A Sterically Accessible Monomeric Stibine Oxide Activates Organotetrel(IV) Halides, Including C-F and Si-F Bonds.

Phosphine oxides and arsine oxides are common laboratory reagents with diverse applications that stem from the chemistry exhibited by these monomeric species. Stibine oxides are, in contrast, generally dimeric or oligomeric species because of the reactivity-quenching self-association of the highly polarized stiboryl (Sb=O/Sb+-O-) group. We recently isolated Dipp3SbO (Dipp = 2,6-diisopropylphenyl), the first example of a kinetically stabilized monomeric stibine oxide, which exists as a bench-stable solid and bears an unperturbed stiboryl group. Herein, we report the isolation of Mes3SbO (Mes = mesityl), in which the less bulky substituents maintain the monomeric nature of the compound but unlock access to a wider range of reactivity at the unperturbed stiboryl group relative to Dipp3SbO. Mes3SbO was found to be a potent Lewis base in the formation of adducts with the main-group Lewis acids PbMe3Cl and SnMe3Cl. The accessible Lewis acidity at the Sb atom results in a change in the reactivity with GeMe3Cl, SiMe3Cl, and CPh3Cl. With these species, Mes3SbO formally adds the E-Cl (E = Ge, Si, C) bond across the unsaturated stiboryl group to form a 5-coordinate stiborane. The biphilicity of Mes3SbO is sufficiently potent to activate even the C-F and Si-F bonds of C(p-MeOPh)3F and SiEt3F, respectively. These results mark a significant contribution to an increasingly rich literature on the reactivity of polar, unsaturated main-group motifs. Furthermore, these results highlight the utility of a kinetic stabilization approach to access unusual bonding motifs with unquenched reactivity that can be leveraged for small-molecule activation.

Reactivity of Tetrel-Functionalized Heptaphosphane Clusters toward Azides.

In this work, the reactivity of tetrel-functionalized phosphorus clusters toward organoazides is probed. Clusters (Me3Si)3P7 (1) and (Me3Ge)3P7 (2) were reacted with benzyl azide, phenyl azide, and 4-bromophenyl azide, and it was found that the [RN] (R = benzyl, phenyl, and 4-bromophenyl) unit from the azide inserted into the phosphorus-tetrel bonds on the cluster, accompanied by N2 elimination. Through control of the azide stoichiometry, the mono-, bis-, and tris-inserted products could be observed, consistent with these insertions proceeding in a stepwise manner. The bonding between the amine moieties and clusters was further investigated by computational chemistry, and the findings were consistent with the phosphorus cluster having undergone a formal oxidation. These insertion reactions are a convenient means of accessing Zintl clusters functionalized with exo-nitrogen-bonded moieties, which, to the best of our knowledge, were previously unknown.

Recent advances in the stabilization of monomeric stibinidene chalcogenides and stibine chalcogenides.

The elucidation of novel bonding situations at heavy p-block elements has greatly advanced recent efforts to access useful reactivity at earth-abundant main-group elements. Molecules with unsaturated bonds between heavier, electropositive elements and lighter, electronegative elements are often highly polarized and competent in small-molecule activations, but the reactivity of these molecules may be quenched by self-association of monomers to form oligomeric species where the polar, unsaturated groups are assembled in a head-to-tail fashion. In this Frontier, we discuss the synthetic strategies employed to isolate monomeric σ2,λ3-stibinidene chalcogenides (RSbCh) and monomeric σ4,λ5-stibine chalcogenides (R3SbCh). These classes of molecules each feature polarized antimony-chalcogenide bonds (Sb = Ch/Sb+-Ch-). We highlight how the synthesis and isolation of these molecules has led to the discovery of novel reactivity and has shed light on fundamental aspects of inorganic structure and bonding. Despite these advances, there are critical aspects of this chemistry that remain underdeveloped and we provide our perspective on yet-unrealized synthetic targets that may be achieved with the continued development of the strategies described herein.

Carbon monoxide poisoning: A problem uniquely suited to a medicinal inorganic chemistry solution.

Carbon monoxide poisoning is one of the most common forms of poisoning in the world. Although the primary mode of treatment, oxygen therapy, is highly effective in many cases, there are instances in which it is inadequate or inappropriate. Whereas oxygen therapy relies on high levels of a low-affinity ligand (O2) to displace a high-affinity ligand (CO) from metalloproteins, an antidote strategy relies on introducing a molecule with a higher affinity for CO than native proteins (Kantidote,CO > Kprotein,CO). Based on the fundamental chemistry of CO, such an antidote is most likely required to be an inorganic compound featuring an electron-rich transition metal. A review is provided of the protein-, supramolecular complex-, and small molecule-based CO poisoning antidote platforms that are currently under investigation.

Variation in pnictogen-oxygen bonding unlocks greatly enhanced Brønsted basicity for the monomeric stibine oxide.

Phosphine oxides and arsine oxides feature highly polarized pnictoryl groups (Pn+-O-/Pn = O; Pn = P, As) and react as Brønsted bases through O-centered lone pairs. We recently reported the first example of a monomeric stibine oxide, Dipp3SbO (Dipp = diisopropylphenyl), allowing periodic trends in pnictoryl bonding to be extended to antimony for the first time. Computational studies suggest that, as the pnictogen atom becomes heavier, delocalization of electron density from the O-centered lone pairs to the Pn-C σ* orbitals is attenuated, destabilizing the lone pairs and increasing the donor capacity of the pnictine oxide. Herein, we assess the Brønsted basicity of a series of monomeric pnictine oxides (Dipp3PnO; Pn = P, As, and Sb). Stoichiometric reactivity between Dipp3PnO and a series of acids demonstrates the greatly enhanced ability of Dipp3SbO to accept protons relative to the lighter congeners, consistent with theoretical isodesmic reaction enthalpies and proton affinities. 1H NMR spectrometric titrations allow for the pKaH,MeCN determination of Dipp3AsO and Dipp3SbO, revealing a 106-fold increase in Brønsted basicity from Dipp3AsO to Dipp3SbO. The increased basicity can be exploited in catalysis; Dipp3SbO exhibits dramatically increased catalytic efficiency in the Brønsted base-catalyzed transesterification between p-nitrophenyl acetate and 2,2,2-trifluoroethanol. Our results unambiguously confirm the drastic increase in Brønsted basicity from Dipp3PO < Dipp3AsO < Dipp3SbO, a direct consequence of the variation in the electronic structure of the pnictoryl bond as the pnictogen atom increases in atomic number.

Models of the putative antimony(V)-diolate motifs in antileishmanial pentavalent antimonial drugs.

The structures of the pentavalent antimonials, small-molecule Sb-containing drugs used to treat the neglected tropical disease leishmaniasis, remain unknown despite their widespread use for over half a century. These drugs are prepared by combination of an Sb(V) precursor and a sugar derivative and proposed structures frequently invoke a cyclic stiborane motif in which a vicinal diolate ligand chelates an Sb(V) center. As a step towards better understanding the structures of the pentavalent antimonial drugs, a series of cyclic organostiboranes spanning the stereochemical space afforded by a vicinal diolate motif has been synthesized and characterized. X-ray crystallography and NMR spectroscopy provide unambiguous characterization of the structures of these model compounds and of the interaction of the diolate with the Sb(V) center. Particularly notable are the systematic trends observed in the NMR spectroscopic signals as a function of the stereochemistry of the diolate. The spectroscopic signatures identified with these model compounds will provide a framework for elucidating the structures of the pentavalent antimonial drugs.

Isolation, bonding and reactivity of a monomeric stibine oxide.

In contrast to phosphine oxides and arsine oxides, which are common and exist as stable monomeric species featuring the corresponding pnictoryl functional group (Pn=O/Pn+-O-; Pn = P, As), stibine oxides are generally polymeric, and the properties of the unperturbed stiboryl group (Sb=O/Sb+-O-) remain unexplored. We now report the isolation of the monomeric stibine oxide, Dipp3SbO (where Dipp = 2,6-diisopropylphenyl). Spectroscopic, crystallographic and computational studies provide insight into the nature of the Sb=O/Sb+-O- bond. Moreover, isolation of Dipp3SbO allows the chemistry of the stiboryl group to be explored. Here we show that Dipp3SbO can act as a Brønsted base, a hydrogen-bond acceptor and a transition-metal ligand, in addition engaging in 1,2-addition, O-for-F2 exchange and O-atom transfer. In all cases, the reactivity of Dipp3SbO differed from that of the lighter congeners Dipp3AsO and Dipp3PO.

Realgar and arsenene nanomaterials as arsenic-based anticancer agents.

Arsenic trioxide (ATO) is an approved therapy for the treatment of acute promyelocytic leukemia, but the extension of arsenic-based therapies to other types of malignancies, notably tumor-forming cancers, has been slow. Nanodelivery vehicles offer a means of effectively delivering ATO to tumors. Very recently, there has been a series of developments in the formulation of arsenic-based nanomedicines that are not simply loaded with ATO. Realgar nanoparticles are comprised of molecular As4S4 units. Current studies suggest that realgar nanoparticles ultimately act in a manner similar to ATO, but with greatly attenuated toxic side effects. A drastically different approach is taken with arsenene nanosheets, a 2-dimensional form of elemental As. The electronic properties of this material allow it to mediate both photothermal therapy and photodynamic therapy. The exploration of these nanomaterials is still in its infancy but is poised to allow arsenic-based therapy to make yet another significant impact on cancer treatment.

Selective Chromium(VI) Trapping by an Acetate-Releasing Coordination Polymer.

We report the high-capacity and selective uptake of Cr(VI) from water using the coordination polymer silver bipyridine acetate (SBA, [Ag(4,4'-bipy)][CH3CO2]·3H2O). Cr capture involves the release of acetate, and we have structurally characterized two of the product phases that form: silver bipyridine chromate (SBC, SLUG-56, [Ag(4,4'-bipy)][CrO4]0.5·3.5H2O) and silver bipyridine dichromate (SBDC, SLUG-57, [Ag(4,4'-bipy)][Cr2O7]0.5·H2O). SBA maintains a high Cr uptake capacity over a wide range of pH values (2-10), reaching a maximum of 143 mg Cr/g at pH 4. This Cr uptake capacity is one of the highest among coordination polymers. SBA offers the additional benefits of a one-step, room temperature, aqueous synthesis and its release of a non-toxic anion following Cr(VI) capture, acetate. Furthermore, SBA capture of Cr(VI) remains >97% in the presence of a 50-fold molar excess of sulfate, nitrate, or carbonate. We also investigated the Cr(VI) sequestration abilities of silver 1,2-bis(4-pyridyl)ethane nitrate (SEN, [Ag(4,4'-bpe)][NO3]) and structurally characterized the silver 1,2-bis(4-pyridyl)ethane chromate (SEC, SLUG-58, [Ag(4,4'-bpe)][CrO4]0.5) product. SEN was, however, a less effective Cr(VI) sequestering material than SBA.

The rippled ß-sheet layer configuration-a novel supramolecular architecture based on predictions by Pauling and Corey.

The rippled ß-sheet is a peptidic structural motif related to but distinct from the pleated ß-sheet. Both motifs were predicted in the 1950s by Pauling and Corey. The pleated ß-sheet was since observed in countless proteins and peptides and is considered common textbook knowledge. Conversely, the rippled ß-sheet only gained a meaningful experimental foundation in the past decade, and the first crystal structural study of rippled ß-sheets was published as recently as this year. Noteworthy, the crystallized assembly stopped at the rippled ß-dimer stage. It did not form the extended, periodic rippled ß-sheet layer topography hypothesized by Pauling and Corey, thus calling the validity of their prediction into question. NMR work conducted since moreover shows that certain model peptides rather form pleated and not rippled ß-sheets in solution. To determine whether the periodic rippled ß-sheet layer configuration is viable, the field urgently needs crystal structures. Here we report on crystal structures of two racemic and one quasi-racemic aggregating peptide systems, all of which yield periodic rippled antiparallel ß-sheet layers that are in excellent agreement with the predictions by Pauling and Corey. Our study establishes the rippled ß-sheet layer configuration as a motif with general features and opens the road to structure-based design of unique supramolecular architectures.

Synthesis and Functionalization of Challenging meso-Substituted Aryl Bis-pocket Porphyrins Accessed via Suzuki-Miyaura Cross-Coupling.

Herein we report an investigation into the synthesis, metalation, and functionalization of bis-pocket porphyrins using the Suzuki-Miyaura cross-coupling reaction. Steric limitations to accessing bis-pocket porphyrins were overcome by using this Pd-catalyzed C-C-bond-forming strategy to introduce steric bulk after macrocyclization: 2,6-dibromo-4-trimethylsilybenzaldehyde was condensed with pyrrole, and a variety of boronic acids were coupled to the resulting porphyrin in up to 95% yield. Furthermore, we show that these porphyrins can be metalated with a variety of metals and sulfonated to create water-soluble bis-pocket porphyrins.

Biomimetic Total Synthesis and Investigation of the Non-Enzymatic Chemistry of Oxazinin A.

We report the first total synthesis of an antimycobacterial natural product oxazinin A that takes advantage of a multi-component cascade reaction of anthranilic acid and a precursor polyketide containing an aldehyde. The route utilized for the synthesis of the pseudodimeric oxazinin A validates a previously proposed biosynthetic mechanism, invoking a non-enzymatic pathway to the complex molecule. We found a 76 : 10 : 9 : 5 ratio of oxazinin diastereomers from the synthetic cascade, which is an identical match to that found in the fermentation media from the fungus Eurotiomycetes 110162. Further investigation of the non-enzymatic formation of oxazinin A using 1 H-15 N HMBC NMR spectroscopy allowed for a plausible determination of the stepwise mechanism. The developed route is highly amenable for the synthesis of diverse sets of analogs around the oxazinin scaffold to study structure-activity relationships (SAR).

A New Amino Acid for Improving Permeability and Solubility in Macrocyclic Peptides through Side Chain-to-Backbone Hydrogen Bonding.

Despite the notoriously poor membrane permeability of peptides, many cyclic peptide natural products show high passive membrane permeability and potently inhibit a variety of "undruggable" intracellular targets. A major impediment to the design of cyclic peptides with good permeability is the high desolvation energy associated with the peptide backbone amide NH groups. While several strategies have been proposed to mitigate this deleterious effect, only few studies have used polar side chains to sequester backbone NH groups. We investigated the ability of N,N-pyrrolidinylglutamine (Pye), whose side chain contains a powerful hydrogen-bond-accepting C═O amide group but no hydrogen-bond donors, to sequester exposed backbone NH groups in a series of cyclic hexapeptide diastereomers. Analyses revealed that specific Leu-to-Pye substitutions conferred dramatic improvements in aqueous solubility and permeability in a scaffold- and position-dependent manner. Therefore, this approach offers a complementary tool for improving membrane permeability and solubility in cyclic peptides.

A water-soluble iron-porphyrin complex capable of rescuing CO-poisoned red blood cells.

We describe herein a small-molecule platform that exhibits key properties needed by an antidote for CO poisoning. The design features an iron-porphyrin complex with bulky substituents above and below the macrocyclic plane to provide a hydrophobic pocket for CO binding and to prevent the formation of inactive oxo-bridged dimers. Peripheral charged groups impart water solubility. We demonstrate that the Fe(II) complex of a porphyrin with 2,6-diphenyl-4-sulfophenyl meso substituents can bind CO, stoichiometrically sequester CO from carboxyhemoglobin, and rescue CO-poisoned red blood cells.

A crystal-structural study of Pauling-Corey rippled sheets.

Following the seminal theoretical work on the pleated ß-sheet published by Pauling and Corey in 1951, the rippled ß-sheet was hypothesized by the same authors in 1953. In the pleated ß-sheet the interacting ß-strands have the same chirality, whereas in the rippled ß-sheet the interacting ß-strands are mirror-images. Unlike with the pleated ß-sheet that is now common textbook knowledge, the rippled ß-sheet has been much slower to evolve. Much of the experimental work on rippled sheets came from groups that study aggregating racemic peptide systems over the course of the past decade. This includes MAX1/DMAX hydrogels (Schneider), L/D-KFE8 aggregating systems (Nilsson), and racemic Amyloid ß mixtures (Raskatov). Whether a racemic peptide mixture is "ripple-genic" (i.e., whether it forms a rippled sheet) or "pleat-genic" (i.e., whether it forms a pleated sheet) is likely governed by a complex interplay of thermodynamic and kinetic effects. Structural insights into rippled sheets remain limited to only a very few studies that combined sparse experimental structural constraints with molecular modeling. Crystal structures of rippled sheets are needed so we can rationally design rippled sheet architectures. Here we report a high-resolution crystal structure, in which (l,l,l)-triphenylalanine and (d,d,d)-triphenylalanine form dimeric antiparallel rippled sheets, which pack into herringbone layer structures. The arrangements of the tripeptides and their mirror-images in the individual dimers were in excellent agreement with the theoretical predictions by Pauling and Corey. A subsequent mining of the PDB identified three orphaned rippled sheets among racemic protein crystal structures.

Encapsulation of closo-dodecaiodododecaborate in 2-hydroxypropyl-γ-cyclodextrin prevents hemolysis.

Na2B12I12 has many of the properties desired by an X-ray contrast agent but is lethal at the concentrations needed for medical imaging. We demonstrate here that PBS solutions with >50 mM Na2B12I12 induce hemolysis, consistent with the previously reported superchaotropic nature of the anion. The presence of <1 equiv. of 2-hydroxypropyl-γ-cyclodextrin prevents hemolysis and suggests a strategy for exploiting B12I122- as an X-ray contrast agent.

H-Atom Assignment and Sb-O Bonding of [Mes3SbOH][O3SPh] Confirmed by Neutron Diffraction, Multipole Modeling, and Hirshfeld Atom Refinement.

Neutron wavelength-resolved Laue diffraction experiments permit accurate refinement of the H-atom positions and anisotropic displacement parameters of [Mes3SbOH][O3SPh]. A multipole-based charge density refinement and a topological analysis of the refined electron density were also performed. Hirshfeld atom refinement (HAR) recovers the neutron-determined H-atom parameters, and the quantum-mechanical electron density used in HAR recovers the electron density topology from the refined multipole model. These results confirm that [Mes3SbOH][O3SPh] does indeed feature a hydroxystibonium cation with a nominal Sb-O single bond and not a stibine oxide with an Sb=O/Sb+-O- bond.

Genomics-driven discovery of chiral triscatechol siderophores with enantiomeric Fe(iii) coordination.

Ferric complexes of triscatechol siderophores may assume one of two enantiomeric configurations at the iron site. Chirality is known to be important in the iron uptake process, however an understanding of the molecular features directing stereospecific coordination remains ambiguous. Synthesis of the full suite of (DHBL/DLysL/DSer)3 macrolactone diastereomers, which includes the siderophore cyclic trichrysobactin (CTC), enables the effects that the chirality of Lys and Ser residues exert on the configuration of the Fe(iii) complex to be defined. Computationally optimized geometries indicate that the Λ/Δ configurational preferences are set by steric interactions between the Lys sidechains and the peptide backbone. The ability of each (DHBL/DLysL/DSer)3 diastereomer to form a stable Fe(iii) complex prompted a genomic search for biosynthetic gene clusters (BGCs) encoding the synthesis of these diastereomers in microbes. The genome of the plant pathogen Dickeya chrysanthemi EC16 was sequenced and the genes responsible for the biosynthesis of CTC were identified. A related but distinct BGC was identified in the genome of the opportunistic pathogen Yersinia frederiksenii ATCC 33641; isolation of the siderophore from Y. frederiksenii ATCC 33641, named frederiksenibactin (FSB), revealed the triscatechol oligoester, linear-(DHBLLysLSer)3. Circular dichroism (CD) spectroscopy establishes that Fe(iii)-CTC and Fe(iii)-FSB are formed in opposite enantiomeric configuration, consistent with the results of the ferric complexes of the cyclic (DHBL/DLysL/DSer)3 diastereomers.

Geometry of Pentaphenylantimony in Solution: Support for a Trigonal Bipyramidal Assignment from X-ray Absorption Spectroscopy and Vibrational Spectroscopic Data.

Pentaphenylantimony (SbPh5) has been previously crystallized in either a square pyramidal or trigonal bipyramidal geometry. Investigation of the solution-state structure of SbPh5 has been hampered by the extreme fluxionality of this compound, but previous vibrational spectroscopic studies concluded that it maintains a square pyramidal geometry in solution. This non-VSEPR-compliant geometry, which is also assumed by BiPh5 in the solid state, stands in contrast to the trigonal bipyramidal geometries of PPh5 and AsPh5. A range of phenomena have been invoked to explain this discrepancy, most notably, the increased importance of relativistic effects as group 15 is descended. We present crystallographic, spectroscopic, and computational data revealing that SbPh5 in fact assumes the VSEPR-compliant trigonal bipyramidal geometry in solution. In particular, Sb X-ray absorption spectroscopy (XAS) was used to obtain geometry-sensitive spectra that do not suffer from the slow spectroscopic time scale that has prevented NMR studies from elucidating the structure of this fluxional molecule. Sb K-edge and LIII-edge XAS spectra of crystalline solids featuring SbPh5 in either a square pyramidal (nonsolvate) or trigonal bipyramidal (cyclohexane hemisolvate or THF hemisolvate) form were compared to spectra of SbPh5 in solution. The solution-state spectra agree with those from solids containing trigonal bipyramidal SbPh5. The most diagnostic spectroscopic feature was the distribution of intensity in the Sb LIII pre-edge features. These distributions were rationalized using time-dependent density functional theory calculations that take into account spin-orbit coupling. Our use of Sb XAS not only resolves a long-standing physical inorganic question but also demonstrates more widely the utility of XAS in establishing the structures of fluxional main-group compounds. This conclusion was further supported by solid- and solution-state Raman data. Finally, we note that the present high-resolution diffraction data allow τ for nonsolvated SbPh5 to be revised to 0.216.