Biosynthesis of Macrocyclic Peptides with C-Terminal ß-Amino-α-keto Acid Groups by Three Different Metalloenzymes.

Advances in genome sequencing and bioinformatics methods have identified a myriad of biosynthetic gene clusters (BGCs) encoding uncharacterized molecules. By mining genomes for BGCs containing a prevalent peptide-binding domain used for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), we uncovered a new compound class involving modifications installed by a cytochrome P450, a multinuclear iron-dependent non-heme oxidative enzyme (MNIO, formerly DUF692), a cobalamin- and radical S-adenosyl-l-methionine-dependent enzyme (B12-rSAM), and a methyltransferase. All enzymes were functionally expressed in Burkholderia sp. FERM BP-3421. Structural characterization demonstrated that the P450 enzyme catalyzed the formation of a biaryl C-C cross-link between two Tyr residues with the B12-rSAM generating ß-methyltyrosine. The MNIO transformed a C-terminal Asp residue into aminopyruvic acid, while the methyltransferase acted on the ß-carbon of this α-keto acid. Exciton-coupled circular dichroism spectroscopy and microcrystal electron diffraction (MicroED) were used to elucidate the stereochemical configuration of the atropisomer formed upon biaryl cross-linking. To the best of our knowledge, the MNIO featured in this pathway is the first to modify a residue other than Cys. This study underscores the utility of genome mining to isolate new macrocyclic RiPPs biosynthesized via previously undiscovered enzyme chemistry.

Biosynthesis of macrocyclic peptides with C-terminal ß-amino-α-keto acid groups by three different metalloenzymes.

Advances in genome sequencing and bioinformatics methods have identified a myriad of biosynthetic gene clusters (BGCs) encoding uncharacterized molecules. By mining genomes for BGCs containing a prevalent peptide-binding domain used for the biosynthesis of ribosomally synthesized and post-translationally modified peptides (RiPPs), we uncovered a new class involving modifications installed by a cytochrome P450, a multi-nuclear iron-dependent non-heme oxidative enzyme (MNIO, formerly DUF692), a cobalamin- and radical S-adenosyl-L-methionine-dependent enzyme (B12-rSAM), and a methyltransferase. All enzymes encoded by the BGC were functionally expressed in Burkholderia sp. FERM BP-3421. Structural characterization with 2D-NMR and Marfey's method on the resulting RiPP demonstrated that the P450 enzyme catalyzed the formation of a biaryl C-C crosslink between two Tyr residues with the B12-rSAM generating ß-methyltyrosine. The MNIO transformed a C-terminal Asp residue into aminopyruvic acid while the methyltransferase acted on the ß-carbon of the α-keto acid. Exciton-coupled circular dichroism spectroscopy and microcrystal electron diffraction (MicroED) were used to elucidate the stereochemical configurations of the atropisomer that formed upon biaryl crosslinking. The conserved Cys residue in the precursor peptide was not modified as in all other characterized MNIO-containing BGCs; However, mutational analyses demonstrated that it was essential for the MNIO activity on the C-terminal Asp. To the best of our knowledge, the MNIO featured in this pathway is the first to modify a residue other than Cys. This study underscores the utility of genome mining to discover new macrocyclic RiPPs and that RiPPs remain a significant source of previously undiscovered enzyme chemistry.

Automated iterative Csp3-C bond formation.

Fully automated synthetic chemistry would substantially change the field by providing broad on-demand access to small molecules. However, the reactions that can be run autonomously are still limited. Automating the stereospecific assembly of Csp3-C bonds would expand access to many important types of functional organic molecules1. Previously, methyliminodiacetic acid (MIDA) boronates were used to orchestrate the formation of Csp2-Csp2 bonds and were effective building blocks for automating the synthesis of many small molecules2, but they are incompatible with stereospecific Csp3-Csp2 and Csp3-Csp3 bond-forming reactions3-10. Here we report that hyperconjugative and steric tuning provide a new class of tetramethyl N-methyliminodiacetic acid (TIDA) boronates that are stable to these conditions. Charge density analysis11-13 revealed that redistribution of electron density increases covalency of the N-B bond and thereby attenuates its hydrolysis. Complementary steric shielding of carbonyl π-faces decreases reactivity towards nucleophilic reagents. The unique features of the iminodiacetic acid cage2, which are essential for generalized automated synthesis, are retained by TIDA boronates. This enabled Csp3 boronate building blocks to be assembled using automated synthesis, including the preparation of natural products through automated stereospecific Csp3-Csp2 and Csp3-Csp3 bond formation. These findings will enable increasingly complex Csp3-rich small molecules to be accessed via automated assembly.

Trioxazolo[23]metacyclophane: synthesis, structural analysis, and optical properties.

The synthesis and characterization of the conjugated macrocycle trioxazolo[23]metacyclophane, C27H15N3O3 (M), is reported. The macrocycle was synthesized in three steps by the multicomponent van Leusen reaction and consists of meta-linked phenylenes connected through positions 4 and 5 of an oxazole heterocyclic ring. The molecular structure was investigated by NMR spectroscopy, mass spectrometry, gel permeation chromatography (GPC), and single-crystal X-ray crystallography. X-ray diffraction (XRD) analysis shows that M possesses a twisted saddle-like shape and interacts with nearby molecules by various π-π interactions. Absorption and emission spectroscopy and density functional theory (DFT) calculations were further used to study the electronic properties of M.

Intramolecular Hydrogen-Bond Interactions Tune Reactivity in Biomimetic Bis(µ-hydroxo)dicobalt Complexes.

Active site hydrogen-bond (H-bond) networks represent a key component by which metalloenzymes control the formation and deployment of high-valent transition metal-oxo intermediates. We report a series of dinuclear cobalt complexes that serve as structural models for the nonheme diiron enzyme family and feature a Co2(µ-OH)2 diamond core stabilized by intramolecular H-bond interactions. We define the conditions required for the kinetically controlled synthesis of these complexes: [Co2(µ-OH)2(µ-OAc)(κ1-OAc)2(pyR)4][PF6] (1R), where OAc = acetate and pyR = pyridine with para-substituent R, and we describe a homologous series of 1R in which the para-R substituent on pyridine is modulated. The solid state X-ray diffraction (XRD) structures of 1R are similar across the series, but in solution, their 1H NMR spectra reveal a linear free energy relationship (LFER) where, as R becomes increasingly electron-withdrawing, the intramolecular H-bond interaction between bridging µ-OH and κ1-acetate ligands results in increasingly "oxo-like" µ-OH bridges. Deprotonation of the bridging µ-OH results in the quantitative conversion to corresponding cubane complexes: [Co4(µ-O)4(µ3-OAc)4(pyR)4] (2R), which represent the thermodynamic sink of self-assembly. These reactions are unusually slow for rate-limiting deprotonation events, but rapid-mixing experiments reveal a 6000-fold rate acceleration on going from R = OMe to R = CN. These results suggest that we can tune reactivity by modulating the µ-OH pKa in the presence of intramolecular H-bond interactions to maintain stability as the octahedral d6 centers become increasingly acidic. Nature may similarly employ dynamic carboxylate-mediated H-bond interactions to control the reactivity of acidic transition metal-oxo intermediates.

Iterative Exponential Growth of Oxygen-Linked Aromatic Polymers Driven by Nucleophilic Aromatic Substitution Reactions.

This work presents the first transition metal-free synthesis of oxygen-linked aromatic polymers by integrating iterative exponential polymer growth (IEG) with nucleophilic aromatic substitution (SNAr) reactions. Our approach applies methyl sulfones as the leaving groups, which eliminate the need for a transition metal catalyst, while also providing flexibility in functionality and configuration of the building blocks used. As indicated by 1) 1H-1H NOESY NMR spectroscopy, 2) single-crystal X-ray crystallography, and 3) density functional theory (DFT) calculations, the unimolecular polymers obtained are folded by nonclassical hydrogen bonds formed between the oxygens of the electron-rich aromatic rings and the positively polarized C-H bonds of the electron-poor pyrimidine functions. Our results not only introduce a transition metal-free synthetic methodology to access precision polymers but also demonstrate how interactions between relatively small, neutral aromatic units in the polymers can be utilized as new supramolecular interaction pairs to control the folding of precision macromolecules.

Near quantitative synthesis of urea macrocycles enabled by bulky N-substituent.

Macrocycles are unique molecular structures extensively used in the design of catalysts, therapeutics and supramolecular assemblies. Among all reactions reported to date, systems that can produce macrocycles in high yield under high reaction concentrations are rare. Here we report the use of dynamic hindered urea bond (HUB) for the construction of urea macrocycles with very high efficiency. Mixing of equal molar diisocyanate and hindered diamine leads to formation of macrocycles with discrete structures in nearly quantitative yields under high concentration of reactants. The bulky N-tert-butyl plays key roles to facilitate the formation of macrocycles, providing not only the kinetic control due to the formation of the cyclization-promoting cis C = O/tert-butyl conformation, but also possibly the thermodynamic stabilization of macrocycles with weak association interactions. The bulky N-tert-butyl can be readily removed by acid to eliminate the dynamicity of HUB and stabilize the macrocycle structures.

Challenges in the Synthesis of Active Site Mimics for [NiFe]-Hydrogenases.

One of the more active areas in bioorganometallic chemistry is the preparation and reactivity studies of active site mimics of the [NiFe]-hydrogenases. One area of particular recent progress involves reactions that interconvert Ni(µ-X)Fe centers for X = OH, H, CO, as described by Song et al. Such reactions illustrate new ways to access intermediates related to the Ni-R and Ni-SI states of the enzyme. Most models are derivatives of the type (diphosphine)Ni(SR)2Fe(CO)3-n(PR'3)n. In recent work, the methodology has been generalized to include FeII(diphosphine) derivatives of Ni(N2S2), where N2S22- is the tetradentate diamine-dithiolate (CH2N(CH3)CH2CH2S-)2. Indeed, models based on Ni(N2S2) have proven valuable, but these studies also highlight challenges in working with heterobimetallic complexes, specifically the tendency of some such Ni-Fe complexes to convert to homometalliic Ni-Ni derivatives. This kind of problem is not readily detected by X-ray crystallography. With this caution in mind, we argue that one series of complexes recently described in this journal are almost certainly misassigned.

Electrochemical Studies of Selected Lanthanide and Californium Cryptates.

Efforts to quantitatively reduce CfIII → CfII in solution as well as studies of its cyclic voltammetry have been hindered by its scarcity, significant challenges associated with manipulating an unusually intense γ emitter, small reaction scales, the need for nonaqueous solvents, and its radiolytic effects on ligands and solvents. In an effort to overcome these impediments, we report on the stabilization of CfII by encapsulation in 2.2.2-cryptand and comparisons with the readily reducible lanthanides, Sm3+, Eu3+, and Yb3+. Cyclic voltammetry measurements suggest that CfIII/II displays electrochemical behavior with characteristics of both SmIII/II and YbIII/II. The °E1/2 values of -1.525 and -1.660 V (vs Fc/Fc+ in tetrahydrofuran (THF)) for [Cf(2.2.2-crypt)]3+/2+ and [Sm(2.2.2-crypt)]3+/2+, respectively, are similar. However, the ΔE values upon complexation by 2.2.2-cryptand for CfIII/II more closely parallels YbIII/II with postencapsulation shifts of 705 and 715 mV, respectively, whereas the shift of SmIII/II (520 mV) mirrors that of EuIII/II (524 mV). This suggests more structural similarities between CfII and YbII in solution than with SmII that likely originates from more similar ionic radii and local coordination environments, a supposition that is corroborated by crystallographic and extended X-ray absorption fine structure measurements from other systems. Competitive-ion binding experiments between EuIII/II, SmIII/II, and YbIII/II were also performed and show less favorable binding by YbIII/II. Connectivity structures of [Ln(2.2.2-cryptand)(THF)][BPh4]2 (Ln = EuII, SmII) are reported to show the important role that THF plays in these redox reactions.

The inclusion of zinc into mineralized collagen scaffolds for craniofacial bone repair applications.

Implant osteoinduction and subsequent osteogenic activity are critical events that need improvement for regenerative healing of large craniofacial bone defects. Here we describe the augmentation of the mineral content of a class of mineralized collagen scaffolds under development for craniomaxillofacial bone regeneration via the inclusion of zinc ions to promote osteogenesis in vitro. Zinc is an essential trace element in skeletal tissue and bone, with soluble zinc being shown to promote osteogenic differentiation of porcine adipose derived stem cells. We report the development of a new class of zinc functionalized scaffolds fabricated by adding zinc sulfate to a mineralized collagen-glycosaminoglycan precursor suspension that was then freeze dried to form a porous biomaterial. We report analysis of zinc functionalized scaffolds via imaging (scanning electron microscopy), mechanical testing (compression), and compositional (X-ray diffraction, inductively coupled plasma mass spectrometry) analyses. Notably, zinc-functionalized scaffolds display morphological changes to the mineral phase and altered elastic modulus without substantially altering the composition of the brushite phase or removing the micro-scale pore morphology of the scaffold. These scaffolds also display zinc release kinetics on the order of days to weeks and promote successful growth and pro-osteogenic capacity of porcine adipose derived stem cells cultured within these zinc scaffolds. Taken together, we believe that zinc functionalized scaffolds provide a unique platform to explore strategies to improve in vivo osteogenesis in craniomaxillofacial bone injuries models. STATEMENT OF SIGNIFICANCE: Craniomaxillofacial bone defects that arise from traumatic, congenital, and post-oncologic origins cannot heal on their own and often require surgical intervention. We have developed a class of mineralized collagen scaffolds that promotes osteogenesis and bone regeneration. Here we describe the inclusion of zinc sulfate into the mineralized collagen scaffold to improve osteogenesis. Zinc functionalized scaffolds demonstrate altered crystallite microstructure but consistent Brushite chemistry, improved mechanics, and promote zinc transporter expression while supporting stem cell viability, osteogenic differentiation, and mineral biosynthesis.

Radical Rebound Hydroxylation Versus H-Atom Transfer in Non-Heme Iron(III)-Hydroxo Complexes: Reactivity and Structural Differentiation.

The characterization of high-valent iron centers in enzymes has been aided by synthetic model systems that mimic their reactivity or structural and spectral features. For example, the cleavage of dioxygen often produces an iron(IV)-oxo that has been characterized in a number of enzymatic and synthetic systems. In non-heme 2-oxogluterate dependent (iron-2OG) enzymes, the ferryl species abstracts an H-atom from bound substrate to produce the proposed iron(III)-hydroxo and caged substrate radical. Most iron-2OG enzymes perform a radical rebound hydroxylation at the site of the H-atom abstraction (HAA); however, recent reports have shown that certain substrates can be desaturated through the loss of a second H atom at a site adjacent to a heteroatom (N or O) for most native desaturase substrates. One proposed mechanism for the removal of the second H-atom  involves a polar-cleavage mechanism (electron transfer-proton transfer) by the iron(III)-hydroxo, as opposed to a second HAA. Herein we report the synthesis and characterization of a series of iron complexes with hydrogen bonding interactions between bound aquo or hydroxo ligands and the secondary coordination sphere in ferrous and ferric complexes. Interconversion among the iron species is accomplished by stepwise proton or electron addition or subtraction, as well as H-atom transfer (HAT). The calculated bond dissociation free energies (BDFEs) of two ferric hydroxo complexes, differentiated by their noncovalent interactions and reactivity, suggest that neither complex is capable of activating even weak C-H bonds, lending further support to the proposed mechanism for desaturation in iron-2OG desaturase enzymes. Additionally, the ferric hydroxo species are differentiated by their reactivity toward performing a radical rebound hydroxylation of triphenylmethylradical. Our findings should encourage further study of the desaturase systems that may contain unique H-bonding motifs proximal to the active site that help bias substrate desaturation over hydroxylation.

Fluorous-Soluble Metal Chelate for Sensitive Fluorine-19 Magnetic Resonance Imaging Nanoemulsion Probes.

Fluorine-19 MRI is an emerging cellular imaging approach, enabling lucid, quantitative "hot-spot" imaging with no background signal. The utility of 19F-MRI to detect inflammation and cell therapy products in vivo could be expanded by improving the intrinsic sensitivity of the probe by molecular design. We describe a metal chelate based on a salicylidene-tris(aminomethyl)ethane core, with solubility in perfluorocarbon (PFC) oils, and a potent accelerator of the 19F longitudinal relaxation time ( T1). Shortening T1 can increase the 19F image sensitivity per time and decrease the minimum number of detectable cells. We used the condensation between the tripodal ligand tris-1,1,1-(aminomethyl)ethane and salicylaldehyde to form the salicylidene-tris(aminomethyl)ethane chelating agent (SALTAME). We purified four isomers of SALTAME, elucidated structures using X-ray scattering and NMR, and identified a single isomer with high PFC solubility. Mn4+, Fe3+, Co3+, and Ga3+ cations formed stable and separable chelates with SALTAME, but only Fe3+ yielded superior T1 shortening with modest line broadening at 3 and 9.4 T. We mixed Fe3+ chelate with perfluorooctyl bromide (PFOB) to formulate a stable paramagnetic nanoemulsion imaging probe and assessed its biocompatibility in macrophages in vitro using proliferation, cytotoxicity, and phenotypic cell assays. Signal-to-noise modeling of paramagnetic PFOB shows that sensitivity enhancement of nearly 4-fold is feasible at clinical magnetic field strengths using a 19F spin-density-weighted gradient-echo pulse sequence. We demonstrate the utility of this paramagnetic nanoemulsion as an in vivo MRI probe for detecting inflammation macrophages in mice. Overall, these paramagnetic PFC compounds represent a platform for the development of sensitive 19F probes.

Product Distribution from Precursor Bite Angle Variation in Multitopic Alkyne Metathesis: Evidence for a Putative Kinetic Bottleneck.

In the dynamic synthesis of covalent organic frameworks and molecular cages, the typical synthetic approach involves heuristic methods of discovery. While this approach has yielded many remarkable products, the ability to predict the structural outcome of subjecting a multitopic precursor to dynamic covalent chemistry (DCC) remains a challenge in the field. The synthesis of covalent organic cages is a prime example of this phenomenon, where precursors designed with the intention of affording a specific product may deviate dramatically when the DCC synthesis is attempted. As such, rational design principles are needed to accelerate discovery in cage synthesis using DCC. Herein, we test the hypothesis that precursor bite angle contributes significantly to the energy landscape and product distribution in multitopic alkyne metathesis (AM). By subjecting a series of precursors with varying bite angles to AM, we experimentally demonstrate that the product distribution, and convergence toward product formation, is strongly dependent on this geometric attribute. Surprisingly, we discovered that precursors with the ideal bite angle (60°) do not afford the most efficient pathway to the product. The systematic study reported here illustrates how seemingly minor adjustments in precursor geometry greatly affect the outcome of DCC systems. This research illustrates the importance of fine-tuning precursor geometric parameters in order to successfully realize desirable targets.

Sterically Stabilized Terminal Hydride of a Diiron Dithiolate.

The kinetically robust hydride [t-HFe2(Me2pdt)(CO)2(dppv)2]+ ([t-H1]+) (Me2pdt2- = Me2C(CH2S-)2; dppv = cis-1,2-C2H2(PPh2)2) and related derivatives were prepared with 57Fe enrichment for characterization by NMR, FT-IR, and NRVS. The experimental results were rationalized using DFT molecular modeling and spectral simulations. The spectroscopic analysis was aimed at supporting assignments of Fe-H vibrational spectra as they relate to recent measurements on [FeFe]-hydrogenase enzymes. The combination of bulky Me2pdt2- and dppv ligands stabilizes the terminal hydride with respect to its isomerization to the 5-16 kcal/mol more stable bridging hydride ([µ-H1]+) with t1/2(313.3 K) = 19.3 min. In agreement with the nOe experiments, the calculations predict that one methyl group in [t-H1]+ interacts with the hydride with a computed CH···HFe distance of 1.7 Å. Although [t-H571]+ exhibits multiple NRVS features in the 720-800 cm-1 region containing the bending Fe-H modes, the deuterated [t-D571]+ sample exhibits a unique Fe-D/CO band at ∼600 cm-1. In contrast, the NRVS spectra for [µ-H571]+ exhibit weaker bands near 670-700 cm-1 produced by the Fe-H-Fe wagging modes coupled to Me2pdt2- and dppv motions.

Quantitative Analysis of Different Formation Modes of Platinum Nanocrystals Controlled by Ligand Chemistry.

Well-defined metal nanocrystals play important roles in various fields, such as catalysis, medicine, and nanotechnology. They are often synthesized through kinetically controlled process in colloidal systems that contain metal precursors and surfactant molecules. The chemical functionality of surfactants as coordinating ligands to metal ions however remains a largely unsolved problem in this process. Understanding the metal-ligand complexation and its effect on formation kinetics at the molecular level is challenging but essential to the synthesis design of colloidal nanocrystals. Herein we report that spontaneous ligand replacement and anion exchange control the form of coordinated Pt-ligand intermediates in the system of platinum acetylacetonate [Pt(acac)2], primary aliphatic amine, and carboxylic acid ligands. The formed intermediates govern the formation mode of Pt nanocrystals, leading to either a pseudo two-step or a one-step mechanism by switching on or off an autocatalytic surface growth. This finding shows the importance of metal-ligand complexation at the prenucleation stage and represents a critical step forward for the designed synthesis of nanocrystal-based materials.

Interplay between Terminal and Bridging Diiron Hydrides in Neutral and Oxidized States.

This study describes the structural, spectroscopic, and electrochemical properties of electronically unsymmetrical diiron hydrides. The terminal hydride Cp*Fe(pdt)Fe(dppe)(CO)H ([1(t-H)]0, Cp*- = Me5C5-, pdt2- = CH2(CH2S-)2, dppe = Ph2PC2H4PPh2) was prepared by hydride reduction of [Cp*Fe(pdt)Fe(dppe)(CO)(NCMe)]+. As established by X-ray crystallography, [1(t-H)]0 features a terminal hydride ligand. Unlike previous examples of terminal diiron hydrides, [1(t-H)]0 does not isomerize to the bridging hydride [1(µ-H)]0. Oxidation of [1(t-H)]0 gives [1(t-H)]+, which was also characterized crystallographically as its BF4- salt. Density functional theory (DFT) calculations indicate that [1(t-H)]+ is best described as containing an Cp*FeIII center. In solution, [1(t-H)]+ isomerizes to [1(µ-H)]+, as anticipated by DFT. Reduction of [1(µ-H)]+ by Cp2Co afforded the diferrous bridging hydride [1(µ-H)]0. Electrochemical measurements and DFT calculations indicate that the couples [1(t-H)]+/0 and [1(µ-H)]+/0 differ by 210 mV. Qualitative measurements indicate that [1(t-H)]0 and [1(µ-H)]0 are close in free energy. Protonation of [1(t-H)]0 in MeCN solution affords H2 even with weak acids via hydride transfer. In contrast, protonation of [1(µ-H)]0 yields 0.5 equiv of H2 by a proposed protonation-induced electron transfer process. Isotopic labeling indicates that µ-H/D ligands are inert.

Synthetic Models for Nickel-Iron Hydrogenase Featuring Redox-Active Ligands.

The nickel-iron hydrogenase enzymes efficiently and reversibly interconvert protons, electrons, and dihydrogen. These redox proteins feature iron-sulfur clusters that relay electrons to and from their active sites. Reported here are synthetic models for nickel-iron hydrogenase featuring redox-active auxiliaries that mimic the iron-sulfur cofactors. The complexes prepared are NiII(µ-H)FeIIFeII species of formula [(diphosphine)Ni(dithiolate)(µ-H)Fe(CO)2(ferrocenylphosphine)]+ or NiIIFeIFeII complexes [(diphosphine)Ni(dithiolate)Fe(CO)2(ferrocenylphosphine)]+ (diphosphine = Ph2P(CH2)2PPh2 or Cy2P(CH2)2PCy2; dithiolate = -S(CH2)3S-; ferrocenylphosphine = diphenylphosphinoferrocene, diphenylphosphinomethyl(nonamethylferrocene) or 1,1'-bis(diphenylphosphino)ferrocene). The hydride species is a catalyst for hydrogen evolution, while the latter hydride-free complexes can exist in four redox states - a feature made possible by the incorporation of the ferrocenyl groups. Mixed-valent complexes of 1,1'-bis(diphenylphosphino)ferrocene have one of the phosphine groups unbound, with these species representing advanced structural models with both a redox-active moiety (the ferrocene group) and a potential proton relay (the free phosphine) proximal to a nickel-iron dithiolate.

Crystal-Packing-Driven Enrichment of Atropoisomers.

Crystal-packing forces can have a significant impact on the relative stabilities of different molecules and their conformations. The magnitude of such effects is, however, not yet well understood. Herein we show, that crystal packing can completely overrule the relative stabilities of different stereoisomers in solution. Heating of atropoisomers (i.e. "frozen-out" conformational isomers) in solution leads to complex mixtures. In contrast, solid-state heating selectively amplifies minor (<25 mole %) components of these solution-phase mixtures. We show that this heating strategy is successful for compounds with up to four rotationally hindered σ bonds, for which a single stereoisomer out of seven can be amplified selectively. Our results demonstrate that common supramolecular interactions-for example, [methyl⋅⋅⋅π] coordination and [C-H⋅⋅⋅O] hydrogen bonding-can readily invert the relative thermodynamic stabilities of different molecular conformations. These findings open up potential new avenues to control the folding of macromolecules.

Impact of Shape Persistence on the Porosity of Molecular Cages.

Porous materials provide a plethora of technologically important applications that encompass molecular separations, catalysis, and adsorption. The majority of research in this field involves network solids constructed from multitopic constituents that, when assembled either covalently or ionically, afford macromolecular arrangements with micro- or meso-porous apertures. Recently, porous solids fabricated from discrete organic cages have garnered much interest due to their ease of handling and solution processability. Although this class of materials is a promising alternative to network solids, fundamental studies are still required to elucidate critical structure-function relationships that govern microporosity. Here, we report a systematic investigation of the effects of building block shape-persistence on the porosity of molecular cages. Alkyne metathesis and edge-specific postsynthetic modifications afforded three organic cages with alkynyl, alkenyl, and alkyl edges, respectively. Nitrogen adsorption experiments conducted on rapidly crystallized and slowly crystallized solids illustrated a general trend in porosity: alkynyl > alkenyl > alkyl. To understand the molecular-scale origin of this trend, we investigated the short and long time scale molecular motions of the molecular cages using ab initio molecular dynamics (AIMD) and classical molecular dynamics (MD) simulations. Our combined experimental and computational results demonstrate that the microporosity of molecular cages directly correlates with shape persistence. These findings discern fundamental molecular requirements for rationally designing porous molecular solids.

Ligand Design for Isomer-Selective Oxorhenium(V) Complex Synthesis.

Recently, N,N-trans Re(O)(LN-O)2X (LN-O = monoanionic N-O chelates; X = Cl or Br prior to being replaced by solvents or alkoxides) complexes have been found to be superior to the corresponding N,N-cis isomers in the catalytic reduction of perchlorate via oxygen atom transfer. However, reported methods for Re(O)(LN-O)2X synthesis often yield only the N,N-cis complex or a mixture of trans and cis isomers. This study reports a geometry-inspired ligand design rationale that selectively yields N,N-trans Re(O)(LN-O)2Cl complexes. Analysis of the crystal structures revealed that the dihedral angles (DAs) between the two LN-O ligands of N,N-cis Re(O)(LN-O)2Cl complexes are less than 90°, whereas the DAs in most N,N-trans complexes are greater than 90°. Variably sized alkyl groups (-Me, -CH2Ph, and -CH2Cy) were then introduced to the 2-(2'-hydroxyphenyl)-2-oxazoline (Hhoz) ligand to increase steric hindrance in the N,N-cis structure, and it was found that substituents as small as -Me completely eliminate the formation of N,N-cis isomers. The generality of the relationship between N,N-trans/cis isomerism and DAs is further established from a literature survey of 56 crystal structures of Re(O)(LN-O)2X, Re(O)(LO-N-N-O)X, and Tc(O)(LN-O)2X congeners. Density functional theory calculations support the general strategy of introducing ligand steric hindrance to favor synthesis of N,N-trans Re(O)(LN-O)2X and Tc(O)(LN-O)2X complexes. This study demonstrates the promise of applying rational ligand design for isomeric control of metal complex structures, providing a path forward for innovations in a number of catalytic, environmental, and biomedical applications.