Access to Stereoblock Polyesters via Irreversible Chain-Transfer Ring-Opening Polymerization (ICT-ROP).

Precise control over polymer microstructure can enable the molecular tunability of material properties and represents a significant challenge in polymer chemistry. Stereoblock copolymers are some of the simplest stereosequenced polymers, yet the synthesis of stereoblock polyesters from prochiral or racemic monomers outside of "simple" isotactic stereoblocks remains limited. Herein, we report the development of irreversible chain-transfer ring-opening polymerization (ICT-ROP), which overcomes the fundamental limitations of single catalyst approaches by using transmetalation (e.g., alkoxide-chloride exchange) between two catalysts with distinct stereoselectivities as a means to embed temporally controlled multicatalysis in ROP. Our combined small-molecule model and catalytic polymerization studies lay out a clear molecular basis for ICT-ROP and are exploited to access the first examples of atactic-syndiotactic stereoblock (at-sb-st) polyesters, at-sb-st polyhydroxyalkanoates (PHAs). We achieve high levels of control over molecular weight, tacticity, monomer composition, and block structures in a temporally controlled manner and demonstrate that stereosequence control leads to polymer tensile properties that are independent of thermal properties.

1,6-Dioxo-2-azaspiro[3.4]oct-2-enes and Related Spirocycles: Heterocycles from [3 + 2] Nitrile Oxide Cycloadditions with 2-Methyleneoxetanes, -Thietanes, and -Azetidines.

Isoxazolines and 4-membered heterocycles are significant structural motifs in numerous synthetic intermediates and natural products. [3 + 2] Cycloadditions between enol ethers and nitrile oxides have been well studied; however, nitrile oxide cycloadditions with 4-membered heterocycles to give spiroisoxazolines are unreported. Here, we showcase the regio- and diastereoselective [3 + 2] nitrile oxide cycloadditions of 2-methyleneoxetanes, -azetidines, and -thietanes to give an array of 1,6-dioxo-2-azaspiro[3.4]oct-2-enes and related spirocycles. 2D NMR experiments suggested that most of the observed diastereoselectivities were dictated by steric interactions; however, dipolarophiles with H bonding donors reversed the stereochemical outcome. X-ray crystallography confirmed the structural assignments.

N,N-Alkylation Clarifies the Role of N- and O-Protonated Intermediates in Cyclen-Based 64Cu Radiopharmaceuticals.

Radioisotopes of Cu, such as 64Cu and 67Cu, are alluring targets for imaging (e.g., positron emission tomography, PET) and radiotherapeutic applications. Cyclen-based macrocyclic polyaminocarboxylates are one of the most frequently examined bifunctional chelators in vitro and in vivo, including the FDA-approved 64Cu radiopharmaceutical, Cu(DOTATATE) (Detectnet); however, connections between the structure of plausible reactive intermediates and their stability under physiologically relevant conditions remain to be established. In this study, we share the synthesis of a cyclen-based, N,N-alkylated spirocyclic chelate, H2DO3AC4H8, which serves as a model for N-protonation. Our combined experimental (in vitro and in vivo) and computational studies unravel complex pH-dependent speciation and enable side-by-side comparison of N- and O-protonated species of relevant 64Cu radiopharmaceuticals. Our studies suggest that N-protonated species are not inherently unstable species under physiological conditions and demonstrate the potential of N,N-alkylation as a tool for the rational design of future radiopharmaceuticals.

Selective Semihydrogenation of Polarized Alkynes by a Gold Hydride Nanocluster.

The hydridic hydrogen in nanogold catalysts has long been postulated as an important intermediate in hydrogenation reactions, but it has not been directly observed. Here, we report the synthesis of a new undecagold cluster with a bidentate phosphine ligand. The chelating effects of the bidentate ligand result in a more symmetric Au11 core with two labile Cl- ligands that can exchange with BH4-, leading to a novel undecagold hydride cluster. The new hydride cluster is discovered to readily undergo hydroauration reaction with alkynes containing electron-withdrawing groups, forming key gold-alkenyl semihydrogenation intermediates, which can be efficiently and selectively converted to Z-alkenes under acidic conditions. All key reaction intermediates are isolated and characterized, providing atomic-level insights into the active sites and mechanisms of semihydrogenation reactions catalyzed by gold-based nanomaterials. The hydridic hydrogen in the undecagold cluster is found to be the key to prevent over hydrogenation of alkenes to alkanes. The current study provides fundamental insights into hydrogenation chemistry enabled by gold-based nanomaterials and may lead to the development of efficient catalysts for selective semihydrogenation or functionalization of alkynes.

Peroxide-Selective Reduction of O2 at Redox-Inactive Rare-Earth(III) Triflates Generates an Ambiphilic Peroxide.

Metal peroxides are key species involved in a range of critical biological and synthetic processes. Rare-earth (group III and the lanthanides; Sc, Y, La-Lu) peroxides have been implicated as reactive intermediates in catalysis; however, reactivity studies of isolated, structurally characterized rare-earth peroxides have been limited. Herein, we report the peroxide-selective (93-99% O22-) reduction of dioxygen (O2) at redox-inactive rare-earth triflates in methanol using a mild metallocene reductant, decamethylferrocene (Fc*). The first molecular praseodymium peroxide ([PrIII2(O22-)(18C6)2(EG)2][OTf]4; 18C6 = 18-crown-6, EG = ethylene glycol, -OTf = -O3SCF3; 2-Pr) was isolated and characterized by single-crystal X-ray diffraction, Raman spectroscopy, and NMR spectroscopy. 2-Pr displays high thermal stability (120 °C, 50 mTorr), is protonated by mild organic acids [pKa1(MeOH) = 5.09 ± 0.23], and engages in electrophilic (e.g., oxygen atom transfer) and nucleophilic (e.g., phosphate-ester cleavage) reactivity. Our mechanistic studies reveal that the rate of oxygen reduction is dictated by metal-ion accessibility, rather than Lewis acidity, and suggest new opportunities for differentiated reactivity of redox-inactive metal ions by leveraging weak metal-ligand binding events preceding electron transfer.

Expanding the Rare-Earth Metal BINOLate Catalytic Multitool beyond Enantioselective Organic Synthesis.

Shibasaki's rare earth alkali metal BINOLate (REMB) framework has provided chemists with a general catalyst platform to access a range of enantioenriched small molecules from the single, commercially available pro-ligand (R)- or (S)-BINOL. A defining feature of these heterobimetallic frameworks is the high level of catalyst tunability, achieved through the simple modulation of the central rare-earth cation and peripheral alkali metal cations. While this family of multifunctional catalysts displays impressive generality and catalytic capability, detailed mechanistic understanding of these complex, multimetallic systems was lacking prior to our investigations. This backdrop served as initial inspiration for our investigations of this privileged class of complexes over the past decade, which have led to new and exciting advances in catalysis and beyond.In this Account, we describe our investigations using Shibasaki's framework focusing on the central metal-ion, the BINOLate ligands, and the secondary sphere cations. Our studies began with an investigation into the Lewis acidity of the complexes, where we demonstrated that Lewis bases readily coordinate to REMB frameworks when lithium occupies the secondary coordination sphere. This observation was contrasted by the complexes containing sodium or potassium in the secondary coordination sphere, as the rare earth cation is evidently less accessible for substrate binding. Our efforts in understanding the ligand exchange of the complexes enabled the discovery that associative processes dominate the mechanism of ligand exchange and LA/LA (Lewis acid/Lewis acid) and LA/BB (Lewis acid/Brønsted base) catalysis by the REMB frameworks. Replacing metal cations in the secondary coordination sphere with the N,N,N',N'-tetramethylguanidinium cation delivered an effective precatalyst that is air and water stable over the course of 6 months.To expand the reactivity of the REMB, we investigated the ability of UIV cations to occupy the primary coordination sphere and ZnEt+ and Cu(DBU)+ cations to occupy the secondary coordination sphere. Synthesizing the REMB complexes using the thiol congener monothioBINOL provided an unusual anionic REMB framework, driven by the oxophilicity of the lithium cations. Using the REMB as a platform for investigating the CeIII/CeIV redox couple, we demonstrated that, while oxidative cerium functionalization is observed in the case of lithium containing REMBs, salt elimination is observed in the sodium, potassium, and cesium containing REMBs. Furthermore, we found that while the rate of heterogeneous electron transfer for CeIII was ks(CsI) > ks(KI) > ks(NaI) > ks(LiI), the rates of reaction with the oxidant trityl chloride trended in the opposite order with kobs(LiI) ≫ kobs(NaI) > kobs(KI) > kobs(CsI). We attribute this to the ability to form inner-sphere complexes with the oxidant, rather than differences in redox potential or reorganization energies.Applying our knowledge in ligand exchange and redox behavior of Ce containing REMB complexes, we detailed the mechanism for oxidation of the heterochiral cerium REMB frameworks, reiterating the importance of the formation of inner-sphere complexes in the oxidation chemistry of cerium. There are many different avenues for both organic and inorganic investigation of Shibasaki's REMB framework, and our works have demonstrated the richness of the structural chemistry and properties of this framework that inform mechanism and properties of these privileged catalysts.

A General Design Strategy Enabling the Synthesis of Hydrolysis-Resistant, Water-Stable Titanium(IV) Complexes.

Despite its prevalence in the environment, the chemistry of the Ti4+ ion has long been relegated to organic solutions or hydrolyzed TiO2 polymorphs. A knowledge gap in stabilizing molecular Ti4+ species in aqueous environments has prevented the use of this ion for various applications such as radioimaging, design of water-compatible metal-organic frameworks (MOFs), and aqueous-phase catalysis applications. Herein, we show a thorough thermodynamic screening of bidentate chelators with Ti4+ in aqueous solution, as well as computational and structural analyses of key compounds. In addition, the hexadentate analogues of catechol (benzene-1,2-diol) and deferiprone (3-hydroxy-1,2-dimethyl-4(1H)-pyridone), TREN-CAM and THPMe respectively, were assessed for chelation of the 45 Ti isotope (t1/2 =3.08 h, ß+ =85 %, Eß+ =439 keV) towards positron emission tomography (PET) imaging applications. Both were found to have excellent capacity for kit-formulation, and [45 Ti]Ti-TREN-CAM was found to have remarkable stability in vivo.

Nanoparticle-Catalyzed Green Chemistry Synthesis of Polybenzoxazole.

Enabling catalysts to promote multistep chemical reactions in a tandem fashion is an exciting new direction for the green chemistry synthesis of materials. Nanoparticle (NP) catalysts are particularly well suited for tandem reactions due to the diverse surface-active sites they offer. Here, we report that AuPd alloy NPs, especially 3.7 nm Au42Pd58 NPs, catalyze one-pot reactions of formic acid, diisopropoxy-dinitrobenzene, and terephthalaldehyde, yielding a very pure thermoplastic rigid-rod polymer, polybenzoxazole (PBO), with a molecular weight that is tunable from 5.8 to 19.1 kDa. The PBO films are more resistant to hydrolysis and possess thermal and mechanical properties that are superior to those of commercial PBO, Zylon. Cu NPs are also active in catalyzing tandem reactions to form PBO when formic acid is replaced with ammonia borane. Our work demonstrates a general approach to the green chemistry synthesis of rigid-rod polymers as lightweight structural materials for broad thermomechanical applications.

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.

Calcium-Ion Binding Mediates the Reversible Interconversion of Cis and Trans Peroxido Dicopper Cores.

Coupled dinuclear copper oxygen cores (Cu2 O2 ) featured in type III copper proteins (hemocyanin, tyrosinase, catechol oxidase) are vital for O2 transport and substrate oxidation in many organisms. µ-1,2-cis peroxido dicopper cores (C P) have been proposed as key structures in the early stages of O2 binding in these proteins; their reversible isomerization to other Cu2 O2 cores are directly relevant to enzyme function. Despite the relevance of such species to type III copper proteins and the broader interest in the properties and reactivity of bimetallic C P cores in biological and synthetic systems, the properties and reactivity of C P Cu2 O2 species remain largely unexplored. Herein, we report the reversible interconversion of µ-1,2-trans peroxido (T P) and C P dicopper cores. CaII mediates this process by reversible binding at the Cu2 O2 core, highlighting the unique capability for metal-ion binding events to stabilize novel reactive fragments and control O2 activation in biomimetic systems.

Low-Symmetry ß-Diketimine Aryloxide Rare-Earth Complexes: Flexible, Reactive, and Selective.

We report the synthesis, characterization, and reactivity of a new low-symmetry ß-diketimine featuring a pendant amino(methyl)phenol donor and its corresponding heteroleptic rare-earth (RE) complexes. This includes the first structurally characterized examples of alcoholysis and insertion from an isolated REIII amide in a ß-diketimine framework. The flexible methylene linkage leads to REIII complexes with tunable dynamic solution behavior that defines their stoichiometric and catalytic reactivity. The addition of a strong neutral donor ligand, tricyclohexylphosphine oxide, suppresses a prevalent catalyst degradation pathway (base-promoted elimination) and dramatically enhances the catalyst performance in the stereospecific ring-opening polymerization of rac-ß-butyrolactone. Our results further demonstrate the importance of ligand reorganization in the stoichiometric and catalytic activity of REIII ions.

Is Less More? Influence of the Coordination Geometry of Copper(II) Picolinate Chelate Complexes on Metabolic Stability.

A growing number of copper(II) complexes have been identified as suitable candidates for biomedical applications. Here, we show that the biocompatibility and stability of copper(II) complexes can be tuned by directed ligand design and complex geometry. We demonstrate that azamacrocycle-based chelators that envelope copper(II) in a five-coordinate, distorted trigonal-bipyramidal structure are more chemically inert to redox-mediated structural changes than their six-coordinate, Jahn-Teller-distorted counterparts, as evidenced by electrochemical, crystallographic, electron paramagnetic resonance, and density functional theory studies. We further validated our hypothesis of enhanced inertness in vitro and in vivo by employing Cu-64 radiolabeling of bifunctional analogues appended to a prostate-specific membrane antigen targeting dipeptide. The corresponding Cu-64 complexes were tested for stability in vitro and in vivo, with the five-coordinate system demonstrating the greatest metabolic stability among the studied picolinate complex series.

Exchange Processes in Shibasaki's Rare Earth Alkali Metal BINOLate Frameworks and Their Relevance in Multifunctional Asymmetric Catalysis.

Shibasaki's rare earth alkali metal BINOLate (REMB) catalysts (REMB; RE = Sc, Y, La - Lu; M = Li, Na, K; B = 1,1-bi-2-naphtholate; RE/M/B = 1/3/3) are among the most successful enantioselective catalysts and have been employed in a broad range of mechanistically diverse reactions. Despite the phenomenal success of these catalysts, several fundamental questions central to their reactivity remain unresolved. Combined reactivity and spectroscopic studies were undertaken to probe the identity of the active catalyst(s) in Lewis-acid (LA) and Lewis-acid/Brønsted-base (LA/BB) catalyzed reactions. Exchange spectroscopy provided a method to obtain rates of ligand and alkali metal self-exchange in the RE/Li frameworks, demonstrating the utility of this technique for probing solution dynamics of REMB catalysts. Isolation of the first crystallographically characterized REMB complex with substrate bound enabled stoichiometric and catalytic reactivity studies, wherein we observed that substrate deprotonation by the catalyst framework was necessary to achieve selectivity. Our spectroscopic observations in LA/BB catalysis are inconsistent with previous mechanistic proposals, which considered only tris(BINOLate) species as active catalysts. These findings significantly expand our understanding of the catalyst structure in these privileged multifunctional frameworks and identify new directions for development of new catalysts.

Air- and water-tolerant rare earth guanidinium BINOLate complexes as practical precatalysts in multifunctional asymmetric catalysis.

Shibasaki's REMB catalysts (REMB; RE = Sc, Y, La-Lu; M = Li, Na, K; B = 1,1'-bi-2-naphtholate; RE/M/B = 1/3/3) are among the most enantioselective asymmetric catalysts across a broad range of mechanistically diverse reactions. However, their widespread use has been hampered by the challenges associated with their synthesis and manipulation. We report here the self-assembly of novel hydrogen-bonded rare earth metal BINOLate complexes that serve as bench-stable precatalysts for Shibasaki's REMB catalysts. Incorporation of hydrogen-bonded guanidinium cations in the secondary coordination sphere leads to unique properties, most notably, improved stability toward moisture in solution and in the solid state. We have exploited these properties to develop straightforward, high-yielding, and scalable open-air syntheses that provide rapid access to crystalline, nonhygroscopic complexes from inexpensive hydrated RE starting materials. These compounds can be used as precatalysts for Shibasaki's REMB frameworks, where we have demonstrated that our system performs with comparable or improved levels of stereoselectivity in several mechanistically diverse reactions including Michael additions, aza-Michael additions, and direct Aldol reactions.

NiXantphos: a deprotonatable ligand for room-temperature palladium-catalyzed cross-couplings of aryl chlorides.

Although the past 15 years have witnessed the development of sterically bulky and electron-rich alkylphosphine ligands for palladium-catalyzed cross-couplings with aryl chlorides, examples of palladium catalysts based on either triarylphosphine or bidentate phosphine ligands for efficient room temperature cross-coupling reactions with unactivated aryl chlorides are rare. Herein we report a palladium catalyst based on NiXantphos, a deprotonatable chelating aryldiphosphine ligand, to oxidatively add unactivated aryl chlorides at room temperature. Surprisingly, comparison of an extensive array of ligands revealed that under the basic reaction conditions the resultant heterobimetallic Pd-NiXantphos catalyst system outperformed all the other mono- and bidentate ligands in a deprotonative cross-coupling process (DCCP) with aryl chlorides. The DCCP with aryl chlorides affords a variety of triarylmethane products, a class of compounds with various applications and interesting biological activity. Additionally, the DCCP exhibits remarkable chemoselectivity in the presence of aryl chloride substrates bearing heteroaryl groups and sensitive functional groups that are known to undergo 1,2-addition, aldol reaction, and O-, N-, enolate-α-, and C(sp(2))-H arylations. The advantages and importance of the Pd-NiXantphos catalyst system outlined herein make it a valuable contribution for applications in Pd-catalyzed arylation reactions with aryl chlorides.

Asymmetric allylation of ketones and subsequent tandem reactions catalyzed by a novel polymer-supported titanium-BINOLate complex.

By using a novel, simple, and convenient synthetic route, enantiopure 6-ethynyl-BINOL (BINOL = 1,1-binaphthol) was synthesized and anchored to an azidomethylpolystyrene resin through a copper-catalyzed alkyne-azide cycloaddition (CuAAC) reaction. The polystyrene (PS)-supported BINOL ligand was converted into its diisopropoxytitanium derivative in situ and used as a heterogeneous catalyst in the asymmetric allylation of ketones. The catalyst showed good activity and excellent enantioselectivity, typically matching the results obtained in the corresponding homogeneous reaction. The allylation reaction mixture could be submitted to epoxidation by simple treatment with tert-butyl hydroperoxide (TBHP), and the tandem asymmetric allylation epoxidation process led to a highly enantioenriched epoxy alcohol with two adjacent quaternary centers as a single diastereomer. A tandem asymmetric allylation/Pauson-Khand reaction was also performed, involving simple treatment of the allylation reaction mixture with Co2(CO)8/N-methyl morpholine N-oxide. This cascade process resulted in the formation of two diastereomeric tricyclic enones in high yields and enantioselectivities.

Synthesis, bonding, and reactivity of a cerium(IV) fluoride complex.

Oxidation of Ce[N(SiMe3)2]3 in the presence of PF6(-) or BF4(-) afforded isolation of CeF[N(SiMe3)2]3. Structural and electrochemical characterization shows that this compound is in its tetravalent oxidation state and contains a terminal fluoride ligand. Spectroscopy and density functional theory have been used to characterize the Ce-F bond as ionic, which is reinforced by an initial reactivity study that demonstrates the nucleophilicity of the fluoride ligand.

Thioglucose-derived tetrasulfide, a unique polysulfide model compound.

Polysulfides have received increased interest in redox biology due to their role as the precursors of H2S and persulfides. However, the compounds that are suitable for biological investigations are limited to cysteine- and glutathione-derived polysulfides. In this work, we report the preparation and evaluation of a novel polysulfide derived from thioglucose, which represents the first carbohydrate-based polysulfide. This compound, thioglucose tetrasulfide (TGS4), showed excellent stability and water solubility. H2S and persulfide production from TGS4, as well as its associated antioxidative property were also demonstrated. Additionally, TGS4 was demonstrated to significantly induce cellular sulfane sulfur level increase, in particular for the formation of hydropersulfides/trisulfides. These results suggest that TGS4 is a useful tool for polysulfide research.

Synthesis and reduction of [(C5H4SiMe3)2Ln(µ-OR)]2 (Ln = La, Ce) complexes: structural effects of bridging alkoxides.

Alcoholysis of Cp'3Ln (Ln = La, Ce; Cp' = C5H4SiMe3) generate high-yielding (72-97%) bimetallic LnIII complexes of [Cp'2Ln(µ-OR)]2 [R = Et, iPr, or C6H4-4-tBu]. Single-crystal X-ray diffraction of these complexes reveal unexpected decreases in Ln⋯Ln distances, increasing Cpcent-Ln-Cpcent angles, and increasing intermolecular C⋯C contacts with bulkier bridging alkoxides, in line with structural control driven by significant dispersion forces. 1H NMR spectroscopy of [Cp'2Ce(µ-OEt)]2 and [Cp'2Ce(µ-OiPr)]2 revealed significantly upfield resonances assigned as methylene and methine moieties of -43.74 and -70.85 ppm, respectively. 2D 1H DOSY NMR experiments of [Cp'2Ce(µ-OiPr)]2 in C6D6 supported a dimeric structure in solution, including in the presence of a Lewis base (i.e., THF). Reduction of [Cp'2La(µ-OiPr)]2 using KC8 in the presence of 2.2.2-cryptand at -78 °C generated a purple solution and X-band EPR spectroscopy revealed an eight-line hyperfine pattern indicative of a LaII species.

2H-Thiopyran-2-thione sulfine, a compound for converting H2S to HSOH/H2S2 and increasing intracellular sulfane sulfur levels.

Reactive sulfane sulfur species such as persulfides (RSSH) and H2S2 are important redox regulators and closely linked to H2S signaling. However, the study of these species is still challenging due to their instability, high reactivity, and the lack of suitable donors to produce them. Herein we report a unique compound, 2H-thiopyran-2-thione sulfine (TTS), which can specifically convert H2S to HSOH, and then to H2S2 in the presence of excess H2S. Meanwhile, the reaction product 2H-thiopyran-2-thione (TT) can be oxidized to reform TTS by biological oxidants. The reaction mechanism of TTS is studied experimentally and computationally. TTS can be conjugated to proteins to achieve specific delivery, and the combination of TTS and H2S leads to highly efficient protein persulfidation. When TTS is applied in conjunction with established H2S donors, the corresponding donors of H2S2 (or its equivalents) are obtained. Cell-based studies reveal that TTS can effectively increase intracellular sulfane sulfur levels and compensate for certain aspects of sulfide:quinone oxidoreductase (SQR) deficiency. These properties make TTS a conceptually new strategy for the design of donors of reactive sulfane sulfur species.