere packings, spring networks, nonspherical packings, and mean-field non-central-force potentials.

Parallel multi-droplet platform for reaction kinetics and optimization.

We present an automated droplet reactor platform possessing parallel reactor channels and a scheduling algorithm that orchestrates all of the parallel hardware operations and ensures droplet integrity as well as overall efficiency. We design and incorporate all of the necessary hardware and software to enable the platform to be used to study both thermal and photochemical reactions. We incorporate a Bayesian optimization algorithm into the control software to enable reaction optimization over both categorical and continuous variables. We demonstrate the capabilities of both the preliminary single-channel and parallelized versions of the platform using a series of model thermal and photochemical reactions. We conduct a series of reaction optimization campaigns and demonstrate rapid acquisition of the data necessary to determine reaction kinetics. The platform is flexible in terms of use case: it can be used either to investigate reaction kinetics or to perform reaction optimization over a wide range of chemical domains.

Early Clinical Development of Lufotrelvir as a Potential Therapy for COVID-19.

Lufotrelvir was designed as a first in class 3CL protease inhibitor to treat COVID-19. Development of lufotrelvir was challenged by its relatively poor stability due to its propensity to epimerize and degrade. Key elements of process development included improvement of the supply routes to the indole and lactam fragments, a Claisen addition to homologate the lactam, and a subsequent phosphorylation reaction to prepare the prodrug as well as identification of a DMSO solvated form of lufotrelvir to enable long-term storage. As a new approach to preparing the indole fragment, a Cu-catalyzed C-O coupling using oxalamide ligands was demonstrated. The control of process-related impurities was essential to accommodate the parenteral formulation. Isolation of an MEK solvate followed by the DMSO solvate ensured that all impurities were controlled appropriately.