Direct Regioselective Dehydrogenation of α-Substituted Cyclic Ketones.

We disclose a highly regioselective, catalytic one-step dehydrogenation of α-substituted cyclic ketones in the presence of 2,3-dichlorobenzo-5,6-dicyano-1,4-benzoquinone (DDQ). The high regioselectivity originates from a phosphoric acid-catalyzed enolization, selectively affording the thermodynamically preferred enol, followed by the subsequent oxidation event. Our method provides reliable access to several α-aryl and α-alkyl substituted α,ß-unsaturated ketones.

Tamoxifen charge transfer complexes with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone and 7,7,8,8-tetracyanoquinodimethan: Synthesis, spectroscopic characterization and theoretical study.

To understand bioactive molecule-receptor interactions it is important to understand the molecular complexation and structural recognition properties of the materials in question. To this aim, the electron donating bioactive molecule tamoxifen (TAM) was combined with the electron accepting molecules 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) to form TAM-DDQ and TAM-TCNQ charge transfer (CT) complexes. The properties of the complexes in solution and solid, their donor-acceptor interactions were investigated, and their stability was assessed in acetonitrile. Solid complexes of TAM-DDQ and TAM-TCNQ were characterized using nuclear magnetic resonance (NMR) and Fourier transform infrared (FTIR) spectroscopies to confirm their formation. Job's and modified Benesi-Hildebrand methods were used to study the stoichiometries and association constants of TAM-DDQ and TAM-TCNQ, from which their stoichiometries were found to be 1:1. The physical parameters of the CT complexes in terms of their molar extension constants, dipole moments, and formation constants were determined to study their stability in solution. The results obtained in this study indicate that the complexes are suitable for assessing TAM in pharmaceutical preparations. The experimental results were complemented by density functional theory (geometry optimization, energy transition, and molecular electrostatic potential maps) at DFT/B3LYPlevel of theory.

Thermodynamic and Computational (DFT) Study of Non-Covalent Interaction Mechanisms of Charge Transfer Complex of Linagliptin with 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and Chloranilic acid (CHA).

This study describes the non-covalent interactions of the charge transfer complex (CT), which was responsible for the synthesis of Linagliptin (LNG) with 2,3-Dichloro-5,6-Dicyano-1,4-benzoquinone (DDQ), or with Chloranilic acid (CHA) complexes in acetonitrile (MeCN) at temperatures of (25 ± 2 °C). Then, a UV-Vis spectrophotometer was utilized to identify Linagliptin (LNG) from these complexes. For the quantitative measurement of Linagliptin in bulk form, UV-Vis techniques have been developed and validated in accordance with ICH criteria for several aspects, including selectivity, linearity, accuracy, precision, LOD, LOQ, and robustness. The optimization of the complex synthesis was based on solvent polarization; the ratio of molecules in complexes; the association constant; and Gibbs energy (ΔG°). The experimental work is supported by the computational investigation of the complexes utilizing density functional theory as well as (QTAIM); (NCI) index; and (RDG). According to the optimized conditions, Beer's law was observed between 2.5-100 and 5-100 µM with correlation coefficients of 1.9997 and 1.9998 for LGN-DDQ and LGN-CHA complexes, respectively. For LGN-DDQ and LGN-CHA complexes, the LOD and LOQ were (1.0844 and 1.4406 µM) and (3.2861 and 4.3655 µM), respectively. The approach was successfully used to measure LGN in its bulk form with high precision and accuracy.

Charge-transfer chemistry of two corticosteroids used adjunctively to treat COVID-19. Part I: Complexation of hydrocortisone and dexamethasone donors with DDQ acceptor in five organic solvents.

COVID-19 is the disease caused by a novel coronavirus (CoV) named the severe acute respiratory syndrome coronavirus 2 (termed SARS coronavirus 2 or SARS-CoV-2). Since the first case reported in December 2019, infections caused by this novel virus have led to a continuous global pandemic that has placed an unprecedented burden on health, economic, and social systems worldwide. In response, multiple therapeutic options have been developed to stop this pandemic. One of these options is based on traditional corticosteroids, however, chemical modifications to enhance their efficacy remain largely unexplored. Obtaining additional insight into the chemical and physical properties of pharmacologically effective drugs used to combat COVID-19 will help physicians and researchers alike to improve current treatments and vaccines (i.e., Pfizer-BioNTech, AstraZeneca, Moderna, Janssen). Herein, we examined the charge-transfer properties of two corticosteroids used as adjunctive therapies in the treatment of COVID-19, hydrocortisone and dexamethasone, as donors with 2,3-dichloro-5,6-dicyano-p-benzoquinone as an acceptor in various solvents. We found that the examined donors reacted strongly with the acceptor in CH2Cl2 and CHCl3 solvents to create stable compounds with novel clinical potential.

DDQ in mechanochemical C-N coupling reactions.

2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) is a commonly known oxidant. Herein, we report that DDQ can be used to synthesize 1,2-disubstituted benzimidazoles and quinazolin-4(3H)-ones via the intra- and intermolecular C-N coupling reaction under solvent-free mechanochemical (ball milling) conditions. In the presence of DDQ, the intramolecular C(sp2)-H amidation of N-(2-(arylideneamino)phenyl)-p-toluenesulfonamides leads to 1,2-disubstituted benzimidazoles and the one-pot coupling of 2-aminobenzamides with aryl/alkyl aldehydes resulted in substituted quinazolin-4(3H)-one derivatives in high yields.

Preparation, spectroscopic, characterizations and biological studies of new charge transfer complexes formed between fluconazole drug with various acceptors.

Charge transfer complexes developed during the interaction of Fluconazole drug (FLU) as an electron donor with different types of electron acceptors, including σ-type as iodine (I2), and π-types as 2,3-dinitrosalsylic acid (HDNS), Tetracyanoethylene (TCNE) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The formed complexes were characterized using various techniques as UV-Vis spectra, Thermal analyses, spectrophotometric measurements, 1H NMR and FTIR Spectroscopy. It was found that the stoichiometry of all developed complexes was a 1:1 M ratio between fluconazole and acceptors (I2, HDNS, TCNE and DDQ). The characteristic physical parameters data such as ionization potential (ID), The oscillator strength (ƒ), formation constant (KCT), transition dipole moment (µ), free energy (ΔG), and energy of interaction (ECT) of the formed CT-complexes have also been reported. Eventually, the synthesized complexes were screened for their microbial and antioxidant activities.

Charge Transfer Complexes of Ketotifen with 2,3-Dichloro-5,6-dicyano-p-benzoquinone and 7,7,8,8-Tetracyanoquodimethane: Spectroscopic Characterization Studies.

The reactions of ketotifen fumarate (KT) with 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and 7,7,8,8-tetracyanoquinodimethane (TCNQ) as π acceptors to form charge transfer (CT) complexes were evaluated in this study. Experimental and theoretical approaches, including density function theory (DFT), were used to obtain the comprehensive, reliable, and accurate structure elucidation of the developed CT complexes. The CT complexes (KT-DDQ and KT-TCNQ) were monitored at 485 and 843 nm, respectively, and the calibration curve ranged from 10 to 100 ppm for KT-DDQ and 2.5 to 40 ppm for KT-TCNQ. The spectrophotometric methods were validated for the determination of KT, and the stability of the CT complexes was assessed by studying the corresponding spectroscopic physical parameters. The molar ratio of KT:DDQ and KT:TCNQ was estimated at 1:1 using Job's method, which was compatible with the results obtained using the Benesi-Hildebrand equation. Using these complexes, the quantitative determination of KT in its dosage form was successful.

New Charge Transfer Complexes of K+-Channel-Blocker Drug (Amifampridine; AMFP) for Sensitive Detection; Solution Investigations and DFT Studies.

UV-Vis spectroscopy was used to investigate two new charge transfer (CT) complexes formed between the K+-channel-blocker amifampridine (AMFP) drug and the two π-acceptors 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and tetracyanoethylene (TCNE) in different solvents. The molecular composition of the new CT complexes was estimated using the continuous variations method and found to be 1:1 for both complexes. The formed CT complexes' electronic spectra data were further employed for calculating the formation constants (KCT), molar extinction coefficients (εCT), and physical parameters at various temperatures, and the results demonstrated the high stability of both complexes. In addition, sensitive spectrophotometric methods for quantifying AMFP in its pure form were proposed and statistically validated. Furthermore, DFT calculations were used to predict the molecular structures of AMFP-DDQ and AMFP-TCNE complexes in CHCl3. TD-DFT calculations were also used to predict the electronic spectra of both complexes. A CT-based transition band (exp. 399 and 417 nm) for the AMFP-TCNE complex was calculated at 411.5 nm (f = 0.105, HOMO-1 → LUMO). The two absorption bands at 459 nm (calc. 426.9 nm, f = 0.054) and 584 nm (calc. 628.1 nm, f = 0.111) of the AMFP-DDQ complex were theoretically assigned to HOMO-1 → LUMO and HOMO → LUMO excitations, respectively.

Charge-transfer chemistry of azithromycin, the antibiotic used worldwide to treat the coronavirus disease (COVID-19). Part III: A green protocol for facile synthesis of complexes with TCNQ, DDQ, and TFQ acceptors.

Investigating the chemical properties of molecules used to combat the COVID-19 pandemic is of vital and pressing importance. In continuation of works aimed to explore the charge-transfer chemistry of azithromycin, the antibiotic used worldwide to treat COVID-19, the disease resulting from infection with the novel SARS-CoV-2 virus, in this work, a highly efficient, simple, clean, and eco-friendly protocol was used for the facile synthesis of charge-transfer complexes (CTCs) containing azithromycin and three π-acceptors: 7,7,8,8-tetracyanoquinodimethane (TCNQ), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ), and tetrafluoro-1,4-benzoquinone (TFQ). This protocol involves grinding bulk azithromycin as the donor (D) with the investigated acceptors at a 1:1 M ratio at room temperature without any solvent. We found that this protocol is environmentally benign, avoids hazardous organic solvents, and generates the desired CTCs with excellent yield (92-95%) in a straightforward means.

An Efficient Metal-Free Oxidative Esterification and Amination of Benzyl C-H Bond.

An esterification and amination of benzylic C-H bonds was developed by using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) under metal- and iodide-free conditions. Both carboxylic acids and amines could be used as ideal coupling partners for the oxidative coupling reactions with various diarylmethanes. A close to equal amount of coupling reagents was enough to afford the product in good to high yields.

Validated spectrophotometric determination of maduramicin ammonium using three charge transfer complexation reactions.

Direct spectrophotometric determination of Maduramicin ammonium (MAD) represents an analytical challenge since it is a weak UV-absorbing and lacking a strong chromophore. This work represents the first spectrophotometric determination of MAD as no direct spectrophotometric or colorimetric determination methods for MAD are available in the literature. The present study illustrates the development of three simple, rapid and inexpensive colorimetric methods for the routine quality control analysis of MAD based on the formation of colored charge transfer complexes with three electron acceptors namely p-chloranilic acid (p-CA), 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) and picric acid (PA). The color products of MAD with p-CA, DDQ and PA were measured at 519, 588 and 405nm respectively. The proposed methods were validated in terms of linearity, ranges, precision, accuracy, robustness and limits of detection and quantification. MAD was effectively determined over concentration ranges of 100-1000, 25-250 and 30-150µg/mL using p-CA, DDQ and PA, respectively with good linearity as shown by the values of correlation coefficients not less than 0.9991. The developed methods were successfully implemented in the assay of MAD powder pharmaceutical formulation for veterinary use.

A chemoenzymatic synthesis of ceramide trafficking inhibitor HPA-12.

A chemoenzymatic synthesis of the title compound has been developed using an efficient and highly enantioselective lipase-catalyzed acylation in a hydrophobic ionic liquid, [bmim][PF6], followed by a diastereoselective asymmetric dihydroxylation as the key steps for incorporating the stereogenic centers. The further conversion to the appropriate intermediates and subsequent acylation with lauric acid furnished the target compound.

Synthesis of Doubly Annulated m-Terphenyl-Based Molecular Tweezers and Their Charge-Transfer Complexes with DDQ as a Guest.

The synthesis of a doubly-annulated m-terphenyl-based tweezer platform has been developed, which affords ready incorporation of various pincer units from monobenzenoid to polybenzenoid electron donors. The complexation study with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as guest has been carried out, and the crystal structure of T-Py∩DDQ reveals the sandwich-type binding mode in the solid state.

Validation of the cocaine versions of the Obsessive Compulsive Drug Use Scale and the Desires for Drug Questionnaire.

BACKGROUND: The Obsessive Compulsive Drug Use Scale (OCDUS) and the Desires for Drug Questionnaire (DDQ) are two frequently used drug craving questionnaires. Although both heroin and cocaine versions of the questionnaires exist, only the heroin versions have been psychometrically evaluated. The present study was conducted to evaluate the psychometric qualities of the cocaine versions of the OCDUS (OCDUS-C) and DDQ (DDQ-C). METHODS: Cocaine-dependent inpatients (n = 101) completed both scales as well as a Visual Analogue Craving Scale (VACS), an alternative, one-item index for assessing momentary craving. We examined the reliability (internal consistency), construct validity (factor structure), and concurrent validity (correlations among both questionnaires, the VACS, and indicators of severity of dependence). A subsample also completed the OCDUS-C and DDQ-C for a second time, one week after the initial administration to obtain a preliminary investigation of the test-retest reliability. RESULTS: In general, both questionnaires displayed good internal consistency, test-retest reliability, and concurrent validity. Further, the construct validity of both the DDQ and OCDUS was demonstrated by means of confirmatory factor analyses showing the expected three-factor models. CONCLUSION: Our results indicate that the OCDUS and DDQ for cocaine are both easy to administer and reliable instruments to assist the clinical practitioner or researcher to measure craving in cocaine dependent subjects. Moreover, the factor structure for the cocaine versions were similar to the heroin versions, indicating the OCDUS and the DDQ can be reliably used to measure craving for both substances, enabling a direct comparison between heroin and cocaine craving.

DDQ anti-aging properties expressed with improved mitophagy in mutant tau HT22 neuronal cells.

The purpose of our study is to develop age-related phosphorylated tau (p-tau) inhibitors, for Alzheimer's disease (AD). There are wide-ranging therapeutic molecules available in the market and tested for age-related p-tau inhibition to enhance phosphatase activity and microtubule stability in AD neurons. Until now there are no such small molecules claimed to show promising results to delay the disease process of AD. However, a recently developed molecule, DDQ, has been shown to reduce abnormal protein-protein interactions and protect neurons from mutant protein-induced toxicities in the disease process. In addition, DDQ reduced age- and Aß-induced oxidative stress, mitochondrial dysfunction, and synaptic toxicity. To date, there are no published reports on the p-tau interaction of DDQ and Sirt3 upregulation with CREB-mediated mitophagy activation in AD neurons. In the current study, HT22 cells were transfected with mutant Tau (mTau) cDNA and treated with the novel molecule DDQ. Cell survival, immunoblotting, and immunofluorescence analysis were conducted to assess cell viability and synaptic and mitophagy proteins in treated and untreated cell groups. As expected, we found cell survival was decreased in mTau-HT22 cells when compared with control HT22 cells. However, cell survival was increased in DDQ-treated mTau-HT22 cells when compared with mTau HT22 cells. P-tau and total tau proteins were significantly reduced in DDQ-treated mTau-HT22 cells, and MAP2 levels were increased. Anti-aging proteins like Sirt3, and CREB levels were increased in DDQ-treated HT22 cells and also in mTau-HT22 cells treated DDQ. Mitophagy proteins were decreased in mTau-HT22 cells and these were increased in DDQ-treated mTau-HT22 cells. These observations strongly suggest that DDQ has anti-p-tau and anti-aging properties, via Sirt3 overexpression and increased mitophagy proteins. Our study findings may have implications for healthy aging to the development of p-tau targeted therapeutics in AD and tauopathies.

A novel spectrophotometric approach relies on a charge transfer complex between atomoxetine with quinone-based π-acceptor. Application to content uniformity test.

Atomoxetine (ATO) belongs to psychoanaleptic drugs and is utilized in attention-deficit hyperactivity syndrome treatment. In this study, two facile and selective approaches are implemented for the spectrophotometric analysis of atomoxetine. The two approaches rely on charge transfer formed between ATO base (n-donor) with p-chloranil and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ; π-acceptor). The generated complexes exhibit absorption intensity maxima at 550 and 460 nm in acetonitrile for p-chloranil and DDQ in the order. Under the optimum reaction condition, Beer's law was followed for p-chloranil and DDQ at concentrations of 30-320 and 10-80 µg mL- 1, respectively. The ICH guidelines were followed for work validation, and the outcomes were excellent and satisfactory. The assessment of ATO in pharmaceutical capsules using the suggested procedures was successful, and the results were contrasted with those obtained using a different published method to show accuracy and precision. Additionally, the two methods were used to assess the homogeneity of ATO content in the commercialized capsule.

Optimization of two charge transfer reactions for colorimetric determination of two beta 2 agonist drugs, salmeterol xinafoate and salbutamol, in pharmaceutical and biological samples.

Beta 2 agonists are well known for their use in the treatment of asthma and COPD however in the last few years new indications of beta 2 agonist appeared like reduction of local fats and treatment of preterm labour which required the formulation of new dosage forms and administration strategies. The new developments require accurate, economic and feasible methods the determination of these drugs to facilitate testing the newly introduced dosage forms and to study the pharmacokinetics and pharmacodynamics regarding the modern uses. In this study two rapid, sensitive and economic colorimetric methods for the determination of salmeterol xinafoate and salbutamol in pharmaceutical dosage forms and spiked plasma were developed and validated. The developed methods depends on the optimized reaction of the studied drugs with two charge transfer reagents, 2,3-dochloro-5,6-dicyano-1,4-benzoquonone (DDQ) and chloranilic acid (CA) to produce coloured complexes measured at 460 and 529 nm for DDQ and CA respectively. The developed methods showed high accuracy of 99.52 ± 1.108, 101.03 ± 0.389, 100.04 ± 1.520 and 100.3 ± 0.951 for salmetrol xinafoate and salbutamol with DDQ and CA respectively. The proposed methods were successfully used for the determination of the studied drugs in their dosage forms and spiked plasma with high accuracy and precision and the results were compared to reported methods.

Descended Social Anxiety Disorder and Craving in Women Heroin Dependence Through Exercise Alerts Plasma Oxytocin Levels.

Purpose: This study explored the association between peripheral blood oxytocin (OT) and social anxiety disorder (SAD) and cue-induced cravings in female heroin addicts. The effect of exercise on alleviation of SAD and OT levels was also explored. Methods: A total of 72 females with heroin dependence were assigned to three groups based on SAD severity. The three groups were Non-SAD control, SAD control, and SAD exercise groups. Subjects in the SAD exercise group underwent aerobic exercise and resistance training for 8 weeks (60 min/day, 5 days/week). Enzyme-linked immunosorbent assay analysis and Liebowitz Social Anxiety Scale (LSAS) scores were used to determine plasma OT concentration and SAD, respectively. Cue-induced craving was assessed using Visual Analog Scale (VAS) and Desires for Drug Questionnaire (DDQ). Mixed-effect analysis of variance and Pearson correlation analysis were used to explore the effect and correlation between different parameters. Results: OT levels in the SAD exercise group were significantly high after exercise (p < 0.01). LSAS, VAS, and DDQ ("Desire and Intention" and "Negative reinforcement") scores in the SAD exercise group were significantly lower after exercise (p < 0.01). Plasma OT level was negatively correlated with LSAS score (r = -0.534, p < 0.001), VAS score (r = -0.609, p < 0.001), "Desire and Intention" score (r = -0.555, p < 0.001), and "Negative reinforcement" score (r = -0.332, p < 0.01) and positively correlated with the "control" score (r = 0.258, p < 0.05). LSAS was positively correlated with VAS score (r = 0.588, p < 0.001) and "Desire and Intention" score (r = 0.282, p < 0.05). Conclusions: The findings of the present study indicate that plasma OT is a potential peripheral biomarker for prediction of the severity of social anxiety in female heroin withdrawal patients. Aerobic exercise combined with resistance training plus incremental load for 8 weeks can increase plasma OT levels and significantly reduce severity of SAD and cue-induced cravings in female heroin addicts.

Systematic measurements of charge transfer complexes caused from 1-phenyl-1,2,3,4-tetrahydroisoquinoline and 4-aminoacetanilide with series of π-acceptors (BQ, DDQ, TCNQ).

Molecular charge-transfer interaction of a series of electron π-acceptors of 1,4-benzoquinone (BQ), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and Tetracyanoquinodimethane (TCNQ) with selected donors of 1-phenyl-1,2,3,4-tetrahydroisoquinoline (PTHIQ) and 4-aminoacetanilide (ACE) have been studied in methanol at room temperature. The stoichiometry of the complexes was determined by photometric titration method and was found to be 1:1, in all the cases. Spectro-kinetic interaction studies along with rate constants and observed formation constants (K) indicated that the strength of the complex formations is PTHIQ-BQ < PTHIQ-DDQ < PTHIQ-TCNQ. Also, Similar observations happened in ACE-BQ and < ACE-DDQ < ACE-TCNQ systems. FT-IR results indicated that the point of interaction was identifying in NH moiety of PTHIQ and NH2 moiety of ACE with series of π-acceptor complexes. The experimental results were compared with Ab initio DFT calculations at the B3LYP/6-31 + G(d) level of theory. The increasing order of the experimentally measured formation constant of CT-complexes (PTHIQ and ACE with series of acceptors) was well supported by theoretical HOMO-LUMO energy gap and drastically changes in Mulliken charges of NH moiety of PTHIQ, NH2 moiety of ACE with complexation with acceptors.

A DFT mechanistic study on oxidative dehydrogenative Diels-Alder reaction of alkylbenzenes.

Cross-dehydrogenative Diels-Alder cycloaddition reaction between readily-available alkyl benzenes and electron-deficient dienophiles is an attractive synthetic route to access carbocyclic compounds which have high utility in the chemical and pharmaceutical industries. This work reports a study at the M06-2X/6-311G(d) and M06-2X/6-311++G(d,p) levels of theory on the reaction of alkyl benzenes with electron-deficient dienophiles in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as an oxidant and hydroquinone as an activator, so as to understand the chemoselectivity of the reaction (addition across the alkene functionality versus the ketone functionality), the role of the activator, the effects of substituents and the effect of solvent on the reaction. The results show the addition of the alkene bonds of methylstyrene across the alkene functionality of the electron-deficient dienophiles has generally low barriers compared to the addition across the carbonyl functionality of the electron-deficient dienophile. Powerful electron-withdrawing group (cyano) on the electron-deficient dienophile decrease the energy barrier for the cycloaddition and decrease the stability of the product whiles weak electron-withdrawing (bromine and chlorine) and electron-donating groups increase the energy barrier for the cycloaddition and decrease the stability of the product. The hydroquinone as an activator decreases the activation barrier for the Diels-Alder cycloaddition reaction.