We report herein the development and scale up of an Ir-catalyzed N-alkylation reaction between a 4-bromopyridin-2-amine (1) and (4-(5-(1,1-difluoroethyl)-1,2,4-oxadiazol-3-yl)bicyclo[2.2.2]octan-1-yl)methanol (2) proceeding via a borrowing hydrogen process. The traditional approach of alcohol oxidation followed by reductive amination posed challenges that are attributed to the poor nucleophilicity of the 2-aminopyridine derivative (1) resulting in lower isolated yields. Several catalysts and bases were evaluated for the successful N-alkylation of 1 with 2, and an Ir (III) catalyst in combination with LiOt-Bu as a base was found to provide optimal conversion. The borrowing hydrogen process was successfully demonstrated on a 1.5 kg scale and afforded >70% yield of 3 without the need for a sealed reactor or any other specialized equipment.

Herein we describe a series of synthetic efforts to prepare an advanced GPR40 agonist (compound 1), with focus on phase-appropriate processes that circumvented key reagents with short supply in the original synthesis. The key transformations refined for large-scale production were an asymmetric aldol reaction, O-alkylation of an unstable intermediate, selective (Z)-olefination, and reduction of a Weinreb amide to aldehyde. Additionally, the new route circumvented stability issues of the core pyrrolidine fragment through de novo synthesis, achieving high d.r. during ring formation. The new improved route was efficiently scaled up to prepare more than 100 g API for toxicology studies.

The development of an exocyclic-selective, chromane-forming Heck reaction is reported. Detailed mechanistic studies revealed the crucial role of a bisphosphine mono-oxide-based Pd complex to promote high exo:endo alkene selectivity (>99:1) in the Heck reaction. Low levels of NMP peroxide in NMP (reaction solvent) can impact this selectivity by overoxidizing the ligand to bisphosphineoxide and promoting catalyst decomposition. The resultant colloidal Pd facilitates isomerization leading to significant levels of the undesired endocyclic alkene (>10%). A second-generation process is therefore developed to mitigate the risk of peroxides in NMP.

This study describes the characterization of conjugation sites for a random, lysine conjugated 2-iminothiolane (2-IT) based antibody-drug-conjugate synthesized from an IgG1 antibody and a duocarmycin analog-based payload-linker. Of the 80 putative lysine sites, 78 were found to be conjugated via tryptic peptide mapping and LC-HRMS. Surprisingly, seven cysteine-linked conjugated peptides were also detected resulting from the conjugation of cysteine residues derived from the four inter-chain disulfide bonds during the reaction. This unexpected finding could be attributed to the free thiols of the 2-IT thiolated antibody intermediates and/or the 4-mercaptobutanamide by-product resulting from the hydrolysis of 2-IT. These free thiols could cause the four inter-chain disulfide bonds of the antibody to scramble via intra- or inter-molecular attack. The presence of only pair of non-reactive (unconjugated) lysine residues, along with the four intact intra-chain disulfide bonds, is attributed to their poor accessibility, which is consistent with solvent accessibility modeling analysis. We also discovered a major by-product derived from the hydrolysis of the amidine moiety of the N-terminus conjugate. In contrast, the amidine moiety in lysine-linked conjugates appeared stable. Based on our results, we propose plausible formation mechanisms of cysteine-linked conjugates and the hydrolysis of the N-terminus conjugate, which provide scientific insights that are beneficial to process development and drug quality control.

The development of an improved short and efficient commercial synthesis of the JAK2 inhibitor, a complex pyrrolopyridine, BMS-911543, is described. During the discovery and development of this synthesis, a Pd-catalyzed C-H functionalization was invented which enabled the rapid union of the key pyrrole and imidazole fragments. The synthesis of this complex, nitrogen-rich heterocycle was accomplished in only six steps (longest linear sequence) from readily available materials.

A tritydopropylamino acid derivative was prepared via Simmons-Smith cyclopropanation of the corresponding alkene. This transformation was plagued by inconsistent conversions, and the opportunity for the removal of the structurally similar alkene contaminant at this stage and downstream via crystallization was limited. These factors combined to make control of the alkene impurity level in the active pharmaceutical ingredient (API) difficult. A removal strategy was developed that utilized downstream, in-process aminoacetoxylation to convert the alkene impurity to structurally dissimilar compounds that purged during crystallization. Using this protocol, the alkene contaminant in the subsequent intermediates, and thus the API, could be controlled to less than 0.1 area percent.

Kinetic, spectroscopic, crystallographic, and computational studies probing a Pd-catalyzed C-H arylation reaction reveal that mono-oxidation of the bis-phosphine ligand is critical for the formation of the active catalyst. The bis-phosphine mono-oxide is shown to be a hemilabile, bidentate ligand for palladium. Isolation of the oxidative addition adduct, with structural elucidation by X-ray analysis, showed that the mono-oxide was catalytically competent, giving the same reaction rate in the productive reaction as the Pd(II)/xantphos precursor. A dual role for the carboxylate base in both catalyst activation and reaction turnover was demonstrated, along with the inhibiting effect of excess phosphine ligand. The generality of the role of phosphine mono-oxide complexes in Pd-catalyzed coupling processes is discussed.

This volume presents the majority of topics in synchrotron science that are of use to the clay science community. The chapters presented in this volume serve not only as significant statements on the state of these applications, but also as useful primers to potential new users of synchrotron facilities.

The Pd-catalyzed α-arylation of cycloheptapyridyl ketone is a key complexity-building step in the synthesis of BMS-846372, a CGRP antagonist. A first-generation process utilized Pd(OAc)2/PtBu3·HBF4 catalyst system with a strong base NaOtBu. Although this process was demonstrated on multi-kilo scale, the harsh conditions led to non-selective metal catalyzed processes, which generated several operational, quality, and throughput issues. By acquiring detailed knowledge around several important process parameters, we were able to design an efficient and scalable second-generation α-arylation process using a Pd(OAc)2/RuPhos catalyst system with the weaker base, K3PO4 in tert-amyl alcohol. This new weak base process was high yielding, efficient, and superior in several respects compared to the strong base process. The strategy behind the reaction and isolation development and the process considerations important to scaling a catalytic reaction from laboratory to manufacturing scale will be discussed.

By ~2.9 Ga, the time of the deposition of the Witwatersrand Supergroup, life is believed to have been well established on Earth. Carbon remnants of the microbial biosphere from this time period are evident in sediments from around the world. In the Witwatersrand Supergroup, the carbonaceous material is often concentrated in seams, closely associated with the gold deposits and may have been a mobile phase 2 billion years ago. Whereas today the carbon in the Witwatersrand Supergroup is presumed to be immobile, hollow hydrocarbon spheres ranging in size from <1 μm to >50 μm were discovered emanating from a borehole drilled through the carbon-bearing seams suggesting that a portion of the carbon may still be mobile in the deep subsurface. ToF-SIMS and STXM analyses revealed that these spheres contain a suite of alkane, alkenes, and aromatic compounds consistent with the described organic-rich carbon seams within the Witwatersrand Supergroup's auriferous reef horizons. Analysis by electron microscopy and ToF-SIMS, however, revealed that these spheres, although most likely composed of biogenic carbon and resembling biological organisms, do not retain any true structural, that is, fossil, information and were formed by an abiogenic process.

A tracer test was performed at the Rifle Integrated Field Research Challenge site to assess the effect of addition of bicarbonate on U(VI) desorption from contaminated sediments in the aquifer and to compare equilibrium and rate‐limited reactive transport model descriptions of mass transfer limitations on desorption. The tracer test consisted of injection of a 37 mM NaHCO3solution containing conservative tracers followed by down‐gradient sampling of groundwater at various elevations and distances from the point of injection. Breakthrough curves show that dissolved U(VI) concentrations increased 1.2–2.6‐fold above background levels, resulting from increases in bicarbonate alkalinity (from injectate solution) and Ca concentrations (from cation exchange). In general, more U(VI) was mobilized in shallower zones of the aquifer, where finer‐grained sediments and higher solid phase U content were found compared to deeper zones. An equilibrium‐based reactive transport model incorporating a laboratory‐based surface complexation model derived from the same location predicted the general trends in dissolved U(VI) during the tracer test but greatly overpredicted the concentrations of U(VI), indicating that the system was not at equilibrium. Inclusion of a multirate mass transfer model successfully simulated the nonequilibrium desorption behavior of U(VI). Local sediment properties such as sediment texture (weight percent <2 mm), surface area, cation exchange capacity, and adsorbed U(VI) were heterogeneous at the meter scale, and it was important to incorporate these values into model parameters in order to produce accurate simulations.

Coupled intragrain diffusional mass transfer and nonlinear surface complexation processes play an important role in the transport behavior of U(VI) in contaminated aquifers. Two alternative model approaches for simulating these coupled processes were analyzed and compared: (1) the physical nonequilibrium approach that explicitly accounts for aqueous speciation and instantaneous surface complexation reactions in the intragrain regions and approximates the diffusive mass exchange between the immobile intragrain pore water and the advective pore water as multirate first‐order mass transfer and (2) the chemical nonequilibrium approach that approximates the diffusion‐limited intragrain surface complexation reactions by a set of multiple first‐order surface complexation reaction kinetics, thereby eliminating the explicit treatment of aqueous speciation in the intragrain pore water. A model comparison has been carried out for column and field scale scenarios, representing the highly transient hydrological and geochemical conditions in the U(VI)‐contaminated aquifer at the Hanford 300A site, Washington, USA. It was found that the response of U(VI) mass transfer behavior to hydrogeochemically induced changes in U(VI) adsorption strength was more pronounced in the physical than in the chemical nonequilibrium model. The magnitude of the differences in model behavior depended particularly on the degree of disequilibrium between the advective and immobile phase U(VI) concentrations. While a clear difference in U(VI) transport behavior between the two models was noticeable for the column‐scale scenarios, only minor differences were found for the Hanford 300A field scale scenarios, where the model‐generated disequilibrium conditions were less pronounced as a result of frequent groundwater flow reversals.

Although “intragranular” pore space within grain aggregates, grain fractures, and mineral surface coatings may contain a relatively small fraction of the total porosity within a porous medium, it often contains a significant fraction of the reactive surface area, and can thus strongly affect the transport of sorbing solutes. In this work, we demonstrate a batch experiment procedure using tritiated water as a high‐resolution diffusive tracer to characterize the intragranular pore space. The method was tested using uranium‐contaminated sediments from the vadose and capillary fringe zones beneath the former 300A process ponds at the Hanford site (Washington). Sediments were contacted with tracers in artificial groundwater, followed by a replacement of bulk solution with tracer‐free groundwater and the monitoring of tracer release. From these data, intragranular pore volumes were calculated and mass transfer rates were quantified using a multirate first‐order mass transfer model. Tritium‐hydrogen exchange on surface hydroxyls was accounted for by conducting additional tracer experiments on sediment that was vacuum dried after reaction. The complementary (“wet” and “dry”) techniques allowed for the simultaneous determination of intragranular porosity and surface area using tritium. The Hanford 300A samples exhibited intragranular pore volumes of ∼1% of the solid volume and intragranular surface areas of ∼20%–35% of the total surface area. Analogous experiments using bromide ion as a tracer yielded very different results, suggesting very little penetration of bromide into the intragranular porosity.

1 groundwater flow and hydrochemistry Physical versus 2 chemical non-equilibrium model 3 4 5 Janek Greskowiak, Michael. B. Hay, Henning Prommer, 6 Chongxuan Liu, Vincent E. A. Post, Rui Ma, James A. Davis, 7 Chunmiao Zheng, John M. Zachara 8 9 10 CSIRO Land and Water, Private Bag No. 5, Wembley WA 6913, Australia 11 Working group Hydrogeology and Landscape Hydrology, Institute for Biology and 12 Environmental Sciences, Carl von Ossietzky University of Oldenburg 13 U. S. Geological Survey, Menlo Park, CA 94025, USA 14 School of Earth and Environment, University of Western Australia, Crawley WA 15 6009, Western Australia 16 Pacific Northwest National Laboratory, Richland, WA 99354, USA 17 Flinders University, Adelaide, Australia 18 Department of Geological Sciences, University of Alabama, Tuscaloosa, Alabama 19 20 21 Submitted to Water Resources Research 22 23

Aqueous-phase X-ray absorption near-edge structure (XANES) spectra were collected on dissolved Al complexes with organic ligands, including desferrioxamine B, EDTA, acetohydroxamate, malate, oxalate, and salicylate. Spectral interpretations were made using the density functional theory-based modeling package StoBe. The goals of this work were to study the geometric and electronic structural characteristics of these complexes relative to Al(H(2)O)(6)(3+) and to examine the utility of the aqueous Al XANES technique as a tool for probing Al speciation and structure. In the case of EDTA, aqueous Fourier-transform infrared spectroscopy was also used to corroborate the structures of the Al(EDTA)(-) and AlOH(EDTA)(2-) complexes. Synthetic XANES spectra calculated with StoBe reproduced the observed spectral differences between Al(H(2)O)(6)(3+), Al(dfoB)(+), and Al(EDTA)(-). The narrower XANES feature observed for Al(dfoB)(+) relative to Al(H(2)O)(6)(3+) can be attributed to a weaker splitting of the Al 3p-O 2p interactions in the former, while Al(EDTA)(-) exhibits split Al 3p-ligand interactions that likely result from the mixed O/N coordination. In complexes with mixed aqua/organic-oxygen ligation (Al-acetohydroxamate, Al-malate, Al-oxalate, and Al-salicylate), spectra exhibit linear, systematic changes in peak width as a function of H(2)O to organic ligand ratio in the Al coordination sphere. These results highlight the sensitivity of the aqueous Al K-edge XANES spectrum to coordination environment and demonstrate its utility as an experimental probe for future studies of Al speciation in complex solutions.