Electrophilic C-H Borylation of Aza[5]helicenes Leading to Bowl-Shaped Quasi-[7]Circulenes with Switchable Dynamics.

The intrinsic relationship between helicenes and circulenes is of fundamental interest and importance in molecular engineering. Herein, electrophilic borylation of phenanthroline-derived aza[5]helicenes is presented, resulting in the incorporation of a boryl unit into two termini of helicenes to afford quasi-[7]circulenes. Their bowl-shaped structures were determined by X-ray diffraction. UV-vis absorption and fluorescence spectroscopy, as well as electrochemical measurements and DFT calculations, gave insight into their electronic properties. Variable-temperature NMR studies and DFT calculations revealed bowl-to-bowl inversion at room temperature and bowl-to-helix equilibria at elevated temperature, highlighting the important role of B ← N bond strength in tuning their dynamic properties.

In vitro activity of N-phenyl-1,10-phenanthroline-2-amines against tachyzoites and bradyzoites of Toxoplasma gondii.

Toxoplasma gondiiis an apicomplexan parasite, the causative agent of toxoplasmosis, a common disease in the world. Toxoplasmosis could be severe, especially in immunocompromised patients. The current therapy is limited, where pyrimethamine and sulfadiazine are the best choices despite being associated with side effects and ineffective against the bradyzoites, the parasitic form present during the chronic phase of the infection. Thus, new therapies against both tachyzoites and bradyzoites from T. gondii are urgent. Herein, we present the anti-T. gondii effect of 1,10-phenanthroline and its N-phenyl-1,10-phenanthroline-2-amine derivatives. The chemical modification of 1,10-phenanthroline tonew derivatives improved the anti-T. gondiiactivity 3.4 fold. The most active derivative presented ED50in the nanomolar range, the smallest value found was for Ph8, 0.1 µM for 96 h of treatment. The host cell viability was maintained after the treatment with the compounds, which were found to be highly selective presenting large selectivity indexes. Treatment with derivatives for 96 h was able to eliminate the T. gondii infection irreversibly. The ultrastructural alterations caused after the treatment with the most effective derivative (Ph8) included signs of cell death, specifically revealed by the Tunel assay for detection of DNA fragmentation. The Phen derivatives were also able to control the growth of the in vitro-derived bradyzoite forms of T. gondii EGS strain, causing its lysis and death. These findings promote the 1,10-phenanthroline derivatives as potential lead compounds for the development of a treatment for acute and chronic phases of toxoplasmosis.

In vitro study of the trypanocidal activity of anilinophenanthrolines against Trypanosoma cruzi.

Chagas disease is present in Latin America, North America, Europe, and Asia, where between 6 and 7 million people are infected. This illness is transmitted mainly by the insect vector during blood feeding and by oral transmission. Chagas disease is treated with benznidazole and its effectiveness depends on which phase of the disease the treatment starts. Therefore, the identification of new compounds with anti-Chagas activities is important. Protozoan parasites present cysteine proteases, important for host cell infection and differentiation, which have been explored as valid targets against pathogenic parasites. In the present study, the effects of 10 new 1,10-phenanthroline derivatives were evaluated on T. cruzi. Three of them were effective against amastigotes (IC50 from 0.5 to 3 µM), epimastigotes (IC50 from 0.5 to at least 10 µM) and trypomastigotes (and LD50 from 1 to 10 µM), and they were not toxic to mammalian cells (CC50 ≥ 20 µM). These compounds also promoted the formation of autophagosomes, alter the level of heterochromatin condensation, caused the loss of kDNA topology, and the elongated cell body shape. Apart from ultrastructural alterations, an increased generation of ROS and decreased mitochondrial membrane potential were observed. Therefore, these drugs revealed potential trypanocidal effects and warrant further antiparasitic studies against Chagas disease.

Photophysical Properties of Fluorescent 2-(Phenylamino)-1,10-phenanthroline Derivatives†.

The present study details the experimental and theoretical characterization of the photophysical properties of 14 examples of 2-(phenylamino)-1,10-phenanthrolines (1). The absorption spectra of 1 are substituent-dependent but in a general manner present absorption bands at wavelengths of ~230; ~300; ~335 and a shoulder at ~380 nm. Electron-donating groups (EDG) and electron-withdrawing groups (EWG), respectively, result in bathochromic and hypsochromic shifts. Compounds 1 are highly luminescent, in contrast to phenanthroline, and emit in the region between 350 and 500 nm with substituent-dependent λmax emission. The emission spectra show a redshift for EDG (4-OMe 62 nm; 4-Me 19 nm) and a blueshift for EWG (4-CN 41 nm; 4-CF3 38 nm) relative to the emission of the unsubstituted parent compound 1a. Plotting the λ max EM against Hammett σ+ constants gave an excellent linear correlation demonstrating the electron-deficient nature of the excited state and how the substituents (de)stabilize S1 . Theoretical calculations revealed a HOMO-LUMO π-π* electronic transition to S1 which in combination with difference (S1 -S0 ) in electron density maps revealed charge-transfer character. Strongly electron-withdrawing substituents switch off the charge transfer to give rise to a local excitation.

A photochemical and theoretical study of the triplet reactivity of furano- and pyrano-1,4-naphthoquionones towards tyrosine and tryptophan derivatives.

The photochemical reactivity of the triplet state of pyrano- and furano-1,4-naphthoquinone derivatives (1 and 2) has been examined employing nanosecond laser flash photolysis. The quinone triplets were efficiently quenched by l-tryptophan methyl ester hydrochloride, l-tyrosine methyl ester hydrochloride, N-acetyl-l-tryptophan methyl ester and N-acetyl-l-tyrosine methyl ester, substituted phenols and indole (k q ∼109 L mol-1 s-1). For all these quenchers new transients were formed in the quenching process. These were assigned to the corresponding radical pairs that resulted from a coupled electron/proton transfer from the phenols, indole, amino acids, or their esters, to the excited state of the quinone. The proton coupled electron transfer (PCET) mechanism is supported by experimental rate constants, isotopic effects and theoretical calculations. The calculations revealed differences between the hydrogen abstraction reactions of phenol and indole substrates. For the latter, the calculations indicate that electron transfer and proton transfer occur as discrete steps.

The 1:1 co-crystal of 2-bromo-naphthalene-1,4-dione and 1,8-di-hydroxy-anthracene-9,10-dione: crystal structure and Hirshfeld surface analysis.

The asymmetric unit of the title co-crystal, C10H5BrO2·C14H8O4 [systematic name: 2-bromo-1,4-di-hydro-naphthalene-1,4-dione-1,8-dihy-droxy-9,10-di-hydro-anthracene-9,10-dione (1/1)], features one mol-ecule of each coformer. The 2-bromo-naphtho-quinone mol-ecule is almost planar [r.m.s deviation of the 13 non-H atoms = 0.060 Å, with the maximum deviations of 0.093 (1) and 0.099 (1) Šbeing for the Br atom and a carbonyl-O atom, respectively]. The 1,8-di-hydroxy-anthra-quinone mol-ecule is planar (r.m.s. deviation for the 18 non-H atoms is 0.022 Å) and features two intra-molecular hy-droxy-O-H⋯O(carbon-yl) hydrogen bonds. Dimeric aggregates of 1,8-di-hydroxy-anthra-quinone mol-ecules assemble through weak inter-molecular hy-droxy-O-H⋯O(carbon-yl) hydrogen bonds. The mol-ecular packing comprises stacks of mol-ecules of 2-bromo-naphtho-quinone and dimeric assembles of 1,8-di-hydroxy-anthra-quinone with the shortest π-π contact within a stack of 3.5760 (9) Šoccurring between the different rings of 2-bromo-naphtho-quinone mol-ecules. The analysis of the Hirshfeld surface reveals the importance of the inter-actions just indicated but, also the contribution of additional C-H⋯O contacts as well as C=O⋯π inter-actions to the mol-ecular packing.

Correction: Copper(ii) catalyzed synthesis of novel helical luminescent benzo[4,5]imidazo[1,2-a][1,10]phenanthrolines via an intramolecular C-H amination reaction.

Correction for 'Copper(ii) catalyzed synthesis of novel helical luminescent benzo[4,5]imidazo[1,2-a][1,10]phenanthrolines via an intramolecular C-H amination reaction' by Ramon Borges da Silva, et al., Org. Biomol. Chem., 2017, DOI: 10.1039/c6ob02508k.

Copper(ii) catalyzed synthesis of novel helical luminescent benzo[4,5]imidazo[1,2-a][1,10]phenanthrolines via an intramolecular C-H amination reaction.

In the present study a series of N-phenyl-1,10-phenanthroline-2-amine derivatives were obtained by heating 2-chlorophenanthroline with aniline derivatives under solvent free conditions in good to excellent yields. The N-phenyl-1,10-phenanthroline-2-amines were employed as substrates in a copper(ii)-catalyzed C-H amination reaction to give derivatives of the novel heterocyclic system benzo[4,5]imidazo[1,2-a][1,10]phenanthroline. The structure of these compounds was predicted to be helical by DFT calculations and single crystal X-ray diffraction of an example of this system confirmed the non-planar helical structure. The luminescence properties of the parent heterocyclic system were characterized.

Single-Component Phosphinous Acid Ruthenium(II) Catalysts for Versatile C-H Activation by Metal-Ligand Cooperation.

Well-defined ruthenium(II) phosphinous acid (PA) complexes enabled chemo-, site-, and diastereoselective C-H functionalization of arenes and alkenes with ample scope. The outstanding catalytic activity was reflected by catalyst loadings as low as 0.75 mol %, and the most step-economical access reported to date to angiotensin II receptor antagonist blockbuster drugs. Mechanistic studies indicated a kinetically relevant C-X cleavage by a single-electron transfer (SET)-type elementary process, and provided evidence for a PA-assisted C-H ruthenation step.

The multicomponent Hantzsch reaction: comprehensive mass spectrometry monitoring using charge-tagged reagents.

A novel strategy for the ESI-MS monitoring of reaction solutions involving the alternate use of permanently charge-tagged reagents has been used for comprehensive mass spectrometry monitoring of the multicomponent Hantzsch 1,4-dihydropyridine reaction. By placing a charge tag on either, or both, of the two key reactants, ion suppression effects for ESI were eliminated or minimized, and comprehensive detection of charge-tagged intermediates was achieved. The strategy allowed the trapping and characterization of the important intermediates in the mechanism for 1,4-dihydropyridine formation.

Theoretical study of photochemical hydrogen abstraction by triplet aliphatic carbonyls by using density functional theory.

The density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) have been used to study the lowest lying spin states of the photochemical hydrogen abstraction reaction by formaldehyde, acetaldehyde, and acetone in the presence of different hydrogen donors: propane, 2-propanol, and methylamine. Calculations of all the critical points on the PES of these reactions were performed at uB3LYP/6-311++G(d,p). Methylamine is the best hydrogen donor, in thermodynamic and kinetic terms, followed by 2-propanol and finally propane. Secondary C-H hydrogen abstraction in 2-propanol and C-H abstraction in methylamine is thermodynamically and kinetically favored with respect to hydrogen abstraction from the OH and NH functional groups. Charge transfer takes place before the transition state when methylamine is the hydrogen donor, and for other hydrogen donors, charge transfer begins only in the transition state. The extent of the charge transfer in the transition states corresponds to about 50% of the total change in electron density of the oxygen atom of the T(1) carbonyl compounds during the course of the hydrogen abstraction reactions. The effect of solvent was investigated using the continuum solvation model for the reaction of triplet acetaldehyde in acetonitrile, which resulted in a barrierless transition state for hydrogen abstraction from methylamine.

Singlet oxygen production by pyrano and furano 1,4-naphthoquinones in non-aqueous medium.

The influence of ring size on the photobehaviour of condensed 1,4-naphthoquinone systems, such as pyrano- and furano-derivatives (1 and 2, respectively) has been investigated. The absorption spectra for both families of naphthoquinones reveal clear differences; in the case of 2 they extend to longer wavelengths. A solvatochromic red shift in polar solvents is consistent with the π,π* character of the S(0)→ S(1) electronic transition in all cases. Theoretical (B3LYP) analysis of the HOMO and LUMO Kohn-Sham molecular orbitals of the S(0) state indicates that they are π and π* in nature, consistent with the experimental observation. A systematic study on the efficiency of singlet oxygen generation by these 1,4-naphthoquinones is presented, and values larger than 0.7 were found in every case. In accordance with these results, laser flash photolysis of deoxygenated acetonitrile solutions led to the formation of detectable triplet transient species with absorptions at 390 and 450 nm (1) and at 370 nm (2), with φ(ISC) close to 1. Additionally, the calculated energies for the T(1) states relative to the S(0) states at UB3LYP/6-311++G** are ca. 47 kcal mol(-1) for 1 and 43 kcal mol(-1) for 2. A comparison of the geometrical parameters for the S(0) and T(1) states reveals a marked difference with respect to the arrangement of the exocyclic phenyl ring whilst a comparison of electronic parameters revealed the change from a quinone structure to a di-dehydroquinone diradical structure.

C-H functionalization of 1,4-naphthoquinone by oxidative coupling with anilines in the presence of a catalytic quantity of copper(II) acetate.

The oxidative addition of anilines (2) with 1,4-naphthoquinone (3) to give N-aryl-2-amino-1,4-naphthoquinones (1) was found to be catalyzed by copper(II) acetate. In the absence of the catalyst, the reactions are slower and give lower yields with the formation of many colateral products. In the presence of 10 mol % hydrated copper(II) acetate, the reactions are generally more efficient in that they are cleaner, higher yielding, and faster.

A laser flash photolysis and theoretical study of hydrogen abstraction from phenols by triplet alpha-naphthoflavone.

The hydrogen abstraction (HA) reaction by the triplet of alpha-naphthoflavone (1) has been investigated experimentally by the use of laser flash photolysis (LFP) and theoretically with density functional theory (DFT) and atoms in molecules (AIM). The triplet excited state of 1, in acetonitrile, has an absorption maximum at 430 nm and lifetime of 10 micros. The quenching rate constants for the triplet of 1 with 1,4-cyclohexadiene, substituted phenols and amines were determined. The low reactivity of this ketone with respect to HA from 1,4-cyclohexadiene is in accord with a pi,pi* excited state. HA from phenols in acetonitrile is proposed to occur in a diffusion controlled reaction from free phenol based upon the determination of the Abraham beta(H)(2) value for acetonitrile and correction of the quenching rate constants for hydrogen bonding of the phenols to acetonitrile. A molecular orbital analysis of the triplet (SOMO and SOMO-1) of 1 reveals contributions from the carbonyl oxygen atom, but principally from the alpha-carbon and the associated pi-bond network, consistent with a pi,pi* excited state. From a thermodynamic point of view, the triplet HA from phenol to oxygen of the carbonyl group is 17 kcal mol(-1) less demanding than the transfer to the alpha-carbon, consistent with the acidic nature of the phenolic hydrogen atom. DFT and AIM analysis of the hydrogen abstraction reaction reveals that the transition state (TS) is pseudo-symmetrically polarized and that HA in the hydrogen bonded exciplex occurs in a concerted manner but not necessarily by simultaneous electron and proton transfer.

(2E)-N-(3,5-Dibromo-4-methoxy-phen-yl)-2-(hydroxy-imino)acetamide.

The title compound, C(9)H(8)Br(2)N(2)O(3), is planar (r.m.s. deviation = 0.030 Å) with the exception of the terminal methyl group which lies out of the plane [1.219 (3) Å]. The conformation about the C=N double bond [1.268 (3) Å] is E. An intra-molecular N-H⋯N hydrogen bond occurs. Linear supra-molecular chains along the b axis mediated by O-H⋯O hydrogen-bonding inter-actions feature in the crystal structure. These chains are also stabilized by weak C-H⋯N contacts.

1,3-Bis(4-bromo-phen-yl)imidazolium chloride dihydrate.

In the title hydrated salt, C(15)H(11)Br(2)N(2) (+)·Cl(-)·2H(2)O, the complete imidazolium cation is generated by a crystallographic twofold axis, with one C atom lying on the axis. The chloride ion and both water mol-ecules of crystallization also lie on a crystallographic twofold axis of symmetry. The cation is non-planar, the dihedral angle formed between the central imidazolium and benzene rings being 12.9 (3)°; the dihedral angle between the symmetry-related benzene rings is 25.60 (13)°. In the crystal, O-H⋯Cl hydrogen bonds result in supra-molecular chains along c mediated by eight-membered {⋯HOH⋯Cl}(2) synthons. These are consolidated by C-H⋯O and π-π [centroid-centroid distance = 3.687 (3) Å] inter-actions.

Methyl 1-{4-[(S)-2-(meth-oxy-carbon-yl)pyrrolidin-1-yl]-3,6-dioxocyclo-hexa-1,4-dien-1-yl}pyrrolidine-2-carboxyl-ate.

The complete mol-ecule of the title diproline ester quinone, C(18)H(22)N(2)O(6), is generated by a crystallographic twofold axis, which passes through the centre of the benzene ring. Both -CO(2)Me groups are orientated to the same side of the benzene ring, with the carbonyl groups pointing roughly towards each other. The conformation of the proline residue is an envelope. In the crystal, a three-dimensional network is sustained by C-H⋯O inter-actions involving both the quinone and carbonyl O atoms.

The three-component biginelli reaction: a combined experimental and theoretical mechanistic investigation.

Biginelli reactions have been monitored by direct infusion electrospray ionization mass spectrometry (ESI-MS) and key cationic intermediates involved in this three-component reaction have been intercepted and further characterized by tandem MS experiments (ESI-MS/MS). Density functional theory calculations were also used to investigate the feasibility of the major competing mechanisms proposed for the Biginelli reaction. The experimental and theoretical results were found to corroborate the iminium mechanism proposed by Folkers and Johnson, whereas no intermediates directly associated with either the more energy demanding Knoevenagel or enamine mechanisms could be intercepted.

Vasodilatory activity of novel carbamate derivatives of isatin.

Isatin (1H-indole-2,3 dione) is an endogenous compound that may act as a physiological regulator of muscle contraction by reducing cGMP production by inhibition of guanylyl cyclase (GC) activity. Intracellular cGMP levels can regulate the contractile response of smooth muscle. Therefore, in the present study we investigated the effects of seven novel carbamate derivatives of isatin, namely C1-C7, on the contractility of aortic rings from Wistar rats. Carbamates C1 and C6 most effectively promoted endothelium-dependent relaxation of aortic rings pretreated with 10 micromol/L phenylephrine (PE) to induce contraction. The concentration of the C1 and C6 carbamates necessary to reduce PE-induced aortic contraction by 50% (IC(50)) was 5.6 +/- 1.0 and 48.4 +/- 3.4 micromol/L, respectively. Carbamate derivative-induced vasodilation required an intact endothelium, which is responsible for nitric oxide (NO) release. Pretreatment of rings with 100 micromol/L naloxone or 10 micromol/L atropine prevented the C1- and C6-mediated vascular relaxation, indicating that the vasodilatory activity was dependent on the activation of opioid or muscarinic receptors, respectively. The results of our studies provide insights into the role of novel carbamates in the regulation of vascular tone. Carbamates could stimulate NO synthesis, which induces vasodilation primarily by stimulation of GC and cGMP production. Taken together, our findings suggest that carbamate derivative-induced vasodilation may be considered an alternative treatment for primary and/or secondary hypertension.

2-Cyano-4-iodoacetanilide: a hydrogen-bonded chain of R(2)(2)(12) and R(2)(2)(14) rings.

The molecules of 2-cyano-4-iodoacetanilide, C(9)H(7)IN(2)O, are linked by N-H...N and C-H...O hydrogen bonds into chains of alternating R(2)(2)(12) and R(2)(2)(14) rings.