Simple and Green Preparation of Tetraalkoxydiborons and Diboron Diolates from Tetrahydroxydiboron.

Tetraalkoxydiborons can be easily prepared by acid-catalyzed reactions of tetrahydroxydiboron or its anhydride with trialkyl orthoformates. Addition of diols to these reaction mixtures afforded diboron diolates in high yield. In both cases, removal of volatile byproducts is all that is required for the isolation of the diboron. These methods constitute a convenient alternative to previous preparations from tetrakis (dimethylamino) diboron and tetrahydroxydiboron.

Access to C(sp3) borylated and silylated cyclic molecules: hydrogenation of corresponding arenes and heteroarenes.

This paper presents a simple and cost-effective hydrogenation method for synthesizing a myriad of cycloalkanes and saturated heterocycles bearing boryl or silyl substituents. The catalyst used are heterogeneous, readily available, bench stable, and recyclable. Also demonstrated is the application of the method to compounds that possess both boryl and silyl groups. When combined with Ir-catalyzed sp2 C-H borylation, such hydrogenations offer a two-step complementary alternative to direct sp3 C-H borylations that can suffer selectivity and reactivity issues. Of practical value to the community, complete stereochemical analyses of reported borylated compounds that were never fully characterized are reported herein.

Deciphering the Mechanism of Base-Triggered Conversion of Ammonia to Molecular Nitrogen and Methylamine to Cyanide.

We report an in-depth investigation into the ammonia oxidation mechanism by the catalyst [RuIII(tpy)(dmabpy)NH3]3+ ([Ru(NH3)]3+). Stoichiometric reactions of [Ru(NH3)]3+ were carried out with exogenous noncoordinating bases to trigger a proposed redox disproportionation reaction, which was followed using variable-temperature NMR spectroscopy. An intermediate species was identified as a dinitrogen-bridged complex using 15N NMR and Raman spectroscopy on isotopically labeled complexes. This intermediate is proposed to derive from coupling of nitridyl species formed upon sequential redox disproportion reactions. Acetonitrile displaces the dinitrogen bridge to yield free N2. DFT calculations support this lower-energy pathway versus that previously reported for ammonia oxidation by the parent [RuIII(tpy)(bpy)NH3]3+ complex. These experimental and computational results are consistent with the interpretation of redox disproportionation involving sequential hydrogen atom transfer reactions by an amide/aminyl intermediate, [Ru(NH2)-]+ ⇔ [Ru(NH2)•]+, formed upon deprotonation of the parent complex. Control experiments employing a large excess of ammonia as a base indicate this new proposed lower-energy pathway contributes to the oxidation of ammonia to dinitrogen in conditions relevant to electrocatalysis. In addition, analogous methylamine complexes, [Ru(NH2CH3)]2+/3+, were prepared to further test the proposed mechanism. Treating [Ru(NH2CH3)]3+ with a base cleanly yields two products [Ru(NH2CH3)]2+ and [Ru(CN)]+ in an ∼3:1 ratio, fully consistent with the proposed cascade of hydrogen atom transfer reactions by an intermediate.

Regiochemical Switching in Ir-Catalyzed C-H Borylation by Altering Ligand Loadings of N,B-Type Diboron Species.

Traditional reaction conditions in Ir-catalyzed C-H borylation consist of a 2:1 ligand to Ir metal ratio, affording C(sp2)-H borylation at the least sterically hindered position. We found that lowering the ligand to metal ratio of a N,B-type diboron (BB) preligand in respect to the IrI precatalyst to 0.5:1 affords the chelate controlled ortho product. Switching from steric-directed to chelate-directed products is shown for various substituted arenes and (hetero)arenes containing Lewis-basic functionalities. This work offers the first example of obtaining complementary regioisomers as the major product by altering the ligand loading in CHB.

Merging Iridium-Catalyzed C-H Borylations with Palladium-Catalyzed Cross-Couplings Using Triorganoindium Reagents.

A versatile and efficient method to prepare borylated arenes furnished with alkyl, alkenyl, alkynyl, aryl, and heteroaryl functional groups is developed by merging Ir-catalyzed C-H borylations (CHB) with a chemoselective palladium-catalyzed cross-coupling of triorganoindium reagents (Sarandeses-Sestelo coupling) with aryl halides bearing a boronic ester substituent. Using triorganoindium cross-coupling reactions to introduce unsaturated moieties enables the synthesis of borylated arenes that would be difficult to access through the direct application of the CHB methodology. The sequential double catalyzed procedure can be also performed in one vessel.

Amide directed iridium C(sp3)-H borylation catalysis with high N-methyl selectivity.

A bidentate monoanionic ligand system was developed to enable iridium catalyzed C(sp3)-H activation borylation of N-methyl amides. Borylated amides were obtained in moderate to good isolated yields, and exclusive mono-borylation allowed the amide to be the limiting reagent. Selectivity for C(sp3)-H activation was demonstrated in the presence of sterically available C(sp3)-H bonds. Competitive kinetic isotope studies revealed a large primary isotope effect, implicating C-H activation as the rate limiting step.

Steric Shielding Effects Induced by Intramolecular C-H⋯O Hydrogen Bonding: Remote Borylation Directed by Bpin Groups.

Regioselectivities in catalytic C-H borylations (CHBs) have been rationalized using simplistic steric models and correlations with nuclear magnetic resonance (NMR) chemical shifts. However, regioselectivity can be significant for important substrate classes where none would be expected from these arguments. In this study, intramolecular hydrogen bonding (IMHB) can lead to steric shielding effects that can direct Ir-catalyzed CHB regiochemistry. Bpin (Bpin = pinacol boronic ester)/arene IMHB can promote remote borylations of N-borylated anilines, 2-amino-N-alkylpyridine, tetrahydroquinolines, indoles, and 1-borylated naphthalenes. Experimental and computational studies support molecular geometries with the Bpin orientation controlled by a C-H⋯O IMHB. IMHB-directed remote CHB appeared operative in the C6 borylation of 3-aminoindazole (seven-membered IMHB) and C6 borylation of an osimertinib analogue where a pyrimidine IMHB creates the steric shield. This study informs researchers to evaluate not only inter- but also intramolecular noncovalent interactions as potential drivers of remote CHB regioselectivity.

Modulating Polymer-siRNA Binding Does Not Promote Polyplex-Mediated Silencing.

The development of delivery vehicles for small interfering RNAs (siRNAs) remains a bottleneck to widespread clinical use. Cationic polymers represent an important class of potential delivery vehicles. In this study, we used alkyne-azide click chemistry to synthesize a variety of cationic poly(propargyl glycolide) backbone polymers to bind and deliver siRNAs. We demonstrated control over the binding interactions of these polymers and siRNAs by varying binding strength by more than three orders of magnitude. Binding strength was found to meet or exceed that of commercially available transfection agents. Our polymers effectively delivered siRNAs with no detectable cytotoxicity. Despite accumulation of siRNAs at levels comparable with commercial reagents, we did not observe silencing of the targeted protein. The implications of our results for future siRNA delivery vehicle design are discussed.

Kinetic analysis of the intracellular processing of siRNAs by confocal microscopy.

Here, we describe a method for tracking intracellular processing of small interfering RNA (siRNA) containing complexes using automated microscopy controls and image acquisition to minimize user effort and time. This technique uses fluorescence colocalization to monitor dual-labeled fluorescent siRNAs delivered by silica nanoparticles in different intracellular locations, including the early/late endosomes, fast/slow recycling endosomes, lysosomes and the endoplasmic reticulum. Combining the temporal association of siRNAs with each intracellular location, we reconstructed the intracellular pathways used in siRNA processing, and demonstrate how these pathways vary based on the chemical composition of the delivery vehicle.

Recent Advances and Challenges of Electrocatalytic N2 Reduction to Ammonia.

Global ammonia production reached 175 million metric tons in 2016, 90% of which is produced from high purity N2 and H2 gases at high temperatures and pressures via the Haber-Bosch process. Reliance on natural gas for H2 production results in large energy consumption and CO2 emissions. Concerns of human-induced climate change are spurring an international scientific effort to explore new approaches to ammonia production and reduce its carbon footprint. Electrocatalytic N2 reduction to ammonia is an attractive alternative that can potentially enable ammonia synthesis under milder conditions in small-scale, distributed, and on-site electrolysis cells powered by renewable electricity generated from solar or wind sources. This review provides a comprehensive account of theoretical and experimental studies on electrochemical nitrogen fixation with a focus on the low selectivity for reduction of N2 to ammonia versus protons to H2. A detailed introduction to ammonia detection methods and the execution of control experiments is given as they are crucial to the accurate reporting of experimental findings. The main part of this review focuses on theoretical and experimental progress that has been achieved under a range of conditions. Finally, comments on current challenges and potential opportunities in this field are provided.

One-Pot Iridium Catalyzed C-H Borylation/Sonogashira Cross-Coupling: Access to Borylated Aryl Alkynes.

Borylated aryl alkynes have been synthesized via one-pot iridium catalyzed C-H borylation (CHB)/Sonogashira cross-coupling of aryl bromides. Direct borylation of aryl alkynes encountered problems related to the reactivity of the alkyne under CHB conditions. However, tolerance of aryl bromides to CHB made possible a subsequent Sonogashira cross-coupling to access the desired borylated aryl alkynes.

Para-Selective, Iridium-Catalyzed C-H Borylations of Sulfated Phenols, Benzyl Alcohols, and Anilines Directed by Ion-Pair Electrostatic Interactions.

Para C-H borylations (CHB) of tetraalkylammonium sulfates and sulfamates have been achieved using bipyridine-ligated Ir boryl catalysts. Selectivities can be modulated by both the length of the alkyl groups in the tetraalkylammonium cations and the substituents on the bipyridine ligands. Ion pairing, where the alkyl groups of the cation shield the meta C-H bonds in the counteranions, is proposed to account for para selectivity. The 4,4'-dimethoxy-2,2'-bipyridine ligand gave superior selectivities.

Electronic and Structural Comparisons between Iron(II/III) and Ruthenium(II/III) Imide Analogs.

To examine structural and electronic differences between iron and ruthenium imido complexes, a series of compounds was prepared with different phosphine basal sets. The starting material for the ruthenium complexes was Ru(NAr/Ar*)(PMe3)3 (Ru1/Ru1*), where Ar = 2,6-(iPr)2C6H3 and Ar* = 2,4,6-(iPr)3C6H2, which were prepared from cis-RuCl2(PMe3)4 and 2 equiv of LiNHAr/Ar*. The starting materials for the iron complexes were the analogous Fe(NAr/Ar*)(PMe3)3 species (Fe1/Fe1*), which were not isolated but could be generated in situ from FeCl2, PMe3, and LiNHAr/Ar*. With both iron and ruthenium, the PMe3 starting materials underwent phosphine replacement with chelating ligands to give new group 8 imido complexes in the +2 oxidation state. Addition of 1,2-bis(diphenylphosphino)ethane (dppe) to M1/M1* gave Ru(NAr/Ar*)(PMe3)(dppe) and Fe(NAr/Ar*)(PMe3)(dppe). Addition of 1,2-bis(dimethylphosphino)ethane (dmpe) provided Ru(NAr/Ar*)(dmpe)2. A triphos ligand, {P(Me)2CH2}3SitBu (tP3), was also examined. Addition of tP3 to Fe1 provided Fe(NAr)(tP3) (Fe4), but a similar reaction with Ru1 only gave intractable materials. Oxidation of Fe4 with AgSbF6 gave {Fe(NAr)(tP3)}+SbF6- (Fe4a). Oxidation of Ru2 with AgSbF6 gave the unstable cation {Ru(NAr)(PMe3)(dppe)}+, which dimerized in the presence of acetonitrile via C-C bond formation at the aryl group C4 positions, affording {Ru(NAr)(PMe3)(NCMe)(dppe)}2+. This suggested that there was substantial radical character in the imide π system on oxidation and that an aromatic group substituted at the 4-position might provide greater stability. The cations {Fe(NAr*)(PMe3)(dppe)}+ (Fe2a*), {Ru(NAr*)(PMe3)(dppe)}+ (Ru2a*), and Fe4a were examined by EPR spectroscopy, which suggested differences in electronic structure depending on the metal and ligand set. CASPT2 calculations on model systems for Ru2a* and Fe2a* suggested that the large differences in electronic structure are related to the energy gap between the π-antibonding HOMO and the π-bonding HOMO-1. Both the geometry of the phosphines, which is slightly different between the iron and ruthenium analogs, and the metal center seem to contribute to this energetic difference.

C-H Borylation Catalysts that Distinguish Between Similarly Sized Substituents Like Fluorine and Hydrogen.

By modifying ligand steric and electronic profiles it is possible to C-H borylate ortho or meta to substituents in aromatic and heteroaromatic compounds, where steric differences between accessible C-H sites are small. Dramatic effects on selectivities between reactions using B2pin2 or 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (HBpin) are described for the first time. Judicious ligand and borane combinations give highly regioselective C-H borylations on substrates where typical borylation protocols afford poor selectivities.

Homogeneous electrocatalytic oxidation of ammonia to N2 under mild conditions.

We report that ruthenium polypyridyl complexes can catalyze ammonia oxidation to dinitrogen at room temperature and ambient pressure. During bulk electrolysis experiments, gas chromatography and mass spectrometry analysis of the headspace in the electrochemical cell showed that dinitrogen and dihydrogen are generated from ammonia with high faradaic efficiencies. A proposed mechanism where a hydrazine complex is the initial N-N bonded intermediate is supported by chemical and electrochemical experiments. This is a well-defined system for homogeneous electrocatalytic ammonia oxidation. It establishes a platform for answering mechanistic questions relevant to using ammonia to store and distribute renewable energy.

Achieving High Ortho Selectivity in Aniline C-H Borylations by Modifying Boron Substituents.

High ortho selectivity for Ir-catalyzed C-H borylations (CHBs) of anilines results when B2eg2 (eg = ethylene glycolate) is used as the borylating reagent in lieu of B2pin2, which is known to give isomeric mixtures with anilines lacking a blocking group at the 4-position. With this modification, high selectivities and good yields are now possible for various anilines, including those with groups at the 2- and 3-positions. Experiments indicate that ArylN(H)Beg species are generated prior to CHB and support the improved ortho selectivity relative to B2pin2 reactions arising from smaller Beg ligands on the Ir catalyst. The lowest-energy transition states (TSs) from density functional theory computational analyses have N-H···O hydrogen-bonding interactions between PhN(H)Beg and O atoms in Beg ligands. Ir-catalyzed CHB of PhN(H)Me with B2eg2 is also highly ortho-selective. 1H NMR experiments show that N-borylation fully generates PhN(Me)Beg prior to CHB. The TS with the lowest Gibbs energy was the ortho TS, in which the Beg unit is oriented anti to the bipyridine ligand.

Ir-Catalyzed ortho-Borylation of Phenols Directed by Substrate-Ligand Electrostatic Interactions: A Combined Experimental/in Silico Strategy for Optimizing Weak Interactions.

A strategy for affecting ortho versus meta/para selectivity in Ir-catalyzed C-H borylations (CHBs) of phenols is described. From selectivity observations with ArylOBpin (pin = pinacolate), it is hypothesized that an electrostatic interaction between the partial negatively charged OBpin group and the partial positively charged bipyridine ligand of the catalyst favors ortho selectivity. Experimental and computational studies designed to test this hypothesis support it. From further computational work a second generation, in silico designed catalyst emerged, where replacing Bpin with Beg (eg = ethylene glycolate) was predicted to significantly improve ortho selectivity. Experimentally, reactions employing B2eg2 gave ortho selectivities > 99%. Adding triethylamine significantly improved conversions. This ligand-substrate electrostatic interaction provides a unique control element for selective C-H functionalization.

As Precious as Platinum: Iron Nitride for Electrocatalytic Oxidation of Liquid Ammonia.

The electrolysis of ammonia (NH3), a potential carrier for hydrogen fuel, has only been studied in detail in systems employing expensive, noble metal anodes such as platinum, ruthenium, and iridium. For NH3 to serve as a practical hydrogen storage medium, the electrolysis process must be energy efficient, scalable, and inexpensive. Clearly, alternatives to precious metals would greatly reduce costs if the performance of less expensive, more abundant metals rivaled those of their expensive counterparts. In this regard, no metal is less expensive than iron. Iron exhibits complex anodic behavior in liquid ammonia (NH3(l)), with a high sensitivity to trace amounts of dissolved water, and a tendency to corrosively dissolve with appropriate applied bias. However, with sufficient applied overpotential in distilled NH3(l), an iron nitride film forms in situ that is resistant to dissolution. On this in situ-modified surface, dinitrogen evolution out-performs anodic dissolution with an efficiency of over 95%. Amazingly, the onset potential for dinitrogen evolution in NH3(l) on this in situ-modified iron surface is almost identical to what is measured on a platinum electrode.

Dextran functionalization enhances nanoparticle-mediated siRNA delivery and silencing.

Understanding the endocytosis and intracellular trafficking of short interfering RNA (siRNA) delivery vehicle complexes remains a critical bottleneck in designing siRNA delivery vehicles for highly active RNA interference (RNAi)-based therapeutics. In this study, we show that dextran functionalization of silica nanoparticles enhanced uptake and intracellular delivery of siRNAs in cultured cells. Using pharmacological inhibitors for endocytotic pathways, we determined that our complexes are endocytosed via a previously unreported mechanism for siRNA delivery in which dextran initiates scavenger receptor-mediated endocytosis through a clathrin/caveolin-independent process. Our findings suggest that siRNA delivery efficiency could be enhanced by incorporating dextran into existing delivery platforms to activate scavenger receptor activity across a variety of target cell types.

Catalytic borylation of methane.

Despite steady progress in catalytic methods for the borylation of hydrocarbons, methane has not yet been subject to this transformation. Here we report the iridium-catalyzed borylation of methane using bis(pinacolborane) in cyclohexane solvent. Initially, trace amounts of borylated products were detected with phenanthroline-coordinated Ir complexes. A combination of experimental high-pressure and high-throughput screening, and computational mechanism discovery techniques helped to rationalize the foundation of the catalysis and identify improved phosphine-coordinated catalytic complexes. Optimized conditions of 150°C and 3500-kilopascal pressure led to yields as high as ~52%, turnover numbers of 100, and improved chemoselectivity for monoborylated versus diborylated methane.