Oxidative Ring Closure Reactions Research Articles

Computational Study Into the Oxidative Ring-Closure Mechanism During the Biosynthesis of Deoxypodophyllotoxin.

The nonheme iron dioxygenase deoxypodophyllotoxin synthase performs an oxidative ring-closure reaction as part of natural product synthesis in plants. How the enzyme enables the oxidative ring-closure reaction of (-)-yatein and avoids substrate hydroxylation remains unknown. To gain insight into the reaction mechanism and understand the details of the pathways leading to products and by-products we performed a comprehensive computational study. The work shows that substrate is bound tightly into the substrate binding pocket with the C7'-H bond closest to the iron(IV)-oxo species. The reaction proceeds through a radical mechanism starting with hydrogen atom abstraction from the C7'-H position followed by ring-closure and a final hydrogen transfer to form iron(II)-water and deoxypodophyllotoxin. Alternative mechanisms including substrate hydroxylation and an electron transfer pathway were explored but found to be higher in energy. The mechanism is guided by electrostatic perturbations of charged residues in the second-coordination sphere that prevent alternative pathways.

(Invited) Interplay Between π–Conjugation and Exchange Magnetism in One-Dimensional Porphyrinoid Polymers

The field of carbon magnetism has gained an increased attention in view of the recent progress made in the synthesis and characterization of open-shell polycyclic aromatic hydrocarbons following a bottom-up synthetic approach[1,2]. Under this scenario, the comprehensive fabrication of magnetic porphyrinoid-based polymers emerges as a highly appealing field of research. However, the vast majority of the porphyrinoid species and polymers studied to date exhibit a closed-shell ground state[3].In this work, we introduce an exemplary approach toward the bottom-up fabrication of unprecedented magnetic porphyrinoid-based polymers homocoupled via surface-catalyzed [3 + 3] cycloaromatization of isopropyl substituents studied on Au(111) under ultra-high vacuum (UHV) conditions. The chemical structure of the polymer, formed by thermal-activated intra- and intermolecular oxidative ring closure reactions followed by controlled tip-induced hydrogen dissociation from the porphyrinoid units, have been clearly elucidated by scanning tunneling microscopy (STM) and non-contact atomic force microscopy (nc-AFM). Scanning tunneling spectroscopy (STS), complemented by computational investigations reveals the open-shell character, i.e. antiferromagnetic singlet ground state (S=0) of the formed polymers, which display singlet−triplet inelastic excitations observed between spins of adjacent porphyrinoid units only along a specific π-conjugation pathway, thus revealing the interplay between π-conjugation and magnetic exchange. We envision that our approach can be a highly relevant step towards the on-surface synthesis of covalently linked 1D magnetic organic polymers with prospects in nanoscale spintronic devices.

Synthesis and coordination of a dipyrrin appended N-confused porphyrin

A hexapyrrane P6 with a terminal N-confused pyrrole was synthesized by acid-catalyzed [3+3] condensation followed by oxidation with DDQ, which did not afford the expected N-confused hexaphyrin. In stead, a rearranged product, i.e., [Formula: see text]-dipyrrin appended N-confused porphyrin 1 was obtained in a yield of 46%. Chelation of 1 with Pt(II) afforded the peripheral complex 1-Pt, which was further coordinated with Rh(I) in the cavity to afford the corresponding bimetallic complex 1-Pt-Rh. Both 1-Pt and 1-Pt-Rh exhibit split Soret-like bands and noticeable Q-like bands tailing to the NIR region up to ca. 1200 nm. Single crystal X-ray diffraction analyses of 1 and 1-Pt revealed that the peripheral coordination of Pt(II) slightly modifies the interplanar angle between the porphyrin macrocycle and the dipyrrin unit, which may modulate the absorption spectra. The results of this work compose an interesting example of synthesizing porphyrinoids appended with conjugated peripheral chains by the oxidative ring closure reaction of an oligopyrrane containing a terminal N-confused pyrrole, and such compounds may be used for both inner and peripheral coordination to afford complexes with tunable NIR absorption.

Interplay between π-Conjugation and Exchange Magnetism in One-Dimensional Porphyrinoid Polymers.

The synthesis of novel polymeric materials with porphyrinoid compounds as key components of the repeating units attracts widespread interest from several scientific fields in view of their extraordinary variety of functional properties with potential applications in a wide range of highly significant technologies. The vast majority of such polymers present a closed-shell ground state, and, only recently, as the result of improved synthetic strategies, the engineering of open-shell porphyrinoid polymers with spin delocalization along the conjugation length has been achieved. Here, we present a combined strategy toward the fabrication of one-dimensional porphyrinoid-based polymers homocoupled via surface-catalyzed [3 + 3] cycloaromatization of isopropyl substituents on Au(111). Scanning tunneling microscopy and noncontact atomic force microscopy describe the thermal-activated intra- and intermolecular oxidative ring closure reactions as well as the controlled tip-induced hydrogen dissociation from the porphyrinoid units. In addition, scanning tunneling spectroscopy measurements, complemented by computational investigations, reveal the open-shell character, that is, the antiferromagnetic singlet ground state (S = 0) of the formed polymers, characterized by singlet–triplet inelastic excitations observed between spins of adjacent porphyrinoid units. Our approach sheds light on the crucial relevance of the π-conjugation in the correlations between spins, while expanding the on-surface synthesis toolbox and opening avenues toward the synthesis of innovative functional nanomaterials with prospects in carbon-based spintronics.

Local Charge Distributions, Electric Dipole Moments, and Local Electric Fields Influence Reactivity Patterns and Guide Regioselectivities in α-Ketoglutarate-Dependent Non-heme Iron Dioxygenases.

Non-heme iron dioxygenases catalyze vital processes for human health related to the biosynthesis of essential products and the biodegradation of toxic metabolites. Often the natural product biosyntheses by these non-heme iron dioxygenases is highly regio- and chemoselective, which are commonly assigned to tight substrate-binding and positioning. However, recent high-level computational modeling has shown that substrate-binding and positioning is only part of the story and long-range electrostatic interactions can play a major additional role.In this Account, we review and summarize computational viewpoints on the high regio- and chemoselectivity of α-ketoglutarate-dependent non-heme iron dioxygenases and how external perturbations affect the catalysis. In particular, studies from our groups have shown that often a regioselectivity in enzymes can be accomplished by stabilization of the rate-determining transition state for the reaction through external charges, electric dipole moments, or local electric field effects. Furthermore, bond dissociation energies in molecules are shown to be influenced by an electric field effect, and through targeting a specific bond in an electric field, this can lead to an unusually specific reaction. For instance, in the carbon-induced starvation protein, we studied two substrate-bound conformations and showed that regardless of what C-H bond of the substrate is closest to the iron(IV)-oxo oxidant, the lowest hydrogen atom abstraction barrier is always for the pro-S C2-H abstraction due to an induced dipole moment of the protein that weakens this bond. In another example of the hygromycin biosynthesis enzyme, an oxidative ring-closure reaction in the substrate forms an ortho-δ-ester ring. Calculations on this enzyme show that the selectivity is guided by a protonated lysine residue in the active site that, through its positive charge, triggers a low energy hydrogen atom abstraction barrier. A final set of examples in this Account discuss the viomycin biosynthesis enzyme and the 2-(trimethylammonio)ethylphosphonate dioxygenase (TmpA) enzyme. Both of these enzymes are shown to possess a significant local dipole moment and local electric field effect due to charged residues surrounding the substrate and oxidant binding pockets. The protein dipole moment and local electric field strength changes the C-H bond strengths of the substrate as compared to the gas-phase triggers the regioselectivity of substrate activation. In particular, we show that in the gas phase and in a protein environment C-H bond strengths are different due to local electric dipole moments and electric field strengths. These examples show that enzymes have an intricately designed structure that enables a chemical reaction under ambient conditions through the positioning of positively and negatively charged residues that influence and enhance reaction mechanisms. These computational insights create huge possibilities in bioengineering to apply local electric field and dipole moments in proteins to achieve an unusual selectivity and specificity and trigger a fit-for-purpose biocatalyst for unique biotransformations.

On-Surface Synthesis of Non-Benzenoid Nanographenes by Oxidative Ring-Closure and Ring-Rearrangement Reactions.

Nanographenes (NGs) have gained increasing attention due to their immense potential as tailor-made organic materials for nanoelectronics and spintronics. They exhibit a rich spectrum of physicochemical properties that can be tuned by controlling the size or the edge structure or by introducing structural defects in the honeycomb lattice. Here, we report the design and on-surface synthesis of NGs containing several odd-membered polycycles induced by a thermal procedure on Au(111). Our scanning tunneling microscopy, noncontact atomic force microscopy, and scanning tunneling spectroscopy measurements, complemented by computational investigations, describe the formation of two nonbenzenoid NGs (2A,B) containing four embedded azulene units in the polycyclic framework, via on-surface oxidative ring-closure reactions. Interestingly, we observe surface-catalyzed skeletal ring rearrangement reactions in the NGs, which lead to the formation of additional heptagonal rings as well as pentalene and as-indacene units in 2A,B, respectively. 2A,B on Au(111) both exhibit narrow experimental frontier electronic gaps of 0.96 and 0.85 eV, respectively, and Fermi level pinning of their HOMOs together with considerable electron transfer to the substrate. Ab initio calculations estimate moderate open-shell biradical characters for the NGs in the gas phase.

Thermally Treated Graphene Oxide/Polyacrylonitrile Based Electrospun Carbon Nanofiber Precursor

Graphene oxide (GO) included polyacrylonitrile (PAN) composite electrospun nanofiber webs were fabricated, and thermal oxidation of PAN/GO composite nanofibers were performed at different temperatures (25, 250, 280, and 300 °C) for different time intervals (0, 1 and 3 h.) to investigate the oxidation process of PAN/GO nanofibers. The thermal oxidation process of PAN has a complex mechanism through the cyclization and dehydrogenation steps. For all oxidized samples, Electrochemical impedance spectroscopy (EIS), X-ray photoelectron spectroscopy (XPS) and Fourier Transform Infrared-Attenuated Total Reflectance (FTIR-ATR) Spectroscopic results were comparatively evaluated to investigate the effect of GO addition onto the nanofiber webs. After heat treatment, change in C1s spectra from virgin PAN to oxidized form was detected and sp² carbon is developed. The presence of GO accelerated the oxidation and development of the final structure. At shorter heat treatment time, less oxidized forms are obtained. The cyclization of nitrile pendant groups of PAN forming polyimine type structure is the main reaction occurs during stabilization. In addition to the imine sequences with three to six units long, the presence of polar groups C═O, OH and COOH in the chains facilitates the initiation of the cyclization process through a nucleophilic attack and accelerates the subsequent oxidative ring closure reactions which these newly formed bonds during thermal oxidation and stabilization steps play an essential role on the carbonization process as an intermediate form of PAN based structures.

Rational Synthesis of 5,5,5-Tricyclic Fused Thia-heptaphyrin (1.1.1.1.1.1.0) From a Helical Oligopyrrin Hybrid.

Oxidation of a thiophene-hexapyrrane hybrid S-P6 afforded a stable conjugated open-chain thiaheptapyrrolic helix 1 with the terminal thiophene and confused pyrrole units lying at a long distance that is adverse for further cyclization. Chelation of 1 with copper(II) ion afforded 1-Cu, which exhibits more distant terminal units. Interestingly, further oxidation of 1 triggered an intramolecular C-N fusion reaction to afford a unique 5,5,5-tricyclic fused linear thiaheptapyrrin 2, with the two terminals positioned in proximity, which favors the oxidative ring-closure reaction to give a unique 5,5,5-tricyclic fused thiaheptaphyrin (1.1.1.1.1.1.0) 3 under air. The inner-fusion strategy for positioning the reactive sites in proximity to promote oxidative cyclization offers a new approach for constructing large porphyrinoids through conjugated oligopyrrins without the assistance of metal ions.

Oxidative cyclization of N-methyl-dopa by a fungal flavoenzyme of the amine oxidase family

Flavin-dependent enzymes catalyze many oxidations, including formation of ring structures in natural products. The gene cluster for biosynthesis of fumisoquins, secondary metabolites structurally related to isoquinolines, in the filamentous fungus Aspergillus fumigatus harbors a gene that encodes a flavoprotein of the amine oxidase family, termed fsqB (fumisoquin biosynthesis gene B). This enzyme catalyzes an oxidative ring closure reaction that leads to the formation of isoquinoline products. This reaction is reminiscent of the oxidative cyclization reported for berberine bridge enzyme and tetrahydrocannabinol synthase. Despite these similarities, amine oxidases and berberine bridge enzyme–like enzymes possess distinct structural properties, prompting us to investigate the structure–function relationships of FsqB. Here, we report the recombinant production and purification of FsqB, elucidation of its crystal structure, and kinetic analysis employing five putative substrates. The crystal structure at 2.6 Å resolution revealed that FsqB is a member of the amine oxidase family with a covalently bound FAD cofactor. N-methyl-dopa was the best substrate for FsqB and was completely converted to the cyclic isoquinoline product. The absence of the meta-hydroxyl group, as e.g. in l-N-methyl-tyrosine, resulted in a 25-fold lower rate of reduction and the formation of the demethylated product l-tyrosine, instead of a cyclic product. Surprisingly, FsqB did not accept the d-stereoisomer of N-methyltyrosine, in contrast to N-methyl-dopa, for which both stereoisomers were oxidized with similar rates. On the basis of the crystal structure and docking calculations, we postulate a substrate-dependent population of distinct binding modes that rationalizes stereospecific oxidation in the FsqB active site.

Structural Dynamics and Barrier Crossing Observed for a Fluorescent O‐Doped Polycyclic Aromatic Hydrocarbon

AbstractThe O‐doped aromatic polycycle peri‐xanthenoxanthene (PXX) was prepared from 1,1′‐bi(2‐naphthol) by means of an oxidative ring closure reaction. In solution, PXX is strongly emissive and displays well‐structured absorption and fluorescence spectra but low‐temperature phosphorescence is not detected. There is little change in geometry on excitation but, in most solvents, nonradiative decay of the excited singlet state is promoted by slight twisting of the molecular backbone. This route is partially blocked in viscous solvents and at low temperature. In the liquid phase under low friction, the rate of nonradiative decay correlates with the inverse viscosity of the solvent. Nonradiative deactivation of the excited singlet state is activated in solution while the Huang–Rhys factor is sensitive to temperature changes in a glassy matrix. Assuming the twisting movement is equivalent to translational motion about the ether linkages, Kramers’ theory allows estimation of the potential curvature at the apex of the barrier.

ChemInform Abstract: Sexterrylenetetracarboxylic Bisimides: NIR Dyes.

AbstractBisamide (I) is prepared by Suzuki cross‐coupling and subsequent oxidative ring closure reactions of the perylene units.

Sexterrylenetetracarboxylic Bisimides: NIR Dyes.

Sexterrylenehexacarboxylic bisimides, extended peri-arylenes with the alignment of six peri-arranged naphthalene units, were prepared by Suzuki cross coupling and subsequent oxidative ring closure reactions of the perylene units and exhibit NIR absorption at 945 nm. Intermediates are strongly fluorescent with an increased Stokes shift because of dynamic processes.

Tetrabenzoperipentacene: Stable Five-Electron Donating Ability and a Discrete Triple-Layered β-Graphite Form in the Solid State.

An oxidative ring-closure reaction of a tetranaphthylpyrene derivative led to the synthesis of a 56 all-carbon conjugated tetrabenzoperipentacene. In the single-crystal X-ray structure, three molecules make a triple-layered cluster by π-stacking, wherein each layer rotates by 120°, and is thus considered a petit β-graphite. As for the optical properties, the Stokes shift is extremely small (10 cm(-1) ), thus indicating its remarkably rigid framework. The tetrabenzoperipentacene exhibits reversible five-electron oxidation waves in cyclic voltammetry, and is regarded as a counterpart to the fullerene C60 in terms of stable multicharge-storage nanocarbon materials.

ELECTROCHEMICAL PROPERTIES OF FLUORINATED HYDRAZINO-PYRAZOLES IN [BMIM+][BF4-] IONIC LIQUID

The electrochemical properties of two fluorinated substrates, namely 1H-3-methyl-4-ethoxycarbonyl-5-(4-fluorobenzylidenehydrazino)-pyrazole (Ia) and 1H-3-methyl-4-ethoxycarbonyl-5-(2-fluoro-benzylidenehydrazino)-pyrazole (Ib) respectively have been investigated in the room temperature ionic liquid (RTIL) 1-butyl-3-methylimidazolium tetrafluoroborate on a platinum electrode. The voltammetric investigation of the above compounds in the mentioned RTIL shows mainly two irreversible anodic peaks on a wide range of scan rates. Mechanistic studies involving the estimation of the diffusion coefficient, number of transferred electrons in the rate-determining step as well as charge transfer coefficients show that the main aspects of the anodic oxidation of the given substrates follows an EC mechanism which is similar to that observed in molecular solvents leading to the assumption that oxidative ring closure reactions may be conducted in RTILs as well, providing a starting point in finding a new more sustainable method of obtaining the latter compound. The aim of the present work is to extend the current findings gathered previously in order to find a more environmentally friendly and sustainable way of obtaining various pyrazolotriazoles.

Synthesis and Properties of Hybrid Porphyrin Tapes

Hybrid porphyrin tapes 3 and 4, consisting of a mixture of 3,5-di-tert-butylphenyl-substituted donor-type Zn(II)-porphyrins and pentafluorophenyl-substituted acceptor-type Zn(II)-porphyrins, were prepared by a synthetic route involving cross-condensation reaction of a Ni(II)-porphyrinyldipyrromethane and pentafluorophenyldipyrromethane with pentafluorobenzaldehyde followed by appropriate demetalation, remetalation, and oxidative ring-closure reaction. The Ni(II)-substituted porphyrin tapes 5 (Ni-Zn-Ni) and 6 (Ni-H(2)-Ni) were also prepared through similar routes. The hybrid porphyrin tapes 3 and 4 are more soluble and more stable than normal porphyrin tapes 1 and 2 consisting of only donor-type Zn(II)-porphyrins. The solid-state and crystal packing structures of 3, 4, and 5 were elucidated by single-crystal X-ray diffraction analysis. Singly meso-meso-linked hybrid porphyrin arrays 12 and 14 exhibit redox potentials that roughly correspond to each constituent porphyrin segments, while the redox potentials of the hybrid porphyrin tapes 3 and 4 are positively shifted as a whole. The two-photon absorption (TPA) values of 1-6 were measured by using a wavelength-scanning open aperture Z-scan method and found to be 1900, 21,000, 2200, 27,000, 24,000, and 26,000 GM, respectively. These results illustrate an important effect of elongation of π-electron conjugation for the enhancement of TPA values. The hybrid porphyrin tapes show slightly larger TPA values than the parent ones.

Triphenylene-Fused Porphyrins

Triphenylene has been successfully fused to the porphyrin periphery through a convenient oxidative ring-closure reaction. Bistriphenylene-fused porphyrins and a dibenzo[fg,op]tetracene-fused porphyrin have also been obtained using a similar approach. These π-extended porphyrins exhibited broadened and bathochromic shifted UV-vis absorptions.

Unexpected Side Chain Oxidation in a Swivel Cruciform Oligothiophene

Two swivel cruciform oligothiophenes are investigated for the occurrence of oxidative ring closure reactions. Surprisingly, instead of intramolecular cyclizations, a regioselective side chain oxidation of two of the four alpha-methylene groups next to the terminal thiophene rings is detected for one of the oligomers. Such side chain oxidations may be one unintended degradation pathway in oligothiophene-based organic semiconductors used as the active layer of organic field effect transistors (OFETs), organic light emitting diodes (OLEDs), and organic solar cells (OSCs).

Determination of the absolute stereochemistry and asymmetric total synthesis of madindolines A and B: a practical improvement to a second-generation approach from the first-generation

In this report, we describe an efficient, highly convergent, stereocontrolled first total synthesis and a second-generation synthesis of madindolines A 1 and B 2 , potent selective inhibitors of interleukin 6. The key steps include (1) asymmetric oxidative ring-closure reaction of tryptophol 3 to construct a chiral 3a-hydroxyfuroindoline 4 using the modified Sharpless asymmetric epoxidation condition, (2) highly diastereoselective acylation to build up the quaternary carbon center, and (3) intramolecular acylation of ester 32 with allylsilanes to produce the full substituted cyclopentenedione units. Our first synthetic route defines for the first time both their relative and absolute configurations. Moreover, a more efficient second-generation synthesis was designed, which is suitable for gram-scale preparation of these compounds.

Oxidative cyclization of aldehyde thiosemicarbazones induced by potassium ferricyanide and by tris(p-bromophenyl)amino hexachloroantimoniate. A joint experimental and computational study

The oxidative ring closure reaction of some aryl-substituted thiosemicarbazones induced by bona fide one-electron abstracting agents was investigated, by means of both experimental and computational techniques. The corresponding 1,2,4-triazole derivatives were the only cyclization products observed. The occurrence of two slightly different mechanistic pathways for the reaction is discussed.

A Novel Dinuclear Ruthenium Complex Bridged through a Substituted Phenazine Ligand Formed by Ruthenium-Promoted Oxidative Assembly of 1,3-Diaminobenzene

The reaction of [Ru(acac)3] (acac=acetylacetonate) with molten 1,3-diaminobenzene affords the crystalline monometallic compound [Ru(L1)(acac)2] (1: L1=N-(3′-aminophenyl)1,2-(3-amino)benzoquinone diimine) along with an unstable dimetallic compound [Ru2(μ-L2)(acac)4] (2: L2=N-4,6-bis(3′-aminophenyl)imino-3,5-diimino-hex-1-ene). Compound 2 transforms to a stable dimetallic compound [Ru2(μ-L3)(acac)4] (3: L3=2-amino-6(3′-aminophenyl)imino-9-imino-phenazine) in boiling 2-methoxyethanol. The above compounds are formed by ruthenium-mediated oxidative di- or trimerization of the diamine with the formation of several new C−N bonds. The products have been thoroughly characterized. FAB mass spectra, along with other physicochemical data, were used for their formulations. The compounds 1, 2, and 3 display intense peaks due to their parent molecular ions at m/z 512, 916, and 914, respectively. Final characterization of complex 3 was made by single-crystal X-ray structure determination. The structure of 3 confirmed the formation of three new C−N bonds and the bridging ligand L3 from 1,3-diaminobenzene. The conversion, 2→3 is an oxidative ring-closure reaction, which is associated with dehydrogenation reactions. The monometallic compound 1, showed a reversible metal-based anodic response at 0.35 V. On the other hand, both the compounds 2 and 3 showed a pair of well-resolved metal-based anodic oxidations, for which the separation between the two successive anodic responses were high (>0.4 V). In addition, all of them showed multiple cathodic responses that were in the range −1.0 to −2.0 V.