Dibenzoheterole-Fused s-Indacenes.

Heterole (pyrrole, thiophene, furan, thiophene-S,S-dioxide)-fused s-indacenes are known for their enhanced paratropic ring-current strength. However, the outcome of the antiaromatic properties for dibenzoheterole-fused s-indacene antiaromatics remained underexplored. Carbazole-, dibenzothiophene-, dibenzofuran-, and dibenzo[b,d]thiophene-5,5-dioxide-fused s-indacenes 1-4, respectively, were synthesized and characterized by experimental (NMR, single-crystal, UV-vis, CV) and computational (DFT) approaches to study the ground-state antiaromatic properties. Sulfone-containing 4 showed the weakest paratropic ring-current strength for the s-indacene unit, while 1-3 showed a relatively greater paratropicity for the s-indacene unit, as evidenced by the changes in 1H NMR chemical shifts of s-indacene protons. Such observation was explained by the electron-withdrawing effect of the sulfone group and loss of 4n + 2 aromaticity of the heterole unit for 4 reducing its s-indacene paratropicity strength as the nonaromaticity of the heterole unit reduces the π-bond character at the dibenzo[b,d]thiophene-5,5-dioxide/s-indacene fusion site to avoid antiaromatic s-indacene ring formation. The modulation of the paratropic ring-current strength of s-indacene for 1-4 was further supported by the NICS(1)zz and ring-current (ACID) calculations.

Constructing 1-Ethoxyphenanthro[9,10-e]acephenanthrylene for the Synthesis of a Polyaromatic Hydrocarbon Containing a Formal Azulene Unit.

peri-Acenoacenes are attractive synthetic targets, but their non-benzenoid isomeric counterparts were unnoticed. 1-Ethoxyphenanthro[9,10-e]acephenanthrylene 8 was synthesized and converted to azulene-embedded 9, which is a tribenzo-fused non-alternant isomeric motif of peri-anthracenoanthracene. Aromaticity and single-crystal analyses suggested a formal azulene core for 9, which showed a smaller highest occupied molecular orbital (HOMO)-lowest unoccupied molecular orbital (LUMO) energy gap with a charge-transfer absorption band and brighter fluorescence than 8 (quantum yield (Φ): 9 = 41.8%, 8 = 8.9%). The reduction potentials of 8 and 9 were nearly identical, and the observations were further supported by density functional theory (DFT) calculations.

Divergent Synthesis of Chelating Aziridines and Cyclic(Alkyl)(Amino)Carbenes (CAACs) from Pyridyl-Tethered Robust Azomethine Ylides.

Azomethine ylides are typically in situ generated synthons for making N-heterocycles through cycloaddition reactions. But an offbeat aspect about them is the isomeric nature of aldiminium-based azomethine ylides and (alkyl/aryl)(amino)carbenes, interconvertible by a formal 1,3-H+ transfer. Herein, two thermally robust azomethine ylides with a N-appended picolyl sidearm are isolated, which cyclize to py aziridines at 80 °C but unprecedentedly result N-pico CAAC-CuCl (CAAC=cyclic(alkyl)(amino)carbene) complexes when heated with CuCl at merely 60 °C. The pendant Npy , as revealed by computational analysis, plays a crucial role in this unusual 1,3-H+ shift using a deprotonation-protonation sequence, as well as in placing the CuCl at the carbenic site in tandem. The softer nature of Cu(I) is also critical. Chelating CAACs are rare and one with a N-tethered additional donor is priorly unknown. Both N-pico CAAC and py aziridine are bidentate chelators giving highly active cationic Rh(I) catalysts for hydrosilylating unactivated olefins by Et3 SiH. Notably, the py aziridine-Rh(I) is superior than the N-pico CAAC-Rh(I) catalyst.

The Natural Products Withaferin A and Withanone from the Medicinal Herb Withania somnifera Are Covalent Inhibitors of the SARS-CoV-2 Main Protease.

The current COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) created a global health crisis. The ability of vaccines to protect immunocompromised individuals and from emerging new strains are major concerns. Hence antiviral drugs against SARS-CoV-2 are essential. The SARS-CoV-2 main protease Mpro is vital for replication and an important target for antivirals. Using CMap analysis and docking studies, withaferin A (wifA) and withanone (win), two natural products from the medicinal herb Withania somnifera (ashwagandha), were identified as promising candidates that can covalently inhibit the viral protease Mpro. Cell culture, enzymatic, LC-MS/MS, computational, and equilibrium dialysis based assays were performed. DFT calculations indicated that wifA and win can form stable adducts with thiols. The cytotoxicity of Mpro was significantly reduced by wifA and win. Both wifA and win were found to irreversibly inhibit 0.5 µM Mpro with IC50 values of 0.54 and 1.8 µM, respectively. LC-MS/MS analysis revealed covalent adduct formation with wifA at cysteines 145 and 300 of Mpro. The natural products wifA and win can irreversibly inhibit the SARS-CoV-2 main protease Mpro. Based on the work presented here we propose that both wifA and win have the potential to be safely used as preventative and therapeutic interventions for COVID-19.

Reversible Stimuli-Dependent Aggregation-Induced Emission from a "Nonfluorescent" Amphiphilic PVDF Graft Copolymer.

A poly(vinylidine fluoride) graft random copolymer of t-butyl aminoethyl methacrylate (tBAEMA) and oligo(ethylene glycol) methyl ether methacrylate (OEGMA, Mn = 300) [PVDF-g-P(tBAEMA-ran-OEGMA), PVBO] is synthesized by atom transfer radical polymerization (ATRP), and PVBO is fractionated to get a highly water-soluble fraction (PVBO-1) showing a reversible on/off fluorescence behavior with gradual increase and decrease in pH, respectively, achieving a maximum quantum yield of 0.18 at pH = 12. PVBO-1 dissolved in water shows large multimicellar aggregates (MMcA), but at pH 12, crumbling of larger aggregates to much smaller micelles occurs, forming nonconjugated polymer dots (NCPDs), as supported by transmission electron microscopy and dynamic light scattering study. The reversible fluorescence on/off behavior also occurs with the decrease and increase of temperature. Theoretical study indicates that, at high pH, most of the amino groups become neutral and exhibit a strong tendency to form aggregates from crowding of a large number of carbonyl and amine groups, minimizing the HOMO-LUMO gap, showing an absorption peak at the visible region, and generating aggregation-induced emission.

External Electric Fields Interrupt the Concerted Cope Rearrangement of Semibullvalene.

The topic of this paper is whether the mechanism of the degenerate Cope rearrangement of semibullvalene can be affected by the presence of electrostatic fields. Herein, we report that the shape of the energy surface, as demonstrated by an "interrupted" (stepwise) mechanism, is altered in the presence of a copper cation, Cu+. Natural bond-orbital and block-localized wave-function energy decomposition analyses suggest that orbital and electrostatic interactions play a major role in altering the shape of the energy surface. Applying additional external electric fields (EEFs) induces a significant change to the energy surface with Cu+ present but negligible effects in the absence of Cu+. These findings are consistent with recent studies that demonstrate that EEFs more readily stabilize/destabilize systems with larger, more polarizable, dipole moments.

TITAN: A Code for Modeling and Generating Electric Fields-Features and Applications to Enzymatic Reactivity.

We present here a versatile computational code named "elecTric fIeld generaTion And maNipulation (TITAN)," capable of generating various types of external electric fields, as well as quantifying the local (or intrinsic) electric fields present in proteins and other biological systems according to Coulomb's Law. The generated electric fields can be coupled with quantum mechanics (QM), molecular mechanics (MM), QM/MM, and molecular dynamics calculations in most available software packages. The capabilities of the TITAN code are illustrated throughout the text with the help of examples. We end by presenting an application, in which the effects of the local electric field on the hydrogen transfer reaction in cytochrome P450 OleTJE enzyme and the modifications induced by the application of an oriented external electric field are examined. We find that the protein matrix in P450 OleTJE acts as a moderate catalyst and that orienting an external electric field along the Fe─O bond of compound I has the biggest impact on the reaction barrier. The induced catalysis/inhibition correlates with the calculated spin density on the O-atom. © 2019 Wiley Periodicals, Inc.

Oriented (Local) Electric Fields Drive the Millionfold Enhancement of the H-Abstraction Catalysis Observed for Synthetic Metalloenzyme Analogues.

This contribution follows the recent remarkable catalysis observed by Groves et al. in hydrogen-abstraction reactions by a) an oxoferryl porphyrin radical-cation complex [Por⋅+ FeIV (O)Lax ] and b) a hydroxoiron porphyrazine ferric complex [PyPzFeIII (OH)Lax ], both of which involve positively charged substituents on the outer circumference of the respective macrocyclic ligands. These charge-coronated complexes are analogues of the biologically important Compound I (Cpd I) and synthetic hydroxoferric species, respectively. We demonstrate that the observed enhancement of the H-abstraction catalysis for these systems is a purely electrostatic effect, elicited by the local charges embedded on the peripheries of the respective macrocyclic ligands. Our findings provide new insights into how electrostatics can be employed to tune the catalytic activity of metalloenzymes and can thus contribute to the future design of new and highly efficient hydrogen-abstraction catalysts.

Kinetic Isotope Effect Determination Probes the Spin of the Transition State, Its Stereochemistry, and Its Ligand Sphere in Hydrogen Abstraction Reactions of Oxoiron(IV) Complexes.

This Account outlines interplay of theory and experiment in the quest to identify the reactive-spin-state in chemical reactions that possess a few spin-dependent routes. Metalloenzymes and synthetic models have forged in recent decades an area of increasing appeal, in which oxometal species bring about functionalization of hydrocarbons under mild conditions and via intriguing mechanisms that provide a glimpse of Nature's designs to harness these reactions. Prominent among these are oxoiron(IV) complexes, which are potent H-abstractors. One of the key properties of oxoirons is the presence of close-lying spin-states, which can mediate H-abstractions. As such, these complexes form a fascinating chapter of spin-state chemistry, in which chemical reactivity involves spin-state interchange, so-called two-state reactivity (TSR) and multistate reactivity (MSR). TSR and MSR pose mechanistic challenges. How can one determine the structure of the reactive transition state (TS) and its spin state for these mechanisms? Calculations can do it for us, but the challenge is to find experimental probes. There are, however, no clear kinetic signatures for the reactive-spin-state in such reactions. This is the paucity that our group has been trying to fill for sometime. Hence, it is timely to demonstrate how theory joins experiment in realizing this quest. This Account uses a set of the H-abstraction reactions of 24 synthetic oxoiron(IV) complexes and 11 hydrocarbons, together undergoing H-abstraction reactions with TSR/MSR options, which provide experimentally determined kinetic isotope effect (KIEexp) data. For this set, we demonstrate that comparing KIEexp results with calculated tunneling-augmented KIE (KIETC) data leads to a clear identification of the reactive spin-state during H-abstraction reactions. In addition, generating KIEexp data for a reaction of interest, and comparing these to KIETC values, provides the mechanistic chemist with a powerful capability to identify the reactive-TS in terms of not only its spin state but also its geometry and ligand-sphere constitution. Since tunneling "cuts through" barriers, it serves as a chemical selectivity factor. Thus, we show that in a family of oxoirons reacting with one hydrocarbon, the tunneling efficiency increases as the ligands become better electron donors. This generates counterintuitive-reactivity patterns, like antielectrophilic reactivity, and induces spin-state reactivity reversals because of differing steric demands of the corresponding 2S+1TS species, etc. Finally, for the same series, the Account reaches intuitive understanding of tunneling trends. It is shown that the increase of ligand's donicity results in electrostatic narrowing of the barrier, while the decrease of donicity and increase of bond-order asymmetry in the TS (inter alia due to Bell-Evans-Polanyi effects) broadens the barrier. Predictions are made that usage of powerful electron-donating ligands may train H-abstractors to activate the strongest C-H bond in a molecule. The concepts developed here are likely to be applicable to other oxometals in the d- and f-blocks.

Kinetic Isotope Effect Probes the Reactive Spin State, As Well As the Geometric Feature and Constitution of the Transition State during H-Abstraction by Heme Compound II Complexes.

What do experimentally measured kinetic isotope effects (KIEs) tell us about H-abstraction reactions with multispin-state reactivity options? Using DFT calculations with tunneling corrections for experimentally studied H-abstraction reactions of porphyrin-Compound II species (Chem.-Eur. J. 2014, 20, 14437; Angew. Chem., Int. Ed. 2008, 47, 7321) with cyclohexane, dihydroanthracene (DHA), and xanthene (Xan), we show here that KIE is a selective probe that identifies the experimentally reactive spin state. At the same time, comparison of calculated and experimental KIE values permits us to determine the structural orientation of the transition states, as well as the presence/absence of an axial ligand, and the effect of porphyrin substituents. The studied compound II (Cpd II) species involve porphine, and porphyrin ligands with different meso-substituents, TPFPP (tetrakis(pentafluorophenyl)porphyrin dianion) and TMP (tetramesitylporphyrin dianion), with and without imidazole axial ligands. The DFT calculations reveal three potential pathways: quintet and triplet σ-pathways (5Hσ and 3Hσ) that possess linear transition state (TS) structures, and a triplet π -pathway (3Hπ) having a bent TS structure. Without an axial ligand, the 5Hσ pathways for these Cpd II complexes cross below the triplet states. The axial ligand raises the barriers for the quintet and triplet σ-pathways and quenches any chances for two-state reactivity, thus proceeding via the 3Hπ pathway. All of these pathways exhibit characteristic KIE values: very large for 3Hπ (48-200), small for 5Hσ (3-9), and intermediate for 3Hσ (23-51). The calculated KIEs for (TPFPP)FeIV═O without an axial ligand reveal that 3Hσ is the only pathway having a KIE that matches the experimental values, for the reactions with DHA and Xan (Angew. Chem., Int. Ed. 2008, 47, 7321). Indeed, theory shows that tunneling significantly lowers the 3Hσ barrier rendering it the sole reactive state for the reaction. A prediction is made for the reactivity and KIE of (TMP)FeIV═O complex, and a comparison is made with the analogous nonheme complexes.

Privileged Role of Thiolate as the Axial Ligand in Hydrogen Atom Transfer Reactions by Oxoiron(IV) Complexes in Shaping the Potential Energy Surface and Inducing Significant H-Atom Tunneling.

An H/D kinetic isotope effect (KIE) of 80 is found at -20 °C for the oxidation of 9,10-dihydroanthracene by [FeIV(O)(TMCS)]+, a complex supported by the tetramethylcyclam (TMC) macrocycle with a tethered thiolate. This KIE value approaches that previously predicted by DFT calculations. Other [FeIV(O)(TMC)(anion)] complexes exhibit values of 20, suggesting that the thiolate ligand of [FeIV(O)(TMCS)]+ plays a unique role in facilitating tunneling. Calculations show that tunneling is most enhanced (a) when the bond asymmetry between C-H bond breaking and O-H bond formation in the transition state is minimized, and (b) when the electrostatic interactions in the O---H---C moiety are maximal. These two factors-which peak for the best electron donor, the thiolate ligand-afford a slim and narrow barrier through which the H-atom can tunnel most effectively.

Computation Sheds Insight into Iron Porphyrin Carbenes' Electronic Structure, Formation, and N-H Insertion Reactivity.

Iron porphyrin carbenes constitute a new frontier of species with considerable synthetic potential. Exquisitely engineered myoglobin and cytochrome P450 enzymes can generate these complexes and facilitate the transformations they mediate. The current work harnesses density functional theoretical methods to provide insight into the electronic structure, formation, and N-H insertion reactivity of an iron porphyrin carbene, [Fe(Por)(SCH3)(CHCO2Et)](-), a model of a complex believed to exist in an experimentally studied artificial metalloenzyme. The ground state electronic structure of the terminal form of this complex is an open-shell singlet, with two antiferromagnetically coupled electrons residing on the iron center and carbene ligand. As we shall reveal, the bonding properties of [Fe(Por)(SCH3)(CHCO2Et)](-) are remarkably analogous to those of ferric heme superoxide complexes. The carbene forms by dinitrogen loss from ethyl diazoacetate. This reaction occurs preferentially through an open-shell singlet transition state: iron donates electron density to weaken the C-N bond undergoing cleavage. Once formed, the iron porphyrin carbene accomplishes N-H insertion via nucleophilic attack. The resulting ylide then rearranges, using an internal carbonyl base, to form an enol that leads to the product. The findings rationalize experimentally observed reactivity trends reported in artificial metalloenzymes employing iron porphyrin carbenes. Furthermore, these results suggest a possible expansion of enzymatic substrate scope, to include aliphatic amines. Thus, this work, among the first several computational explorations of these species, contributes insights and predictions to the surging interest in iron porphyrin carbenes and their synthetic potential.

Fluorenyl-tethered N-heterocyclic carbene (NHC): an exclusive C-donor ligand for heteroleptic calcium and strontium chemistry.

Exclusive C-donating ligands are rarely used with kinetically labile heavier alkaline earths (Ca, Sr, Ba). We report herein the aptitude of a combination of NHC with fluorenyl connected by a flexible -(CH2)2- linker as a ligand support for heteroleptic Ca- and Sr-N(SiMe3)2 and iodides. The Ca-N(SiMe3)2 complex even catalyzes the intramolecular hydroamination of aminoalkenes to showcase the effectiveness of this ligand framework.

Flexible NHC-aryloxido aluminum complex and its zwitterionic imidazolium aluminate precursor in ring-opening polymerization of ε-caprolactone.

Anionic donor-functionalized NHC (N-heterocyclic carbene) complexes of Al are rare. We report one such case here, an NHC-aryloxido AlMe2 complex [Al(L)Me2] (2), following a stepwise synthesis from the proligand [HO-4,6-tBu2-C6H2-2-CH2{CH(NCHCHNAr)}]Br [LH2Br; Ar = 2,6-iPr2-C6H3 (Dipp)] and AlMe3via the zwitterionic intermediate [Al(LH)Me2Br] (1). The ligand's flexibility in 2 is evident from the conformational fluxionality revealed by VT-1H NMR spectroscopic analysis. The ∠O-Al-C (ca. 100.5°) bite angle is also wider than the ∠O-Ti-C (ca. 80.6°) as seen in our recently reported Ti complex [Ti(L)(NMe2)2Br]. DFT analysis showed that the CNHC-Al bond is significantly ionic, as is the CNHC-Ti bond. Both 1 and 2 are active in the ring-opening polymerization (ROP) of ε-caprolactone (CL). 2, similar to [Ti(L)(NMe2)2Br], exhibits bifunctional MLC-type monomer activation, but only at an elevated temperature. However, the 2/BnOH combination is catalytically active at room temperature, likely through a zwitterionic [Al(LH)Me2(OBn)]. The 1/BnOH combination follows a similar mechanism but surprisingly at a faster rate.

A Thiophenoradialene-Embedded Polycyclic Heteroterphenoquinone Exhibiting Dominant Antiaromatic Traits.

A thiophenoradialene-embedded polycyclic heteroterphenoquinone (PHTPQ) derivative of diindeno[1,2-b:2',1'-d]thiophene-2,8-dione, with antiaromatic characteristics, was synthesized by dehydrogenating its fluorescent dihydro PHTPQ precursor. The antiaromatic character was evidenced by the visible absorption band with a weakly intense tail extending to 800 nm in the near-infrared region (forbidden HOMO → LUMO transition) and non-emissive and amphoteric redox properties. Single-crystal and (anti)aromaticity analyses found a non-aromatic thiophene core while suggesting antiaromaticity/paratropicity of the pentafulvene subunits dominating the overall ground state properties.

Dominating Antiaromatic Character of as-Indacene Decides Overall Properties of a Formally Aromatic Dicyclopenta[c]fluorenothiophene.

Dicyclopenta[c]fluorenothiophene 5 was synthesized as the isoelectronic polycyclic heteroarene analogue of an as-indacenodifluorene with a (4n + 2)π-electron perimeter. Single-crystal and 1H NMR analyses indicated a quinoidal ground state for 5, which was supported by theoretical calculations while suggesting a degree of antiaromaticity of the as-indacene subunit greater than that for s-indacenodifluorene 3. The dominant antiaromaticity for 5 was evidenced by the broad weakly intense absorption tail reaching the near-IR region, four-stage redox amphotericity, and small HOMO-LUMO energy gap.

Electrocatalytic reduction of CO2 to CO by a series of organometallic Re(I)-tpy complexes.

A series of organometallic Re(I)(L)(CO)3Br complexes with 4'-substituted terpyridine ligands (L) has been synthesised as electrocatalysts for CO2 reduction. The complexes' spectroscopic characterisation and computationally optimised geometry demonstrate a facial geometry around Re(I) with three cis COs and the terpyridine ligand coordinating in a bidentate mode. The effect of substitution on the 4'-position of terpyridine (Re1-5) on CO2 electroreduction was investigated and compared with a known Lehn-type catalyst, Re(I)(bpy)(CO)3Br (Re7). All complexes catalyse CO evolution in homogeneous organic media at moderate overpotentials (0.75-0.95 V) with faradaic yields of 62-98%. The electrochemical catalytic activity was further evaluated in the presence of three Brønsted acids to demonstrate the influence of the pKa of the proton sources. The TDDFT and ultrafast transient absorption spectroscopy (TAS) studies showed combined charge transfer bands of ILCT and MLCT. Amongst the series, the Re-complex containing a ferrocenyl-substituted terpyridine ligand (Re5) shows an additional intra-ligand charge transfer band and was probed using UV-Vis spectroelectrochemistry.

Unveiling two antiaromatic s-indacenodicarbazole isomers with tunable paratropicity.

Linear and curved antiaromatic s-indacenodicarbazole isomers were synthesized and characterized to show the tunable paratropicity of s-indacene, as analyzed by NICS(1)zz and ACID (ring-current) calculations. The curved isomer showed a greater degree of antiaromaticity than the linear isomer, as predicted by the Glidewell-Lloyd rule. This degree of antiaromaticity was further validated by the red-shifted UV-vis absorption and smaller HOMO-LUMO energy gap.

Structure-activity relationship of photocytotoxic iron(III) complexes of modified dipyridophenazine ligands.

Iron(III) complexes [FeL(B)] (1-5) of a tetradentate trianionic phenolate-based ligand (L) and modified dipyridophenazine bases (B), namely, dipyrido-6,7,8,9-tetrahydrophenazine (dpqC in 1), dipyrido[3,2-a:2',3'-c]phenazine-2-carboxylic acid (dppzc in 2), dipyrido[3,2-a:2',3'-c]phenazine-11-sulfonic acid (dppzs in 3), 7-aminodipyrido[3,2-a:2',3'-c]phenazine (dppza in 4) and benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (dppn in 5), have been synthesized and their photocytotoxic properties studied along with their dipyridophenazine analogue (6). The complexes have a five electron paramagnetic iron(III) center, and the Fe(III)/Fe(II) redox couple appears at about -0.69 V versus SCE in DMF-0.1 M TBAP. The physicochemical data also suggest that the complexes possess similar structural features as that of its parent complex [FeL(dppz)] with FeO3N3 coordination in a distorted octahedral geometry. The DNA-complex and protein-complex interaction studies have revealed that the complexes interact favorably with the biomolecules, the degree of which depends on the nature of the substituents present on the dipyridophenazine ring. Photocleavage of pUC19 DNA by the complexes has been studied using visible light of 476, 530, and 647 nm wavelengths. Mechanistic investigations with inhibitors show formation of HO(•) radicals via a photoredox pathway. Photocytotoxicity study of the complexes in HeLa cells has shown that the dppn complex (5) is highly active in causing cell death in visible light with sub micromolar IC(50) value. The effect of substitutions and the planarity of the phenazine moiety on the cellular uptake are quantified by determining the total cellular iron content using the inductively coupled plasma-optical emission spectrometry (ICP-OES) technique. The cellular uptake increases marginally with an increase in the hydrophobicity of the dipyridophenazine ligands whereas complex 3 with dppzs shows very high uptake. Insights into the cell death mechanism by the dppn complex 5, obtained through DAPI nuclear staining in HeLa cells, reveal a rapid programmed cell death mechanism following photoactivation of complex 5 with visible light. The effect of substituent on the DNA photocleavage activity of the complexes has been rationalized from the theoretical studies.

Generation of cationic two-coordinate group-13 ligand systems by spontaneous halide ejection: remarkably nucleophile-resistant (dimethylamino)borylene complexes.

Spontaneous ejection of chloride from a three-coordinate boron Lewis acid can be effected by employing very electron rich metal substituents and leads to the formation of a sterically unprotected terminal (dimethylamino)borylene complex that has a short metal-boron bond and remarkable resistance to attack by nucleophilic and protic reagents.