Fast free energy estimates from λ-dynamics with bias-updated Gibbs sampling.

Relative binding free energy calculations have become an integral computational tool for lead optimization in structure-based drug design. Classical alchemical methods, including free energy perturbation or thermodynamic integration, compute relative free energy differences by transforming one molecule into another. However, these methods have high operational costs due to the need to perform many pairwise perturbations independently. To reduce costs and accelerate molecular design workflows, we present a method called λ-dynamics with bias-updated Gibbs sampling. This method uses dynamic biases to continuously sample between multiple ligand analogues collectively within a single simulation. We show that many relative binding free energies can be determined quickly with this approach without compromising accuracy. For five benchmark systems, agreement to experiment is high, with root mean square errors near or below 1.0 kcal mol-1. Free energy results are consistent with other computational approaches and within statistical noise of both methods (0.4 kcal mol-1 or less). Notably, large efficiency gains over thermodynamic integration of 18-66-fold for small perturbations and 100-200-fold for whole aromatic ring substitutions are observed. The rapid determination of relative binding free energies will enable larger chemical spaces to be more readily explored and structure-based drug design to be accelerated.

Interplay Between Applied Force and Radical Attack in the Mechanochemical Chain Scission of Poly(acrylic acid).

Sonication and radical attack are both known to contribute to breaking down polymers. Quantum chemical models show how the two can operate together, where radical attack is shown to reduce the effective tensile strength of the material. Using poly(acrylic acid) (PAA) as a model, hydrogen atom abstraction in PAA was found to improve the thermodynamics and kinetics of bond scission. The force needed for bond rupture was estimated to decrease from 4.7 to 2.5 nN. This occurs because hydrogen atom abstraction drastically alters the potential energy surface of the scissile bond. Bond activation was also found to decrease the magnitude of the changes in bond scission geometries and energetics in response to the applied force. While radical abstraction is overall beneficial for mechanical bond scission, the polymer also becomes less responsive to force than the unactivated polymer. This finding places upper limits on the efficacy of the synergy between radical attack and applied force. In addition, the importance of reaction pathway optimization is also shown, where comparisons to the COGEF method show the latter to be qualitatively incapable of describing chain scission after radical activation.

Activation Mechanism of Nickel(0) N-Heterocyclic Carbene Catalysts Stabilized by Fumarate Ligands.

Nickel(0) catalysts of N-heterocyclic carbenes (NHCs) that are stabilized by electron-deficient alkenes possess desirable properties of air tolerance and ease of handling while also retaining high catalytic activities. Since catalyst stability often comes at the expense of catalytic activity, we have undertaken a detailed study of the activation mechanism of an IMes-nickel(0) catalyst stabilized by di(o-tolyl) fumarate that converts the stable precatalyst form into a catalytically active species. Computational evaluation provided evidence against a simple ligand exchange as the activation mechanism for this catalyst, and a stoichiometric activation process that covalently modifies the stabilizing ligand was identified. A detailed computational picture for the activation process was developed, with predictive insights that elucidate an unexpected catalyst activation pathway that operates when ligand exchange is thermodynamically unfavorable.

Giving superabsorbent polymers a second life as pressure-sensitive adhesives.

An estimated 6.3 billion metric tons of post-consumer polymer waste has been produced, with the majority (79%) in landfills or the environment. Recycling methods that utilize these waste polymers could attenuate their environmental impact. For many polymers, recycling via mechanical processes is not feasible and these materials are destined for landfills or incineration. One salient example is the superabsorbent material used in diapers and feminine hygiene products, which contain crosslinked sodium polyacrylates. Here we report an open-loop recycling method for these materials that involves (i) decrosslinking via hydrolysis, (ii) an optional chain-shortening via sonication, and (iii) functionalizing via Fischer esterification. The resulting materials exhibit low-to-medium storage and loss moduli, and as such, are applicable as general-purpose adhesives. A life cycle assessment demonstrates that the adhesives synthesized via this approach outcompete the same materials derived from petroleum feedstocks on nearly every metric, including carbon dioxide emissions and cumulative energy demand.

Nickel-Catalyzed Three-Component Cycloadditions of Enoates, Alkynes, and Aldehydes.

A method for the three-component cycloaddition of enoates, alkynes, and aldehydes has been developed. Building upon previous work by this group in which stoichiometrically generated metallacycles undergo alkylation, we report a catalytic, alkylative [3 + 2] cycloaddition. From simple starting materials, structurally complex cyclopentenones may be rapidly assembled. Computational investigation of the mechanism (ωB97X-D3/cc-pVTZ//ωB97X/6-31G(d)) identified three energetically feasible pathways. Based on the relative rates of ketene formation compared to isomerization to a seven-membered metallacycle, the most likely mechanism has been determined to occur "ketene-first", with carbocyclization prior to aldol addition. Deuterium labeling studies suggest that formation of the seven-membered metallacycle becomes possible when an α-substituted enoate is used. This observed change in selectivity is due to the increased difficulty of phenoxide elimination with the inclusion of additional steric bulk of the α-substituent. The net transformation results in a [3 + 2] cycloaddition accompanied by an alkylation of the enoate substituent.

Learning To Predict Reaction Conditions: Relationships between Solvent, Molecular Structure, and Catalyst.

Reaction databases provide a great deal of useful information to assist planning of experiments but do not provide any interpretation or chemical concepts to accompany this information. In this work, reactions are labeled with experimental conditions, and network analysis shows that consistencies within clusters of data points can be leveraged to organize this information. In particular, this analysis shows how particular experimental conditions (specifically solvent) are effective in enabling specific organic reactions (Friedel-Crafts, Aldol addition, Claisen condensation, Diels-Alder, and Wittig), including variations within each reaction class. Network analysis shows data points for reactions tend to break into clusters that depend on the catalyst and chemical structure. This type of clustering, which mimics how a chemist reasons, is derived directly from the network. Therefore, the findings of this work could augment synthesis planning by providing predictions in a fashion that mimics human chemists. To numerically evaluate solvent prediction ability, three methods are compared: network analysis (through the k-nearest neighbor algorithm), a support vector machine, and a deep neural network. The most accurate method in 4 of the 5 test cases is the network analysis, with deep neural networks also showing good prediction scores. The network analysis tool was evaluated by an expert panel of chemists, who generally agreed that the algorithm produced accurate solvent choices while simultaneously being transparent in the underlying reasons for its predictions.

Stable, Well-Defined Nickel(0) Catalysts for Catalytic C-C and C-N Bond Formation.

The synthesis and catalytic activity of several classes of NHC-Ni(0) pre-catalysts stabilized by electron-withdrawing alkenes are described. Variations in the structure of fumarate and acrylate ligands modulate the reactivity and stability of the NHC-Ni(0) pre-catalysts and lead to practical and versatile catalysts for a variety of transformations. The catalytic activity and efficiency of representative members of this class of catalysts have been evaluated in reductive couplings of aldehydes and alkynes and in N-arylations of aryl chlorides.

4,4',4"-trimethyl-2,2':6',2"-terpyridine by oxidative coupling of 4-picoline.

Alkylated terpyridine ligands are an increasingly important component of catalysis and dyes but are costly because their synthesis is challenging and often low-yielding. We report an improved method for the Pd/C-catalyzed dehydrogenative coupling of 4-picoline to form the bi- and terpyridine. The addition of MnO2 improves the yield of the reaction, making the reaction useful on a large scale (up to 200 mmol). The use of Pd(OAc)2 or Pd/C/pivalic acid leads to the selective formation of bipyridine.