The threat of chemical warfare agents (CWAs), assured by their ease of synthesis and effectiveness as a terrorizing weapon, will persist long after the once-tremendous stockpiles in the U.S. and elsewhere are finally destroyed. As such, soldier and civilian protection, battlefield decontamination, and environmental remediation from CWAs remain top national security priorities. New chemical approaches for the fast and complete destruction of CWAs have been an active field of research for many decades, and new technologies have generated immense interest. In particular, our research team and others have shown metal-organic frameworks (MOFs) and polyoxometalates (POMs) to be active for sequestering CWAs and even catalyzing the rapid hydrolysis of agents. In this Forum Article, we highlight recent advancements made in the understanding and evaluation of POMs and Zr-based MOFs as CWA decontamination materials. Specifically, our aim is to bridge the gap between controlled, solution-phase laboratory studies and real-world or battlefield-like conditions by examining agent-material interactions at the gas-solid interface utilizing a multimodal experimental and computational approach. Herein, we report our progress in addressing the following research goals: (1) elucidating molecular-level mechanisms of the adsorption, diffusion, and reaction of CWA and CWA simulants within a series of Zr-based MOFs, such as UiO-66, MOF-808, and NU-1000, and POMs, including Cs8Nb6O19 and (Et2NH2)8[(α-PW11O39Zr(μ-OH)(H2O))2]·7H2O, (2) probing the effects that common ambient gases, such as CO2, SO2, and NO2, have on the efficacy of the MOF and POM materials for CWA destruction, and (3) using CWA simulant results to develop hypotheses for live agent chemistry. Key hypotheses are then tested with targeted live agent studies. Overall, our collaborative effort has provided insight into the fundamental aspects of agent-material interactions and revealed strategies for new catalyst development.

Development of technologies for protection against chemical warfare agents (CWAs) is critically important. Recently, polyoxometalates have attracted attention as potential catalysts for nerve-agent decomposition. Improvement of their effectiveness in real operating conditions requires an atomic-level understanding of CWA decomposition at the gas-solid interface. We investigated decomposition of the nerve agent Sarin and its simulant, dimethyl chlorophosphate (DMCP), by zirconium polytungstate. Using a multimodal approach, we showed that upon DMCP and Sarin exposure the dimeric tungstate undergoes monomerization, making coordinatively unsaturated Zr(IV) centers available, which activate nucleophilic hydrolysis. Further, DMCP is shown to be a good model system of reduced toxicity for studies of CWA deactivation at the gas-solid interface.

Developing novel and more efficient filters for chemical warfare agent (CWA) decomposition remains an important challenge for modern technology due to the continuous threat those weapons present in the event of use. Recently, metal–organic frameworks (MOFs) have attracted attention as potential catalysts for nerve agent decomposition. However, in order to improve their performance under battlefield conditions, it is crucial to understand the influence of ambient contaminants such as carbon dioxide on CWA adsorption and decomposition. Here, we present a comprehensive experimental and computational study on the influence of CO2 on the adsorption and decomposition of the CWA simulant dimethyl methyl phosphonate (DMMP) by the Zr-based MOF-808. The study combined in situ synchrotron powder X-ray diffraction (PXRD) with variable-temperature infrared spectroscopy (VTIR) and computations. PXRD and experiments with pure CO2 revealed that the MOF framework contracts by 0.2% after CO2 saturation and CO2 adsorbs with...

We report computational studies of (O,O-dimethyl)-(O-4-nitrophenyl)-phosphate (DMNP) and (O,O-dimethyl)-(O-phenyl)-phosphate (DMPP) decomposition by the Zr-substituted Polyoxometalate {α-PW11O39Zr(μ-OH)(H2O)}4−, which has been recently shown to be a catalytic active species in the reaction of (Et2NH2)8[{α-PW11O39Zr(μ-OH)(H2O)}2]·7H2O with nerve agents. We studied two possible mechanisms of this reaction described as “hydrolysis first” and “OH-transfer first”. Both reaction pathways are initiated from the same pre-reaction complex (H2O)-(OH)-POM-(nerve agent). The “hydrolysis first” pathway starts by the concerted dissociation of the adsorbed water molecule and nucleophilic addition of the resulting OH group to the nerve agent. Conversely, the “OH-transfer first” pathway starts by nucleophilic addition of the Zr-coordinated OH ligand to the phosphorus of the nerve agent simulant. Calculations show that the “OH-transfer first” pathway exhibits a lower energy barrier for the decomposition of DMPP by ZrPOM. Thus, the presence of a hydroxo ligand in the coordination sphere of Zr(IV) introduces a mechanism switch from “hydrolysis first” [which was recently reported for the Sarin (GB) decomposition mechanism by the hexaniobate POM Cs8Nb6O19] to “OH-transfer first”. These findings imply that the pH of the catalytic solution could play a critical role and potentially control the mechanism of nerve agent and simulant decomposition by polyoxometalates. We also predict and corroborate that the presence of a strong electron-withdrawing para-substituent in the substrate phenyl group accelerates this reaction: DMNP decomposition by ZrPOM occurs with a smaller rate-limiting energy barrier. The calculations reveal several factors of the DMNP decomposition by the Zr(IV)-substituted polyoxometalates that provide design elements of Zr-based materials (including MOFs and POMs) for catalytic CWA decomposition under ambient conditions.

Practical and scalable syntheses were developed that were used to prepare multikilogram batches, of GSK1292263A (1) and GSK2041706A (15), two potent G, protein-coupled receptor 119 (GPR119) agonists. Both syntheses employed relatively cheap and readily available starting materials, and both took advantage of an SNAr synthetic strategy.

A synthesis of the benzothiazepine phosphonic acid 3, employing both enzymatic and transition metal catalysis, is described. The quaternary chiral center of 3 was obtained by resolution of ethyl (2-ethyl)norleucinate (4) with porcine liver esterase (PLE) immobilized on Sepabeads. The resulting (R)-amino acid (5) was converted in two steps to aminosulfate 7, which was used for construction of the benzothiazepine ring. Benzophenone 15, prepared in four steps from trimethylhydroquinone 11, enabled sequential incorporation of phosphorus (Arbuzov chemistry) and sulfur (Pd(0)-catalyzed thiol coupling) leading to mercaptan intermediate 18. S-Alkylation of 18 with aminosulfate 7 followed by cyclodehydration afforded dihydrobenzothiazepine 20. Iridium-catalyzed asymmetric hydrogenation of 20 with the complex of [Ir(COD)2BArF] (26) and Taniaphos ligand P afforded the (3R,5R)-tetrahydrobenzothiazepine 30 following flash chromatography. Oxidation of 30 to sulfone 31 and phosphonate hydrolysis completed the synthesis of 3 in 12 steps and 13% overall yield.

A new synthesis of Lapatinib, an orally active drug for breast cancer, is described. The synthesis involves a palladium catalyzed regioselective arylation of furfural with 6-bromo-N-(3-chloro-4-((3-fluorobenzyl)oxy)phenyl)quinazolin-4-amine. This key step replaces an atom inefficient Suzuki cross coupling reaction used in a previously disclosed route and significantly shortens the synthesis.

High throughput screening enabled the development of a Cu-based catalyst system for the asymmetric hydrogenation of prochiral aryl and heteroaryl ketones that operates at H2 pressures as low as 5 bar. A ligand combination of (R,S)-N-Me-3,5-xylyl-BoPhoz and tris(3,5-xylyl)phosphine provided benzylic alcohols in good yields and enantioselectivities. The electronic and steric characteristics of the ancillary triarylphosphine were important in determining both reactivity and selectivity.

A highly selective method for the alkoxycarboxylation and acylation of primary alcohols of pyranose derivatives is described. The reaction is high yielding and proceeds under mild conditions with 0.151 mol-% Sc(OTf)3 used in combination with anhydrides or pyrocarbonates at 4050 degrees C. Selectivities observed for alkoxycarboxylation of unprotected pyranose derivatives are > 95?%, and this constitutes a significant advantage over existing methods. Mechanistic implications, including the role of steric demand and metalheteroatom coordination are also discussed.

The triple reuptake inhibitor GSK1360707F was synthesized via an efficient and scalable route that features an enyne cycloisomerization reaction catalyzed by either Pt(II) or Au(I). Key aspects of this work such as the choice of the nitrogen protecting group and initial enantioselectivity studies are discussed.

Dimethyl methylphosphonate (DMMP) is a widely used simulant for chemical warfare agents and pesticides. This work examined the room temperature reaction of DMMP with ozone on alumina-supported manganese oxide. The reaction on the MnOx/Al2O3 surface shows a long period (approximately nine hours) of relatively constant, sustained product formation, yielding five times as much gas-phase carbon, in the form of CO2 and CO, as does the same reaction on supported iron oxide. CO2 and CO (COx) were the major products observed, with most experiments yielding equal amounts of the two gases. The DMMP decomposition reaction still appears to be stoichiometric, as observed in investigations with other supported oxides, but in this case, at the lower loadings, virtually every manganese ion on the support is reactive. Additionally, the number of COx species produced per manganese ion is in excess of four at the lower manganese loadings and on average each DMMP molecule that reacts yields one molecule of CO2 and one of CO. Thus, the average DMMP:Mn stoichiometry is found to be 2:1 at the lower loadings/higher dispersions. This reaction system demonstrates a very high capacity for the room temperature destruction of DMMP, and may prove to be an important tool for protecting against or mitigating exposure to chemical warfare agents, pesticides, and other toxic chemicals.