Rate and Yield Enhancements in Nucleophilic Aromatic Substitution Reactions via Mechanochemistry.

A variety of nucleophilic aromatic substitution reactions were carried out mechanochemically to great advantage. On average, reactions rates were nine-times faster. The corresponding kinetic studies presented provide the clearest head-to-head kinetic comparisons between mechanochemical and conventional systems at identical temperatures. Attempts are provided at classifying the kinetics of one example. Removal of polar, protic solvents from these reactions presents environmental benefits to a reaction class whose kinetics are heavily dependent on such solvents.

Decoupling the Arrhenius equation via mechanochemistry.

Mechanochemistry continues to reveal new possibilities in chemistry including the opportunity for "greening" reactions. Nevertheless, a clear understanding of the energetic transformations within mechanochemical systems remains elusive. We employed a uniquely modified ball mill and strategically chosen Diels-Alder reactions to evaluate the role of several ball-milling variables. This revealed three different energetic regions that we believe are defining characteristics of most, if not all, mechanochemical reactors. Relative to the locations of a given ball mill's regions, activation energy determines whether a reaction is energetically easy (Region I), challenging (Region II), or unreasonable (Region III) in a given timeframe. It is in Region II, that great sensitivity to mechanochemical conditions such as vial material and oscillation frequency emerge. Our unique modifications granted control of reaction vessel temperature, which in turn allowed control of the locations of Regions I, II, and III for our mill. Taken together, these results suggest envisioning vibratory mills (and likely other mechanochemical methodologies) as molecular-collision facilitating devices that act upon molecules occupying a thermally-derived energy distribution. This unifies ball-milling energetics with solution-reaction energetics via a common tie to the Arrhenius equation, but gives mechanochemistry the unique opportunity to influence either half of the equation. In light of this, we discuss a strategy for translating solvent-based reaction conditions to ball milling conditions. Lastly, we posit that the extra control via frequency factor grants mechanochemistry the potential for greater selectivity than conventional solution reactions.

Base-modified thymidines capable of terminating DNA synthesis are novel bioactive compounds with activity in cancer cells.

Current FDA-approved chemotherapeutic antimetabolites elicit severe side effects that warrant their improvement; therefore, we designed compounds with mechanisms of action focusing on inhibiting DNA replication rather than targeting multiple pathways. We previously discovered that 5-(α-substituted-2-nitrobenzyloxy)methyluridine-5'-triphosphates were exquisite DNA synthesis terminators; therefore, we synthesized a library of 35 thymidine analogs and evaluated their activity using an MTT cell viability assay of MCF7 breast cancer cells chosen for their vulnerability to these nucleoside derivatives. Compound 3a, having an α-tert-butyl-2-nitro-4-(phenyl)alkynylbenzyloxy group, showed an IC50 of 9±1µM. The compound is more selective for cancer cells than for fibroblast cells compared with 5-fluorouracil. Treatment of MCF7 cells with 3a elicits the DNA damage response as indicated by phosphorylation of γ-H2A. A primer extension assay of the 5'-triphosphate of 3a revealed that 3aTP is more likely to inhibit DNA polymerase than to lead to termination events upon incorporation into the DNA replication fork.