Programmable synthesis of well-defined, glycosylated iron(ii) supramolecular assemblies with multivalent protein-binding capabilities.

Multivalency plays a key role in achieving strong, yet reversible interactions in nature, and provides critical chemical organization in biological recognition processes. Chemists have taken an interest in designing multivalent synthetic assemblies to both better understand the underlying principles governing these interactions, and to build chemical tools that either enhance or prevent such recognition events from occurring in biology. Rationally tailoring synthetic strategies to achieve the high level of chemical control and tunability required to mimic these interactions, however, is challenging. Here, we introduce a systematic and modular synthetic approach to the design of well-defined molecular multivalent protein-binding constructs that allows for control over size, morphology, and valency. A series of supramolecular mono-, bi-, and tetrametallic Fe(ii) complexes featuring a precise display of peripheral saccharides was prepared through coordination-driven self-assembly from simple building blocks. The molecular assemblies are fully characterized, and we present the structural determination of one complex in the series. The mannose and maltose-appended assemblies display strong multivalent binding to model lectin, Concanavalin A (K d values in µM), where the strength of the binding is a direct consequence of the number of saccharide units decorating the molecular periphery. This versatile synthetic strategy provides chemical control while offering an easily accessible approach to examine important design principles governing structure-function relationships germane to biological recognition and binding properties.

An Organometallic Gold(III) Reagent for 18F Labeling of Unprotected Peptides and Sugars in Aqueous Media.

The 18F labeling of unprotected peptides and sugars with a Au(III)-[18F]fluoroaryl complex is reported. The chemoselective method generates 18F-labeled S-aryl bioconjugates in an aqueous environment in 15 min with high radiochemical yields and displays excellent functional group tolerance. This approach utilizes an air and moisture stable, robust organometallic Au(III) complex and highlights the versatility of designer organometallic reagents as efficient agents for rapid radiolabeling.

Electronic Structure of Superoxidized Radical Cationic Dodecaborate-Based Clusters.

The expanding field of boron clusters has attracted continuous theoretical efforts to understand their diverse structures and unique bonding. We recently discovered a new reversible redox event of B12(O-3-methylbutyl)12 in which the superoxidized radical cationic form [B12(O-3-methylbutyl)12]•+ was identified and isolated for the first time. Herein, comprehensive (TD-)DFT studies in tandem with electrochemical experiments were employed to demonstrate the generality of the reported behavior across perfunctionalized B12(OR)12 clusters (R = aryl or alkyl). While the spin density of radical cationic clusters is delocalized in the core region, the oxidation brings about notable gains of positive partial charges on the supporting groups whose electronics can readily tune the redox potential of the 0/•+ couple. The underlying changes of frontier orbitals were elucidated, and the resulting [B12(OR)12]•+ species manifest a general diagnostic absorption as a consequence of mixed local/charge-transfer excitations.

An Organometallic Strategy for Cysteine Borylation.

Synthetic bioconjugation at cysteine (Cys) residues in peptides and proteins has emerged as a powerful tool in chemistry. Soft nucleophilicity of the sulfur in Cys renders an exquisite chemoselectivity with which various functional groups can be placed onto this residue under benign conditions. While a variety of reactions have been successful at producing Cys-based bioconjugates, the majority of these feature sulfur-carbon bonds. We report Cys-borylation, wherein a benchtop stable Pt(II)-based organometallic reagent can be used to transfer a boron-rich cluster onto a sulfur moiety in unprotected peptides forging a boron-sulfur bond. Cys-borylation proceeds at room temperature and tolerates a variety of functional groups present in complex polypeptides. Further, the bioconjugation strategy can be applied to a model protein modification of Cys-containing DARPin (designed ankyrin repeat protein). The resultant bioconjugates show no additional toxicity compared to their Cys alkyl-based congeners. Finally, we demonstrate how the developed Cys-borylation can enhance the proteolytic stability of the resultant peptide bioconjugates while maintaining the binding affinity to a protein target.

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.

Dynamic Nuclear Polarization Using 3D Aromatic Boron Cluster Radicals.

A set of two dodecaborate [B12(OR)12]1- radical cluster anions containing a dense layer of fluorinated end-groups provides nuclear spin hyperpolarization via the dissolution dynamic nuclear polarization (D-DNP) technique. We show that these clusters can enhance 19F nuclear magnetic resonance (NMR) signals. Importantly, given the inherent radical delocalization in dodecaborate-based clusters, these species are compatible with reactive compounds such as Lewis acids, providing ∼1000-2000 times of signal enhancement for B(C6F5)3 in liquid state NMR spectroscopy experiments at 9.4 Tesla. This observation suggests that 3D aromatic radicals can provide advantages over the conventional radical species that are currently used for DNP such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) by showing superior chemical compatibility. The ability to hyperpolarize reactive compounds using [B12(OR)12]1- cluster radicals opens up new applications of reaction monitoring by D-DNP NMR spectroscopy, including the observation of catalytically active species in complex reaction mixtures.

A Super-Oxidized Radical Cationic Icosahedral Boron Cluster.

While the icosahedral closo-[B12H12]2- cluster does not display reversible electrochemical behavior, perfunctionalization of this species via substitution of all 12 B-H vertices with alkoxy or benzyloxy (OR) substituents engenders reversible redox chemistry, providing access to clusters in the dianionic, monoanionic, and neutral forms. Here, we evaluated the electrochemical behavior of the electron-rich B12(O-3-methylbutyl)12 (1) cluster and discovered that a new reversible redox event that gives rise to a fourth electronic state is accessible through one-electron oxidation of the neutral species. Chemical oxidation of 1 with [N(2,4-Br2C6H3)3]•+ afforded the isolable [1]•+ cluster, which is the first example of an open-shell cationic B12 cluster in which the unpaired electron is proposed to be delocalized throughout the boron cluster core. The oxidation of 1 is also chemically reversible, where treatment of [1]•+ with ferrocene resulted in its reduction back to 1. The identity of [1]•+ is supported by EPR, UV-vis, multinuclear NMR (1H, 11B), and X-ray photoelectron spectroscopic characterization.

Tunable Dopants with Intrinsic Counterion Separation Reveal the Effects of Electron Affinity on Dopant Intercalation and Free Carrier Production in Sequentially Doped Conjugated Polymer Films.

Carrier mobility in doped conjugated polymers is limited by Coulomb interactions with dopant counterions. This complicates studying the effect of the dopant's oxidation potential on carrier generation because different dopants have different Coulomb interactions with polarons on the polymer backbone. Here, dodecaborane (DDB)-based dopants are used, which electrostatically shield counterions from carriers and have tunable redox potentials at constant size and shape. DDB dopants produce mobile carriers due to spatial separation of the counterion, and those with greater energetic offsets produce more carriers. Neutron reflectometry indicates that dopant infiltration into conjugated polymer films is redox-potential-driven. Remarkably, X-ray scattering shows that despite their large 2-nm size, DDBs intercalate into the crystalline polymer lamellae like small molecules, indicating that this is the preferred location for dopants of any size. These findings elucidate why doping conjugated polymers usually produces integer, rather than partial charge transfer: dopant counterions effectively intercalate into the lamellae, far from the polarons on the polymer backbone. Finally, it is shown that the IR spectrum provides a simple way to determine polaron mobility. Overall, higher oxidation potentials lead to higher doping efficiencies, with values reaching 100% for driving forces sufficient to dope poorly crystalline regions of the film.

A molecular boron cluster-based chromophore with dual emission.

Bromination of the luminescent borane, anti-B18H22, via electrophilic substitution using AlCl3 and Br2, yields the monosubstituted derivative 4-Br-anti-B18H21 as an air-stable crystalline solid. In contrast to the unsubstituted parent compound, 4-Br-anti-B18H21 possesses dual emission upon excitation with UV light and exhibits fluorescence at 410 nm and phosphorescence at 503 nm, with Φtotal = 0.07 in oxygen-free cyclohexane. Increased oxygen content in cyclohexane solution quenches the phosphorescence signal. The fluorescent signal intensity remains unaffected by oxygen, suggesting that this molecule could be used as a ratiometric oxygen probe.

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.

Organometallic Gold(III) Reagents for Cysteine Arylation.

An efficient method for chemoselective cysteine arylation of unprotected peptides and proteins using Au(III) organometallic complexes is reported. The bioconjugation reactions proceed rapidly (<5 min) at ambient temperature in various buffers and within a wide pH range (0.5-14). This approach provides access to a diverse array of S-aryl bioconjugates including fluorescent dye, complex drug molecule, affinity label, poly(ethylene glycol) tags, and a stapled peptide. A library of Au(III) arylation reagents can be prepared as air-stable, crystalline solids in one step from commercial reagents. The selective and efficient arylation procedures presented in this work broaden the synthetic scope of cysteine bioconjugation and serve as promising routes for the modification of complex biomolecules.

Cobalt and Vanadium Trimetaphosphate Polyanions: Synthesis, Characterization, and Electrochemical Evaluation for Non-aqueous Redox-Flow Battery Applications.

An electrochemical cell consisting of cobalt ([CoII/III(P3O9)2]4-/3-) and vanadium ([VIII/II(P3O9)2]3-/4-) bistrimetaphosphate complexes as catholyte and anolyte species, respectively, was constructed with a cell voltage of 2.4 V and Coulombic efficiencies >90% for up to 100 total cycles. The [Co(P3O9)2]4- (1) and [V(P3O9)2]3- (2) complexes have favorable properties for flow-battery applications, including reversible redox chemistry, high stability toward electrochemical cycling, and high solubility in MeCN (1.09 ± 0.02 M, [PPN]4[1]·2MeCN; 0.77 ± 0.06 M, [PPN]3[2]·DME). The [PPN]4[1]·2MeCN and [PPN]3[2]·DME salts were isolated as crystalline solids in 82 and 68% yields, respectively, and characterized by 31P NMR, UV/vis, ESI-MS(-), and IR spectroscopy. The [PPN]4[1]·2MeCN salt was also structurally characterized, crystallizing in the monoclinic P21/c space group. Treatment of 1 with [(p-BrC6H4)3N]+ allowed for isolation of the one-electron-oxidized spin-crossover (SCO) complex, [Co(P3O9)2]3- (3), which is the active catholyte species generated during cell charging. The success of the 1-2 cell provides a promising entry point to a potential future class of transition-metal metaphosphate-based all-inorganic non-aqueous redox-flow battery electrolytes.

Second-Coordination-Sphere Assisted Selective Colorimetric Turn-on Fluoride Sensing by a Mono-Metallic Co(II) Hexacarboxamide Cryptand Complex.

The preparation of a selective turn-on colorimetric fluoride sensor was achieved through single cobalt(II) ion insertion into a macrobicyclic cryptand. Monometallic [Co(mBDCA-5t-H3)]- (1) and [Zn(mBDCA-5t-H3)]- (2) complexes were prepared in 74 and 84% yields, respectively. Structural characterization of 1 confirmed the presence of a proximal hydrogen-bonding network consisting of carboxamide N-H donors. The reaction of 1 with F- was accompanied by a distinct colorimetric turn-on response in mixed aqueous/organic media, and 1 was capable of selective fluoride sensing in the presence of large quantities of potentially competitive anions. Complex 1 represents a unique example of a fluoride sensor wherein selective F- binding takes place directly at a transition-metal center and induces a color change based upon metal-centered transitions. The metal(II) fluoride complexes [F⊂Co(mBDCA-5t-H3)]2- (3) and [F⊂Zn(mBDCA-5t-H3)]2- (4) were both fully characterized, including single crystal X-ray analyses. Fluoride binding is synergistic involving hydrogen-bond donors from the second-coordination sphere together with metal(II) ion complexation.

Terminal Titanyl Complexes of Tri- and Tetrametaphosphate: Synthesis, Structures, and Reactivity with Hydrogen Peroxide.

The synthesis and characterization of tri- and tetrametaphosphate titanium(IV) oxo and peroxo complexes is described. Addition of 0.5 equiv of [OTi(acac)2]2 to dihydrogen tetrametaphosphate ([P4O12H2]2-) and monohydrogen trimetaphosphate ([P3O9H]2-) provided a bis(µ2,κ2,κ2) tetrametaphosphate titanyl dimer, [OTiP4O12]24- (1; 70% yield), and a trimetaphosphate titanyl acetylacetonate complex, [OTiP3O9(acac)]2- (2; 59% yield). Both 1 and 2 have been structurally characterized, crystallizing in the triclinic P1̅ and monoclinic P21 space groups, respectively. These complexes contain Ti≡O units with distances of 1.624(7) and 1.644(2) Å, respectively, and represent rare examples of structurally characterized terminal titanyls within an all-oxygen coordination environment. Complexes 1 and 2 react with hydrogen peroxide to produce the corresponding peroxotitanium(IV) metaphosphate complexes [O2TiP4O12]24-(3; 61% yield) and [O2TiP3O9(acac)]2- (4; 65% yield), respectively. Both 3 and 4 have been characterized by single-crystal X-ray diffraction studies, and their solid-state structures are presented. Complex 3 functions as an oxygen atom transfer (OAT) reagent capable of oxidizing phosphorus(III) compounds (P(OMe)3, PPh3) and SMe2 at ambient temperature to result in the corresponding organic oxide with regeneration of dimer 1.

Crystalline Metaphosphate Acid Salts: Synthesis in Organic Media, Structures, Hydrogen-Bonding Capability, and Implication of Superacidity.

Metaphosphate acids cannot be thoroughly studied in aqueous media because their acidity is leveled by the solvent, and the resulting metaphosphates are susceptible to acid-catalyzed hydrolysis. Exploration of metaphosphate acid chemistry has now been made possible with the development of a general synthetic method for organic media soluble metaphosphate acids. Protonation of the [PPN](+) salts ([PPN](+) = [N(PPh3)2](+)) of tri-, tetra-, and hexametaphosphates results in five new metaphosphate acids, [PPN]2[P3O9H] (2), [PPN]4[(P4O12)3H8] (3), [PPN]4[P6O18H2]·2H2O (4), [PPN]3[P6O18H3] (5), and [PPN]2[P6O18H2(H3O)2] (6), obtained in yields of 80, 71, 66, 88, and 76%, respectively. Additionally, our synthetic method can be extended to pyrophosphate to produce [PPN][P2O7H3] (7) in 77% yield. The structural configurations of these oxoacids are dictated by strong hydrogen bonds and the anticooperative effect. Intramolecular hydrogen bonds are observed in 2, 4, and 5 and the previously reported [PPN]2[P4O12H2] (1), while intermolecular hydrogen bonds are observed in 3, 6, and 7. The hydrogen bonds in 3-7 possess short distances and are classified as low-barrier hydrogen bonds. Gas-phase acidity computations reveal that the parent tri- and tetrametaphosphoric acids are superacids. Their remarkable acidity is attributable to the stabilization of their corresponding conjugate bases via intramolecular hydrogen bonding.

Multi-electron reactivity of a cofacial di-tin(ii) cryptand: partial reduction of sulfur and selenium and reversible generation of S3˙.

Cofacial bimetallic tin(ii) ([Sn2(mBDCA-5t)]2-, 1) and lead(ii) ([Pb2(mBDCA-5t)]2-, 2) complexes have been prepared by hexadeprotonation of hexacarboxamide cryptand mBDCA-5t-H6 together with double Sn(ii) or Pb(ii) insertion. Reaction of 1 with elemental sulfur or selenium generates di-tin polychalcogenide complexes containing µ-E and bridging µ-E5 ligands where E = S or Se, and the Sn(ii) centers have both been oxidized to Sn(iv). Solution and solid-state UV-Vis spectra of [(µ-S5)Sn2(µ-S)(mBDCA-5t)]2- (4) indicate that the complex acts reversibly as a source of S3˙- in DMF solution with a Keq = 0.012 ± 0.002. Reductive removal of all six chalcogen atoms is achieved through treatment of [(µ-E5)Sn2(µ-E)(mBDCA-5t)]2- with PR3 (R = t Bu, Ph, OiPr) to produce six equiv. of the corresponding EPR3 compound with regeneration of di-tin(ii) cryptand complex 1.

Pushing Single-Oxygen-Atom-Bridged Bimetallic Systems to the Right: A Cryptand-Encapsulated Co-O-Co Unit.

A dicobalt(II) complex, [Co2(mBDCA-5t)](2-) (1), demonstrates a cofacial arrangement of trigonal monopyramidal Co(II) ions with an inter-metal separation of 6.2710(6) Å. Reaction of 1 with potassium superoxide generates an encapsulated Co-O-Co core in the dianionic complex, [Co2O(mBDCA-5t)](2-) (2); to form the linear Co-O-Co core, the inter-metal distance has diminished to 3.994(3) Å. Co K-edge X-ray absorption spectroscopy data are consistent with a +2 oxidation state assignment for Co in both 1 and 2. Multireference complete active space calculations followed by second-order perturbation theory support this assignment, with hole equivalents residing on the bridging O-atom and on the cryptand ligand for the case of 2. Complex 2 acts as a 2-e(-) oxidant toward substrates including CO and H2, in both cases efficiently regenerating 1 in what represent net oxygen-atom-transfer reactions. This dicobalt system also functions as a catalase upon treatment with H2O2.

Role of axial base coordination in isonitrile binding and chalcogen atom transfer to vanadium(III) complexes.

The enthalpy of oxygen atom transfer (OAT) to V[(Me3SiNCH2CH2)3N], 1, forming OV[(Me3SiNCH2CH2)3N], 1-O, and the enthalpies of sulfur atom transfer (SAT) to 1 and V(N[t-Bu]Ar)3, 2 (Ar = 3,5-C6H3Me2), forming the corresponding sulfides SV[(Me3SiNCH2CH2)3N], 1-S, and SV(N[t-Bu]Ar)3, 2-S, have been measured by solution calorimetry in toluene solution using dbabhNO (dbabhNO = 7-nitroso-2,3:5,6-dibenzo-7-azabicyclo[2.2.1]hepta-2,5-diene) and Ph3SbS as chalcogen atom transfer reagents. The V-O BDE in 1-O is 6.3 ± 3.2 kcal·mol(-1) lower than the previously reported value for 2-O and the V-S BDE in 1-S is 3.3 ± 3.1 kcal·mol(-1) lower than that in 2-S. These differences are attributed primarily to a weakening of the V-Naxial bond present in complexes of 1 upon oxidation. The rate of reaction of 1 with dbabhNO has been studied by low temperature stopped-flow kinetics. Rate constants for OAT are over 20 times greater than those reported for 2. Adamantyl isonitrile (AdNC) binds rapidly and quantitatively to both 1 and 2 forming high spin adducts of V(III). The enthalpies of ligand addition to 1 and 2 in toluene solution are -19.9 ± 0.6 and -17.1 ± 0.7 kcal·mol(-1), respectively. The more exothermic ligand addition to 1 as compared to 2 is opposite to what was observed for OAT and SAT. This is attributed to less weakening of the V-Naxial bond in ligand binding as opposed to chalcogen atom transfer and is in keeping with structural data and computations. The structures of 1, 1-O, 1-S, 1-CNAd, and 2-CNAd have been determined by X-ray crystallography and are reported.

The stannylphosphide anion reagent sodium bis(triphenylstannyl) phosphide: synthesis, structural characterization, and reactions with indium, tin, and gold electrophiles.

Treatment of P4 with in situ generated [Na][SnPh3] leads to the formation of the sodium monophosphide [Na][P(SnPh3)2] and the Zintl salt [Na]3[P7]. The former was isolated in 46% yield as the crystalline salt [Na(benzo-15-crown-5)][P(SnPh3)2] and used to prepare the homoleptic phosphine P(SnPh3)3, isolated in 67% yield, as well as the indium derivative (XL)2InP(SnPh3)2 (XL = S(CH2)2NMe2), isolated in 84% yield, and the gold complex (Ph3P)AuP(SnPh3)2. The compounds [Na(benzo-15-crown-5)][P(SnPh3)2], P(SnPh3)3, (XL)2InP(SnPh3)2, and (Ph3P)AuP(SnPh3)2 were characterized using multinuclear NMR spectroscopy and X-ray crystallography. The bonding in (Ph3P)AuP(SnPh3)2 was dissected using natural bond orbital (NBO) methods, in response to the observation from the X-ray crystal structure that the dative P:→Au bond is slightly shorter than the shared electron-pair P-Au bond. The bonding in (XL)2InP(SnPh3)2 was also interrogated using (31)P and (13)C solid-state NMR and computational methods. Co-product [Na]3[P7] was isolated in 57% yield as the stannyl heptaphosphide P7(SnPh3)3, following salt metathesis with ClSnPh3. Additionally, we report that treatment of P4 with sodium naphthalenide in dimethoxyethane at 22 °C is a convenient and selective method for the independent synthesis of Zintl ion [Na]3[P7]. The latter was isolated as the silylated heptaphosphide P7(SiMe3)3, in 67% yield, or as the stannyl heptaphosphide P7(SnPh3)3 in 65% yield by salt metathesis with ClSiMe3 or ClSnPh3, respectively.