Cyclooctyne-based reagents for uncatalyzed click chemistry: A computational survey

With the goal of identifying alkyne-like reagents for use in click chemistry, but without Cu catalysts, we used B3LYP density function theory (DFT) to investigate the trends in activation barriers for the 1,3-dipolar cycloadditions of azides with various cyclooctyne, dibenzocyclooctyne, and azacyclooctyne compounds. Based on these trends, we find monobenzocyclooctyne-based reagents that are predicted to have dramatically improved reactivity over currently employed reagents

Lancifodilactone G : insights about an unusually stable enol

From quantum mechanics calculations we confirm that the naturally occurring enol lancifodilactone G is stable over the keto form (by 2.6 kcal/mol in water), the only known stable aliphatic enol (devoid of conjugated or bulky aromatics and lacking a 1,3-diketone structural motif known to stabilize enols). We determine architectural elements responsible for the enol stabilization and find a mechanism for keto-enol conversion in solution. In addition, we correct previously reported computational results that were performed on the misinterpreted structure demonstrating that the enol form of this natural product is more stable than previously thought

Oligomerization Route to Py-Im Polyamide Macrocycles

Cyclic eight-ring pyrrole−imidazole polyamides are sequence-specific DNA-binding small molecules that are cell permeable and can regulate endogenous gene expression. Syntheses of cyclic polyamides have been achieved by solid-phase and solution-phase methods. A rapid solution-phase oligomerization approach to eight-ring symmetrical cyclic polyamides yields 12- and 16-membered macrocycles as well. A preference for DNA binding by the 8- and 16-membered oligomers was observed over the 12-ring macrocycle, which we attributed to a conformational constraint not present in the smaller and larger systems

Solution-phase synthesis of pyrrole-imidazole polyamides

Pyrrole−imidazole polyamides are DNA-binding molecules that are programmable for a large repertoire of DNA sequences. Typical syntheses of this class of heterocyclic oligomers rely on solid-phase methods. Solid-phase methodologies offer rapid assembly on a micromole scale sufficient for biophysical characterizations and cell culture studies. In order to produce gram-scale quantities necessary for efficacy studies in animals, polyamides must be readily synthesized in solution. An 8-ring hairpin polyamide 1, which targets the DNA sequence 5′-WGWWCW-3′, was chosen for our synthesis studies as this oligomer exhibits androgen receptor antagonism in cell culture models of prostate cancer. A convergent solution-phase synthesis of 1 from a small set of commercially available building blocks is presented which highlights principles for preparing gram quantities of pyrrole−imidazole oligomers with minimal chromatography

A Singularity-Avoiding Moving Least Squares Scheme for Two Dimensional Unstructured Meshes

Moving least squares interpolation schemes are in widespread use as a tool for numerical analysis on scattered data. In particular, they are often employed when solving partial differential equations on unstructured meshes, which are typically needed when the geometry defining the domain is complex. It is known that such schemes can be singular if the data points in the stencil happen to be in certain special geometric arrangements, however little research has addressed this issue specifically. In this paper, a moving least squares scheme is presented which is an appropriate tool for use when solving partial differential equations in two dimensions, and the precise conditions under which singularities occur are identified. The theory is then applied in the form of a stencil building algorithm which automatically detects singular stencils and corrects them in an efficient manner, while attempting to maintain stencil symmetry as closely as possible. Finally, the scheme is used in a convection-diffusion equation solver, and the results of a number of simulations are presented

Cyclic pyrrole-imidazole polyamides targeted to the androgen response element

Hairpin pyrrole−imidazole (Py-Im) polyamides are a class of cell-permeable DNA-binding small molecules that can disrupt transcription factor−DNA binding and regulate endogenous gene expression. The covalent linkage of antiparallel Py-Im ring pairs with an γ-amino acid turn unit affords the classical hairpin Py-Im polyamide structure. Closing the hairpin with a second turn unit yields a cyclic polyamide, a lesser-studied architecture mainly attributable to synthetic inaccessibility. We have applied our methodology for solution-phase polyamide synthesis to cyclic polyamides with an improved high-yield cyclization step. Cyclic 8-ring Py-Im polyamides 1−3 target the DNA sequence 5′-WGWWCW-3′, which corresponds to the androgen response element (ARE) bound by the androgen receptor transcription factor to modulate gene expression. We find that cyclic Py-Im polyamides 1−3 bind DNA with exceptionally high affinities and regulate the expression of AR target genes in cell culture studies, from which we infer that the cycle is cell permeable

Initiation mechanisms and kinetics of pyrolysis and combustion of JP-10 hydrocarbon jet fuel

In order to investigate the initiation mechanisms and kinetics associated with the pyrolysis of JP-10 (exo-tricyclo[5.2.1.0^2,6]decane), a single-component hydrocarbon jet fuel, we carried out molecular dynamics (MD) simulations employing the ReaxFF reactive force field. We found that the primary decomposition reactions involve either (1) dissociation of ethylene from JP-10, resulting in the formation of a C8 hydrocarbon intermediate, or (2) the production of two C5 hydrocarbons. ReaxFF MD leads to good agreement with experiment for the product distribution as a function of temperature. On the basis of the rate of consumption of JP-10, we calculate an activation energy of 58.4 kcal/mol for the thermal decomposition of this material, which is consistent with a strain-facilitated C−C bond cleavage mechanism in JP-10. This compares well with the experimental value of 62.4 kcal/mol. In addition, we carried out ReaxFF MD studies of the reactive events responsible for oxidation of JP-10. Here we found overall agreement between the thermodynamic energies obtained from ReaxFF and quantum-mechanical calculations, illustrating the usefulness of ReaxFF for studying oxidation of hydrocarbons. The agreement of these results with available experimental observations demonstrates that ReaxFF can provide useful insights into the complicated thermal decomposition and oxidation processes of important hydrocarbon fuels

ReaxFF Reactive Force Field for Molecular Dynamics Simulations of Hydrocarbon Oxidation

To investigate the initial chemical events associated with high-temperature gas-phase oxidation of hydrocarbons, we have expanded the ReaxFF reactive force field training set to include additional transition states and chemical reactivity of systems relevant to these reactions and optimized the force field parameters against a quantum mechanics (QM)-based training set. To validate the ReaxFF potential obtained after parameter optimization, we performed a range of NVT−MD simulations on various hydrocarbon/O_2 systems. From simulations on methane/O_2, o-xylene/O_2, propene/O_2, and benzene/O_2 mixtures, we found that ReaxFF obtains the correct reactivity trend (propene > o-xylene > methane > benzene), following the trend in the C−H bond strength in these hydrocarbons. We also tracked in detail the reactions during a complete oxidation of isolated methane, propene, and o-xylene to a CO/CO_2/H_2O mixture and found that the pathways predicted by ReaxFF are in agreement with chemical intuition and our QM results. We observed that the predominant initiation reaction for oxidation of methane, propene, and o-xylene under fuel lean conditions involved hydrogen abstraction of the methyl hydrogen by molecular oxygen forming hydroperoxyl and hydrocarbon radical species. While under fuel rich conditions with a mixture of these hydrocarbons, we observed different chemistry compared with the oxidation of isolated hydrocarbons including a change in the type of initiation reactions, which involved both decomposition of the hydrocarbon or attack by other radicals in the system. Since ReaxFF is capable of simulating complicated reaction pathways without any preconditioning, we believe that atomistic modeling with ReaxFF provides a useful method for determining the initial events of oxidation of hydrocarbons under extreme conditions and can enhance existing combustion models

The ReaxFF Monte Carlo Reactive Dynamics Method for Predicting Atomistic Structures of Disordered Ceramics: Application to the Mo_3VO_x Catalyst

The ReaxFF computational approach is used to resolve partial or mixed occupation of crystallographic sites of the Mo_3VO_x multimetal oxide (MMO) catalyst. It provides insight into the oxidation state and coordination environment of the metal sites, identifies donor-acceptor networks in the catalyst, and predicts selectivity for molecular diffusion into channels of the framework

Analysis of instability patterns in non-Boussinesq mixed convection using a direct numerical evaluation of disturbance integrals

The Fourier integrals representing linearised disturbances arising from an initially localised source are evaluated numerically for natural and mixed convection flows between two differentially heated plates. The corresponding spatio-temporal instability patterns are obtained for strongly non-Boussinesq high-temperature convection of air and are contrasted to their Boussinesq counterparts. A drastic change in disturbance evolution scenarios is found when a large cross-channel temperature gradient leads to an essentially nonlinear variation of the fluid's transport properties and density. In particular, it is shown that non-Boussinesq natural convection flows are convectively unstable while forced convection flows can be absolutely unstable. These scenarios are opposite to the ones detected in classical Boussinesq convection. It is found that the competition between two physically distinct instability mechanisms which are due to the action of the shear and the buoyancy are responsible for such a drastic change in spatio-temporal characteristics of instabilities. The obtained numerical results confirm and complement semi-analytical conclusions of Suslov 2007 on the absolute/convective instability transition in non-Boussinesq mixed convection. Generic features of the chosen numerical approach are discussed and its advantages and shortcomings are reported