Ultrafast Au(III)-Mediated Arylation of Cysteine.

Through mechanistic work and rational design, we have developed the fastest organometallic abiotic Cys bioconjugation. As a result, the developed organometallic Au(III) bioconjugation reagents enable selective labeling of Cys moieties down to picomolar concentrations and allow for the rapid construction of complex heterostructures from peptides, proteins, and oligonucleotides. This work showcases how organometallic chemistry can be interfaced with biomolecules and lead to a range of reactivities that are largely unmatched by classical organic chemistry tools.

Assessment of Iron-Based Spin-Orbit Coupling Effects in Pt-Fe Heterobimetallic Lantern Complexes via 57Fe Mössbauer Spectroscopy.

A series of heterobimetallic lantern complexes, [PtFe(SOCR)4(pyX)] where R = Me, X = H (1), X = NH2 (2), X = SMe (3); R = Ph, X = H (4), X = NH2 (5), X = SMe (6), have been prepared and characterized spectroscopically. Compounds 1, 4, and 5 are reported herein for the first time. The high-spin iron(II) sites of 1-6 have been investigated using 57Fe Mössbauer spectroscopy. Although the isomer shift of these species is nearly identical, their quadrupole splitting exhibits a much larger variation. Moreover, the zero-field Mössbauer spectra of 3-5 show surprising changes over time which are likely indicative of small structural distortions. The field dependent Mössbauer study of 1 and 6 revealed a zero field splitting (ZFS) characterized by a relatively large and positive D value. The combined Density Functional Theory (DFT) and ab initio Complete Active Space Self-Consistent Field (CASSCF) investigation of 1-6 indicates that their ground state is best described using a linear combination of {|xz⟩, |yz⟩} states. Our theoretical analysis suggests that the ZFSs and magnitude of the quadrupole splitting of 1-6 are determined by the spin-orbit coupling of the three lowest orbital states which have a T2g parentage.

Vertex Differentiation Strategy for Tuning the Physical Properties of closo-Dodecaborate Weakly Coordinating Anions.

We report the synthesis and characterization of various compounds containing the 1,7,9-hydroxylated closo-dodecahydrododecaborate (B12H9(OH)32-) cluster motif. Specifically, we show how the parent compound can be synthesized on the multigram scale and further perhalogenated, leading to a new class of vertex-differentiated weakly coordinating anions. We show that a postmodification of the hydroxyl groups by alkylation affords further opportunities for tailoring these anions' stability, steric bulk, and solubility properties. The resulting dodecaborate-based salts were subjected to a full thermal and electrochemical stability evaluation, showing that many of these anions maintain thermal stability up to 500 °C and feature no redox activity below ∼1 V vs Fc/Fc+. Mixed hydroxylated/halogenated clusters show enhanced solubility compared to their purely halogenated analogs and retain weakly coordinating properties in the solid state, as demonstrated by ionic conductivity measurements of their Li+ salts.

3-Ferrocenyl-estra-1,3,5 (10)-triene-17-one: Synthesis, Crystal Structure, Hirshfeld Surface Analysis, DFT Studies, and Its Binding to Human Serum Albumin Studied through Fluorescence Quenching and In Silico Docking Studies.

3-ferrocenyl-estra-1,3,5 (10)-triene-17-one (2), [Fe(C5H5)(C24H25O3)], crystallizes in the monoclinic space group C2. The cyclopentadienyl (Cp) rings adopt a nearly eclipsed conformation, and the Cp plane is tilted by 87.66° with respect to the substituted phenyl plane. An average Fe-C(Cp) bond length of 2.040(13) Å was determined, similar to the one reported for ferrocene. Hirshfeld surfaces and two-dimensional fingerprint plots were generated to analyze weak intermolecular C-H···π and C-H···O interactions. Density functional theory studies revealed a 1.15 kcal/mol rotational barrier for the C3-O1 single bound. Fluorescence quenching studies and in silico docking studies suggest that human serum albumin forms a complex with 2 via a static mechanism dominated by van der Waals interactions and hydrogen bonding interactions.

Development of a Ratiometric Fluorescent Cu(II) Indicator Based on Poly(N-isopropylacrylamide) Thermal Phase Transition and an Aminopyridyl Cu(II) Ligand.

An aqueous Cu2+ and Zn2+ indicator is reported based on copolymerizing aminopyridine ligands and the environment-sensitive dansyl fluorophore into the responsive polymer poly(N-isopropylacrylamide) (PNIPAm). The metal ion binding creates charge and solvation that triggers PNIPAm's thermal phase transition from hydrophobic globule to hydrophilic open coil. As a basis for sensing the metal-binding, the dansyl fluorescence emission spectra provide a signal at ca. 530 nm and a signal at 500 nm for the hydrophobic and hydrophilic environment, respectively, that are ratiometrically interpreted. The synthesis of the title pyridylethyl-pyridylmethyl-amine ligand (acronym PEPMA) with a 3-carbon linker to the copolymerizable group, aminopropylacrylamide (PEPMA-C3-acrylamide), is reported, along with a nonpolymerizable model ligand derivative. The response of the polymer is validated by increasing temperature from 25 °C to 49 °C, which causes a shift in maximum emission wavelength from 536 nm to 505 nm, along with an increase in the ratio of emission intensity of 505 nm/536 nm from 0.77 to 1.22 (λex = 330 nm) as the polymer releases water. The addition of divalent Cu or Zn to the indicator resulted in a dansyl emission shift of 10 nm to a longer wavelength, accompanied by fluorescence quenching in the case of Cu2+. The addition of EDTA to the Cu2+-loaded indicator reversed the fluorescence shift at 25 °C to 35 °C. The affinities of Cu2+ and Zn2+ for the PEPMA derivatives are log Kf = 11.85 and log Kf = 5.67, respectively, as determined by potentiometric titration. The single-crystal X-ray structure of the Cu2+-PEPMA derivative is five-coordinate, of-geometry intermediate between square-pyramidal and trigonal-bipyramidal, and is comparable to that of Cu2+ complexes with similar formation constants.

Utilizing Experiment and Theory to Evaluate Rhodamine B ethylenediamine as a Fluorescent Sensor for G-type Nerve Agents.

Nerve gas mimic binding with Rhodamine B ethylenediamine (1) was studied in organic media. Binding of the nerve gas mimic, diethyl chlorophosphate (DCP), with the probe generated a non-fluorescent intermediate and a fluorescent product. Fluorescent and non-fluorescent products generated were identified using mass spectrometry and X-ray crystallography. Time-dependent density functional theory calculations were also used to investigate the electronic structure of the fluorescent probe in the ground and lowest lying π → π* singlet excited state. Though good agreement between theory and experiment can be obtained for the intense peak in the experimental spectrum using non-hybrid functionals, care must be taken when modelling these complexes due to the appearance of an n → π* transition that is too low in energy and appears to fall in the shoulders of the π → π* transitions.

Configurational Lability at Tetrahedral Phosphorus: syn/anti-Isomerization of a P-Stereogenic Phosphiranium Cation by Intramolecular Epimerization at Phosphorus.

Tetrahedral main-group compounds are normally configurationally stable, but P-epimerization of the chiral phosphiranium cations syn- or anti-[Mes*P(Me)CH2 CHPh][OTf] (Mes*=2,4,6-(t-Bu)3 C6 H2 ) occurred under mild conditions at 60 °C in CD2 Cl2 , resulting in isomerization to give a syn-enriched equilibrium mixture. Ion exchange with excess [NBu4 ][Δ-TRISPHAT] (Δ-TRISPHAT=Δ-P(o-C6 Cl4 O2 )3 ) followed by chromatography on silica removed [NBu4 ][OTf] and gave mixtures of syn- and anti-[Mes*P(Me)CH2 CHPh][Δ-TRISPHAT]⋅x[NBu4 ][Δ-TRISPHAT]. NMR spectroscopy showed that isomerization proceeded with epimerization at P and retention at C. DFT calculations are consistent with a mechanism involving P-C cleavage to yield a hyperconjugation-stabilized carbocation, pyramidal inversion promoted by σ-interaction of the P lone pair with the neighboring ß-carbocation, and ring closure with inversion of configuration at P.

Expedient Total Syntheses of Pladienolide-Derived Spliceosome Modulators.

Atom and step economical total syntheses of spliceosome modulating natural products pladienolides A and B are described. The strategic functionalization of an unsaturated macrolide precursor enabled the most concise syntheses of these natural products to date and provides convenient, flexible access to stereodefined macrolides to streamline medicinal chemistry explorations. Notably, this synthetic route does not depend on protecting group manipulations that traditionally define synthesis planning for polyhydroxylated natural products of polyketide origin. Its utility is further demonstrated by the enantioselective total synthesis of H3B-8800, a hitherto semisynthetic pladienolide-derived spliceosome modulator undergoing clinical trials for hematological malignancies.

Hard-Soft Chemistry Design Principles for Predictive Assembly of Single Molecule-Metal Junctions.

The achievement of atomic control over the organic-inorganic interface is key to engineering electronic and spintronic properties of molecular devices. We leverage insights from inorganic chemistry to create hard-soft acid-base (HSAB) theory-derived design principles for incorporation of single molecules onto metal electrodes. A single molecule circuit is assembled via a bond between an organic backbone and an under-coordinated metal atom of the electrode surface, typically Au. Here, we study molecular composition factors affecting the junction assembly of coordination complexes containing transition metals atoms on Au electrodes. We employ hetero- and homobimetallic lantern complexes and systematically change the coordination environment to vary the character of the intramolecular bonds relative to the electrode-molecule interaction. We observe that trends in the robustness and chemical selectivity of single molecule junctions formed with a range of linkers correlate with HSAB principles, which have traditionally been used to guide atomic arrangements in the synthesis of coordination complexes. We find that this similarity between the intermolecular electrode-molecule bonding in a molecular circuit and the intramolecular bonds within a coordination complex has implications for the design of metal-containing complexes compatible with electrical measurements on metal electrodes. Our results here show that HSAB principles determine which intramolecular interactions can be compromised by inter molecule-electrode coordination; in particular on Au electrodes, soft-soft metal-ligand bonding is vulnerable to competition from soft-soft Au-linker bonding in the junction. Neutral donor-acceptor intramolecular bonds can be tuned by the Lewis acidity of the transition metal ion, suggesting future synthetic routes toward incorporation of transition metal atoms into molecular junctions for increased functionality of single molecule devices.

Arene-Perfluoroarene Interactions in Solution.

A systematic study of arene-perfluoroarene interactions in solution is presented. Using a combination of NMR titration experiments, X-ray crystallography, and computational analysis, we analyze the effects of fluorination, substituents, ring size, and solvation on the arene-perfluoroarene interaction. We find that fluorination, extension of the π systems, and enhancement of solvent polarity greatly stabilize the stacking energy up to 3 orders of magnitude (Ka = <1 to 6000 M-1), with the highest Ka achieved for the interaction of water-soluble variants of perfluoronaphthalene and anthracene in buffered D2O (pD = 12). Combining computational and experimental results, we conclude that this impressive binding energy is a result of enthalpically favorable electrostatic and dispersion interactions as well as the entropically driven hydrophobic effect. The enhanced understanding of arene-perfluoroarene interactions in aqueous solution sets the stage for the implementation of this abiotic intermolecular interaction in biology and medicine.

Remote Substituents as Potential Control Elements for the Solid-State Structures of Hypervalent Iodine(III) Compounds.

Hypervalent iodine (HVI) compounds are very important selective oxidants often employed in organic syntheses. Most HVI compounds are strongly associated in the solid state involving interactions between the electropositive iodine centers and nearby electron lone pairs of electronegative atoms. This study examines the impact of remote substituents on select families of HVI compounds as means to achieve predictable two-dimensional extended solid-state materials. Crystallographic analyses of 10 HVI compounds from several related classes of λ3 organoiodine(III) compounds, (diacetoxyiodo)benzenes, (dibenzoatoiodo)benzenes, [bis(trifluoroacetoxy)iodo]benzenes, and µ-oxo-[(carboxylateiodo)benzenes], provide insights into how remote substituents and the choice of carboxylate groups can impact intermolecular interactions in the solid state.

Gold(III) Aryl Complexes as Reagents for Constructing Hybrid Peptide-Based Assemblies via Cysteine S-Arylation.

Organometallic complexes have recently gained attention as competent bioconjugation reagents capable of introducing a diverse array of substrates to biomolecule substrates. Here, we detail the synthesis and characterization of an aminophosphine-supported Au(III) platform that provides rapid and convenient access to a wide array of peptide-based assemblies via cysteine S-arylation. This strategy results in the formation of robust C-S covalent linkages and is an attractive method for the modification of complex biomolecules due to the high functional group tolerance, chemoselectivity, and rapid reaction kinetics associated with these arylation reactions. This work expands upon existing metal-mediated cysteine arylation by introducing a class of air-stable organometallic complexes that serve as robust bioconjugation reagents enabling the synthesis of conjugates of higher structural complexity including macrocyclic stapled and bicyclic peptides as well as a peptide-functionalized multivalent hybrid nanocluster. This organometallic-based approach provides a convenient, one-step method of peptide functionalization and macrocyclization, and has the potential to contribute to efforts directed toward developing efficient synthetic strategies of building new and diverse hybrid peptide-based assemblies.

Crystalline Hydrogen-Bonding Networks and Mixed-Metal Framework Materials Enabled by an Electronically Differentiated Heteroditopic Isocyanide/Carboxylate Linker Group.

Mixed-metal solid-state framework materials are emerging candidates for advanced applications in catalysis and chemical separations. Traditionally, the syntheses of mixed-metal framework systems rely on postsynthetic ion exchange, metalloligands, or metal-deposition techniques for the incorporation of a second metal within a framework material. However, these methods are often incompatible with the incorporation of low-valent metal centers, which preferentially bind to electronically "soft" ligands according to the tenets of hard/soft acid/base theory. Here we present the electronically differentiated isocyanide/carboxylate heteroditopic linker ligand 1,4-CNArMes2C6H4CO2H (TIBMes2H; TIB = terphenyl isocyanide benzoate; ArMes2 = 2,6-(2,4,6-Me3C6H2)2C6H2), which is capable of selective binding of low-valent metals via the isocyano group and complexation of hard Lewis acidic metals through the carboxylate unit. This heteroditopic ligand also possesses an encumbering m-terphenyl backbone at the isocyanide function to foster coordinative unsaturation. The treatment of TIBMes2H with [Cu(NCMe)4]PF6 in a 3:1 ratio results in preferential binding of the isocyanide group to the Cu(I) center as assayed by multinuclear NMR and IR spectroscopies. IR spectroscopy also provides strong evidence for the formation of a copper(I) tris(isocyanide) complex, wherein the carboxylic acid group remains unperturbed. The addition of TIBMes2 to [Cu(NCMe)4]PF6 in a 4:1 ratio results in crystallization of the hydrogen-bonding network, [Cu(TIBMes2H)4]PF6, in which the formation of R22(8) hydrogen bonds results in a 7-fold interpenetrated diamondoid lattice structure. The preassembly of a copper(I) tris(isocyanide) complex using TIBMes2H, followed by deprotonation and the introduction of ZnCl2, generates a novel and unusual zwitterionic solid-state phase (denoted as Cu/Zn-ISOCN-5; ISOCN = isocyanide coordination network) consisting of a coordinatively unsaturated [Cu(CNR)3]+ cationic secondary building unit (SBU) and an anionic, paddlewheel-type Zn(II)-based SBU of the formulation [Cl2Zn2(O2CR)3]-. Inductively coupled plasma mass spectrometry analysis provided firm evidence for a 2:1 Zn-to-Cu ratio in the network, thereby indicating that the isocyanide and carboxylate groups selectively bind soft and hard Lewis acidic metal centers, respectively. The extended structure of Cu/Zn-ISOCN-5 is a densely packed, noninterpenetrated AB-stacked layer network with modest surface area. However, it is thermally robust, and its formation and compositional integrity validate the use of an electronically differentiated linker for the formation of mixed-metal frameworks incorporating low-valent metal centers.

Tuning the Properties of Azadipyrromethene-Based Near-Infrared Dyes Using Intramolecular BO Chelation and Peripheral Substitutions.

Tetraphenylazadipyrromethenes (ADPs) are attractive near-infrared (NIR) dyes because of their simple synthesis and exceptional optical and electronic properties. The typical BF2 and less explored intramolecular BO coordination planarize the molecule, making them promising π-conjugated materials for organic electronic applications. However, their use has been mostly limited to vacuum-deposited devices. To improve the properties, we synthesized and characterized a series of ADP complexes and used density functional theory calculations to further explain the properties. Hexyloxy solubilizing groups increase the complexes' solubility in organic solvents and enable film formation from solution. Phenylethynyls at the pyrrolic positions extend π conjugation, red-shift absorption and emission peaks, and increase the ionization potential (IP) and electron affinity. When the properties of complexes with hexyloxy and phenyethynyl substitutions are compared, the BO complex is more planar and has a smaller IP than the corresponding BF2 complex because of increased electron density on the proximal phenyls. The BO complex has an unusual combination of properties: a solution λmax of 781 nm, emission at 805 nm, a small Stokes shift, and a quantum yield of 6%. It forms transparent films with a low optical gap of 1.22 eV. This new complex is a promising candidate for transparent solar cells and NIR photodetectors.

Icosahedral m-Carboranes Containing Exopolyhedral B-Se and B-Te Bonds.

Chalcogen-containing carboranes have been known for several decades and possess stable exopolyhedral B(9)-Se and B(9)-Te σ bonds despite the electron-donating ability of the B(9) vertex. While these molecules are known, little has been done to thoroughly evaluate their electrophilic and nucleophilic behavior. Herein, we report an assessment of the electrophilic reactivity of m-carboranylselenyl(II), -tellurenyl(II), and -tellurenyl(IV) chlorides and establish their reactivity pattern with Grignard reagents, alkenes, alkynes, enolates, and electron-rich arenes. These electrophilic reactions afford unique electron-rich B-Y-C (Y = Se, Te) bonding motifs not commonly found before. Furthermore, we show that m-carboranylselenolate, and even m-carboranyltellurolate, can be competent nucleophiles and participate in nucleophilic aromatic substitution reactions. Arene substitution chemistry is shown to be further extended to electron-rich species via palladium-mediated cross-coupling chemistry.

Thiolate-Thione Redox-Active Ligand with a Six-Membered Chelate Ring via Template Condensation and Its Pt(II) Complexes.

A new template condensation reaction has been discovered in a mixture of Pt(II), thiobenzamide, and base. Four complexes of the general form [Pt(ctaPhR)2], R = CH3 (1a), H (1b), F (1c), Cl (1d), cta = condensed thioamide, have been prepared under similar conditions and thoroughly characterized by 1H NMR and UV-vis-NIR spectroscopy, (spectro)electrochemistry, elemental analysis, and single-crystal X-ray diffraction. The ligand is redox active and can be reduced from the initial monoanion to a dianionic and then trianionic state. Chemical reduction of 1a with [Cp2Co] yielded [Cp2Co]2[Pt(ctaPhCH3)2], [Cp2Co]2[1a], which has been similarly characterized with the addition of EPR spectroscopy and SQUID magnetization. The singly reduced form containing [1a]1-, (nBu4N)[Pt(ctaPhCH3)2], has been generated in situ and characterized by UV-vis and EPR spectroscopies. DFT studies of 1b, [1b]1-, and [1b]2- confirm the location of additional electrons in exclusively ligand-based orbitals. A detailed analysis of this redox-active ligand, with emphasis on the characteristics that favor noninnocent behavior in six-membered chelate rings, is included.

An Active-Site Sulfonate Group Creates a Fast Water Oxidation Electrocatalyst That Exhibits High Activity in Acid.

The storage of solar energy in chemical bonds will depend on pH-universal catalysts that are not only impervious to acid, but actually thrive in it. Whereas other homogeneous water oxidation catalysts are less active in acid, we report a catalyst that maintained high electrocatalytic turnover frequency at pH values as low as 1.1 and 0.43 (kcat =1501±608 s-1 and 831±254 s-1 , respectively). Moreover, current densities, related to catalytic reaction rates, ranged from 15 to 50 mA cm-2 mM-1 comparable to those reported for state-of-the-art heterogeneous catalysts and 30 to 100 times greater than those measured for two prominent literature homogeneous catalysts at pH 1.1 and 0.43. The catalyst also exhibited excellent durability when a chemical oxidant was used (CeIV , 7400 turnovers, TOF 0.88 s-1 ). Preliminary computational studies suggest that the unusual active-site sulfonate group acts a proton relay even in strong acid, as intended.

Oxidative Generation of Boron-Centered Radicals in Carboranes.

We report the first indirect observation and use of boron vertex-centered carboranyl radicals generated by the oxidation of modified carboranyl precursors. These radical intermediates are formed by the direct oxidation of a B-B bond between a boron cluster cage and an exopolyhedral boron-based substituent (e.g., -BF3K, -B(OH)2). The in situ generated radical species are shown to be competent substrates in reactions with oxygen-based radicals, dichalcogenides, and N-heterocycles, yielding the corresponding substituted carboranes containing B-O, B-S, B-Se, B-Te, and B-C bonds. Remarkably, this chemistry tolerates various electronic environments, providing access to facile substitution chemistry at both electron-rich and electron-poor B-H vertices in carboranes.

Synthesis of Anhydroryanodol.

A stereoselective entry to ryanoids is described that culminates in the synthesis of anhydroryanodol and thus the formal total synthesis of ryanodol. The pathway described features an annulation reaction conceived to address the uniquely complex and highly oxygenated polycyclic skeleton common to members of this natural product class. It is demonstrated that metallacycle-mediated intramolecular coupling of an alkyne and a 1,3-diketone can proceed with a highly functionalized enyne and with outstanding levels of stereoselection. Furthermore, the first application of this technology in natural product synthesis is demonstrated here. More broadly, the advances described demonstrate the value that programs in natural product total synthesis have in advancing organic chemistry, here through the design and realization of an annulation reaction that accomplishes what previously established reactions do not.

An Organometallic Strategy for Assembling Atomically Precise Hybrid Nanomaterials.

For decades, chemists have strived to mimic the intricate design and diverse functions of naturally occurring systems through the bioinspired synthesis of programmable inorganic nanomaterials. The development of thiol-capped gold nanoparticles (AuNPs) has driven advancement in this area; however, although versatile and readily accessible, hybrid AuNPs are rarely atomically precise, which limits control over their surface topology and therefore the study of complex structure-function relationships. Here, we present a bottom-up approach to the systematic assembly of atomically precise hybrid nanoclusters employing a strategy that mimics the synthetic ease with which thiol-capped AuNPs are normally constructed, while producing well-defined covalent nanoscale assemblies with diverse surface topologies. For the first time, using a structurally characterized cluster-based organometallic building block, we demonstrate the systematic synthesis of nanoclusters with multivalent binding capabilities to complex protein targets.