Nickel(ii)-catalyzed tandem C(sp2)–H bond activation and annulation of arenes with gem-dibromoalkenes

A nickel(ii)/silver(i)-catalyzed tandem C(sp²)–H activation and intramolecular annulation of arenes with dibromoalkenes has been successfully achieved, which offers an efficient approach to the 3-methyleneisoindolin-1-one scaffold. Attractive features of this system include its low cost, ease of operation, and its ability to access a wide range of isoindolinones.

A nickel(ii)/silver(i)-catalyzed tandem C(sp²)–H activation and intramolecular annulation of arenes with dibromoalkenes has been successfully achieved, which offers an efficient approach to the 3-methyleneisoindolin-1-one scaffold.

Over the past years, the transition-metal-catalyzed oxidative C–H/C–H cross-coupling reaction has emerged as a useful, atom- and step-economic synthetic protocol to construct a series of important N-heterocycles.¹ In this context, the synthesis of isoindolinones has attracted considerable attention owing to their interesting biological and pharmaceutical properties,² as well as their usefulness as precursors for the synthesis of structurally diverse and complex molecules (Scheme 1).^2c,3 Several methods have successfully been developed toward isoindolinone synthesis based on Pd,⁴ Cu,⁵ Ru,⁶ and Rh⁷ salts. Among these reactions, the oxidative coupling reactions of benzamides with alkenes^4b,6,7a,f,g or alkynes^5a,5d exhibit high atom economy and the application of this strategy to simple arenes is still largely underdeveloped.⁸ For instance, in 2015, Zhang''s group⁹ revealed cobalt-catalyzed oxidative alkynylation and cyclization of simple arenes and terminal alkynes with silver-cocatalyst via 2-fold C–H bond and N–H bond cleavage and C–C bond and C–N bond formation. In 2016, Song''s group¹⁰ developed a method of a cobalt(ii)-catalyzed decarboxylative C–H activation/annulation of benzamides and alkynyl carboxylic acids and nickel(ii)-catalyzed C(sp²)–H alkynylation/annulation cascade with terminal alkynes to synthesize 3-methyleneiso-indolin-1-ones. Zhang also reported a nickel-catalyzed oxidative alkynylation with amides and terminal acetylenes.^10c In addition, from an environmentally point of view, in 2015, wei''s group¹¹ described an operationally simple, Pd-catalyzed C–H functionalization for the synthesis of important and useful isoindolinones from readily available carboxamides and carboxylic acids or anhydrides. The protocol avoided the use of excess oxidants including benzoquinone, Cu(OAc)₂, or Ag₂CO₃ of previous all the reactions, thus generating stoichiometric amounts of undesired wastes.Open in a separate windowScheme 1Representative isoindolinones with biological and pharmaceutical.To our knowledge, the synthesis of alkynes is among the most fundamental and important synthetic transformations due to the unique reactivity of alkynes including addition, oxidation, reduction, and in particular cyclization.¹² However, the lack of reactivity of alkynes, more electron-deficient than the corresponding alkenes, makes it harder to couple them with heteroarenes. As a consequence, terminal alkyne precursors have been developed to facilitate acetylene exchange.¹³ Halogenoalkynes,¹⁴ hypervalent alkynyliodoniums,¹⁵acetylenic sulfones,¹⁶ copper acetylides¹⁷ and α,β-ynoic acids¹⁸ allowed the generation of more activated alkyne moieties thus broadening the applications of direct alkynylation reactions to heterocycles. Among these alternatives, gem-dihaloalkenes emerged as more efficient coupling partners than the corresponding monohalogenated alkynes along with being inexpensive and readily-available.¹⁹ Indeed, the two geminal halogen atoms on the alkenyl carbon enhance the reactivity of metal complexes thus facilitating cross coupling reactions.²⁰ Stable and readily-available 1,1-dibromo-1-alkenes and our interests in the C–H activation²¹ led us to consider using these reagents in the C–H functionalization to construct the valuable isoindolinones. We can envision that the abundance and structural diversity of the aldehydes (used the preparation of gem-dibromoethylenes via wittig reaction) as well as the merits of C–H functionalization would make the synthetic methods desirable and attractive. Herein, we wish to disclose the nickel(ii)/silver(i)-mediated tandem transformation involving sequential C(sp²)–H/C(sp²)–H alkynylation and intramolecular annulation of unactivated arenes with dibromoethylenes with the assistance of 8-aminoquinoline (Scheme 2). These features of this approach operational simplicity, a wide-ranging substrate scope, and tolerance of various synthetically useful functional groups.Open in a separate windowScheme 2Nickel(ii)/silver(i)-catalyzed alkynylation/annulation of arenes with dibromoalkenes.     

C–P bond formation of cyclophanyl-, and aryl halides via a UV-induced photo Arbuzov reaction: a versatile portal to phosphonate-grafted scaffolds

A new versatile method for the C–P bond formation of (hetero)aryl halides with trimethyl phosphite via a UV-induced photo-Arbuzov reaction, accessing diverse phosphonate-grafted arenes, heteroarenes and co-facially stacked cyclophanes under mild reaction conditions without the need for catalyst, additives, or base is developed. The UV-induced photo-Arbuzov protocol has a wide synthetic scope with large functional group compatibility exemplified by over 30 derivatives. Besides mono-phosphonates, di- and tri-phosphonates are accessible in good to excellent yields. Mild and transition metal-free reaction conditions consolidate this method''s potential for synthesizing pharmaceutically relevant compounds and precursors of supramolecular nanostructured materials.

UV-induced C–P bond formation of aryl halides via photo Arbuzov reaction: a versatile portal to phosphonate-grafted scaffolds.

Aryl phosphonates and phosphonic acids, as an important class of organophosphorus products, have elicited enormous interest in pharmaceutical science for their biological application,^1–5 in catalysis as precursors of privileged phosphine ligands,^6–8 and in materials science as supramolecular tectons.^9–11 For the synthesis of aryl phosphonates, besides conventional Grignard or organolithium protocols, the development of the palladium-catalyzed Hirao cross-coupling of H-phosphonates with aryl halides is a convenient method,¹² and several modified protocols have been reported in recent years.^13,14Development of new and generally useful C–P bond formation methods with controlled selectivity that are widely applicable, cheap, and operationally simple have been an outstanding objective since phosphonylated products have a broad spectrum of applications. For instance, phosphono-fluoresceins due to the influence of the phosphoryl moiety insertion, show an almost 70-fold increase in intracellular brightness, compared to the analogous sulfono-, and carboxy-fluorescein, as recently reported by Miller and co-workers.² Recent trends to realize C–P bond formation are focused on visible-light-driven reactions, where Toste and co-workers first developed a dual catalytic strategy by combining gold and ruthenium photoredox catalysis for the oxidative P-arylation of H-phosphonates.¹⁵ Similarly, König and co-workers reported the ruthenium-catalyzed phosphonylation of electron-rich arenes mediated by C^Ar–H activation employing trialkyl phosphites.¹⁶ Metal-free variants using either organic dyes,^17–20 hypervalent iodine reagents,²¹ or strong base²² are additionally emerged as a useful tool to promote C–P bond formation (Fig. 1).Open in a separate windowFig. 1Selected methods previously reported for light-induced C–P bond formation.Strategies that employ trialkyl phosphites have the drawback of expensive reagents, transition metal catalysts, or large catalyst loadings. The UV-induced photo-Arbuzov reaction has mostly been neglected, even though it is more than 50 years old.^23–25 The original publication by Griffin and coworkers describes the reaction of aryl iodides with trialkyl phosphites at low temperatures (−8 to 0 °C).²⁴ The phosphonylation of aryl triflates with trialkyl phosphites via photo-induced Arbuzov-type reaction, using UV light in combination with a base as additive has recently been realized.²⁶ The need for aryl iodides and poor substrate scope foreclosed this reaction to become broadly applicable. Advancing the UV-induced photo-Arbuzov reaction for the preparation of aryl phosphonates, in this work, we report a new and more effective method for C–P bond formation under mild conditions without the need for catalysts, additives, or a base employing a wide array of functionalized aryl-, heteroaryl and thiacyclophanyl halides. The P-arylation proceeds with excellent functional group tolerance regardless of the steric hindrance and represents an important step forward in enabling C–P bond formation. Multiple and domino approach was investigated under the optimized conditions form the application perspective of the phosphonates as molecular tectons in nanostructured materials.     

Synthesis of novel benzopyran-connected pyrimidine and pyrazole derivatives via a green method using Cu(ii)-tyrosinase enzyme catalyst as potential larvicidal,antifeedant activities

A series of benzopyran-connected pyrimidine (1a–g) and benzopyran-connected pyrazole (2a–i) derivatives were synthesized via Biginelli reaction using a green chemistry approach. Cu(ii)-tyrosinase was used as a catalyst in the synthesis of compounds 1a–g and 2a–ivia the Biginelli reaction. The as-synthesized compounds were characterized by IR, ¹H NMR, ¹³C NMR, mass spectroscopy, and elemental analysis. The as-synthesized compounds were screened for larvicidal and antifeedant activities. The larvicidal activity was evaluated using the mosquito species Culex quinquefasciatus, and the antifeedant activity was evaluated using the fishes of Oreochromis mossambicus. The compounds 2a–i demonstrated lethal effects, killing 50% of second instar mosquito larvae when their LD₅₀ values were 44.17, 34.96, 45.29, 45.28, 75.96, and 28.99 μg mL⁻¹, respectively. Molecular docking studies were used for analysis based on the binding ability of an odorant binding protein (OBP) of Culex quinquefasciatus with compound 2h (binding energy = −6.12 kcal mol⁻¹) and compound 1g (binding energy = −5.79 kcal mol⁻¹). Therefore, the proposed target compounds were synthesized via a green method using Cu(ii)-enzyme as a catalyst to give high yield (94%). In biological screening, benzopyran-connected pyrazole (2h) was highly active compared with benzopyran-connected pyrimidine (1a–g) series in terms of larivicidal activity.

Cu(ii)-tyrosinase catalytic help with the synthesis of benzopyran-connected pyrimidine and pyrazole derivatives and their larvicidal activity.

Benzopyrans (coumarins) are an important group of naturally occurring compounds widely distributed in the plant kingdom and have been produced synthetically for many years for commercial uses.¹ In addition, these core compounds are used as fragrant additives in food and cosmetics.² The commercial applications of coumarins include dispersed fluorescent brightening agents and as dyes for tuning lasers.³ Some important biologically active natural benzopyran (coumarin) derivatives are shown in Fig. 1. Mosquitoes are the vectors for a large number of human pathogens compared to other groups of arthropods.⁴ Their uncontrollable breeding poses a serious threat to the modern humanity. Every year, more than 500 million people are severely affected by malaria. The mosquito larvicide is an insecticide that is specially targeted against the larval life stage of a mosquito. Particularly, the compound bergapten (Fig. 1), which shows the standard of larivicidal activity,⁵ is commercially available, and it was used as a control in this study for larvicidal screening. Moreover, the antifeedant screening defense mechanism makes it a potential candidate for the development of eco-friendly ichthyocides. Coumarin derivatives exhibit a remarkably broad spectrum of biological activities, including antibacterial,^6,7 antifungal,^8–10 anticoagulant,¹¹ anti-inflammatory,¹² antitumor,^13,14 and anti-HIV.¹⁵Open in a separate windowFig. 1Biologically active natural benzopyran compound.Coumarin and its derivatives can be synthesized by various methods, which include the Perkin,¹⁶ Knoevenagel,¹⁷ Wittig,¹⁸ Pechmann,¹⁹ and Reformatsky reactions.Among these reactions, the Pechmann reaction is the most widely used method for the preparation of substituted coumarins since it proceeds from very simple starting materials and gives good yields of variously substituted coumarins. For example, coumarins can be prepared by using various reagents, such as H₂SO₄, POCl₃,²⁰ AlCl₃,²¹ cation exchange resins, trifluoroacetic acid,²² montmorillonite clay,²³ solid acid catalysts,²⁴ W/ZrO₂ solid acid catalyst,²⁵ chloroaluminate ionic liquid,²⁶ and Nafion-H catalyst.²⁷Keeping the above literature observations, coumarin derivatives 1a–g and 2a–i are usually prepared with the conventional method involving CuCl₂·2H₂O catalysis with using HCl additive. This reduces the yield and also increases the reaction time. To overcome this drawback, we used mushroom tyrosinase as a catalyst without any additive, a reaction condition not reported previously. The as-synthesized compounds were used for the biological screening of larvicidal and antifeedant activities (marine fish). In addition, in this study, we considered the molecular docking studies study based on previous studies for performing the binding ability of hydroxy-2-methyl-4H-pyran-4-one (the root extract of Senecio laetus Edgew) with the odorant binding protein (OBP) of Culex quinquefasciatus.²⁸     

Synthesis of 3-selanylbenzo[b]furans promoted by SelectFluor®

A simple and practical protocol for the synthesis of 3-selanyl-benzo[b]furans mediated by the SelectFluor® reagent was developed. This novel methodology provided a greener alternative to generate 3-substituted-benzo[b]furans via a metal-free procedure under mild conditions. The intramolecular cyclization reaction was carried out employing an electrophilic selenium species generated in situ through the reaction between SelectFluor® and organic diselenides. The formation of this electrophilic selenium species (RSe-F) was confirmed by heteronuclear NMR spectroscopy, and its reactivity was explored.

This novel methodology provided a greener alternative to generate 3-substituted-benzo[b]furans mediate by Selectfluor® reagent. The formation of this electrophilic selenium species (RSe-F) was confirmed by heteronuclear NMR spectroscopy.

The benzo[b]furan scaffold is an important structural motif that is present in natural products and in synthetic compounds with therapeutic proprieties.¹ Substituted benzo[b]furans have shown a broad range of biological activities,² being found in a variety of pharmaceutical targets, such as Viibryd® and Ancoron® (Fig. 1).³ These drugs are used for treatment of depression and for cardiac arrhythmias, respectively. An efficient method to obtain substituted benzo[b]furans is the intramolecular cyclization reaction between 2-alkynylphenol or 2-alkynylanisole derivatives with different electrophilic species to generate a wide variety of 3-substituted-benzo[b]furans. This strategy is especially useful because of the atom-economic synthesis under mild conditions.⁴Open in a separate windowFig. 1Substituted benzo[b]furans in commercial drugs.Organoselenium compounds have attracted great interest due the large number of biological applications and their versatile reactivity.⁵ From a synthetic point of view, the ease cleavage of the Se–Se bond in diselenide compounds can generate species with different reactivity, as radical, electrophile, and nucleophile. This ample usefulness becomes the diselenides in key synthetic intermediates to introduce selenium moiety in organic compounds or to catalyse organic transformations.^5,6Despite the recent advances in the synthesis of 3-selanyl-benzo[b]furans, new electrophiles and reactional conditions were explored (Scheme 1).^{7–9,11–15} Initially, the establishing work by Larock and co-workers toward the synthesis of 3-selanyl-benzo[b]furans through the intramolecular cyclization of 2-(phenylethynyl)anisole with PhSeCl in CH₂Cl₂ at room temperature.⁷ In 2009, Zeni and co-workers demonstrated the synthesis of 3-selanyl-benzo[b]furans employing PhSeBr as an active electrophile.⁸ A pioneering protocol was reported by Zeni and co-workers, which employed FeCl₃ (1.0 equiv.) and diorganyl diselenides in CH₂Cl₂ at 45 °C.⁹ Additionally, Lewis acids have been used as effective catalysts in Se–Se bonding cleavage to access functionalized selenium compounds.¹⁰ Afterward, alternative methods were developed, such as the synthesis of 3-selanyl-benzo[b]furans mediated by PdCl₂/I₂, I₂/water, and CuI (1.5 equiv.).^11–14 More recently, Liu and co-workers reported a radical cyclization reaction using selenium powder as selenium source and AgNO₃ as catalyst in DMSO at 100 °C.¹⁵Open in a separate windowScheme 1Methodologies to prepare 3-selanyl-benzo[b]furans.Although, there are different methodologies to prepare 3-selanyl-benzo[b]furans and other functionalized selenium compounds through the reaction between diselenides compounds with oxidant reagents or Lewis acids, alternative electrophilic selenium species should be employed to avoid metals and/or toxic reagents.^9–15 Furthermore, RSeCl and RSeBr,^7,8 obtained from the reaction of diselenides with SO₂Cl₂ (or Cl₂) and Br₂ respectively, are commercially available and largely used as selenylating agent. However, these species present a low stability under moisture, and the high nucleophilicity of chloride and bromide leaving groups can lead to undesirable side reactions.On the other hand, SelectFluor® is a versatile reagent used for different applications, such as fluorination reactions,¹⁶ C–H functionalization¹⁷ and organic function transfer.¹⁸ In addition, SelectFluor® has been used as an efficient method for intramolecular annulation reactions, due its higher reactivity.¹⁹ This ample application together with the desirable characteristics of the SelectFluor®, such as the higher stability, non-hydroscopic solid and hazard-free source of fluorine,²⁰ promoted new possibilities to investigate fluorine chemistry. In 2004, Poleschner and Seppelt prepared PhSeF derivatives by the reaction between diorganyl diselenides and XeF₂ in CH₂Cl₂ as a solvent at −40 °C.²¹ The products were characterized by low-temperature ¹⁹F and ⁷⁷Se NMR, and it was the first confirmation of this type of electrophilic selenium compound. Although electrophilic selenium catalysis (ESC) with electrophilic fluoride reagents as oxidants has been demonstrated in the functionalization of alkenes,²² fewer knowledge about the reactivity of this selenium electrophilic species is available in the literature.²³Based on the development of new electrophilic selenium reagents,^9–14,24 herein, we describe a metal-free synthesis of 3-selanyl-benzo[b]furans under mild conditions using this very reactive electrophilic selenium species (RSe-F), generated in situ at room temperature by the reaction of diorganyl diselenides with SelectFluor® reagent (Scheme 1). Moreover, the higher reactivity of RSe-F species could be explored for the insertion of selenium moiety in other building blocks because the environmentally friendly reactional condition, and the replacing chlorine and bromine by the non-nucleophilic fluorine counter ion, can partially circumvented some side reactions.     

Synthesis and biological evaluation of novel quinolone derivatives dual targeting histone deacetylase and tubulin polymerization as antiproliferative agents

A strategy to develop chemotherapy agents by combining two complimentary chemo-active groups into a single molecule may have higher efficacy and fewer side effects than that of single-target drugs. In this article, we describe the synthesis and evaluation of a series of novel dual-acting levofloxacin–HDACi conjugates to target both histone deacetylase (HDAC) and tubulin polymerization. These bifunctional conjugates exhibited potent inhibitory activities against HDACs and tubulin polymerization. In docking analysis provides a structural basis for HDACs inhibition activities. Moreover, these conjugates showed selective anticancer activity that is more potent against MCF-7 compared to other four cancer cells A549, HepG2, PC-3, HeLa, but they had no toxicity toward normal cells.

Synthesis of a series of novel dual-acting levofloxacin–HDACi conjugates, which show potent inhibitory activities against HDACs, tubulin polymerization, and significant antiproliferative effect on MCF-7 cells.

Cancer is a highly complex multifactorial disease involving multiple cross-talking between signaling networks. Almost all single-target-based drugs suffer from severe toxicities or other undesirable side effects. In contrast, combination therapy, which combines multiple anticancer agents working with different mechanisms, might have superior efficacy and fewer side effects compared to single-target treatments.^1,2Histone deacetylases (HDACs) are epigenetic enzymes that are capable of removing acetyl groups from ε-amino groups of lysine residues in histone or other nonhistone proteins.³ Abnormal expression of HDACs has been observed in various types of cancer,^4–6 and these enzymes have emerged as important targets in the development of anticancer drugs. Consequently, inhibition of HDAC activity is now recognized as a powerful strategy for cancer therapy. There are 18 human HDAC isoforms categorized into four major classes: class I (HDACs 1, 2, 3, 8), class IIa (HDACS 4, 5, 7, 9), class IIb (HDACs 6 and 10), and class IV (HDAC 11) are Zn²⁺-dependent metalloenzymes, while class III (SirTs 1–7) are NDA⁺-dependent sirtuins.^7,8 Of these HDAC isoforms, only HDACs 1, 2, 3, and 6 have shown biologically relevant deacetylation ability.⁹ Specially, selective inhibition of HDAC6 may have fewer side effects than pan-HDAC and class I isoform.^10–12To date, more than twenty HDAC inhibitors have been initiated in clinical trials, and four HDAC inhibitors vorinostat (SAHA),¹³ romidepsin (FK-228),¹⁴ belinostat (PXD-101),^15,16 panobinostat (LBH-589),¹⁷ have been approved by FDA for the treatment of T-cell lymphoma, cutaneous T-cell lymphoma and multiple myeloma. However, most of them are pan-HDAC (SAHA, LBH-589) or class I selective (FK-228, PXD-101) inhibitors, which usually lead to several mild to severe side effects.^16,18,19 In addition, most of HDAC inhibitors lack visible efficacy against solid tumor,^14,20 the doses given in clinical are much higher, which severely limit their clinical utility for the treatment of broad spectrum of cancer. Therefore, preclinical evaluation of new HDAC inhibitors will need to focus on improving HDAC isoform selectivity and enhancing potency against solid tumors. One strategy may be able to ameliorate the shortcomings of current inhibitors, which is to develop a dual-acting HDAC inhibitor (HDACi) by incorporation of the surface recognition group of prototypical HDACi into other anticancer drugs, forming a single molecule that can modulate intracellular multiple targets, other than various HDAC isoforms. So far, a few examples of bifunctional HDACi-derived conjugates have been obtained.^21–26 Expansion of the diversity of such bifunctional conjugates could lead to broad acting, therapeutically viable anticancer drugs.In another aspect, fluoroquinolones (FQs) have recently been proven as an excellent class of broad-spectrum anticancer drugs against a variety of cancer cells such as bladder cancer,²⁷ non-small cell lung carcinoma,²⁸ colorectal carcinoma cells,²⁹etc. For instance, it has been demonstrated that levofloxacin (Lv) displays antiproliferative activity against various cancer cells.^30,31 Additionally, many of fluoroquinolones were potent inhibitors of tubulin polymerization and exhibited selective activity against some tumor cell types.^32,33 More importantly, fluoroquinolones have favorable pharmacokinetic profiles and good adsorption, which possess an established record of safety.³⁴ Therefore, on the basis of therapeutic effectives of aforementioned HDACi as well as fluoroquinolone, we conceived that concurrent inhibition of HDAC and tubulin polymerization would be a viable alternative approach for cancer treatment.In this work, we describe the design, synthesis and biological evaluation of novel dual-action levofloxacin–HDACi conjugates, which can be prepared conveniently by direct connection of levofloxacin with a triazole-liked SAHA (Fig. 1). The levofloxacin–SAHA conjugates (compounds 8a–c and 9a–c) of this design not only have HDACi unit but also have a second pharmacologically quinolone scaffold. Thus, they expand the exploration of bifunctional HDACi-derived conjugates. For comparison, the carboxylic acid analogues (by replacing the hydroxamic acid (–CONHOH) group with (–COOH), compounds 6a–c and 7a–c) were also prepared and evaluated for their HDAC and tubulin polymerization inhibition activity, antiproliferative activity and cell-type selectivity, etc.Open in a separate windowFig. 1Design of dual-acting levofloxacin–HDACi conjugates.     

A top-down design for easy gram scale synthesis of melem nano rectangular prisms with improved surface area

An unprecedented top-down design for the preparation of melem by 1 h stirring of melamine-based g-C₃N₄ in 80 °C concentrated sulfuric acid (95–98%) was discovered. The melem product was formed selectively as a monomer on the gram scale without the need for controlled conditions, inert atmosphere, and a special purification technique. The as-prepared air-stable melem showed a distinctive nano rectangular prism morphology that possesses a larger surface area than the melems achieved by traditional bottom-up designs making it a promising candidate for catalysis and adsorption processes.

A novel practical method for the gram scale preparation of melem possessing a nano rectangular prism morphology and improved specific surface area through a top-down depolymerization design was developed.

Triamino-s-heptazine or 2,5,8-triamino-tri-s-triazine known as “melem”, is a mysterious molecule and invaluable intermediate in the density of melamine rings to graphitic carbon nitride (g-C₃N₄) with a rigid heptazine structure with three pendant amino substituents.¹ Melem does not bear two of the strongest emission quenchers, namely C–H and O–H groups;² In this way it has unique optical properties³ and is known as an efficient metal-free luminescent material.⁴ High stability, the possibility for supramolecular self-assembly, tunable band gap, and an already rich physicochemical chemistry are some of the known properties for melem.^1b For this reason, melem has the potential to be used in photocatalysts, MOFs, COFs, electrochemistry sensors, flame retardants, TADF and related OLEDs, and liquid crystals.¹ The use of melem in solar hydrogen evolution⁵ and bioimaging⁶ is also known.Very few reports of its catalytic application are available, nevertheless, in recent years it has attracted much attention because of exploring its unique properties. Metal-free g-C₃N₄/melem hybrid photocatalysts have been used for visible-light-driven hydrogen evolution.⁷ Lei et al. used melem single crystal nanorods as a photocatalyst with modulated charge potentials and dynamics.⁸ Recently, Liu et al. improved the photocatalytic properties of carbon nitride for water splitting by attaching melem to Schiff base bonds.⁹ In another report, a promotion in photocatalytic activity was obtained by construction of melem/g-C₃N₄ vermiculite hybrid photocatalyst for photo-degradation of tetracycline.¹⁰ Lei et al. reported that H₂ evolution activity of melem derived g-C₃N₄ was 18 times higher than g-C₃N₄.¹¹ Melem was also utilized as a precursor for the preparation of rod-like g-C₃N₄/V₂O₅ heterostructure with enhanced sonophotocatalytic degradation for tetracycline antibiotics.¹² CO₂ cycloaddition into cyclic carbonates,¹³ non-sacrificial photocatalytic H₂O₂ production,³ water treatment,¹⁴ simultaneous reductions of Cr(vi) and degradation of 5-sulfosalicylic acid,¹⁵ are some of the catalytic applications of melem at various fields of sciences.The main protocol of preparing melem is the annealing of cyanamide, dicyanamide, or melamine, which requires precise temperature control under an inert atmosphere such as N₂ or argon. Just recently, the synthesis approaches for molecular s-heptazines as well as their applications and properties have been reviewed by Audebert et al.^1b Most of the reported methods do not lead to the preparation of pure monomer melem and are often mixed with its oligomers and polymerized derivatives,¹⁶ meanwhile the possibility of forming triazine oligomers or oligomers between melem and triazine cannot be precluded.^5,16c Complete polymerization of melamine at 500–550 °C leads to g-C₃N₄ and at 400–450 °C leads to melem-like derivatives,¹⁷ mostly a mixture of different products requiring careful attention during isolation and purification.⁵ Recently, Kessler and his colleague investigated the thermolysis of melamine, the formation of melem, and the formation of poly(triazine imide) from melem precursor via ionothermal as well as thermal condensation (conventional synthesis) as the back reaction of the melem condensation.¹⁸The growing demands for employing melem in new applications besides the serious problems in preparing pure samples necessitate the development of a simple and operational scale-up method that does not have any acute and controlled conditions.It is well-known that the polycondensation mode of g-C₃N₄ and consequently the chemical and thermal stability as well as texture properties strongly depend on the nitrogen rich precursors (cyanamide, dicyandiamide, urea, and melamine) as well as annealing temperature.¹⁹The interaction between the molecular precursors and/or intermediate compounds are critical factors.¹⁷ Due to some drawbacks associated with the g-C₃N₄ such as low electronic conductivity, a high rate of photogenerated electron–hole pairs, a low surface area, poor visible-light absorption, low quantum yield, and low solubility in almost all of the traditional solvents,²⁰ it has been subjected to various acid treatments, to promote its properties and photochemical activity.²¹ Various nanosheets with different properties and morphologies have been obtained depending on the precursor used, acid nature and concentration, as well as reaction temperature and time.²² However, the oxidation products such as cyameluric or cyanuric acids (Scheme 1) under high reaction temperatures and times have been reported.^21cOpen in a separate windowScheme 1The selective production of the monomer melem from melamine-based g-C₃N₄ presented in this work. Other molecules are possible decomposition and/or oxidation products of g-C₃N₄.Inspired by the previous reports to prepare the acidified g-C₃N₄, we started with melamine to synthesize the g-C₃N₄ by calcining at 550 °C under air,²³ followed by the treatment with H₂SO₄. Nevertheless, we discovered that stirring the melamine-based g-C₃N₄ at concentrated H₂SO₄ (95–98%) at 80 °C for a limited time (1 h), afforded selectively monomer melem in high yield (Scheme 1). Following the intercalation, chemical exfoliation, and protonation of nitrogen atoms of the g-C₃N₄ sheets at concentrated H₂SO₄,^22,24 the bridging C–NH–C groups between s-heptazine units breaks which releases the triamino-s-heptazine (melem) molecules as monomer (Scheme S1^†). Under these conditions the formation of oligomers was precluded because of the effective breaking of the bridging amino groups, however, the limited reaction time and moderate temperature prevented the tri-s-triazine ring-opening as well as the formation of the oxidation products such as cyameluric (or cyanuric) acids.^21c Thus, we developed a facile and easy gram-scale synthesis of melem from acidic depolymerization of melamine-based g-C₃N₄ with no need for controlled conditions, and inert atmosphere. The air-stable white powder was insoluble in most common solvents (H₂O, C₂H₅OH, CH₃OH, DMF, CH₃CN, acetone, etc.) and only dissolved in DMSO with a very limited solubility exactly like that reported for the isolated pure monomer melem.^5,25 A new and distinctive rectangular prism morphology with an improved surface area was detected for the as-prepared melem,^5,8,26 which makes our study even more unique and novel.^5,8,27 It is well known that both morphology and specific surface area play important roles in affecting the photocatalytic activity of semiconductors.^22,28 Thus, our study not only provides a novel practical method for the preparation of nanostructured monomer melem, but also paves a new pathway for increasing its surface area. The chemical structure and purity of the as-prepared melem were verified by the combination of different techniques including FT-IR, ¹H and ¹³C NMR, mass spectra, elemental analysis, XRD, XPS, DRS, and photoluminescence spectroscopy.FT-IR spectrum of g-C₃N₄ and the as-prepared melem are depicted in Fig. 1. While the peaks at 803 and 796 cm⁻¹ exhibited the vibrations of tri-s-triazine moieties in g-C₃N₄ and melem respectively, two intense bands at 1622 and 1471 cm⁻¹, consistent with those of monomer melem. The lack of obvious C–NH–C vibrations at around 1230 cm⁻¹ featured the absence or negligible amount of dimelem or further melem-oligomers in the product.^29a,5,8 In the region of NH-stretching frequencies, a spectrum characteristic of amides is observed: three diffuse absorption bands (3415, 3360, and 3106 cm⁻¹) indicate the presence of strong intermolecular hydrogen bonds and strong interaction between the amino-groups and the ring.^29a Inspection of the characteristic bands of melem presented in Fig. 1, no evidence for the formation of cyameluric acid or other oxidation products (Scheme 1) was detected.²⁹Open in a separate windowFig. 1FT-IR of the as-synthesized g-C₃N₄ and Melem.In the ¹³C NMR spectrum (Fig. S1^†), two signals at 165.8 and 156 ppm are assigned to carbon atoms adjacent to the amino groups and CN3 groups in heptazine rings, respectively.^1a,5 The ¹H NMR (Fig. S1^†) showed a sharp signal at 7.4 ppm assigned to six protons of the terminal amino groups of melem along with two weak broad signals at ∼8 ppm which can be attributed to the partial protonation of some nitrogens. The lack of the signal at 149.37 ppm in ¹³C NMR^29b and a high-field signal at ¹H NMR (10.9 ppm or higher)³⁰ strongly confirmed that our method precludes the formation of cyameluric acid accompanied by the desired melem.The mass spectrometry depicted in Fig. S2^† shows that the bulk material contains almost entirely monomer melem evidenced by the main peak at m/z 218 pertinent to a single unit of melem and a very little peak at m/z 419 corresponding to dimelem and nothing of higher mass.³¹ Also, no trace of the oxidation products was observed in mass spectra (m/z 129 and 221 for cyanuric and cyameluric acids, respectively).The C/N atomic ratio is one of the most significant clues to prove the successful formation of melem. The ratio of 0.605 found for the produced melem is very close to the theoretical value in the monomer melem (C/N = 0.6).^5,8A substantial evidence for the exclusive formation of monomer melem was achieved by the XRD pattern. Fig. 2 shows XRD patterns of melem and its polymeric graphitic carbon nitride used in this work. A great match with literature was observed.⁵ Two characteristic peaks of g-C₃N₄ at 2θ = 13.28° (100) and 27.47° (002) related to the in-plane structural packing motif, and interlayer-stacking of aromatic systems respectively, significantly changed after treatment with 80 °C concentrated sulfuric acid for 1 h and showed strong evidence for the formation of the monomer melem.^5,8 The former peak (100) became pronounced and shifted to a lower angle of 12.52°, while the latter one (002) was shortened in the melem and shifted to the higher angle of 2θ = 27.6° caused by decreased stacking distance between the melem inter-layers. More important is the emergence of a new intense peak at 6.16°, which is the unique characteristic of monomer melem,⁵ while, other weak peaks located at about 19, 23, 25, 29 and, 31 are almost looked at in the XRD patterns of both monomer and oligomers.^5,8 No trace of cyameluric acid as the possible oxidation product was detected in the XRD pattern of the resulting product.^21c,30Open in a separate windowFig. 2XRD patterns of g-C₃N₄ and the as-synthesized melem.Next, XPS was used to identify the chemical environments of the product as shown in Fig. 3 and S3.^† Only C, N, and trace amounts of O and S caused by the negligible remaining sulfuric acid and water can be detected (Fig. S3^†). The C1s signals (Fig. 3 left) can be fitted into five components with binding energies of 284.5 eV, 285.18 eV, 287.78 eV, 288.58 eV, and 293.58 eV. The C signal at 284.5 eV is exclusively assigned to carbon atoms (C–C bonding) in a pure carbon environment, such as graphitic or amorphous carbons.^26,32 The signals at 285.16 and 287.78–288.3 eV attributed to graphitic carbon sp² C–C, and the sp² trigonal C–N bonding (s-triazine ring), respectively, characteristic of melem structure.^8,33 The advent of a high-energy satellite at 293.7 eV corresponds to the Π-electron delocalization in the heptazine system of melem.²⁷ The N 1s signals (Fig. 3 right) were deconvolved into five peaks. The signals with binding energies of 398.4, 400, and 401–404 eV are associated with the sp²-hybridized nitrogen (C N–C), tertiary nitrogen (N–(C)₃), and protonated amino groups (C–N–H) in melem, respectively.^33a,34 The emergence of (N–(C)₃) undoubtedly indicated the preservation of tri-s-triazine units (C₆N₇, basic part of melem molecule) during treatment with 80 °C concentrated acid. Thus, no significant changes in the carbon nitride heterocycles such as the oxidation transformation of terminal C–NH–C to C–OH–C and/or tri-s-triazine ring-opening reactions occurred.^21c,36 The advent of a satellite at high binding energy of 406 eV corresponds to the partial protonation of some nitrogens (N–H⁺).³⁵Open in a separate windowFig. 3XPS spectra of the as-prepared melem, left: C 1s and right: N 1s.The morphology of the as-synthesized product was determined by FESEM (Fig. 4A). The FESEM images clearly show microsized rectangular prisms with thickness ranging from ∼50 to 350 nm, which was completely different with carbon nitride with the main nanosheets morphology.³⁷ To the best of our knowledge, this is the first report for such a morphology for melem,⁸ that aroused our curiosity to assess its surface properties. The porosity of the samples was determined by N₂ physisorption experiments. The N₂ adsorption/desorption isotherms and pore size distributions of the as-prepared melem are given in Fig. 4B. The sample exhibited typical type IV isotherms with H3 hysteresis loop according to the IUPAC classification,²⁷ suggesting mesoporous structures with slit-shaped pores resulting from the aggregation of plate-like particles.³⁸ The BET specific surface area of the as-synthesized melem was found to be 19.54 m² g⁻¹ which is about 3–4 folds larger than those reported for bulk melems as 5.63 m² g⁻¹,²⁷ and 7.02 m² g⁻¹,¹² as well as melem nanorods as 4.87 m² g⁻¹,⁸ obtained from the condensation of melamine. These results clearly show the superiority of our easy-to-make melem over the other samples obtained by the traditional bottom-up design under quite controlled conditions.^5,8,27 The mesoporous nature of the as-synthesized melem was further supported by the pore-size distribution analysis depicted as an inset of isotherm (in Fig. 4B) indicating an average diameter of pore size at 2.1 nm.Open in a separate windowFig. 4(A) FESEM image and (B) BET N₂ adsorption/desorption isotherms of the as-synthesized melem.The TG analysis of the as-synthesized melem exhibited three mass loss steps (Fig. S4^†). At the first step, the sample lost about 10% of its weight at less than 200 °C caused by removing water and ethanol molecules absorbed during the elution process. The second one was begun at around 240 °C and continued to 500 °C with the evolution of ammonia and small amounts of HCN, attributed to the condensation polymerization of the monomer.The third thermal decomposition was accelerated above 500 °C (with releasing HCN and C₂N₂),⁶ rendering strong evidence for the absence of triazine derivatives (or lower) in the as-prepared product and once again ruled out the tri-s-triazine ring-opening reactions during the synthesis of melem in this work.^21c,39 The high thermal stability of the produced melem,⁶ is comparable with the parent g-C₃N₄, making it more appropriate for comparative studies and applied goals that add further benefits to our sample.Lastly, the optical properties of the sample were evaluated using UV-Vis diffuse reflectance spectroscopy (DRS). As shown in Fig. S5,^† the absorption maximum wavelength of the resulting melem locates at 310 nm coincides with that reported in the literature.^5,40 The band edge of melem shifted to the lower wavelength (380 nm) compared to the polymer g-C₃N₄ (460 nm), caused by decreasing in Π-electron delocalization in the heptazine system of melem which stretches the band gap from 2.7 eV (polymer) to 3.45 eV (monomer melem) in excellent agreement with reported theoretical value for monomer melem (3.497 eV).^5,27 Further support for this claim was obtained by fluorescence spectra. Fig. 5 shows the comparative fluorescence spectra of the as-synthesized melem, under 355 nm light excitation. As shown in Fig. 5, it is found that the fluorescence emission of polymer g-C₃N₄ peaked at 476 nm,^40a shifted to 412 nm in the melem coincide with Ricci report (415 nm).⁴¹ In addition, the photoluminescence intensity of the resulting melem increased significantly compared to polymer g-C₃N₄ in broad agreement with literature indicating that the condensation of melem to g-C₃N₄ causes the weaker photoluminescence.^40aOpen in a separate windowFig. 5Photoluminescence spectra of g-C₃N₄ and the as-synthesized melem under 355 nm light excitation.Finally, our formulation is very simple and robust with respect to processing conditions to overcome the potential scale-up problems to make it operational and amenable to scalability readily. As an example, a 5 fold semi-scaled-up procedure using 1.0 g g-C₃N₄ led to the isolation of the related pure monomer melem in 95% yield within 1 h.In summary, we developed a novel operational protocol for easy gram scale preparation of air-stable monomer melem through a top-down synthesis design with no need for any control conditions and further purification. Our analyses ruled out the presence of the starting polymer as well as the formation of oligomers and oxidation products in the final product highlighting the selectivity of the method toward the monomer of melem. The distinctive nano rectangular prism morphology with desired surface area and thermal stability, as well as the appropriate photoluminescence property qualifies our synthesized melem for applied goals and makes it a promising alternative for catalysis and adsorption processes which is under investigation in our lab.     

Preparation of solution processed photodetectors comprised of two-dimensional tin(ii) sulfide nanosheet thin films assembled via the Langmuir–Blodgett method

We report the manufacture of fully solution processed photodetectors based on two-dimensional tin(ii) sulfide assembled via the Langmuir–Blodgett method. The method we propose can coat a variety of substrates including paper, Si/SiO₂ and flexible polymer allowing for a potentially wide range of applications in future optoelectronic devices.

Norton et al. report the manufacture of fully solution processed photodetectors based on two-dimensional tin(ii) sulfide assembled via the Langmuir–Blodgett method.

Two-dimensional (2D) materials are condensed matter solids formed of crystalline atomic layers held together via weak van der Waals forces.¹ They have a wide range of applications including use as channel materials in transistors,² absorber layers in solar cells,³ light emission,⁴ energy storage⁵ and drug delivery⁶ among others. 2D materials often have different properties from their bulk counterparts such as increased strength⁷ and electrical conductivity.⁸ 2D semiconductors may exhibit a change in electronic states from confinement in 1D.⁹ Thin films are often required for the creation of devices from nanomaterials for practical applications and can often be made into flexible devices such as thin film solar cells¹⁰ or photodetectors.^11,12 Thin film solar cells in particular have several advantages over conventional solar cells including lower materials consumption and are lightweight, yet have the potential for high power conversion efficiency.¹⁰Many of the two-dimensional materials produced thus far have been derived from mechanical exfoliation, where Scotch tape or an equivalent is manually used to remove single crystalline layers from a bulk van der Waals solid followed by transfer to a substrate. Whilst this method in general produces extremely high quality crystalline atomic layers,¹³ and is therefore often used to produce prototype devices, it inherently lacks scalabilty. In order to address the problem of mass manufacture of two dimensional materials, liquid phase exfoliation (LPE) was introduced as a cost effective method for producing two dimensional nanomaterials¹⁴ with the possibility of 100 L scales being produced and production rates up to 5.3 g h⁻¹ demonstrated by Coleman et al. with both NMP and aqueous surfactant solutions utilised.¹⁵ This method also does not require the high temperatures needed for methods such as CVD¹⁶ or transfer between the growth and final substrates. Liquid phase exfoliated nanomaterials are also directly processable from solution.¹⁵ Furthermore, LPE has been shown to be effective for the production of a wide range of 2D materials such as graphene,¹⁵ transition metal dichalcogenides¹⁷ and monochalcogenides such as SnSe.¹⁸Tin(ii) sulfide (SnS) is a van der Waals solid with a puckered ab structure consisting of alternating Sn and S atoms, and is isostructural and isoelectronic with black phosphorus.¹⁹ The bulk material has attracted interest due to its indirect band gap energy of 1.07 eV,²⁰ similar to bulk silicon at 1.14 eV. This band gap energy for SnS is useful for applications such as photodetection²¹ and due to its higher theoretical Shockley–Queisser efficiency limit (24%) for solar cells.²² The liquid phase exfoliation method established by Coleman et al. enables nanosheets to be separated from the bulk into solution utilising matching surface energies of the material and solvent.²³ Liquid phase exfoliation of SnS was first reported by Lewis et al. it was established that as layer number reduced, band gap energy increased, and by tuning layer number the onset of photon absorption can be tuned over the near infrared²³ to visible range.²⁴ Overall, LPE is capable of creating large quantities of nanosheets, with potential for industrial scale production. Liquid phase exfoliated SnS has, for example, recently been used in the creation of photoelectrochemical systems with strong stability under both acidic and alkali conditions.²⁵ Many of the functional devices produced thus far have been derived from micromechanical exfoliation and manual nanomanipulation. A far more elegant solution to producing functional devices is to assemble them from solution, for example Kelly et al. recently reported a transistor based on exfoliated WSe₂ nanosheets.²The Langmuir–Blodgett method involves the use of a trough with a layer of water and controllable barriers to compress the film. Nanomaterials in solution are added to the surface of the water and spread evenly to reduce their surface energy,²⁶ often by using a low surface tension spreading solvent such as chloroform.²⁷ The surface pressure is measured as the film is compressed with the substrate being withdrawn when the film becomes solid.²⁸ The Langmuir–Blodgett method has the advantages of large area deposition and improved control of the film at the nanoscale in comparison to vacuum filtration as well as the advantage of requiring no volatile solvents in comparison to liquid–liquid assembly methods. The use of movable barriers also allows for greater film compression.²⁶This method has been used to assemble large scale films of exfoliated MoS₂ by Zhang et al. MoS₂ was exfoliated using n-butyl lithium followed by solvent exchange. MoS₂ was deposited onto the water surface using a 1 : 1 mix of DMF and dichloroethane. Substrates up to 130 cm² were coated with a surface coverage of 85–95%.²⁶ Collapse mechanisms of MoS₂ Langmuir films have also been studied²⁹ alongside MoS₂ deposition on the surface of water with an upper hexane layer.³⁰ Graphene films have also been prepared using the Langmuir–Blodgett method.³¹ The Langmuir–Blodgett method has been used for the assembly of organo-clay hybrid films via the coating of octadecylammonium chloride in a 4 : 1 chloroform : ethanol solution onto a 2D nanoclay liquid phase exfoliated film using an electrospray method.³² A solvent mix of chloroform and NMP has also been utilised for the deposition of nanosheet films.³³ Recently the Langmuir–Blodget method has been used for the assembly of unmodified clay nanosheets,³⁴ Ti₃C₂Tx MXene nanosheet films for the removal of Cr(vi) and methyl orange from an aqueous environment³⁵ as well as for the growth of rGO wrapped nanostructures for use in electrocatalysts.³⁶Given the chemical similarity of the basal planes of inorganic 2D materials, we hypothesised that the assembly of group IV–VI nanomaterials such as SnS should also be possible at the air water interface. Due to their interesting semiconducting and properties described, it should also be possible to produce prototype optoelectronic devices from a fully solution processed pathway. In this paper we now communicate a methodology to assemble thin films comprised of 2D SnS nanosheets using the Langmuir–Blodgett technique (Scheme 1a). We report the use of these films in simple photodetectors. This represents a scalable methodology to produce fully solution processed devices based on 2D materials.Open in a separate windowScheme 1Preparation of SnS nanosheet thin films via the Langmuir–Blodgett method. (a) Cartoon of Langmuir–Blodgett film preparation. (b) Image of Langmuir–Blodgett trough with compressed SnS film. (c) Surface pressure profile during film compression. (d) Image of sample prepared on Si/SiO₂ substrate with edges masked (scale bar 1.5 cm). Scheme 1(a) shows the step by step process of film preparation. Firstly, bulk SnS is broken down by liquid phase exfoliation from the bulk material to produce a stable dispersion of crystalline nanosheets. Characterisation of the exfoliated nanomaterials was undertaken using atomic force and electron microscopy yielding average sheet dimensions of 23.9 nm height × 224 nm longest side length (Fig. S1^†). The nanosheets were then deposited onto the water air interface. The film is then compressed whilst an immersed substrate is withdrawn, leading to the creation of a densely packed nanosheet film. Scheme 1(b) shows that SnS can be successfully deposited on the water–air interface via the addition of chloroform as a spreading solvent, as shown previously with other Langmuir based films.²⁷Scheme 1(a) shows a z-type deposition of SnS as the hydrophilic glass and Si with a 300 nm oxide layer is withdrawn through the film at 1 atm pressure. The film compression occurred at a rate of 5.88 cm² s⁻¹. No further treatments were performed to change the hydrophilicity of the substrates, the oxide layer present was sufficient to provide hydrophilicity to the substrate.³⁷Scheme 1(c) shows a gradual increase in surface pressure as the area was decreased from 1175 cm² to 298 cm² before a sharp increase in pressure, indicating the film has reached full compression. The sharp increase in surface pressure during compression is common in Langmuir–Blodgett assembled films of nanomaterials.³⁸ In response to compression the surface pressure profile in Scheme 1(c) rises rapidly until it reaches a maximum due to the size of the sheets and the potential difficulty in sliding over each other compared to polymers or smaller nanomaterials. Scheme 1(d) shows that the film is capable of being coated onto Si/SiO₂ with a mask defining the areas covered.We characterised the resulting structural and electronic properties of the thin film of SnS nanosheets deposited via the Langmuir–Blodgett method using a range of techniques. Fig. 1(a) shows a height profile AFM image of a film edge with an average on-film roughness (R_a) of 31.9 nm and an average film thickness of 78.6 nm (Fig S3^† provides an additional film profile). Previous work on Langmuir–Blodgett deposition has produced thinner films. The use of high centrifugation speeds yielded 7 nm thick films for a single deposition³¹ whilst the use of lithium ion intercalation before exfoliation enabled film thicknesses of under 2 nm per layer to be realised.²⁶ The average film thickness is above the average sheet thickness, suggesting that the film is made up of overlapping flake multilayers. However, the thickness of the films is significantly lower than those grown via chemical bath deposition (e.g. 290 nm (ref. 39)) indicating that thinner films can be produced compared to chemical bath methods, and potentially at a much lower cost than methods such as CVD. Images of the film morphology in plan view SEM (Fig. 1(b)) suggest no notable alignment of the nanosheets in the lateral dimension as the film is formed and deposited (see Fig S4^† for statistical analysis of sheet angle measurement). The coverage of the film is 94.6% as determined by image thresholding using imagej software to determine the area left uncovered. This gives a coverage of 0.0142 gm⁻² as calculated from average thickness, SnS density and % coverage of the substrate. Preliminary SEM results also suggest that the Langmuir–Blodgett method is effective at coating SnS onto a variety of substrates including polyolefin films (Parafilm®), aluminium foil and paper (Fig S6^†). We also probed the structure of the thin films by powder X-ray diffraction (XRD). After exfoliation and film assembly, the diffraction peak associated with the (400) of SnS is still the most intense reflection but is characterised by a much larger FWHM compared to that of bulk SnS under the same recording conditions (0.442° ± 18.5% compared to 0.175° ± 5%). This indicates a successful breakdown of the crystal structure and thinning of the material in the (400) plane during exfoliation due to the reduction in long range order⁴⁰ (reflections for bulk SnS are assigned to orthorhombic SnS and indexed in Fig S2^†). The lack of any additional peaks indicates that there has not been any significant degradation of the material to the corresponding oxide which is in agreement with previous works.^24,25 The reflections at 88° and 94° are unlikely to be from crystalline silicon⁴¹ due to the thick oxide layer and low angle of incidence used. We tentatively ascribe these peaks to the 3,0,−3 and 3,2,4 peaks for SnS.⁴¹ However a confident assignment of this reflection requires further studies.Open in a separate windowFig. 1Structural characterisation of SnS nanosheet thin films assembled by the Langmuir-Bllodgett method. (a) AFM image of LB assembled SnS film edge. Inset film profile, scale bar = 10 μm. (b) SEM image of LB assembled film on Si/SiO₂ at 3 kV using secondary electron imaging, scale bar = 1 μm. (c) XRD pattern of coated film and bulk SnS powder, (additional peaks labelled in Fig. S2^†). (d) Raman spectra and for bulk and Langmuir–Blodgett assembled SnS nanosheets. (e) UV-Vis spectra of SnS suspension and deposited SnS film on glass (f) Tauc plot of SnS solution and film.We also characterised the optical properties of the nanosheet thin films using Raman and UV-Vis-NIR absorption spectroscopy. No shifts in the Raman peak positions B₃g, Ag and B₃u from bulk SnS to Langmuir–Blodgett film were observed. The broad feature at around 300 cm⁻¹ for the LB film may potentially be due to SnS₂ and Sn₂S₃ impurities.⁴² It is predicted that due to the lower density compared to SnS⁴³ the impurities may increase in concentration compared to the bulk after centrifugation. These impurities may have significant effects on the efficiency of the devices produced.⁴⁴A shift in peak positions is typically observed in nanomaterials which exhibit quantum confinement,⁴⁵ this occurs at 14 nm for SnS.⁴⁶Fig. 1(e) shows a UV-Vis spectra from which the absorption coefficients at fixed wavelengths may be obtained, for 350 nm, 405 nm, 450 nm, 500 nm, 600 nm and 800 nm the values obtained were: 2.26 × 10⁵ cm⁻¹, 2.21 × 10⁵ cm⁻¹, 2.16 × 10⁵ cm⁻¹, 2.04 × 10⁵ cm⁻¹, 1.67 × 10⁵ cm⁻¹ and 1.05 × 10⁵ cm⁻¹ respectively, this matches well to the absorption coefficients of SnS in literature (greater than 10⁴ cm⁻¹).⁴⁷ It also suggests there may be a greater response at shorter wavelengths. Fig. 1(f) shows a band gap of 0.92 eV for the exfoliated SnS in NMP which is below the expected value of 1.07 eV (ref. 20) although lies within the reasonable error introduced by the use of Tauc plots.⁴⁸ The band gap also matches well with SnS exfoliated in NMP in previous work.²⁴ The band gap of the film appears to change from nanosheet suspension to film in 1(f). This has been observed previously for Langmuir–Blodgett⁴⁹ and other deposited films. It has also been observed that apparent decreases in band gap may occur due to the presence of scattering artefacts within films of nanoscale objects.⁵⁰We then produced simple prototype photodetectors via the printing of Ag nanoparticles to form interdigitated electrodes on top of the SnS nanosheet film. Additionally, SnS films were deposited onto lithographically defined Au interdigitated electrodes for characterisation and referencing to the printed devices.Previously SnS photodetectors have been created via methods such as electron beam deposition,⁵¹ thermal evaporation⁵² and chemical bath deposition.⁵³ The Langmuir–Blodgett method allows SnS to be directly processed into a film from a liquid phase exfoliated solution, allowing them to be produced cheaply and with the potential for scalability.Inset to Fig. 2(a) is an image of an interdigitated Ag electrode SnS photodetector device with an area of 6.4 × 10⁻⁵ m². The electrodes can be clearly identified with an average spacing of 99 μm, and an average RMS edge roughness value of 1.89 μm (determined for individual contact lines using the imageJ ‘analyze_stripes’ plugin⁵⁴ (Fig S7^†)). Fig. 2(a) shows an increase in the slope of the I–V curve in the third quadrant indicating a reduction in resistance under 1 sun illumination (1000 W m⁻²) with the AM1.5 spectrum. No short circuit current under illumination was observed indicating that the device functions as a photoconductor. The non-linear response upon negative biasing is due to initial trap filling which once equilibrium has been reached results in linear device operation. Previously it has been shown that silver diffusion into SnS has an interstitial doping effect, neutralising defect states and lowering the film resistivity.^55,56 It is also possible that the Ag ink morphology and the concentration of nanoparticles in the ink may play an effect on the device properties.⁵⁷ A resistivity of 2.85 × 10⁶ Ω sq⁻¹ was obtained for the device which is significantly higher than SnS films prepared by physical vapour deposition (250 Ω sq⁻¹),⁵⁸ likely due to poor carrier mobility between flakes.Open in a separate windowFig. 2(a) IV curves of printed contacts SnS device under darkness and AM1.5 illumination with inset photograph of pseudo Langmuir–Blodgett device with printed Ag contacts scale bar 5 mm. (b) Device under +40 V bias under fixed darkness/illumination cycle. Fig. 2(b) indicates that a clear response is present under illumination when an external bias is applied (giving a field strength of 0.4 V μm⁻¹). Closer inspection shows a fast and slow decay component following the illumination being blocked. This biexponential decay indicates the capture of trapped carriers and the presence of trap states within the device.^59,60 This again supports the photoconductive nature of the device operation with a rise time of ∼0.22 s and a fall time of ∼2.83 s,⁶¹ both being longer than the shutter closing/opening time of 3.7 ms (which was considered negligible). The rise time is the time taken to get from 10% to 90% of the light current with the fall time being the time taken from 90% of the light current to 10%.Previous work performed by Jiang et al. has shown a slow fall time in Ag/SnS photoconductor devices arising from carrier trapping.⁶² Similarly, in our devices the large rise time may also be due to the presence of a high trap density which must be filled upon light exposure.The mean dark current is 2.78 × 10⁻¹⁰ A with a standard deviation of 2.02 × 10⁻¹¹ A. The mean light current was found to be 3.92 × 10⁻¹⁰ A with a standard deviation of 4.03 × 10⁻¹¹ A. A poor signal to noise ratio appears to be present within the device, possibly due to the large number of SnS nanosheets involved in charge carrier transit, leading to a low signal, hence a low signal to noise ratio. The noise could be reduced via surface passivation⁶³ or the use of a diode like structure to reduce leakage current under reverse bias.⁶⁴ A low responsivity of 2.00 × 10⁻⁹ A W⁻¹ ± 1.5 × 10⁻¹⁰ A W⁻¹ was found for energies above the band gap energy of 0.6 eV for the deposited film.The low responsivity may be due to poor bridging between individual SnS nanosheets and the poor transport of holes between adjacent flakes (hopping) relative to the higher mobility within each flake.⁶⁵ There are potentially hundreds of nanosheets between the contacts as determined by the average length obtained (Fig S1^†). To confirm that the optical response was due to the presence of the SnS a reference device was tested (without SnS deposition, Fig S8^†) with no photoresponse observed. Despite the low responsivity, it is notable that the SnS devices fabricated are one of the few examples of a thin film photodetector device based on 2D materials requiring only solution processing at ambient temperature and atmospheric pressure.To demonstrate that the observed behaviour originates from the photoresponse of the SnS flakes a second device was fabricated by pseudo Langmuir–Blodgett deposition on to lithographically defined Au interdigitated electrodes (15 μm separation) on fused silica (inset Fig. 3(b)). This enabled us to remove any effect of photoinduced Ag migration from the observed behaviour as well as eliminating the issue of potential printing irregularities. Fig. 3(a) shows that the devices display a similar photoresponse to the devices with printed Ag electrodes when exposed to modulated AM1.5 illumination. The dark current remains similar at ∼0.3 nA, though during illumination the current is higher (0.7 nA vs. 0.4 nA). This increase directly correlates to the higher electric field strength (0.66 V μm⁻¹vs. 0.4 V μm⁻¹) between the interdigitated electrodes. The responsivity of the device was determined to be 1.79 × 10⁻⁸ A W⁻¹, with a photoresponse rise and fall time of 0.77 s and 0.85 s respectively. The responsivity is lower than for photodetectors prepared by Guo et al.⁶⁶ Improvements to the device to improve the responsivity could include methods to improve the lateral size of nanosheets such as intercalation.⁶⁷ Other routes to improve the device may include doping^68,69 or a change in architecture to a phototransistor type device.⁷⁰ The removal of potential SnS₂ and Sn₂S₃ impurities via methods such as annealing at 500 °C, 500 mbar pressure under argon or the use of higher quality starting material may also be a key route to improve the efficiency of the device.⁴²Open in a separate windowFig. 3(a) Device under 30 s off, 30 s on solar simulator illumination at 1 sun and 10 V bias (b) IV curves under darkness and 350 nm illumination with inset optical microscopy image of contacts (c) monochromatic illumination responses under 10 V bias mapped onto UV-Vis transmission spectra (d) device response under fixed 10 V bias under 350 nm and 405 nm monochromatic illumination.It is also noticeable that the level of noise present in Fig. 3(a) is reduced compared to that in Fig. 2(b), indicating that the Ag electrodes themselves (in addition to the SnS sheets) also affect the performance.When exciting using AM1.5 illumination it is possible that thermal effects may be present which could give rise to the observed behaviour.In order to demonstrate a true photoresponse monochromatic illumination was used to determine if illumination energies above the band gap generated a photocurrent response in the device. Fig. 3(b) shows a small response under 350 nm (3.54 eV) illumination. (IV curves for other wavelengths are available in Fig. S9^†). Fig. 3(c) shows an increased response for 350 nm wavelength as determined via the IV curves. This increased response is likely due to increased absorption as shown in the UV-Vis spectra (Fig. 1e), the signal at longer wavelengths is difficult to observe due to the low responsivity. A higher response at lower wavelength has been observed previously for SnS.⁵³ Fig. 3(d) shows that an increase in current is present under 350 nm and 405 nm illumination which can be cycled on and off. A rise and fall time of 1.09 of 1.44 seconds respectively was observed for 405 nm illumination. A light/dark current ratio of 1.03 was obtained under 405 nm. To account for noise the on and off section had their current averaged using origin software. A drift in current during measurement was observed, this was considered as the reason for the significant difference between the dark current for 350 nm and 405 nm. To further reduce noise surface passivation may also be used to improve the device properties.⁶³ Alternatively, an increase in bias voltage or an increase in monochromatic illumination intensity may improve the signal: noise ratio though may risk damage to the device. A magnified off/on cycle for 405 nm is shown in Fig. S10.^†In conclusion, we report here a methodology for the assembly of 2D SnS nanosheets into thin films using the Langmuir–Blodgett method, and the testing of the films as prototype all-solution processed photodetectors. Tin(ii) sulfide was successfully exfoliated with an average sheet thickness of 33 nm with the average longest side length of 224 nm. A nanosheet based film was coated onto a variety of substrates via the Langmuir–Blodgett method with the addition of chloroform as a spreading solvent. The films were found to be polycrystalline with an average thickness of 78.6 nm with a high surface coverage up to 94.6% for an Si/SiO₂ substrate. The films were found to be semiconductive with the ability to respond to light under bias as shown by AM1.5 and monochromatic illumination. Proof-of-concept photodetectors have been successfully produced. It was also confirmed that the response was due to the photoresponse as opposed to a heating effect. This deposition method could potentially be used to create a variety of SnS films using different exfoliated nanosheet sizes separated via cascade centrifugation as well as the potential for future flexible photodetector devices. Despite the low responsivity, large rise and fall times further work could allow the gain to be optimised. We also note that the use of the Langmuir–Blodgett trough is an easily scalable technology and could provide coatings over very large area substrates not only for photodetectors but for other devices such as thin film solar cells.     

Hyperpolarization study on remdesivir with its biological reaction monitoring via signal amplification by reversible exchange

Our experiments indicate hyperpolarized proton signals in the entire structure of remdesivir are obtained due to a long-distance polarization transfer by para-hydrogen. SABRE-based biological real-time reaction monitoring, by using a protein enzyme under mild conditions is carried out. It represents the first successful para-hydrogen based hyperpolarization application in biological reaction monitoring.

Hyperpolarized proton signals in the entire structure of remdesivir are obtained due to a long-distance polarization transfer by para-hydrogen. Biological real-time reaction monitoring, by using a protein enzyme under mild conditions is carried out.

Nuclear magnetic resonance is a versatile and powerful analytical method for real-time monitoring of significant bio-catalyzed reactions. However, even though NMR has great potential as a reaction monitoring system, providing much structural information, it has not been studied in depth due to low sensitivity. To enhance the sensitivity, the hyperpolarization technique has been suggested which has long been acknowledged as a breakthrough in reaction monitoring by NMR.There are major hyperpolarization techniques, generating non-Boltzmann population distribution for hyperpolarized signal to noise such as dynamic nuclear polarization,^1–5 spin-exchange optical pumping,^6–8para-hydrogen induced polarization (PHIP),^9–11 and signal amplification by reversible exchange (SABRE).^12–14 In the case of para-hydrogen-based SABRE, the substrate and the para-hydrogen bind to a catalyzing metal complex together, thus allowing polarization to be transferred to the substrate through scalar coupling. To achieve better enhancement, the iridium N-heterocyclic carbene complex¹⁵ exhibits the highest polarization transfer efficiency, which delivering an 8100-fold enhancement in ¹H NMR signal amplification relative to non-hyperpolarized pyridine. Additionally, enhancements can be increased by employing the bulky electron-donating phosphines of the Crabtree catalyst.¹⁶ Most iridium N-heterocyclic carbene catalysts are produced as [Ir(H)₂(NHC)(substrate)₃]Cl while they are capable of delivering various NMR signal gains such as ¹H,^17–1913C,^9,20,2115N,^22–2419F,^25,2631P.²⁷ Recently, a published work has described the extension of the SABRE substrate scope to include a wide range of common drugs such as tuberculosis drugs,²⁸ antifungal,²⁹ and antibiotic agents.^30,31 It is mainly N-heterocyclic compounds with low molecular weight. Hyperpolarization experiments using large molecular weight COVID-19 drug candidates have rarely been reported.³² Here, we extend the current scope of biologically relevant SABRE substrates to remdesivir and monitor its enzymatic hydrolysis.SABRE has been widely considered as a potentially promising reaction monitoring tool for the real-time reaction via hyperpolarization.^33,34 After its successful application on the amide-coupling reaction monitoring, it could not be applied to the biological reaction monitoring due to the solvent used for the reaction, mild biological reaction conditions, and mostly, small molecule polarization capacity. Therefore, its direct application on the biological reaction could open up new possibilities in the real-time reaction monitoring via hyperpolarization.To overcome this COVID-19 pandemic, many researchers have engaged in drug development including drug repurposing. Recently, remdesivir has received emergency use authorization from the FDA, as the first organic medicine to treat COVID-19 around the world. Its prodrug form has been controversial as its intact form is not detectable even after two hours post-injection and as its efficiency for all clinical treatment should also be catalyzed by several key biological reactions including esterase hydrolysis reaction.^35–37 Therefore, further research on its molecular level of understanding is still required for enhanced drug development. Along with that, repurposing nucleoside analogue drugs have been considered as the attractive future drug candidates to overcome this pandemic and beyond. They target the RNA polymerase and prevent viral RNA synthesis in a broad spectrum of RNA viruses, including human coronaviruses.^38,39 Thus, to develop the most appropriate repurposing nucleoside analogue drug candidates for COVID-19, in-depth timely research on its pharmacokinetics and pharmacodynamics at the molecular level is also essential to overcome this pandemic and its consequent recurrences.In our previous study, we reported the hyperpolarization on the several anti-viral drug candidates of COVID-19.³² However, these drug candidates have been reported rather ineffective in treating COVID-19.⁴⁰ Furthermore, even though those unprecedented hyperpolarization on the large drug molecules are new, their polarizations are only done in methanol solvent, which is not applicable in a biological form.³² Our research results indicate successful hyperpolarization of remdesivir via SABRE under mild conditions and hyperpolarization performed in DMSO, a more non-toxic solvent for in vitro application. To provide a more clinical perspective of using this technique, its biological reaction by enzyme was successfully monitored by signal enhancement via SABRE. Moreover, to widen its future applications, we added one more Ir-catalyst by matching external magnetic field condition for efficient polarization transfer to remdesivir. Our findings will expand newly applicable research areas, not only in biological reaction monitoring via NMR, but also in other biomedicine research, in order to cope with dreadful diseases in the future.Remdesivir structure has several potential key polarization sources for SABRE: nitrile, amine, and triazine. However, its complex structure and large molecular weight have been considered as the limiting factors for hyperpolarization. Fig. 1 depicts the normal signal and its hyperpolarized signal after SABRE using IMes-Ir-catalyst, which shows the different extent of hyperpolarization of remdesivir. Among the amplified proton signals, proton 6 represents the highest hyperpolarization attached to the 5′-carbon of the nucleoside. However, its polarization indicates no major difference compared to those protons in the whole structure.Open in a separate windowFig. 1Remdesivir molecular structure and its normal ¹H NMR signal in the methanol-d₄ solvent (black spectrum). Hyperpolarized signals from remdesivir after SABRE in the presence of 130 G external magnetic field in the methanol-d₄ solvent (red spectrum).Therefore, we can anticipate its polarization transfer is mostly from the SABRE-Relay^41–43 or SPINOE,^44–46 which are discussed more on conclusion. To optimize hyperpolarization, the external magnetic field is changed, and its polarization is maximized at around 130 G.However, no major difference was noted in the extent of hyperpolarization in different magnetic fields, which could have been due to Ir-catalyst''s fast exchange. Furthermore, its polarization transfer could be from other factors such as SPINOE, other than from the Zeeman effect and J-coupling matching condition. Referring to a recent study on the SABRE hyperpolarization difference between Ir-catalysts,⁴⁷ we tested the SABRE with Crabtree''s-Ir-catalyst, which indicates the different polarization number. Interestingly, its polarization confirmed that the number of hyperpolarization using the Crabtree''s-Ir-catalyst was slightly higher than IMes-Ir-catalyst. The hyperpolarization patterns in the different magnetic field also present no major changes from the different Ir-catalyst (Fig. 2 and S1^† for structures of Ir-catalysts). Remdesivir is considered to be one of the most important treatments amid this pandemic due to its usage in blocking viral RNA production, leading to an additional study on hyperpolarization in which a more biological solvent has been conducted. Interestingly, SABRE in the CD₃SOCD₃ with IMes-Ir-catalyst shows the highest polarization efficiency with approximately 17-fold enhanced signal (Fig. 3). DMSO has various biological impacts, such as the ability to increase the skin penetration of chemicals. It can pass through biological membranes, including human skin, probably by changing lipid packing structure and producing breaks in the bilayer.^48,49 This result observed in the current research opens a new possibility for applying the in vitro experiment with biological tests since DMSO has been widely used in the in vitro drug test.^50,51 Its polarization result of remdesivir among the Ir-catalyst led to higher IMes-Ir-catalyst than Crabtree''s-Ir-catalyst, different from the CD₃OD. This indicates the polarization transfer mechanism with chelating structure is not solely dependent on the solvent or catalyst. Furthermore, the polarization trend in its structure is the highest in the proton of 9, followed by the proton of 5, which bonded with 5′-carbon of the nucleoside. This different trend in each Ir-catalyst indicates that the polarization transfer efficiency varies depending on solvents in different external magnetic fields and different solvent systems.Open in a separate windowFig. 2Signal amplification value (SE) of individual protons from hyperpolarized remdesivir using IMes-Ir-catalyst and Crabree''s-Ir-catalyst.Open in a separate windowFig. 3(a) ¹H spectrum of remdesivir before (black spectrum) and after SABRE (red spectrum) in the DMSO-d₆; (b) signal amplification value (SE) of individual protons from hyperpolarized remdesivir using IMes-Ir-catalyst and Crabtree''s-Ir-catalyst.Remdesivir activates analogue, inhibits RNA-dependent RNA polymerase, and prevents viral RNA synthesis as a phosphoramidate prodrug.⁵² The activation pathway of remdesivir has been proposed to have four steps: (1) cell entrance; (2) enzymatic elimination of masking group with 2-ethylbutyl ester and phenoxy; (3) phosphorylation; and (4) incorporation into COVID-19 RNA.⁵³ The masking group of remdesivir performs increasing hydrophobicity to facilitate cellular entry.⁵⁴ Also its inventor found that the proton of 7 was shifted to 3 to 4 ppm when the masking group of remdesivir was removed.^55,56 Monitoring hydrolysis of a 2-ethylbutyl ester by esterase confirmed the proton of 7* in 3.2 ppm via hyperpolarization (Fig. 4a). The splitting pattern of 7* is controversial because of its doublet instead of quartet. It attributes to several factors. Because of the 5-membered ring intermediate from remdesivir, the splitting pattern of 7* could be affected. The initial metabolism of remdesivir produces an intermediate of cyclopentane containing 7* is made.⁵⁷ Therefore, stereochemical relations in the equilibrium among protons in 5-membered rings cannot be determined by simply measuring coupling constants, except in cases where the substitution pattern of the specific ring system has been carefully investigated. It could be covered by a water peak close to 7*. Another possibility is that hyperpolarized proton 8 of the 2-ethyl butyl group that is released by enzymatic hydrolysis can be observed. However, the cleavage of the phenoxy group is hard to prove via spectra due to little variation in the signal of aromatic region (Fig. S2^†). Its normal cleaved remdesivir signal after the same reaction time and condition was not shown in a scan and its maximum polarization was calculated by ∼22 enhancement after comparing with the multiple scan average (Fig. 4b and S3^†). To the best of our knowledge, this is the first study that conducts hyperpolarization reaction monitoring via SABRE in biological condition is conducted for the first time. Furthermore, its NMR-based reaction monitoring on a biologically important prodrug suggests that significantly wide applications in biomedical research. Its application can be significantly widened in the biomedical researches.Open in a separate windowFig. 4(a) ¹H spectra of enzymatic hydrolysis monitoring of remdesivir; elimination of 2-ethylbutyl ester group; (b) ¹H spectra of remdesivir; enzymatic hydrolysis after 120 min (black spectrum) and amplified through hyperpolarization (red spectrum) at the same time.     

E–Z isomerization of 3-benzylidene-indolin-2-ones using a microfluidic photo-reactor

Here, we report controlled E–Z isomeric motion of the functionalized 3-benzylidene-indolin-2-ones under various solvents, temperature, light sources, and most importantly effective enhancement of light irradiance in microfluidic photoreactor conditions. Stabilization of the E–Z isomeric motion is failed in batch process, which might be due to the exponential decay of light intensity, variable irradiation, low mixing, low heat exchange, low photon flux etc. This photo-μ-flow light driven motion is further extended to the establishment of a photostationary state under solar light irradiation.

(E)-3-Benzylidene-indolin-2-ones were efficiently converted to their corresponding (Z) -isomers at low temperature in the presence of light.

Functionalized 3-benzylidene-indolin-2-ones are an important structural motif in organic chemistry and are embedded in many naturally occurring compounds.¹ They found wide applications in molecular-motors,² energy harvesting dyes,³ pharmaceutical chemistry (sunitinib, tenidap),⁴ protein kinase inhibitors,⁵ pesticides,⁶ flavors,⁷ and the fragrance industry.⁸ In the last few decades, numerous protocols have been developed for the synthesis of novel indolin-2-ones. For instance, palladium (Pd)-catalysed intramolecular hydroarylation of N-arylpropiolamides,⁹ Knoevenagel condensation of oxindole and aldehyde,¹⁰ two-step protocols such as Ni-catalyzed CO₂ insertion followed by coupling reaction,¹¹ Pd-catalysed C–H functionalization/intramolecular alkenylation,¹² Pd(0)/monophosphine-promoted ring–forming reaction of 2-(alkynyl)aryl isocyanates with organoboron compound, and others.¹³Knoevenagel condensation is one of the best methods for the preparation of 3-benzylidene-indolin-2-ones, but often it gives mixture of E/Z isomeric products. Otherwise, noble metal-catalysed protocols received enormous interest. However, the limited availability, high price, and toxicity of these metals diminished their usage in industrial applications. Therefore, several research groups have been engaged in search of an alternative greener and cleaner approach under metal-free conditions. To address the diastereoisomeric issue, Tacconi et al. reported a thermal (300–310 °C) isomerization reaction of 3-arylidene-1,3-dihydroindol-2-ones,¹⁴ which suffers from poor reaction efficiency and E/Z selectivity. Therefore, transformations controlling E/Z ratio of 3-benzylidene-indolin-2-ones remains a challenging task and highly desirable (Scheme 1).Open in a separate windowScheme 1Functionalized 3-benzylidene-indolin-2-ones and alkenes in bioactive compounds and the accessible methods.On the other hand, selective E/Z stereo-isomerization of alkenes has been well established using various methods in the presence of light stimuli,^15a cations,^15b halogens or elemental selenium,¹⁶ palladium-hydride catalyst,¹⁰ cobalt-catalyst,¹⁷ Ir-catalyst,¹⁸ organo-catalysts.¹⁹ Among these, light-induced photostationary E/Z stereoisomerization is very attractive, due to its close proximity towards the natural process. In recent years, several light-driven molecular motors (controlled motion at the molecular level), molecular propellers,²⁰ switches,²¹ brakes,²² turnstiles,²³ shuttles,²⁴ scissors,²⁵ elevators,²⁶ rotating modules,²⁷ muscles,²⁸ rotors,²⁹ ratchets,³⁰ and catalytic self-propelled objects have been developed.³¹ Further, equipment''s relying on molecular mechanics were rapidly developed, particularly in the area of health care.Till date, controlled photo-isomerization of functionalized 3-benzylidene-indolin-2-ones is one of the puzzling problems to the scientific community. Photochemical reactions in batch process have serious drawbacks with limited hot-spot zone due to inefficient light penetration with increasing light path distance through the absorbing media, and the situation becomes poorer when the reactor size increases.^32,33 In contrast, the capillary microreactor platform has emerged as an efficient the artificial tool with impressive advantages, such as excellent photon flux, uniform irradiation, compatibility with multi-step syntheses, excellent mass and heat transfer, which lead to significant decrease the reaction time with improved yield or selectivity over batch reactors.^33a,34 To address the aforementioned challenges, it is essential to develop a highly efficient photo-microchemical flow approach for the controlled isomerization of functionalized 3-benzylidene-indolin-2-ones in catalyst-free and an environment friendly manner.     

Retracted Article: Facile preparation of bithiazole-based material for inkjet printed light-emitting electrochemical cell

Light-emitting electrochemical cell of bithiazole-based material was fabricated by solution processing rendered high external quantum efficiency over 12.8% and luminance of 1.8 10⁴ cd m⁻².

Light-emitting electrochemical cell of bithiazole-based material was fabricated by solution processing rendered high external quantum efficiency over 12.8% and luminance of 1.8 10⁴ cd m^−2.

It is well known that inkjet printing works as precise and versatile patterning method for printed electronics.^1,2 As for its advantages, it is already being exploited widespread for printing electronics.^3,4 Those merits are easily processed from solutions and conveniently used for air-stable electrodes.^5,6Light-emitting electrochemical cells (LECs) have emerged as an active layer,^7,8 arousing tremendous attention over the years.^9–11 Nevertheless, LECs are simpler than organic light-emitting diodes (OLEDs).^12,13 Due to its single layer architecture, low fabrication price and operating voltages, LECs are considered as a promising, next-generation, emissive thin-film technology.^14–16The most efficient device used to date for LECs are biscyclometalated iridium(iii) (Ir) complexes, because they have highly efficient and stable devices spanning the whole visible range.^17–19 However, avoiding the use of Ir is strongly desired because of its high cost and limited supply.^20–22 Till now, thiazole has worked as active component in a LECs system with a long-lived charge-separation molecule, without additional ions in its active layer.^23–26 As for its advantages, it can reduce recombination of charge carriers and facilitate carrier transfer.^27–29 More and more importance has been attached to thiazole compounds, especially bithiazole-based ones.^30–33 Therefore, these have aroused interest in the syntheses of bithiazoles.^34–36Based on our previous research,^37–41 the use of bithiazole ligands already explored by our group for photocatalytic technology has the advantage of an easy transformation of neutral complexes into charged ones by substitution on the N-atom of the thiazole moiety.^42,43 Furthermore, we demonstrate the fabrication of LEC devices by a combination of inkjet printing and spin coating, on A4 paper substrates for low cost, disposable and flexible conductive pattern.^44,45 Their corresponding material characteristics were closely investigated, a detailed report of the material properties of the resulting coatings, and an envisaged proof of concept application are disclosed in this paper. These fully printed devices demonstrate the potential upscaling of the fabrication of optoelectronic devices.Herein we report the design for a range of bithiazole derivatives 1a–1c (Fig. 1, their synthesis is shown in Scheme S1^†), and explore their properties. First of all, the UV-visible diffuse-reflectance (UV-vis DRS) spectra of those specimens at room temperature are displayed in Fig. 2 and the data are collected in Table S1.^† This enhancement was ascribed to the increase of aromatic rings, which has an intense absorption in the visible-light region. And their bandgap energies (E_g) are between 2.97–3.01 eV (Table S1^†), and are estimated from these absorption spectra according to the Kubelka–Munk method. Expanding the conjugated system and electron density with these donor groups, it can lead to a larger bathochromic shift of the absorption maximum.^46,47Open in a separate windowFig. 1Chemical structures of compounds 1a–1c described in this work.Open in a separate windowFig. 2UV-vis DRS spectra of 1a–1c.All of the three compounds are photoluminescent at room temperature, the relevant fluorescence peak maximum ranges from 360 to 398 nm (Fig. 3). They emit blue light when they are being excited. In agreement with Fig. 3, the presence of electron-releasing groups would shift the emission maximum. Among them, the most electron-donating carbazole unit would give the most red-shifted peak at 398 nm for 1c (Table S1^†). The PL quantum yield (ϕ_PL) studies show that both 1a and 1b are as high as 62 and 78%, while another one is 85% (Table S1^†). The data for their fluorescent quantum yields largely depends on interaction effect with molecules 1a–1c in the crystal packing. In this context, π–π intermolecular interactions can inhibit the fluorescence.⁴⁸Open in a separate windowFig. 3Typical PL spectra of 1a–1c.It may indicate that enlarging the conjugation length and electron density with these donor groups plays an important role in increasing the ϕ_PL.⁴⁹ Moreover, those with high ϕ_PL may be suitable for application as efficient light-emitting material in LECs.⁵⁰In addition, time-resolved measurements of the donor lifetime (τ) in 1a–1c were carried out, and their corresponding values are given in Table S1.^† The bithiazole derivatives 1a–1c showed long-lived singlet fluorescence lifetimes (τ_F), ranging between 1.04 and 9.54 ns (Table S1^†). This was on average more than double the fluorescence lifetime of the bithiazole starting material.⁵¹ These three samples possess relatively high decay time, as a result of their inhomogeneity.⁵² Compound 1c exhibited the longest fluorescence lifetime decay τ_F = 9.54 ns. The sensitivity of the emission to the polarity of the solvent is beneficial for an intramolecular charge transfer (ICT)-like emission.⁵³ This difference probably accounts for the high concentration of donor units in the bithiazole backbone, low rates of intersystem crossing to reactive triplet states.^48,54Consequently, the composite 1c was the best performing LEC and chosen for the below test. The EL spectra obtained for both devices were almost identical, with a main peak at 498 nm and other peak at 504 nm wavelength as illustrated in Fig. 4a. It may account for trapping, cavity, and self-absorption effects from within the LEC device 1c multilayer-structure. The spin-coated emission is quantified by the commission Internationale de L’Eclairage (CIE) coordinates of (0.28, 0.42), and a colour rendering index (CRI) of 65 (Table S2^†). While inkjet-printed light emission with CIE coordinates of (0.34, 0.43) and a CRI value of 83 was achieved for device 1c (Table S2^†). It exhibits good colour rendering indices (CRI > 70), this device exhibited a warm-white appearance, and the colour rendering is considered sufficient for indoor lighting applications.Open in a separate windowFig. 4Comparison of device characteristics with spin-cast and inkjet printer emitting layer for 1c: (a) electroluminescent spectra, (b) luminance vs. voltage, (c) current density vs. voltage, (d) efficiency vs. luminance behaviour.The time-dependent brightness and current density under constant biases of 2.9–3.3 V for device 1c are shown in Fig. 4b and c. Interestingly, the device with the inkjet-printed emitting layer (EML) produced a light output of around 3600 cd m⁻², whereas 4600 cd m⁻² was achieved with the spin-coated EML. In other words, the device with the inkjet printed EML obtained about 78.3% of brightness compared with the reference device. The differences between the two devices regarding current efficiency (J) and power efficiency (PE) were rather closed, as listed in the Table S2.^† A luminous efficiency much larger than 10 cd A⁻¹ was achieved for the inkjet-printed EML, which tended to be 73.9%, and is similar to the spin-coated emitting layer.The performance gap between the devices (Fig. 4d) can be attributed to differences in the height and surface roughness of the emitting layer.⁵⁵ Lateral sizing histograms (Fig. S11^†) show that the spin-coated EML possessed a thickness of 35 nm and a very smooth surface. The inferior performance of the inkjet-printed EML is caused by a less homogeneous surface morphology and an overall fatter layer.⁵⁶ The depth of the inkjet-printed EML ranged from 25 nm (pixel centre) to 35 nm (pixel edges). As a consequence, it is an inkjet deposition process and the related evaporation dynamics reduces the light output and efficiency, but also postpones the stability of the device in the system.^10,57We then shifted our attention to the turn-on kinetics, efficiency and long-term stability of the LEC device for 1c; the typical evolution of current density and light emission is presented in Fig. 5a and b, showing a slow turn-on followed by a progressive decay over time.Open in a separate windowFig. 5(a) Current density (closed symbols) and brightness (open symbols) versus time at 3 V for a device with the representative sample 1c; (b) EQE versus time at an applied voltage of 3 V.The build-up of the light output is synchronous with that of the current density. This time-delayed response is one of the striking features of the operation of an electrochemical cell and reflects the mechanism of device operation.²² The champion device in this set exhibited a peak power efficiency (PE) of 17.4 lm W⁻¹ at a luminance of 18 000 cd m⁻². Meanwhile, the current density began to decrease, possibly due to the electrochemical oxidation or electro corrosion that occurred on component 1c through accumulated electroinduced holes, and then it kept up a durative datum.⁵⁸ Apparently it exhibited outstanding long-term operation stability beyond 40 h (Fig. 5b).The time-dependent external quantum efficiency (EQE) of LEC for the representative substrate 1c are shown in Fig. 5b. It also exhibited similar temporal tendency in device efficiency. When a bias was applied on the LECs, the EQE quickly increased since balanced carrier injection was achieved by the formation of the doped layers.⁵⁹ After attaining the crest value, the device current was still rising while the EQE reduced little by little. It implied that both growing the doped layers and weakening of the EQE was resulting from exciton quenching near the bithiazlole core in persistently extended doped layers.⁶⁰ Doping-induced self-absorption was rather adaptable to the temporal roll-off in device efficiency. This configuration shows the best performance (EQE = 12.8%) compared to those devices prepared with the single compounds, which is given in Table S3.^† The reason may be that the steady-state recombination zone in 1c device was close to the central active layer.⁶¹ Besides it contains fluorenes on its side chains, constructing plane structure, benefiting from good electron injection abilities, leading to enhancing the EQE itself.⁶²The fabrication of inkjet-printed bithiazole interdigitated electrode (IDE) is illustrated in Fig. 6. All the prepared varieties of bithiazole-based ink have been found to be highly stable with nil or miniscule precipitation in over 180 days being stored on the shelf (Fig. 6a). After HCl treatment of the paper substrate, the prepared inks have filled within ink cartridges of a low-cost desktop printer Canon iP1188 (Fig. 6b). Fig. 6c shows the photograph of inkjet-printed conductive patterns.Open in a separate windowFig. 6(a) The representative ink based on sample 1c was stable for 180 days; (b) electrode printing using Canon iP1188 printer; (c) scale showing size of printed electrodes; (d) interdigitated electrode (inset shows small size printed pattern).In addition, the most attractive prospect of the bilayer device structure at this stage is the possibility for patterned emission for the creation of a static display. Fig. 7 presents a photograph of a small portion of a larger static display, with a resolution of 170 PPI, which repeatedly exhibits a message in the form of the word “LEC”. As shown in Fig. 7, the pixel array produced are fairly luminous. The EL spectra were collected from each pixel on the substrate, the emission peak wavelength was about 510 nm and the full width at half maximum was about 170 nm. The low variation in emission intensity in the different pixels implies a small variation in thickness of the solution-coated layers. More specifically, if we assume a minimum diameter of 20 μm for an inkjetted electrolyte droplet, and a smallest inter-droplet distance of 10 μm, we attain a pitch of 30 μm, which corresponds to a high display resolution of 850 PPI. Finally, we draw attention to the herein presented static-display LEC that comprises solely air-stabile materials, and that we routinely fabricate the bilayer stack under ambient atmosphere.Open in a separate windowFig. 7(a) The patterned light emission from a bilayer LEC, with the emission pattern defined by the selected positions of the ink jetted electrolyte droplets. (b) The droplet diameter and pitch were 50 and 150 μm, respectively, and the device was driven at V = 3 V. The scale bar measures 300 μm.     

Synthesis of a metal–organic framework by plasma in liquid to increase reduced metal ions and enhance water stability

Synthesis of a metal–organic framework by plasma in liquid was demonstrated with HKUST-1 as an example. HKUST-1 synthesized by this method contains a higher amount of monovalent copper ions than that synthesized by other conventional methods. The enhanced water stability was also confirmed.

Plasma in liquid provides a method for the synthesis of HKUST-1 with increased reduced metal ions and high water stability.

Metal–organic frameworks (MOFs) are a class of hybrid materials composed of organic linkers and metal nodes. They have high surface areas with tunable pore size and functionality.^1,2 Because of these features, MOFs have potential applications in the fields of gas adsorption/storage,^3,4 catalysis,^5,6 drug delivery,^7,8 and fabrication of luminescent materials.^9,10 Many methods have been proposed for synthesizing MOFs; these include solvothermal methods,^11,12 microwave-assisted methods,^13,14 ultrasonic-assisted methods,^15,16 mechanochemical methods,¹⁷ and electrosynthesis methods.¹⁸ Different synthesis methods result in the different crystallinity and size. Further, the synthesis method can influence the physicochemical and semiconductor properties.¹⁹Recently, a method for synthesizing MOFs in liquid contacting gas-phase dielectric barrier discharges has been reported.^20,21 However, MOFs synthesized by plasma have not been sufficiently characterized yet, thereby demanding further research. Plasma is a unique reaction field and has the advantage of being able to reduce and functionalize species using electrons and radicals. These characteristics have been widely utilized even in liquid phase for the synthesis of various materials such as carbon materials^22,23 and metal nanoparticles^24,25 and for introducing functional groups in materials.²⁶ Using plasma, it may be possible to synthesize functional MOFs with reduced metal ions or additional functional groups. Plasma in liquid generally have higher density of electrons and radicals than plasma in the gas phase,²⁷ and the influence of reactive species can be observed more prominently.In this study, we focused on [Cu₃(BTC)₂]_n (BTC = 1,3,5-benzenetricarboxylate). This is known as HKUST-1 and is one of the most widely researched MOFs. This MOF is assembled from copper nodes and BTC, with each copper coordinated with four oxygen atoms. HKUST-1 is a promising candidate for applications such as H₂ and SO₂ storage.^28,29 However, the crystal structure of HKUST-1 is changed by water molecules, and its surface area decreases.^30,31 To ensure the practical applications of HKUST-1, it is important to increase its resistance to water. To improve its stability to water, strategies such as incorporation of other materials, including graphite oxide³² and carboxyl-functionalized attapulgite,³³ have been developed. In the post-processing using plasma, the adsorption of water molecules on HKUST-1 is inhibited by introducing hydrophobic groups with perfluorohexane.³⁴ In another method, the adsorption of water molecules on unsaturated metal sites was prevented by irradiating the HKUST-1 with oxygen plasma.³⁵ In addition, to improve the water tolerance, reduction of Cu(ii) ions in HKUST-1 was also proposed.³⁶ However, in the above-mentioned methods, mixing of other materials or post-treatment steps was essential.In this work, we synthesized HKUST-1 containing Cu(i) by plasma in liquid; the method involved in situ plasma treatment during the synthesis activated also by plasma. Its resistance to water was compared with HKUST-1 synthesized by conventional methods such as heating or addition of triethylamine at room temperature.HKUST-1 was synthesized using the plasma generated by applying a bipolar pulse voltage to the electrode in an ethanol–water solution containing copper nitrate trihydrate and BTC (Fig. S1 and S2^†). Hereafter in this paper, the thus-synthesized HKUST-1 will be referred to as PL-HKUST-1. For comparison, HKUST-1 was synthesized by the conventional heating method and by the addition of triethylamine at room temperature,¹⁹ and the HKUST-1 formed are referred to as CH-HKUST-1 and RT-HKUST-1, respectively. The details of the synthetic methods are described in the ESI.^†All the samples were characterized by X-ray diffraction (XRD) and thermogravimetric analysis. The XRD patterns of CH-HKUST-1, RT-HKUST-1, and PL-HKUST-1 are shown in Fig. 1. In all the cases, the characteristic diffraction peaks of HKUST-1 were identified, confirming the phase-pure formation of HKUST-1 samples irrespective of the synthetic method.^37,38 Thermogravimetric analysis of HKUST-1 revealed that the thermal stability of PL-HKUST-1 was similar to those of CH-HKUST-1 and RT-HKUST-1 (Fig. S3^†).Open in a separate windowFig. 1XRD patterns of CH-HKUST-1, RT-HKUST-1, and PL-HKUST-1 before and after immersion in water. Fig. 2 shows the fluorescence (FL) spectra of CH-HKUST-1, RT-HKUST-1, and PL-HKUST-1 upon excitation at 310 nm at room temperature. Note that a broad peak around 520 nm was observed only for PL-HKUST-1 and not for CH-HKUST-1 and RT-HKUST-1. Such a behavior has been previously reported for Cu(i) complexes and is attributed to the metal-to-ligand charge transfer (MLCT) from Cu(i) to an empty antibonding π* orbital of the ligand.^39–42 Thus, the FL spectrum indicates that a certain amount of Cu(i) is formed in PL-HKUST-1, which highly contrasted to CH-HKUST-1 and RT-HKUST-1.Open in a separate windowFig. 2FL spectra of CH-HKUST-1, RT-HKUST-1, and PL-HKUST-1 (λ_ex = 310 nm).The existence of Cu(i) in PL-HKUST-1 was also confirmed by X-ray photoelectron spectroscopy (XPS). The XPS spectrum of PL-HKUST-1 showed peaks at 932.2 and 934.6 eV, assignable to Cu(i) and Cu(ii), respectively (Fig. S4^†).^43,44 Although the reduction to Cu(i) inevitably proceeded upon X-ray irradiation,⁴⁵ the concentration of Cu(i) in PL-HKUST-1 was apparently higher than those in CH-HKUST-1 and RT-HKUST-1, which was consistent with the FL spectra. The plasma has ample free electrons and ions, which can reduce metal ions via electrochemical reactions.⁴⁶ The temperature of the plasma in liquid could be as high as 1000–7000 K,²⁷ and the reduction of Cu(ii) to Cu(i) by heat might occur.⁴⁷To examine the water stability of the MOFs, HKUST-1 was immersed in water at room temperature for 12 h. The XRD patterns of the samples after immersion in water were compared with those of the as-synthesized samples. The water treatment resulted in the appearance of new peaks at 2θ ≈ 9.4°–9.7°, 10.1°, 11.1°, 17.3°, and 19.6° for CH-HKUST-1 and RT-HKUST-1 (Fig. 1). Notably, the XRD patterns of PL-HKUST-1 before and after immersion in water were identical, with no detectable changes.The effect of water treatment on the morphology of HKUST-1 was also investigated using scanning electron microscopy (SEM). Particles with octahedral shape were obtained by the plasma in liquid method, similar to those obtained by the conventional heating method (Fig. 3). After immersion in water, the formation of particles with a thread-like morphology was observed for CH-HKUST-1 and RT-HKUST-1, suggesting the decomposition of HKUST-1.^30,48 In contrast, although PL-HKUST-1 contained a portion of the etched corners, the particle shape and size remained unchanged after water treatment.Open in a separate windowFig. 3SEM images of (a and b) CH-HKUST-1, (c and d) RT-HKUST-1, and (e and f) PL-HKUST-1 before and after immersion in water.Fourier transform infrared (FTIR) spectra of HKUST-1 before and after the water treatment are shown in Fig. 4. All as-synthesized samples showed the typical characteristic peaks of HKUST-1. The bands from 1300 to 1700 cm⁻¹ are associated with the carboxylate group of the BTC ligand.⁴⁹ The two peaks in the range 1371–1448 cm⁻¹ correspond to the symmetric stretching vibrations of the carboxylate group.⁵⁰ The bands at 730 and 758 cm⁻¹ correspond to the in-plane C–H bending mode.⁴⁹ Peaks observed below 600 cm⁻¹ correspond to the bonds involving copper ions.⁴⁹ After immersion in water, the FTIR spectrum of PL-HKUST-1 did not show any significant change whereas those of CH-HKUST-1 and RT-HKUST-1 showed shifts in the peaks and formation of new peaks. When exposed to water, peaks corresponding to COO vibrations were observed for CH-HKUST-1 and RT-HKUST-1 between 1200 and 1700 cm⁻¹ due to a change in the environments of the linker BTC.⁴⁸ The peak around 1640 cm⁻¹ shifted to longer wavelengths, and a new peak appeared around 1570 cm⁻¹, which is consistent with previous research.³⁸ The Raman spectra of CH-HKUST-1 and RT-HKUST-1 also showed the structural change in the coordination bonding upon the water treatment (Fig. S5^†).⁵¹Open in a separate windowFig. 4FTIR spectra of CH-HKUST-1, RT-HKUST-1, and PL-HKUST-1 before and after immersion in water. Fig. 5). The BET surface areas of CH-HKUST-1, RT-HKUST-1, and PL-HKUST-1 were 888, 574, and 739 m² g⁻¹, respectively. After immersion in water, the amount adsorbed by CH-HKUST-1 and RT-HKUST-1 was lowered compared to that before immersion, and their BET surface areas were 407 and 351 m² g⁻¹, respectively. By contrast, in the case of PL-HKUST-1, the adsorption amount remained high even after immersion in water, and its BET surface area was 811 m² g⁻¹.Brunauer–Emmett–Teller surface areas of CH-HKUST-1, RT-HKUST-1, and PL-HKUST-1 before and after immersion in water

Insight into trifluoromethylation – experimental electron density for Togni reagent I

3,3-Dimethyl-1-(trifluoromethyl)-1,3-dihydro-1-λ3,2-benziodoxole represents a popular reagent for trifluoromethylation. The σ hole on the hypervalent iodine atom in this “Togni reagent” is crucial for adduct formation between the reagent and a nucleophilic substrate. The electronic situation may be probed by high resolution X-ray diffraction: the experimental charge density thus derived shows that the short intermolecular contact of 3.0 Å between the iodine and a neighbouring oxygen atom is associated with a local charge depletion on the heavy halogen in the direction of the nucleophile and visible polarization of the O valence shell towards the iodine atom. In agreement with the expectation for λ3-iodanes, the intermolecular O⋯I–C_aryl halogen bond deviates significantly from linearity.

The experimentally observed electron density for the “Togni reagent” explains the interaction of the hypervalent iodine atom with a nucleophile.

A “halogen bond” denotes a short contact between a nucleophile acting as electron density donor and a (mostly heavy) halogen atom as electrophile;^1,2 halogen bonds are a special of σ hole interactions.^3–5 Such interactions do not only play an important role in crystal engineering;^6–11 rather, the concept of a nucleophile approaching the σ hole of a neighbouring atom may also prove helpful for understanding chemical reactivity.The title compound provides an example for such a σ hole based reactivity: 3,3-dimethyl-1-(trifluoromethyl)-1,3-dihydro-1-λ3,2-benziodoxole, 1, (Scheme 1) commonly known as “Togni reagent I”, is used for the electrophilic transfer of a trifluoromethyl group by reductive elimination. The original articles in which the application of 1¹² and other closely related “Togni reagents”¹³ were communicated have been and still are highly cited. Trifluoromethylation is not the only application for hypervalent iodine compounds; they have also been used as alkynylating¹⁴ or azide transfer reagents.^15,16 The syntheses of hypervalent iodanes and their application in organofluorine chemistry have been reviewed,¹⁷ and a special issues of the Journal of Organic Chemistry has been dedicated to Hypervalent Iodine Catalysis and Reagents.¹⁸ Recently, Pietrasiak and Togni have expanded the concept of hypervalent reagents to tellurium.¹⁹Open in a separate windowScheme 1Lewis structure of the Togni reagent, 1.Results from theory link σ hole interactions and chemical properties and indicate that the electron density distribution associated with the hypervalent iodine atom in 1 is essential for the reactivity of the molecule in trifluoromethylation.²⁰ Lüthi and coworkers have studied solvent effects and shown that activation entropy and volume play relevant roles for assigning the correct reaction mechanism to trifluoromethylation via1. These authors have confirmed the dominant role of reductive elimination and hence the relevance of the σ hole interaction for the reactivity of 1 in solution by ab initio molecular dynamics (AIMD) simulations.^21,22 An experimental approach to the electron density may complement theoretical calculations: low temperature X-ray diffraction data of sufficient resolution allow to obtain the experimental charge density and associate it with intra- and inter-molecular interactions.^23–25 Such advanced structure models based on aspherical scattering factors have also been applied in the study of halogen bonds.^26–30 In this contribution, we provide direct experimental information for the electronic situation in Togni reagent I, 1; in particular, we analyze the charge distribution around the hypervalent iodine atom.Excellent single crystals of the title compound were grown by sublimation.^§ The so-called independent atom model (IAM), i.e. the structure model based on conventional spherical scattering factors for neutral atoms, confirms the solid state structure reported by the original authors,¹² albeit with increased accuracy. As depicted in Fig. 1, two molecules of 1 interact via a crystallographic center of inversion. The pair of short intermolecular O⋯I contacts thus generated can be perceived as red areas on the interaction-sensitive Hirshfeld surface.³¹Open in a separate windowFig. 1Two neighbouring molecules of 1, related by a crystallographic center of inversion. The short intermolecular I⋯O contacts show up in red on the Hirshfeld surface³² enclosing the left molecule. (90% probability ellipsoids, H atoms omitted, symmetry operator 1 − x, 1 − y, 1 − z).The high resolution of our diffraction data ^¶ for 1 allowed an atom-centered multipole refinement^33,34 and thus an improved model for the experimental electron density which takes features of chemical bonding and lone pairs into account. Fig. 2 shows the deformation density, i.e. the difference electron density between this advanced multipole model and the IAM in the same orientation as Fig. 1.^|| The orientation of an oxygen lone pair (blue arrow) pointing towards the σ hole of the heavy halogen in the inversion-related molecule and the region of positive charge at this iodine atom (red arrow) are clearly visible. Single-bonded terminal halides are associated with one σ hole opposite to the only σ bond, thus resulting in a linear arrangement about the halogen atom. Different geometries and potentially more than a single σ hole are to be expected for λ3-iodanes such as our target molecule, and as a tendency, the resulting halogen bonds are expected to be weaker than those subtended by single-bonded iodine atoms.³⁵ In agreement with these theoretical considerations, the closest I⋯O contacts in 1 amount to 2.9822(9) Å. This distance is significantly shorter than the sum of the van-der-Waals radii (I, 1.98 Å; O, 1.52 Å (ref. 36)) but cannot compete with the shortest halogen bonds between iodine and oxygen^37,38 or iodine and nitrogen.^39–41Fig. 1 and ​and22 show that the C_aryl–I⋯O contacts are not linear; they subtend an angle C10–I1⋯O1′ of 141.23(3)° at the iodine atom. On the basis of theoretical calculations, Kirshenboim and Kozuch³⁵ have suggested that the split σ holes should be situated in the plane of the three substituents of the hypervalent atom and that halogen and covalent bonds should be coplanar. Fig. 3 shows that the C_aryl–I⋯O interaction in 1 closely matches this expectation, with the next oxygen neighbour O1′ only 0.47 Å out of the least-squares plane through the heavy halogen I1 and its three covalently bonded partners C1, O1 and C10.Open in a separate windowFig. 2Deformation density for the pair of neighbouring molecules in 1; the dashed blue and red arrows indicate regions of opposite charge. (Contour interval 0.10e Å⁻³; blue lines positive, red lines negative, green lines zero contours, symmetry operator 1 − x, 1 − y, 1 − z).Open in a separate windowFig. 3A molecule of 1, shown [platon] along O1⋯C1, and its halogen-bonded neighbour O1ⁱ. Symmetry operator 1 − x, 1 − y, 1 − z.The Laplacian, the scalar derivative of the gradient vector field of the electron density, emphasizes local charge accumulations and depletions and it allows to assess the character of intra- and inter-molecular interactions. A detailed analysis of all bonds in 1 according to Bader''s Atoms In Molecules theory⁴² is provided in the ESI.^‡ We here only mention that the electron density in the bond critical point (bcp) of the short intermolecular I⋯O contact amounts to 0.102(5)e Å⁻³; we are not aware of charge density studies on λ3-iodanes, but both the electron density and its small positive Laplacian match values experimentally observed for halogen bonds involving O and terminal I in the same distance range.⁴³The crystal structure of 1 necessarily implies additional contacts beyond the short halogen bond shown in Fig. 1 and ​and2.2. The shortest among these secondary interactions is depicted in Fig. 4: it involved a non-classical C–H⋯F contact with a H⋯F distance of 2.55 Å.Open in a separate windowFig. 4C–H⋯F contact in 1; additional information has been compiled in the ESI.^‡ Symmetry operators i = 1 − x, 1 − y, 1 − z; ii = 1 − x, 1 − y, −z.The topological analysis of the experimental charge density reveals that this non-classical C–H⋯F hydrogen bond and all other secondary contacts are only associated with very small electron densities in the bcps. Table S8 in the ESI^‡ provides a summary of this analysis and confirms that the I⋯O halogen bond discussed in Fig. 1 and ​and22 represents by far the most relevant intermolecular interaction.The relevance of this halogen bond extends beyond the crystal structure of 1: Insight into the spatial disposition of electrophilic and nucleophilic regions and hence into the expected reactivity of a molecule may be gained from another electron-density derived property, the electrostatic potential (ESP). The ESP for the pair of interacting molecules in 1 is depicted in Fig. 5.Open in a separate windowFig. 5Electrostatic potential for a pair of molecules in 1 mapped on an electron density isosurface (ρ = 0.5e Å⁻³; program MoleCoolQt^44,45). Fig. 5 underlines the complementary electrostatic interactions between the positively charged iodine and the negatively charged oxygen atoms. One can easily imagine to “replace” the inversion-related partner molecule in crystalline 1 by an incoming nucleophile.The ESP tentatively obtained for a single molecule in the structure of 1 did not differ significantly from that derived for the inversion-related pair (Fig. 5), and even the results from theoretical calculations in the gas phase for an isolated molecule²⁰ are in good qualitative agreement with our ESP derived from the crystal structure. In the absence of very short contacts, polarization by neighbouring molecules only has a minor influence on the ESP. The experimentally observed electron density matches the proven reactivity for the title compound, and we consider it rewarding to extend our charge density studies on related hypervalent reagents.     

Resistive non-volatile memories fabricated with poly(vinylidene fluoride)/poly(thiophene) blend nanosheets

Ferroelectric poly(vinylidene fluoride)/semiconductive polythiophene (P3CPenT) blend monolayers were developed at varying blend ratios using the Langmuir–Blodgett technique. The multilayered blend nanosheets show much improved surface roughness that is more applicable for electronics applications than spin-cast films. Because of the precisely controllable bottom-up construction, semiconductive P3CPenT were well dispersed into the ferroelectric PVDF matrix. Moreover, the ferroelectric matrix contains almost 100% β crystals: a polar crystal phase responsible for the ferroelectricity of PVDF. Both the good dispersion of semiconductive P3CPenT and the outstanding ferroelectricity of the PVDF matrix in the blend nanosheets guaranteed the success of ferroelectric organic non-volatile memories based on ferroelectricity-manipulated resistive switching with a fresh high ON/OFF ratio and long endurance to 30 days.

Ferroelectric poly(vinylidene fluoride)/semiconductive polythiophene blend nanosheets show good resistive non-volatile memory performance with a fresh high ON/OFF ratio and long endurance to 30 days.

Ferroelectric capacitors memorize information by the two antiparallel polarization states coded as “0” or “1”, even after removing the applied power, serving as non-volatile memory.^1,2 However, the reading out of the stored information in such memories will change the polarization state, which is known as destructive read-out. To realize non-destructive read-out and low-energy writing in such devices, conjugated polymers were introduced into a ferroelectric polymer matrix to form phase-separated blends, which contributed to novel ferroelectric resistive switches with very simple two-terminal sandwiched devices superior to the complicated transistor type electronic elements.^3,4 In the ferroelectric nonvolatile memories, the bi-stable polarization states in ferroelectric polymers such as poly(vinylidene fluoride) (PVDF) derivatives were used to manipulate the charge transfer and injection in conjugated polymers (CPs).^3–7 This manipulation results in different resistance at on-state and off-state of the devices controlled by the ferroelectric polarization directions. Consequently, non-destructive low-voltage operation was realized in which the ferroelectric PVDF provides switching functionality. The read-out operation is performed by conduction through a nearby semiconducting layer.⁵ Thereafter, the operational mechanism of ferroelectric-driven organic resistive switches was clarified by Kemerink et al.⁸ They stressed that the stray field of the polarized ferroelectric phase can modulate the charge injection from a metallic electrode into the organic semiconductor, switching the diode from injection-limited to space-charge-limited.Although the devices show promising applications, the random phase-separation morphology gives them uncertain properties.^9,10 The most important obstacle is to prepare well-dispersive PVDF–CP phase-separated blend nanofilms because a well-dispersive hybrid nanofilm is indispensable for higher information storage density. In other words, embedding semiconductor polymers into ferroelectric polymer matrixes with domain size of CPs smaller than a few tens of nanometers (e.g. 50 nm) has remained extremely challenging to date.^6,9 Phase-separated films prepared using traditional methods such as spin-coating show a much disordered surface with root-mean-square (RMS) roughness exceeding 39.97 nm.¹¹ Such a highly rough surface tends to induce large leakage current. Especially, the annealing treatment for PVDF materials to increase crystallinity and ferroelectric phase crystals also brings a significant increment to the phase-separated domain size. From another perspective, to decrease the writing and read-out operational voltages, ultrathin blend films (thinner than 100 nm) with high-content ferroelectric crystals are also necessary. However, the reported methods to prepare polymer ferroelectric ultrathin films, e.g. spin-coating are usually performed at the cost of decreasing the ferroelectric phase or requiring high energy consumption.Previous reports have proposed a versatile method to achieve highly oriented ferroelectric polymer Langmuir–Blodgett (LB) nanofilms consisting of ferroelectric poly(vinylidene fluoride) (PVDF) and tiny amphiphilic poly(N-dodecylacrylamide) (pDDA) supplying film stability at the air–water interface and transfer properties (Fig. 1a).^12,13 The LB nanofilms, with a controllable film thickness at several nanometers'' scale and a smooth film surface, can be transferred onto solid and flexible substrates irrespective of their surface wettability. The contents of ferroelectric β crystals in the as-prepared nanofilms with no post-treatment can be up to 95%, which is the best content in such thin films ever reported.^2,14 Therefore, we investigated a strongly enhanced ferroelectricity of the PVDF LB nanofilms with no electrical poling showing one of the highest ferroelectric remanent polarization values, 6.6 μC cm⁻², for nanometer-scale films, in addition to long endurance because of the high orientation of β crystals.² The PVDF–pDDA LB nanofilms benefit both from the good film-formation properties of amphiphilic pDDA and the functionality of ferroelectric PVDF. To extend their applications, the PVDF–pDDA LB nanofilms are promising for application as a platform and matrix to combine with other functional materials such as organic functional materials and inorganic nanoparticles. Similarly, it is promising for production of well-dispersive ferroelectric/semiconductive polymer blends by addition of a third composition: semiconductive polymers at the air–water interface. Moreover, we have reported that semiconductive poly(3-hexylthiophene) (P3HT) monolayers were stabilized by mixing with the amphiphilic poly(N-dodecylacrylamide) (pDDA) at the air–water interface for field-effect transistors.¹⁵Open in a separate windowFig. 1(a) Chemical structures of poly(vinylidene fluoride) (PVDF), poly[3-(5-carboxypentyl) thiophene-2,5-diyl] (P3CPenT) and poly(N-dodecylacrylamide) (pDDA), (b) surface pressure (π)–area (A) isotherms, and (c) compressibility modulus (C_s⁻¹)–surface area (A) isotherms of PVDF–P3CPenT–pDDA Langmuir films for various weight contents of P3CPenT relative to PVDF. The straight arrow in (b) indicates the line extrapolated to determine the limiting surface area.This study examines the facile preparation of blend nanosheets of ferroelectric PVDF and semiconductive polymer, by incorporating poly[3-(5-carboxypentyl) thiophene-2,5-diyl] (P3CPenT) into PVDF–pDDA Langmuir–Blodgett (LB) nanofilms. P3CPenT is a conjugated polythiophene carboxylate (Fig. 1a) that occupies superior charge transport performance resulting from a delicate balance between its solubility and solid-state film morphologies.^16,17 The blend LB nanosheets can be transferred readily and regularly from the air–water interface onto various substrates. Phase-separation morphologies were studied based on the varying P3CPenT contents. Resistive switching properties were demonstrated in a simple sandwiched device of Al/PVDF–P3CPenT–pDDA/Au at the opposite polarization direction of the PVDF matrix.The PVDF–P3CPenT–pDDA monolayers were prepared by spreading PVDF–P3CPenT mix solution and pDDA solution onto water surface in sequence at a molar ratio of 50 : 1 (see ESI^† for details). Fig. 1b shows surface pressure (π)–area (A) isotherms of PVDF–P3CPenT–pDDA Langmuir films at varying P3CPenT contents (relative to PVDF) at 20 °C: they are designated as P3CPenT 6 wt%, P3CPenT 9 wt% and P3CPenT 23 wt%. The sharply rising curves with high collapse surface pressures up to 50 mN m⁻¹ are indicative of the formation of stable and compact Langmuir blend monolayers at the air–water interface. These pressure values are much higher than those of pure PVDF (25 mN m⁻¹) or P3CPenT (15 mN m⁻¹) (Fig. S1^†). Results suggest that amphiphilic pDDA can greatly improve film stability at the air–water interface because of excellent hydrogen bonding interactions that occur among the amide groups in pDDA backbones.¹³ The compressibility modulus (or elasticity) C_s⁻¹ was calculated from isotherm data based on eqn (1) to obtain the monolayer elastic behavior.¹⁸C_s⁻¹ = −A(dπ/dA)1In the C_s⁻¹–A curves shown in Fig. 1c, each compressed Langmuir film shows a peak value of C_s⁻¹*, manifesting the formation of a critical concentrated solid state.^19–22 Table S1^† shows the limiting surface area (S_aver), collapse surface pressure (π_c), peak compressibility modulus (C_s⁻¹*), corresponding surface pressure (π*), and corresponding occupied area (A*) for the respective P3CPenT contents. The change in the limiting surface area from 0.0224 (6 wt%) to 0.0250 nm² (23 wt%) shows the successful introduction of P3CPenT into the PVDF matrix.After confirming the film formation properties, the monolayers were transferred onto hydrophobic silicon substrates regularly (Fig. S2^†). The transfer ratios for both downstrokes and upstrokes are almost unity, based on eqn (S1).^† Low surface roughness is a crucially important parameter for electronic applications. In earlier reports, lowering the root-mean-square (RMS) roughness below 30 nm is quite a challenge for the ferroelectric/semiconductive polymer blend films because of the crystalline properties of the two polymers. The AFM images (Fig. 2a–d) of the as-prepared PVDF–P3CPenT blend LB nanosheets manifest much smoother surfaces, even for the 80-layer nanosheets by an RMS value of 10.8 nm. This value is smaller than that of the reported spin-coating films.^6,11 In Fig. 2c, the nanofiber structures in the P3CPenT 23 wt% monolayer orientate at one direction as the black arrow indicates. All the nanofibers show a regular size of 7.9 nm (Fig. 2e). In contrast, such nanofiber structures do not appear in the monolayers at low contents of P3CPenT in Fig. 2a and b, which proves that the nanofiber structures originate from P3CPenT molecules. In Fig. 2d and S3,^† the interlaced nanofiber networks in the 80-layer LB blend nanosheet caused by repeated deposition of Langmuir monolayers will provide the nodal points for electric conductivity. EDX mapping images show homogeneous dispersion of P3CPenT in PVDF, which also ensured the continuous conducting path (Fig. S4^†), while the nano-domains were not clear seen. It may originate from the similar solubility of PVDF and P3CPenT in NMP, which made the unclear phase-separation structure.Open in a separate windowFig. 2AFM images of (a)–(c) PVDF–P3CPenT–pDDA blend LB monolayer at 6, 9, and 23 wt% P3CPenT, (d) an 80-layer blend LB nanosheet (P3CPenT 23 wt%), and (e) height profile of the fiber structures in (c).The blend monolayers were readily transferred onto various substrates such as rigid silicon and flexible PET substrates (Fig. 3). The uniform interference colours of the macroscopic films at each layer number are indicative of the regular layer structures and homogeneous film transfer from water surface to the substrates. The result also evidenced the controllable preparation of functional polymer blends at several nanometres'' scale for the present work, which cannot be achieved by general film preparation methods such as drop casting and spin-coating. UV-vis spectra in Fig. 4a show a broad absorbance peak near 462 nm for P3CPenT and PVDF–P3CPenT solutions in NMP. The detected absorbance peaks at 442, 428, and 415 nm at 23 wt%, 9 wt%, and 6 wt%, respectively, evidenced the successful introduction of P3CPenT into the PVDF LB nanofilms (Fig. 4b). The tunable domain size and controllable film thickness are not the only virtues of the blend nanosheets. In Fig. 5a, the FT-IR spectra of the blend nanosheets show significant peaks at 508, 840, 1276, and 1400 cm⁻¹ at each content, which are assigned for the ferroelectric β crystals (Form I).^23–25 Characteristic peaks of paraelectric α crystals (763 and 976 cm⁻¹) were not detected. The rich β phase formation was also confirmed using XRD patterns, which showed the appearance of 110/200 reflection at 20.1° (Fig. S5^†).^12,25 The PVDF–pDDA LB films were crystalline films with a crystallinity of 50%.¹² Results confirmed that the blend nanosheets contain almost 100% ferroelectric β crystal, which is consistent with the reported value for PVDF–pDDA LB nanofilms,¹² indicating that the addition of P3CPenT did not affect the crystal structures of PVDF. The result ensures that the ferroelectric matrix in the blend nanosheets can supply a stable and large polarization electric field to modulate charge transfer and accumulation. Monolayer thickness was confirmed as 2.3, 2.6, and 2.6 nm respective for 6 wt%, 9 wt%, and 23 wt% P3CPenT containing LB nanosheets by XRD spectra (Fig. S6 and Table S2^†). All the monolayers can be uniformly and repeatedly transferred to substrates to adjust the film thickness. Therefore, the film thickness of the nanosheets can be finely modulated at several nanometres'' scale.² This report is the first of the relevant literature to describe success on the preparation of blend LB nanosheets with highly ferroelectric matrix and well-dispersive semiconductive P3CPenT.Open in a separate windowFig. 3Photographs of blend LB nanosheets with 23 wt% P3CPenT at various layers on Si substrate (left) and a 30-layer blend nanosheet on flexible PET membrane (right).Open in a separate windowFig. 4UV-vis absorption spectra of (a) P3CPenT and PVDF–P3CPenT solutions in NMP and (b) the blend LB nanosheets for various weight contents of P3CPenT relative to PVDF.Open in a separate windowFig. 5FT-IR spectra of 80-layer PVDF–P3CPenT–pDDA blend nanosheets for various P3CPenT contents.Memory devices were constructed with a simple sandwiched structure: glass substrate/gold (Au)/blend LB nanofilms/aluminum (Al) (see the inset of Fig. S7 and ESI^†).^26,27 Fig. S7a^† shows typical current (I)–voltage (V) characteristics of 30-layer blend nanosheets (78 nm), which demonstrated a reversal current hysteresis with voltage sweeping between ±20 V.^9,11 The cross-sectional SEM image of the memory device is shown in Fig. S7b,^† indicating a well-defined layer structure. The current can only flow through the P3CPenT domains because of the insulation characteristic of PVDF matrix, however, no hysteresis loop was obtained for the blend LB nanosheets. This is due to the conducting path formed by the interlaced P3CPenT nanofibers even with the presence of rich ferroelectric β phase. So our device will not follow Asadi''s mechanism as introduced in the Introduction part.Local surface potential patterns were visualized using Kelvin probe microscopy to investigate the polarization state of the devices.¹² A two-step measurement was conducted (Fig. 6a). First, a positive/negative bias voltage was applied to the conductive AFM cantilever under ambient conditions, making the sample surface polarized with a square shape. Then, the KFM mode was conducted to obtain images of the polarized patterns, which is called the reading procedure. Fig. 6b and c portray the surface potential images before and after polarization. Clearly, the inverse profile of the positive and negative polarized area is seen in Fig. 6b, which indicates the LB films are ferroelectric.Open in a separate windowFig. 6(a) Schematic illustration of Kelvin probe force microscopy measurement and surface potential images (b) before polarization and (c) after polarization.To investigate whether the device is resistive switching or not, we applied a polarizing pulse for information writing with pulse width of 2.5 s and voltage of 30 V to induce polarization states of the ferroelectric matrix in a 40-layer blend nanosheet (104 nm) as shown in Fig. 7a. The pristine state refers to as-fabricated devices that have not undergone any electrical poling. The writing voltage magnitude for both ON and OFF states is set as 30 V for 2.5 s higher than its coercive voltage: 20 V (195 MV m⁻¹ × 104 nm)² of the PVDF LB nanosheet, as we previously reported, to ensure the high polarization value in the ferroelectric matrix. The read-out operation was operated at quite low voltage by detecting the current flow in the devices. The blend nanosheet after polarizing at +30 V exerts ten-fold improved current density (ON-state) in comparison with the pristine nanosheet before polarization (Fig. 7b). In contrast, the current density decreased after polarization at −30 V (OFF-state). The results verified the resistive switching characteristics and the non-volatility nature of the memory devices fabricated with the blend nanosheets. For comparison, a control experiment for pure pDDA LB nanofilms showed no ferroelectric polarization-reversal-induced resistive switching (Fig. S8^†). It is noteworthy that by combining the ferroelectric PVDF nanosheet with semiconductive polymer, the read-out voltage is optimized even to lower than 1 V. Results show that it is highly competitive over the ferroelectric capacitors without semiconductive components, which require a reading-out voltage higher than coercive voltage, about 20 V for the 100 nm-thick films.² The ON/OFF ratio values were recorded at varying reading voltages (Fig. 7c). The maximum value of the ON/OFF ratio was approximately 891 with increasing read-out voltage to 15 V, which hit one of the highest records over the previous ferroelectric polymer – thiophene-based semiconductor polymer blend memories.^3,5,11,28 This result derives from the synergetic effects of uniform dispersion of semiconductive domains and improved ferroelectricity of the PVDF matrix. The ultrathin PVDF matrix can survive at a strong electric field up to 500 MV m⁻¹ as our previous work reported, which ensured a large operation window for reading out the stored information as well as high ON/OFF ratio values. In other words, the bottom-up construction method for functional polymer blends affords us a novel platform for materials design and micro/nanostructures manipulation. At the first stage of the work design, we expected a band bending mechanism to explain the resistive switching. However, the I–V curve in Fig. S7a^† indicated Asadi''s mechanism is not applicable for our devices. The resistive switching toward ferroelectric polarization shows similar behaviour to the reported devices.²⁸ They used a symmetric device of Au–PVDF/P3HT–Au, however, the layer structure was asymmetric because they spin-coated P3HT on the patterned P(VDF–TrFE) layer. It seems that P3HT has a continuous phase through the layer, which is different from the clearly phase-separated structures.^3,4 As mentioned above, P3CPenT took a conductive path in the nanosheet sandwiched with two different electrodes, leading to no band bending formation at the interfaces. A lot of work is necessary in the future to optimize the device structure and materials combination to understand the operation mechanism in terms of structure–property relationship, e.g. using other semiconductive polymers with different solubility from PVDF. We also investigated the device cycle endurance (fatigue property) and retention properties for the blend-nanosheet-based ferroelectric nonvolatile memories (Fig. 7d). The devices show reversible switching over many cycles up to 1000 cycles in spite of a little linear decrease of ON-current and increase of OFF-current as a function of cycle numbers, which is consistent with the reported values.²⁹ The retention of current density was demonstrated with consistent current density at the ON state up to 4 days (Fig. 7d, bottom) and the OFF state up to 30 days (Fig. S9^†). A slight degradation of current density at the ON state was observed after 4 days, which might be ascribed to the interfacial charge induced depolarization of ferroelectric domains.³⁰Open in a separate windowFig. 7(a) Schematic illustration of the operation program for the ferroelectric nonvolatile memories, (b) current density (J)–voltage (V) characteristics of the blend LB nanosheets (P3CPenT 23 wt%, 40 layers) before and after polarization, (c) ON/OFF ratios at varying read voltage, and (d) (top) the device cycle endurance at ON- and OFF-states reading at 1 V and (bottom) the retention property at ON-state reading at 3 V. Dashed lines represent the linear fits at different states.In conclusion, a bottom-up construction of ferroelectric PVDF/semiconductive P3CPenT nanoblends was achieved simply by in situ mixing at the air–water interface. The PVDF matrix manifests ultrahigh ferroelectric crystal content, approaching 100% and guaranteeing the ferroelectricity necessary for the modulation of charge transfer and accumulation. Semiconductive P3CPenT components uniformly dispersed in PVDF matrix with some nanostructures such as particles and nanofibers. Ferroelectric nonvolatile memories based on the blend nanosheets were demonstrated with resistive switching properties along with the reversal of ferroelectric polarization direction. The ON/OFF ratio values and retention time are superior to most of the previously reported values, indicative of a great potential for application of such blend nanosheets to flexible electronics.     

Photocatalytic degradation of organic pollutants through conjugated poly(azomethine) networks based on terthiophene–naphthalimide assemblies

A conjugated poly(azomethine) network based on ambipolar terthiophene–naphthalimide assemblies has been synthesized and its electrochemical and UV-vis absorption properties have been investigated. The network has been found to be a promising candidate for the photocatalytic degradation of organic pollutants in aqueous media.

A conjugated two-dimensional poly(azomethine) network based on ambipolar terthiophene–naphthalimide assemblies has been synthesized and its electrochemical and UV-vis absorption properties have been investigated.

Due to the rapid growth of urbanization and intensive industrialization, pollution has evolved into a serious concern that produces a great negative impact on human health and the environment.^1,2 Therefore, many efforts are currently devoted to addressing environmental remediation through the degradation and removal of hazardous contaminants.^3–5 In this regard, photocatalysis has been identified as a suitable approach for environmental remediation given that it is an energy efficient technique that does not require chemical input and does not produce sludge residue.⁶ In recent years, organic semiconducting polymers have evolved into a new type of metal-free and heterogeneous photocatalyst suitable for solar-energy utilization.⁷ The modularity of organic polymers allows the efficient tunning of their electronic and optical properties by bottom-up organic synthesis through the choice of suitable monomeric building blocks.^8–10 Within this context, there is a growing demand for new organic polymeric semiconductors carefully designed to have suitable energy levels of the frontier orbitals, an appropriate bandgap and good intrinsic charge mobility.¹¹For the design of suitable polymeric semiconductors for photocatalysis, it is not only important that the photocatalysts absorb light in the visible light range but also an efficient dissociation of the photogenerated charge carriers is required. The combination of electron-poor acceptor (A) and electron-rich donor (D) moieties in the polymer structure may prevent a fast recombination process following photoexcitation.¹² In addition, it has been found that polymers networks bearing conjugated moieties may exhibit π-stacked columns that can facilitate charge transport.¹³In this respect, molecular and polymeric materials based on the combination of oligothiophene^14,15 and naphthalimide moieties^16,17 connected through conjugated linkers have shown to be very effective in order to efficiently tune their frontier orbital levels and produce tunable organic semiconductors with good charge transport properties.^18–24 As an example, in Fig. 1 is depicted the structure of NIP-3T, an ambipolar organic semiconductor, for which the one-electron HOMO–LUMO excitation consists of the displacement of the electron density from the HOMO, primarily localized on the oligothiophene fragment, to the LUMO, localized on the naphthalimide unit.²⁵Open in a separate windowFig. 1(a) Monomer containing an electron donor terthiophene system directly conjugated with an electron acceptor naphthalimide moiety through a conjugated pyrazine linker (NIP-3T). (b) HOMO and (c) LUMO computed orbital topologies for NIP-3T.²⁵Among conjugated polymers, poly(azomethine)s have found application as organic semiconductors in heterogeneous photocatalysis because of their π-conjugated system and suitable band levels matching the redox window of water.²⁶ The incorporation of D–A monomeric assemblies into poly(azomethine) networks represents an efficient strategy to obtain ambipolar polymeric networks with tunable frontier orbital levels for photocatalytic applications. Thus, in this communication we report the synthesis of a novel donor–acceptor poly(azomethine) network (NIP3T-ANW, Scheme 1) based on NIP-3T monomers. The potential of this system as photodegrading agent for the elimination of contaminant organic dyes in aqueous media is also explored.Open in a separate windowScheme 1Schematic representation of the synthesis of NIP3T-ANW.The synthesis of the macromolecular poly(azomethine) network NIP3T-ANW is acomplished through Schiff-base reactions between trigonal monomers endowed with amine functionalities (TAPB,²⁷Scheme 1) and linear naphthalimide–thiophene-based monomers endowed with complementary aldehyde functional groups (NIP3T2CHO,²⁴Scheme 1). Typically, both monomers were dissolved in an o-dichlorobenzene/n-butanol/acetic acid (1 : 1 : 0.1) mixture, which was then heated at 120 °C under solvothermal reaction conditions for 72 h. A black solid was obtained which was insoluble in common solvents such as water, acetone, THF, toluene or chlorinated solvents like dichloromethane or chloroform. The obtained solid was washed several times with THF to remove the starting materials and low-molecular weight by-products. After drying under vacuum, a black solid was obtained. The yield, as determined by weight, was 98%.To investigate the chemical nature of the material, as well as to determine the conversion of the functional groups after the reaction, we have employed attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy (Fig. 2). The bands arising from the NH₂ stretching (3000–3400 cm⁻¹) and NH₂ deformation (1650 cm⁻¹) vibrations of the primary amine group of TAPB and the signals from the aldehyde groups of NIP3T2CHO around 2870 (C–H stretching) and 1663 cm⁻¹ (C O stretching) are virtually absent in the NIP3T-ANW spectrum. In addition, a prominent new band is found at 1573 cm⁻¹, which can be assigned to the C N stretching vibration of the imine linkages within the newly formed poly(azomethine) network.^28–30Open in a separate windowFig. 2(a) IR spectra of NIP3T2CHO (blue), TAPB (red) and NIP3T-ANW (black). (b) Solid-state ¹³C CP-MAS NMR spectrum of NIP3T-ANW.Solid-state ¹³C cross-polarization magic angle spinning NMR (¹³C CP-MAS NMR) spectrum (Fig. 2) reveals the characteristic imide signals of the 1,8-naphthalimide moiety at 164.4 ppm, as well as the signal corresponding to the imine carbon at 154 ppm and a signal at 148 ppm which can be assigned to the aromatic carbon neighbouring the nitrogen of the C N group. The absence of the sp² carbons from the NIP3T2CHO ²⁴ aldehyde functionalities above 180 ppm satisfactorily confirms the condensation between the aldehyde and the amine derivatives.Due to the rigidity and geometry of the building blocks, the imine linkers could be ideally generated in such a way that result in a canonical layered hexagonal structure³¹ as predicted by theoretical calculations (Fig. S1 and S2^†). However, in the actual framework, X-ray diffraction (XRD) measurements indicate that the material is mainly amorphous with only some ordered regions, as indicated by the good agreement between the weak and broad diffraction peaks observed at 2θ values larger than 3 and those predicted by calculations for the ideal canonical layered hexagonal structure (Fig. S3^†). In this regard, NIP3T-ANW was submitted to an exfoliation process following a previously described protocol³² for the exfoliation of two-dimensional polymers (see ESI^† for details). The exfoliated material was analysed by dynamic light scattering (DLS) showing a monomodal size distribution of ca. 400 nm (Fig. S4^†) and transmission electron microscopy (TEM) reveals a sheet-like structural aspect (Fig. S5^†).Thermogravimetric analysis of the poly(azomethine) network NIP3T-ANW shows that the degradation starts at around 450 °C and only 40% weight loss is observed at 700 °C (Fig. S6^†). This thermal stability is significantly higher than that observed for NIP3T (Fig. 1), the analogous molecular system based on terthiophene connected with naphthalimide through pyrazine for which the degradation starts at 200 °C (Fig. S6^†).^22,25In photocatalysis mediated by semiconductors, electron–hole pairs (excitons) are generated after light absorption and afterwards dissociate into free charge carriers that can be utilized for redox reactions^33,34 such as CO₂ fixation,³⁵ water splitting³⁶ or organic mineralization.³⁷ Some of the crucial factors that make the photocatalytic process favourable are the levels of conduction and valence as well as the width of the band gap.^38–40 Thus, in order to characterize these parameters, the electrochemical and optical properties of NIP3T-ANW have been analysed.The electrochemical properties of NIP3T and NIP3T-ANW were studied by cyclic voltammetry (Fig. 3). Both materials show ambipolar redox behaviour in which the reversible reduction processes are characteristic of the naphthalimide unit, while the oxidation processes can be ascribed to the conjugated oligothiophene moiety.^19–22,24 For NIP3T-ANW, the first reversible reduction wave (−1.29 V) is shifted to less negative values in comparison with NIP-3T (−1.41 V). On the other hand, the first oxidation half wave potential for NIP3T is observed at +0.41 V and for NIP3T-ANW at +0.44 V. These shifts agree with the electron acceptor ability of the imine linker.Open in a separate windowFig. 3(a) The UV-vis DRS spectra of NIP3T and NIP3T-ANW. (b) Cyclic voltammetry of the NIP3T monomer and the corresponding polymer.The absorption spectrum of NIP3T-ANW as determined by UV-vis diffuse reflectance spectroscopy (UV-vis DRS, Fig. 3) shows a strong absorption in all the UV-vis range, extending even to the near infrared. This broad absorption is red-shifted in comparison with the one observed for NIP3T (Fig. 3), which reflects the formation of the new polymer network with an extended conjugation through the alpha positions of the terthiophenes.Using the corresponding cut-off wavelengths, the optical band gaps E_g found for NIP3T and NIP3T-ANW are 1.59 and 1.42 eV respectively. This optical result suggests that the incorporation of the NIP3T core into an extended conjugated system efficiently harvests photons from the visible range, even extending into the near IR region.To shed some light into the degree of crystallinity of the synthesized NIP3T-ANW network, we have carried out a battery of density functional theory (DFT)-based calculations with the QUANTUM ESPRESSO plane-wave DFT simulation code⁴¹ (see details in ESI^†). We have considered periodic boundary conditions to obtain a fully-relaxed ground-state crystal structure. Optimization of the cell-shape and size, simultaneously to the relaxation of the structure, reveals a hexagonal 2D lattice with an optimized parameter of 48.46 Å. Different interlayer stacking fashions have been tested, with only one yielding a good agreement with the experimental diffractogram from 2θ values >3°. The most favourable stacking predicted by theory consists in an intermediate configuration between the perfectly eclipsed and staggered configurations, with an interlayer distance of 3.42 Å, and permits an adequate accommodation of the layers profiting adjacent pores. Details on the structure can be found in the ESI.^†Additionally, we have computed the electronic band diagram of the obtained crystal structure along the high-symmetry k-path Γ → K → M → Γ, revealing a wide-gap (1.91 eV) semiconducting character, with rather dispersive valence and conduction bands, mainly resembling the molecular HOMO and LUMO of the molecular building blocks (see Fig. S7^†). Besides, computed time-dependent DFT (TDDFT) UV-vis spectrum manifests an excellent agreement with the experimental UV-vis spectra (Fig. S8^†). A broad and pronounced peak-feature is obtained between 600 and 800 nm, centred at around 720 nm (1.7 eV), which agrees with the optical gap of 1.6 eV found for NIP3T from Fig. 3a. This feature corresponds to electronic transitions between the valence and conduction bands, with an energy difference of around 0.2 eV between the optical and the electronic gap, which indicates that charge relaxation in excited states is not much significative. The good agreement between theoretical predictions on the canonically periodic computed system and the experimental evidences seems to justify the presence of some high-crystallinity regions from the synthesis.The band gap of a semiconductor material and the reduction and oxidation potentials are key parameters which determine its light-harvesting properties and types of reaction that can be conducted and therefore the overall photo-catalytic activity. A shift in the adsorption edge of a semiconductor towards longer wavelengths implies a narrower band gap and the efficient harvesting of a wider photons range.⁴²NIP3T-ANW seems to be an appealing material to be utilized as photocatalyst given (i) the optimal light harvesting properties as shown by the optical characterization, (ii) the efficient generation of electron–hole pairs owing to the insertion of terthiophene moieties, and (iii) the right energy band positions for the material.⁷ We therefore evaluated the photocatalytic activity of NIP3T-ANW under white light for the degradation of a model organic pollutant (Rhodamine B dye, RhB) in aqueous solution.⁴³ In the absence of catalyst, RhB remains stable in solution under illumination (Fig. 4a and S9^†). However, in presence of NIP3T-ANW nearly 90% of RhB in an aqueous solution is degraded after 120 min, showing the enhanced catalytic activity of the material (Fig. 4a and S10^†). Furthermore, a good stability is shown upon 4 straight catalytic cycles (Fig. 4b, S11 and S12^†). In contrast, in the presence of the NIP3T moiety, only a 55% degradation of RhB is observed in the same timeframe (Fig. 4a and S11^†).Open in a separate windowFig. 4RhB degradation curves. (a) Comparison between the degradation effect of NIP3T, NIP3T-ANW and without catalyst. (b) NIP3T-ANW stability after four recycling cycles.In the photocatalytic degradation of organic pollutants, they are typically broken down through the attack of superoxide and hydroxyl species, formed when atmospheric oxygen reacts with photogenerated electrons or when water or OH ions are oxidized by holes, respectively.⁴⁴ Additionally, electron–hole pairs (or excitons) can directly reduce or oxidize organic pollutants in aqueous environments. Consequently, the evaluation of the photodegradation mechanism of organic pollutants, despite challenging, can provide meaningful insights about the nature of a semiconductor photocatalyst.⁴⁵ With the aim of evaluating the photodegradation mechanism we performed the measurements in the presence of different scavengers, namely an aqueous solution of AgNO₃ (100 mg L⁻¹), which captures photogenerated electrons, or triethanolamine (TEOA), which traps photogenerated holes (Fig. S13^†).^46,47 In the presence of Ag⁺ we could observe that the photocatalytic efficiency is enhanced, while the addition of TEOA quenched the performance, therefore suggesting that holes are the active specie in the photodegradation mechanism (Fig. S14^†).In summary, we have presented an approach towards the incorporation of D–A π-conjugated monomeric assemblies into poly(azomethine) networks to yield a purely organic semiconductor for the photocatalytic degradation of organic pollutants in aqueous media. The poly(azomethine) network benefits from a straightforward poly(condensation) approach which favourably competes with the elaborate high-temperature protocols applied for the preparation of inorganic materials. This work enriches the family of donor–acceptor organic semiconductor networks and, given its modular nature, paves the way for the development of a promising family of materials for photocatalytic applications.     

Influence of SiO2 or h-BN substrate on the room-temperature electronic transport in chemically derived single layer graphene

The substrate effect on the electronic transport of graphene with a density of defects of about 0.5% (^0.5%G) is studied. Devices composed of monolayer ^0.5%G, partially deposited on SiO₂ and h-BN were used for transport measurements. We find that the ^0.5%G on h-BN exhibits ambipolar transfer behaviours under ambient conditions, in comparison to unipolar p-type characters on SiO₂ for the same flake. While intrinsic defects in graphene cause scattering, the use of h-BN as a substrate reduces p-doping.

Defects in graphene cause scattering and basal plane interactions shift the Dirac-point.

Wet-chemically prepared graphene from graphite can be stabilized in solution by covalently bound oxo-groups using established oxidation protocols.^1–3 In general, the materials obtained are termed graphene oxide (GO). However, the chemical structure varies and the carbon lattice may even be amorphous due to the evolution of CO₂ during synthesis.⁴ Thus, in this study we use oxo-functionalized graphene (oxo-G), a type of GO with a more defined structure, as proven in our previous work.³ The oxygen-containing groups on the graphene basal plane and rims of flakes and holes make GO a p-type semiconductor with a typical resistance of 10¹⁰–10¹³ Ω sq^−1 5,6 and a band gap of about 2.2 eV.^7,8 The reductive defunctionalization of GO leads to a certain type of graphene (G), often named reduced GO (r-GO).^4,9 Removal of oxo-groups from the surface can be achieved by chemical reduction,^9,10 electrochemical methods,^11,12 electron beam treatment¹³ and was observed in situ by transmission electron microscopy.¹³ Thermal processing of GO instead leads to a disproportionation reaction forming carbon with additional vacancy defects and CO₂.¹⁴ In general, the reduction of GO turns r-GO from a semi-conductive material to a semi-metal. Mobility values were determined in field effect transistor (FET) devices.^15,16 Generally, the quality of graphene strongly depends on the integrity of the hexagonal carbon lattice. Thus, mobility values of 10⁻³ and up to 10³ cm² V⁻¹ s⁻¹ were reported,^3,17,18 with the resistance fluctuating between 10³ and 10⁶ Ω sq⁻¹.^19–21 We reported on the highest mobility values of chemically reduced oxo-G (with about 0.02% of lattice defects) of 1000 cm² V⁻¹ s⁻¹,³ determined by Hall-bar measurements at 1.6 K.Hexagonal boron nitride (h-BN) has been proved to be an excellent substrate for matching graphene-based materials owing to its atomic flatness, chemical inertness and electronic insulation due to a bandgap of ∼5.5 eV.²² Up to now, most studies with graphene deposited on h-BN were restricted to measurements with virtually defect-free graphene.²³ To the best of the authors knowledge, no studies reported transport measurements based on single layers of GO or oxo-G on h-BN substrates. No studies are reported with graphene derived from GO or oxo-G on single-layer level. Recently, we found that chemical reactions can be selectively conducted close to the rims of defects.²⁴ However, before functionalized devices can be studied, the lack of knowledge on the ambient environment device performances of graphene with defects and the influence of substrates must be addressed. Therefore, we fabricated the devices composed of ^0.5%G, partially deposited on SiO₂ (SiO₂/^0.5%G) and h-BN (h-BN/^0.5%G) (Fig. 1). Areas of the same flake on both materials are used to ensure reliable measurements and to prove that the results stem from the influence of the substrate rather than from the difference between devices. Thereby, the ^0.5%G exhibits an I_D/I_G ratio of about 3–4, corresponding to 0.5% of defects, according to the model introduced by Lucchese and Cançado.^25–28 Our results demonstrate that the h-BN layer is responsible for a downshift of the Dirac point and a more narrow hysteresis, resulting in ambipolar transfer behaviours in h-BN/^0.5%G.Open in a separate windowFig. 1(a) Optical image of the fabricated h-BN/^0.5%G heterostructure on SiO₂. (b) The h-BN/^0.5%G heterostructure device. Electrodes 1 and 2 define the SiO₂/^0.5%G FET device. Electrodes 1 and 3 define the ^0.5%G on overlapped SiO₂/h-BN hetero-substrate device. Electrodes 3 and 4 define the h-BN/^0.5%G FET device. Distance between the electrodes 1–2 and 3–4 is 1.5 μm and 3 μm, respectively. (c) 3D illustration of the h-BN/^0.5%G transistor device.     

Preparation of Ni-microsphere and Cu-MOF using aspartic acid as coordinating ligand and study of their catalytic properties in Stille and sulfoxidation reactions

In this study, the thermal and catalytic behavior of Ni-microsphere and Cu-MOF were investigated with aspartic acid as the coordinating ligand with different morphologies. The Ni-microsphere and Cu-MOF with aspartic acid, as the coordinating ligand, were prepared via a solvothermal method. The morphology and porosity of the obtained Ni microsphere and Cu-MOF were characterized by XRD, FTIR, TGA, DSC, BET and SEM techniques. The catalytic activity of the Ni-microsphere and Cu-MOF was examined in Stille and sulfoxidation reactions. The Ni microsphere and Cu-MOF were easily isolated from the reaction mixtures by simple filtration and then recycled four times without any reduction of catalytic efficiency.

In this study, the thermal and catalytic behavior of Ni-microsphere and Cu-MOF were investigated with aspartic acid as the coordinating ligand with different morphologies.

Cross-coupling reaction is one of the most significant methods to create carbon–carbon bonds in organic synthesis. There are many approaches, including, Suzuki, Stille, and Sonogashira cross-coupling reactions, which are well recognized and highly applicable in organic synthesis. Among them, the Stille reaction, which is an increasingly versatile tool for the formation of carbon–carbon bonds, involves the coupling of aryl halides with organotin reagents.¹ However, these reactions generally require expensive transition metal catalysts such as Pd.² Therefore, it is necessary to develop a new economic, green, and efficient methodology to reduce the environmental impact of the reaction. They are also important intermediates in organic chemistry and have been widely used as ligands in catalysis. The direct oxidation of sulfides is an important method in organic chemistry. Besides, they are also valuable synthetic intermediates for the construction of chemically and biologically important molecules, which usually synthesized by transition metal complexes.³ In this regard, different transition metal complexes of mercury(ii) oxide/iodine,⁴ oxo(salen) chromium(v),⁵ rhenium(v) oxo,⁶ H₅IO₆/FeCl₃,⁷ Na₂WO₄/C₆H₅PO₃H₂,⁸ chlorites and bromites,⁹ NBS¹⁰etc. have been introduced as catalysts. However, these catalysts have several drawbacks; including, separation problems from the reaction medium, harsh reaction conditions, and generating a lot of waste. In order to solve these drawbacks, of separation and isolation of expensive homogeneous catalysts is the heterogenization of homogeneous catalysts and generation of a new heterogeneous catalytic system. Metal–organic frameworks (MOFs) are a class of porous crystalline materials, which show great advantages, i.e. their enormous structural and chemical diversity in terms of high surface area,^11,12 pore volumes,¹³ high thermal,¹⁴ and chemical stabilities,¹⁵ various pore dimensions/topologies, and capabilities to be designed and modified after preparation.¹⁶ In this sense, it is worth mentioning that these features would result in viewing these solids as suitable heterogeneous catalysts for organic transformations.^17–22 MOFs materials are prepared using metal ions (or clusters) and organic ligands in solutions (i.e. solvothermal or hydrothermal synthesis). MOF structures are affected by metal and organic ligands, leading to have more than 20 000 different MOFs with the largest pore aperture (98 Å) and lowest density (0.13 g cm⁻³).²³ Generally, surface area and pore properties of MOFs seem quite dependent on their metal and ligand type as well as synthesis conditions and the applied post-synthesis modifications. The largest surface area was measured in Al-MOF (1323.67 m² g⁻¹)^24,25 followed by ZIF-8-MOF (1039.09 m² g⁻¹),²⁶ while the lowest value was with Zn-MOF (0.86 m² g⁻¹),²⁷ followed by γ-CD-MOF (1.18 m² g⁻¹)²⁸ and Fe₃O(BDC)₃ (7.6 m² g⁻¹).²⁹ Microspheres are either microcapsule or monolithic particles, with diameters in the range (typically from 1 μm to 1000 μm),²⁹ depending on the encapsulation of active drug moieties. In this regard, there are two types of microspheres: microcapsules, defined, as spherical particles in the size range of about 50 nm to 2 mm and micro matrices.³⁰ Microsphere structures have recently attracted much attention due to their unique properties, such as large surface area,³¹ which make them suitable for tissue regenerative medicine,³²i.e. as cell culture scaffolds,³³ drug-controlled release carriers³⁴ and heterogeneous catalysis.³⁵ Many chemical synthetic methods has been developed for their synthesis, including seed swelling,³⁶ hydrothermal or solvothermal methods,³⁶ polymerization,³⁷ spray drying³⁸ and phase separation.³⁹ Among these methods, the solvothermal synthesis has been used as the most suitable methodology to prepare a variety of nanostructural materials, such as wire, rod,⁴⁰ fiber,⁴¹ mof⁴² and microsphere.⁴³ In this sense, the synthesis process involves the use of a solvent under unusual conditions of high pressure and high temperature.⁴⁴ The properties of microspheres are highly dependent on the number of pores, pore diameter and structure of pore.⁴⁵ The degree of porosity depends on various factors such as temperature, pH, stirring speed, type, and concentration of porogen, polymer, and its concentration.⁴⁶ There have been numerous studies to investigate the coordination behavior of a ligand with different metals under the same conditions.^47–49 Herein, we aim at comparing the catalytic behavior of Ni-microsphere and Cu-MOF with aspartic acid as the coordinating ligand in Stille and sulfoxidation reactions (Scheme 1).Open in a separate windowScheme 1(a) Schematic synthesis of Ni microsphere and Cu-MOF and their application as catalyst (b) topological structure of Cu-MOF (c) topological of Ni microsphere.     

Direct synthesis of covalent triazine-based frameworks (CTFs) through aromatic nucleophilic substitution reactions

Despite extensive efforts, only three main strategies have been developed to synthesize covalent triazine-based frameworks (CTFs) thus far. We report herein a totally new synthetic strategy which allows C–C bonds in the CTFs to be formed through aromatic nucleophilic substitution reactions. The as-synthesized CTF-1 and CTF-2 exhibited photocatalytic water splitting activity comparable to the CTFs made using ionothermal or Brønsted acid-catalyzed polymerization. Interestingly, CTF-2 distinguished itself by its two-photon fluorescence (emission at ∼530 nm under irradiation at either 400 nm or 800 nm).

Triazine-based frameworks (CTFs) were synthesized through a new synthetic strategy in which C–C bonds were formed through aromatic nucleophilic substitution reaction.

Covalent organic networks (CONs), usually porous and physicochemically stable light-weight materials,¹ can accommodate, interact with, and discriminate molecules, which provides CONs with many potential applications in catalysis,^1i,2 gas separation/storage,^1b,1i,2a,3 chemical sensing,⁴ drug delivery,⁵ and photovoltaic light harvesting.^1b,2a,2b,6 As a subclass of CONs, covalent triazine-based frameworks (CTFs) have attracted researchers'' increasing attention worldwide. CTFs represent a class of functionalized polymers based on the trimerization and subsequent oligomerization of aromatic dinitrile monomers in the presence of a catalyst. In brief, there have been three main strategies to synthesize CTFs from aromatic dinitrile monomers: (1) polymerization⁷ of aromatic dinitrile monomers mediated by ZnCl₂ (ionothermal process), or catalyzed by strong Brønsted acid; (2) Friedel–Crafts reaction using 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride);⁸ and (3) nickel-catalyzed Yamamoto-type Ullmann cross-coupling of 2,4,6-tris-(4-bromo-phenyl)-[1,3,5]triazine.⁹ While the ZnCl₂-mediated ionothermal reaction is still the most widely used method, the high reaction temperature (400 °C) and long reaction time (40 h) limited its practical application. Although variations of the method to reduce the reaction time have been reported, the difficulty of completely removing residual ZnCl₂ remained as another obstacle.^7b The Brønsted acid method allows the polymerization to occur at ambient temperature, but it can only be applied to certain kinds of aromatic dinitrile monomers. An important environmental issue should not be overlooked in using aromatic dinitrile monomers, especially at large scale, as the dinitrile monomers were often made using over stoichiometric amounts of toxic cyanides, which is of neither economical nor ecological interest. Friedel–Crafts alkylation could work even without any addition of solvent, and is time-efficient, but residues of activating and/or bulking agents need to be removed and recovered upon framework formation. In addition, this approach is only limited to rigid and sterically demanding building blocks. Very recently, Baek''s group¹⁰ described a synthesis of CTFs at 400 °C through P₂O₅-mediated condensation of aromatic amide, which can be considered as a variation of ionothermal method of nitriles since P₂O₅ is known to catalyze the dehydration of amides into nitriles. Impressively, the approach that Jin, Tan and co-workers¹¹ recently reported was by way of condensation of aldehyde and amidine under mild reaction conditions.Herein, we are reporting a new synthetic strategy in which C–C bonds in the CTFs were formed through aromatic nucleophilic substitution reactions under mild reaction condition (refluxing in toluene). To the best of our knowledge, this is the first time that aromatic nucleophilic substitution was used for C–C bond formation in CTFs, and our method is different in many ways from the previously reported strategies. The as-synthesized CTFs exhibited photocatalytic water splitting activity comparable to the CTFs made using previously reported methods.While electrophilic substitution reactions are common for aromatic compounds, only some aryl halides can undergo substitution reactions with strong nucleophiles,¹² and some of such reactions have been used in covalent organic frameworks (COFs) preparation.¹³ We therefore envisioned that the chlorines in cyanuric chloride could be displaced by a strong nucleophilic reagent, for example, phenyllithium, and such a reaction could be used to prepare CTFs. To test the feasibility of this idea, we carried out a model reaction of phenyllithium (PhLi) and cyanuric chloride, which, we delightly found, gave 2,4,6-triphenyl-1,3,5-triazine (TriPh-triazine) in an isolated yield of 87% (Scheme 1 and ESI^†).Open in a separate windowScheme 1Reaction of phenyllithium and cyanuric chloride.Under very similar reaction conditions employed in the model reaction, two covalent triazine frameworks, CTF-1 and CTF-2 were successfully synthesized in gram-scale through aromatic nucleophilic substitution reaction of cyanuric chloride with para-dilithiumaromatic reagents in yields of 88% and 96%, respectively. The para-dilithiumaromatic reagents (1,4-dilithiumbenzene and 4,4′-dilithiumbiphenyl) used in the CTFs preparation were obtained through reactions of para-diiodoaromatic reagents with n-butyllithium, a widely used reagent in organic synthesis (caution: a highly reactive reagent and standard operating procedure should be strictly followed) (Scheme 2 and ESI^†). Albeit aromatic nucleophilic substitution reactions of cyanuric chloride was previously employed in the preparation COFs through the formation of C–X (X = N, S, O) bonds,¹⁴ such reactions have not been used to prepare COFs through C–C bond formation.Open in a separate windowScheme 2Synthesis of CTF-1 and CTF-2.CTF-1 and CTF-2 were characterized by Fourier transform infrared (FTIR) spectroscopy, solid-state ¹³C cross polarization magic angle spinning nuclear magnetic resonance spectroscopy (¹³C CP/MAS NMR), X-ray photoelectron spectroscopy (XPS) analysis, thermogravimetric (TG) analysis, field emission scanning electron microscopy (FE-SEM), field emission transmission electron microscopy (FE-TEM), powder X-ray diffraction (PXRD) analysis, ultraviolet-visible diffuse reflectance spectroscopy (UV-Vis DRS) and solid-state photoemission spectroscopy.The solid-state ¹³C NMR spectra of CTF-1 and CTF-2 (Fig. 1A) showed the presence of sp²-hybridized carbon of the triazine unit (∼170 ppm) as well as peaks of the aromatic rings (150–120 ppm).^7d In the FTIR spectrum of CTF-1 (Fig. 1B) (CTF-2, see ESI, Fig. S12^†), the disappearance of characteristic C–Cl band of cyanuric chloride at 850 cm⁻¹,⁸ together with the appearance of vibrational bands of triazine units at 1510 cm⁻¹ (C–N stretching) and 1360 cm⁻¹ (benzene ring breathing) implied the formation of CTFs.¹⁵Open in a separate windowFig. 1(A) Solid-state ¹³C CP/MAS NMR and repeating units of CTFs; (B) FTIR of CTF-1; (C) XPS survey spectra of CTFs; (D) TGA of CTFs; (E) PXRD of CTFs.In the XPS spectra of the CTFs, the appearance of the peaks with binding energies of 286.2 eV and 398.4 eV, assigned to C 1s and N 1s of the triazine (C–N C) ring, respectively, together with the peak at ∼284.3 eV, assigned to C 1s of the aromatic carbons,^7d,16 implied the existence of the triazine and aromatic units. The ratios of C_triazine : C_phenyl in the XPS spectra of CTF-1 and CTF-2 were 1 : 2.55 and 1 : 5.71, respectively, which were close to their theoretical values of 1 : 3 and 1 : 6 (Fig. 1C, S6 and S7 in ESI^†). The O 1s peaks seen in Fig. 1C are from physically adsorbed oxygen or water molecules which are usually found in carbon-based materials.^9b,17 Scarcely any Cl or I peaks were found in the XPS spectra of CTF-1 and CTF-2 (Fig. 1C and Tables S1 and S2, ESI^†), which indicated the completeness of aromatic nucleophilic substitution of cyanuric chloride with the corresponding aryl dilithium reagents. TG analysis shows that both CTF-1 and CTF-2 started decomposition at ∼300 °C and experienced ∼60% weight loss at 1000 °C in nitrogen atmosphere (Fig. 1D). Extended porous network structures with branched morphologies for the as-synthesized CTFs were observed by using FE-SEM (Fig. S19, ESI^†) and TEM images (Fig. S19, ESI^†). Powder X-ray diffraction (PXRD) patterns of the CTFs showed no distinct sharp peaks, but curved broad peaks at around 2θ = ∼19–20° (Fig. 1E) were observed, declaring their amorphous nature. No long-range crystallographic order for both CTFs indicated that the pore structures of the resulted CTFs maybe formed from unordered stacking and curling of the products. Such PXRD results are expected as the reaction was carried out under refluxing in toluene with vigorous stirring – the conditions unfavourable for the formation of crystalline products.The porous properties of the both CTFs were evaluated by nitrogen adsorption–desorption measurement at 77 K. Both samples exhibited the type IV adsorption isotherm character,¹⁸ typical for materials with mesoporous porosity (Fig. S8, ESI^†). The BET surface areas of CTF-1 and CTF-2 are ca. 40–100 m² g⁻¹, and their pore diameters were calculated to be around 15–24 nm by Barrett–Joyner–Halenda (BJH) method (Table S3, ESI^†). The surface areas of the CTFs synthesized using our method are larger than those of the CTFs obtained though Brønsted-acid method (5–8 m² g⁻¹),^7d but smaller than that of the CTF-1 obtained through ionothermal (ZnCl₂) process (791 m² g⁻¹).^7b In the ionothermal (ZnCl₂) process, zinc chloride might act as template and present in the as-synthesized CTFs products, removing the zinc chloride from the as-synthesized CTFs products could potentially result in higher porosity.¹⁹The UV-Vis diffuse reflectance spectra (UV-Vis DRS) of CTF-1 and CTF-2 (Fig. S10, ESI^†) showed the intrinsic absorptions in the range of visible light, which are attributed to π → π* electron transition of C_sp² and N_sp² in the polymeric networks.^7d The Kubelka–Munk transformed reflectance spectra,²⁰ as the mathematical equivalent transformation of UV-Vis DRS, showed band gaps of 2.62 eV and 2.90 eV of CTF-1 and CTF-2 (Fig. 2A), respectively.Open in a separate windowFig. 2(A) Kubelka–Munk transformed reflectance spectra of CTFs (inset: optical images of CTFs under visible light); (B) water-splitting reaction catalyzed by the two CTFs.Theoretical calculation (DFT) indicated that the top levels of the valence band (VB) of the CTFs were more positive than the redox potential of O₂/H₂O (1.23 V vs. NHE), while the bottom levels of their conduction band (CB) were more negative than the redox potential of H⁺/H₂ (0 V vs. NHE) (Fig. S9, ESI^†), which implied that the CTFs could be used in photocatalytic water splitting, like those described in previous work.^7d,21 The photo-catalytic water splitting abilities (hydrogen evolution reaction, HER) of the as-synthesized CTFs were thus evaluated in comparison with those of previously reported results under visible light (>420 nm) irradiation with triethanolamine (TEOA) as a photogenerated hole scavenger (ESI^†). Both CTFs showed water splitting ability under visible light (>420 nm), with CTF-2 possessing a slightly better catalytic activity than CTF-1 (Fig. 2B). Nonetheless, significant improvement was obviously needed on the photocatalytic activity toward water splitting for either CTFs.In addition to the absorption property and photo-catalytic water splitting abilities (HER) of the as-synthesized CTFs, the emission property of the CTFs was also evaluated. Both CTFs exhibits similar fluorescence spectra under identical higher-energy irradiation (400 nm, violet), as shown in Fig. 3A and B.Open in a separate windowFig. 3(A) Solid-state single photo fluorescence spectra (A) (400 nm excitation) and two-photo fluorescence spectra (B) (800 nm excitation) (the intensities of incident light on CTFs at 400 nm and 800 nm are the same, respectively).Interestingly, CTF-2 was found to display distinct two-photo-excited fluorescence (TPF) under lower-energy irradiation using a femtosecond laser pulse (800 nm, infrared) (red curve in Fig. 3B). The observation of two-photon excited fluorescence property, or up-conversion phenomenon, of CTF-2 implied that CTF-2 has a higher two-photo absorption cross section. The difference in the two-photo absorption cross section between CTF-1 and CTF-2 could possibly be attributed to their structural difference. As described in a previous report,²² structural features including effectiveness of conjugation, increased conjugation length, good planarity and strong electron donating ability were all critical to enhance the two-photon absorption cross sections. While the aromatics-linked triazine frameworks in repetitive structures made the both CTFs maintain good planarity, the effectively conjugated aryl units are longer in the biphenyl-linked CTF-2. The molecular force field (MM2)²³ calculation (ESI^†) indicated that the charge distributions of triazine rings (electron deficient parts) in the two CTFs were almost the same (C_triazine[+0.318]) (ESI^†), but the electron rich portions (aryl rings) of CTF-1 and CTF-2 hold different charge distributions (CTF-1 C_aromatic [−0.035] and CTF-2 C_aromatic [−0.041]), which could partially explain why CTF-2 has a higher two-photo absorption cross section value. The up-conversion phenomenon of CTF-2 implies that CTF-2 could be excited to the same excited state by either absorbing one photo under higher-energy irradiation (400 nm) or absorbing two photons under lower-energy irradiation (800 nm). As lower-energy irradiation (800 nm) provides a better penetration in scattering or absorbing media,²⁴ especially in organic and biological materials,²² CTF-2 could possibly be used in non-destructive photoimaging and optical memory.²⁵     

Synthesis of fully protected trinucleotide building blocks on a disulphide-linked soluble support

In recent years, preparation of fully protected trinucleotide phosphoramidites as synthons for the codon-based synthesis of gene libraries as well as for the assembly of oligonucleotides from blockmers has gained much attention. We here describe the preparation of such trinucleotide synthons on a soluble support using a disulphide linker.

Fully protected trinucleotides are synthesized on a tetrapodal soluble support using a disulphide linkage that upon reductive cleavage allows release of the trinucleotide with free 3′-OH group for further conversion to a phosphoramidite.

The synthesis of fully protected trinucleotide synthons for codon-based assembly of oligonucleotides has a long history and originally was motivated by the need for methods of combinatorial and evolutionary protein engineering, which combine combinatorial gene synthesis with functional screening or genetic selection applied at the phenotype level to an ensemble of many structural variants generated in parallel.^1–3 Among a host of related methods, the use of mixtures of pre-formed trinucleotide blocks representing codons for the 20 canonical amino acids stands out as allowing fully controlled randomization individually at any number of arbitrarily chosen codon positions of a given gene.^4–6 The chance of functional proteins in such libraries is increased, as randomization independent from the degenerated genetic code is possible and thus bias to amino acids represented by more than one codon as well as stop codons can be avoided.^6–9 The power of this method has been successfully demonstrated for randomization of immunoglobulins or at the example of a gene library of tHisF from the hyperthermophile Thermotoga maritima.^7,10 Apart from the preparation of gene libraries with controlled randomization, fully protected trinucleotides have potential as building blocks for oligonucleotide synthesis from blockmers (n = 1, 2, 3, 4, …), in particular then, when the oligomer is composed of repetitive sequence patches. In an ideal case, one previously synthesized blockmer can be coupled several times to obtain the desired oligomer. Moreover, oligonucleotide assembly from blockmers is advantageous in terms of easier purification, since n − 1, −2, … side products cannot be formed. A number of routes to fully protected trinucleotide building blocks have been developed, based on strategies in solution, on solid phase or on soluble supports (Fig. 1).^4,11,12 Traditionally, trinucleotide synthons have been prepared in solution, paying special attention to the pair of orthogonal protecting groups for the 5′- and 3′-OH functions, when synthesizing a dinucleotide that subsequently can be extended in 5′- or 3′-direction.^1,13–19Open in a separate windowFig. 1Strategies for preparation of fully protected trinucleotides in solution (A), on solid support (B) and on soluble phase (C); PG = protecting group.Synthesis in solution requires isolation of products after each synthesis step, which can become rather tedious. Therefore, we^11,20 and others¹⁹ have developed strategies for trinucleotide synthesis on solid support as an attractive alternative to protocols in solution.The key issue is the attachment of the 3′-start nucleoside to the solid support via a suitable linker, allowing to cleave off the trinucleotide after synthesis without loss of the protecting groups. With regard to trinucleotide synthesis, an oxalyl anchor¹⁹ or a disulphide linker have been described.^11,21In recent years, protocols for the synthesis of oligonucleotides on soluble supports have emerged,^12,21–24 and those have also been used with particular attention to the preparation of fully protected trinucleotides.^12,21 The general strategy involves iterative cycles of reaction steps in solution and precipitation for isolation/purification of reaction products. Several soluble supports have been used for oligomer synthesis (reviewed in ref. 25), among those, pentaerythritol-derived cores, which are easily precipitated from methanol.²⁴ Fully protected trinucleotides have been prepared on the pentaerythritol-derived core with the start nucleoside being tethered to the polymer via a disulphide bridge²¹ or hydroquinone-O,O′-diacetic acid (Q-linker).¹² In both strategies, phosphotriester chemistry has been used for trimer assembly, which in the disulphide strategy resulted in a trinucleotide with 3′-terminal ortho-chlorophenylphosphate.²¹ This 3′-remnant may be activated as a phosphotriester, but in standard automated DNA synthesis, where phosphoramidite coupling is strongly preferred, it would require to be selectively removed in order to convert the trinucleotide to the 3′-O-phosphoramidite building block. Moreover, the reductive cleavage of the disulphide bridge was performed in conditions that caused premature loss of the 5′-dimethoxytrityl (DMT) protecting group.²¹Based on our previous experience,^11,14,20 we here report on the preparation of fully protected trinucleotides on a pentraerythritol-derived soluble support using phosphoramidite chemistry for nucleotide coupling. As we have reported previously, tethering the start nucleoside to a solid support (polystyrene) via a dithiomethyl linkage is a superior strategy for assembly of blockmers that upon release from the support by reductive cleavage carry protecting groups at all functionalities, but offer a free 3′-OH group for conversion to the phosphoramidite building block.^11,20 Application of this immobilization strategy to the pentaerythritol-derived core, first required appropriate functionalization of the core. This was achieved as described previously by conjugation of commercially available S-propargyl thioacetate to the tetrakis-O-[4-(azidomethylphenyl)pentaerythritol] support²¹ by Cu(i) catalyzed 1,3-dipolar cycloaddition,^26,27 yielding tetrakis-O-{4-[4-[(acetylthiomethyl)]-1H-1,2,3-triazol-1-ylmethyl]-phenyl} pentaerythritol (1) (Scheme 1). The 3′-O-methylthiomethyl (MTM) modified start nucleosides (T and Bz-dA) were synthesized as described²⁰ following the strategy originally developed for synthesis of 2′-O-DTM functionalized ribonucleotide building blocks.²⁸ Aminolysis of the thioacetate on the support with butylamine in methanol delivered the free thiol function (2) required for immediate reaction with the nucleoside derivative to form the disulphide linkage. To this end, the 3′-O-MTM functionalized nucleoside (3a–b) was activated by treatment with sulfuryl chloride to give the 3′-O-chloromethyl ether (4a–b) in a Pummerer rearrangement, which immediately was converted in the presence of potassium thiotosylate to the reactive species (5a–b). This subsequently reacted with the support bound thiol (2) to form the desired loaded tetrapodal soluble support (6a–b, Scheme 1).Open in a separate windowScheme 1Reaction scheme for coupling of start nucleoside to soluble support.To start trinucleotide assembly, the support carrying the start nucleoside (6a–b) was treated with 4% dichloroacetic acid in ethylene dichloride to cleave off the 5′-O-DMT group (Fig. 2). The acid treatment was quenched by addition of pyridine, the solvents were evaporated, and the support linked with the deprotected start nucleoside (7a–b) was precipitated from methanol. The coupling reaction was carried out by taking up the precipitate in acetonitrile containing six equivalents of the N-acyl-5′-O-DMT protected nucleoside phosphoramidite in 0.1 M concentration, and addition of benzylmercapto-tetrazole²⁹ as activator. The resulting dimer 8a–b was oxidized by addition of a 0.2 M solution of iodine in trimethylpyridine/ACN/H₂O (1/11/5) to give the dinucleotide product 9a–b (Fig. 2). The support-linked dinucleotide 9a–b was directly precipitated from the reaction mixture by addition of methanol. The solid was filtered off and used for the next coupling cycle. All steps including deprotection, coupling and oxidation were repeated to obtain the fully protected trinucleotide on the soluble support (10a–b–12a–b, Fig. 2).Open in a separate windowFig. 2Reaction scheme of trinucleotide assembly on soluble support.NMR spectroscopy was used to analyse success of the synthesis. However, as long as the start nucleoside as well as the intermediate dinucleotide and the final trinucleotide were bound to the soluble support, complexity of the products and their modest solubility in common deuterated solvents retarded the analysis. Consequently, detailed NMR characterization was applicable only for the products released from the support. After assembly of the trinucleotide was finished, it was released in fully protected form from the support by reductive cleavage of the disulphide linkage with TCEP at pH 7.5 ³⁰ (13a–b, Fig. 2). After treatment with TCEP, the support was thoroughly washed with acetonitrile, acetone, ethanol and ethyl acetate, in order to separate the cleaved off trinucleotide. Traces of TCEP and of the tetrapodal support, which remained after this work up, were finally removed by chromatographic purification, which yielded sufficiently pure trinucleotide blockmers CTA and GGT in 43% and 35% overall isolated yield, respectively (both synthesized in tens of μmol scale). Extensive analysis by various NMR techniques (¹H, ¹³C, DEPT, HSQC, DQF-COSY, for detailed information see ESI^†) unambiguously confirmed the identity and purity of the desired products. For further application as synthons for DNA synthesis, the trinucleotides were converted to 3′-O-methylphosphoramidites following the standard procedure for phosphitylation (Fig. 3).³¹ The methyl group was chosen for protection of the phosphorous, because of its higher stability as compared with the β-cyanoethyl group and thus easier handling. Nevertheless, it should be noted, that also β-cyanoethyl protection can be used, both for the phosphate moieties in the trinucleotide and in the final trinucleotide 3′-O-phosphoramidite, if all steps of synthesis, purification and storage are carried out with particular care, partially requiring specific conditions.¹⁴ After aqueous work up and extensive drying, 0.1 M solutions of both trinucleotide phosphoramidites in appropriate solvents (see below) were prepared and used for coupling on the DNA synthesizer. Both trinucleotide synthons CTA (14a) and GGT (14b) were coupled in individual syntheses onto a short oligomer (CTT) on CPG. The 5′-terminal DMT group was left on, and the resulting 6mers 5′-CTACTT-3′ and 5′-GGTCTT-3′ were cleaved from the support by concentrated ammonia. RP-HPLC analysis was used to evaluate the coupling efficiency of the trinucleotide blockmers (Fig. 4).Open in a separate windowFig. 3Reaction scheme of trinucleotide phosphitylation, (i) N,N-diisopropyl-methyl-phosphonamidic-chloride, TEA, DCM, 3.5 h, rt; PG = protecting group.Open in a separate windowFig. 4HPLC analysis of CTACTT (A) and GGTCTT (B) (DMT-on). (A) peak 1: abortive fragments, peak 2: CTACTT; (B) peak 1: abortive fragments, peak 2: GGTCTT; AU = absorption unit. Conditions for (A and B) nucleodur 125/4, CV = 1.571 ml, 1 ml min⁻¹; buffer (A) 5% ACN, 0.1 M TEAAc; buffer (B) 30% ACN, 0.1 M TEAAc; gradient: starting with 0% buffer (B) for 4 CV, to 40% buffer (B) over 3 CV, to 60% buffer (B) over 7 CV, to 100% buffer (B) over 2 CV, then 100% buffer (B) for another 2 CV, to 0% buffer (B) over 3 CV.It has been discussed in the past that some but not all trinucleotide synthons are soluble in acetonitrile^1,32 or various compositions of acetonitrile–dichloromethane mixtures^12,16,19 with or without addition of DMF.¹⁸ The fully protected trinucleotide CTA showed poor solubility in acetonitrile and therefore was dissolved in dichloromethane. Solubility was clearly better than in acetonitrile, but not fully satisfying. Accordingly, HPLC analysis of the 6mer after coupling and deprotection showed a rather low coupling yield (Fig. 4A). This result may be interpreted as a consequence of a low effective concentration of the CTA blockmer and of the missing acetonitrile being the ideal solvent for phosphoramidite coupling. For dissolving the second trinucleotide GGT, we applied a 3 : 1 mixture of dichloromethane and acetonitrile, which allowed to prepare a 0.1 M solution of the trinucleotide phosphoramidite ready for coupling. A double coupling cycle was used to increase the coupling efficiency. The results are shown in Fig. 4B. A clearly higher coupling yield was achieved for the trinucleotide synthon GGT as compared to CTA (Fig. 4A). HPLC peak areas designated as final 6mers and abortive fragments would give rough estimation for the coupling yields, being about 17% for the CTA synthon and 72% for the GGT synthon under the described conditions (see ESI^† for details). The identity of the assembled 6mers was confirmed by MS analysis (see ESI^†). For GGT, the estimated coupling yield is well in the range of that for trinucleotide synthons reported in the literature,^15,16,32 although the coupling yields given there are usually just concluded from detritylation values on the synthesizer,^1,12,18,32 or it is not at all specified how those were determined.^15,19 Therefore, it is difficult if not impossible to compare coupling yields among the different protocols. Trinucleotide synthons that we had prepared in the past, showed coupling yields in DNA synthesis comparable to that achieved here in the range of 70 to 90%.¹⁴ This certainly can be further optimized in a systematic study including various solvents and solvent compositions for trinucleotide phosphoramidites, which however would require larger amounts of trinucleotide synthons than produced here. The focus of this work is on preparation of the trinucleotides on a soluble support, which has been successfully achieved, and the general functionality of the prepared trinucleotide synthons in automated DNA synthesis was demonstrated, although suitable conditions for efficient coupling still need to be determined.     

A concise and sequential synthesis of the nitroimidazooxazole based drug,Delamanid and related compounds

A concise, protection-group free and sequential route has been developed for the synthesis of the nitroimidazole based FDA-approved multi-drug resistant anti-tuberculosis drug, Delamanid and anti-leishmanial lead candidate VL-2098. The synthesis required chiral epoxides (11 and 17) as key intermediates. The chiral epoxide 11 was synthesised by sequential reaction cascades viz., allylation, selective N-arylation, Mitsunobu etherification, Sharpless asymmetric dihydroxylation and epoxidation, which do not require any special/dry reaction conditions. The steps involved towards the synthesis of epoxide also worked nicely in gram scales. After the synthesis of epoxide 11, the synthesis of Delamanid was achieved by reaction with 2-bromo-4-nitroimidazole 12 with an overall yield of 27%. Similarly, anti-leishmanial lead candidate VL-2098 was also synthesized in an overall yield of 36%.

A concise, protection-group free and sequential route has been developed for the synthesis of the nitroimidazole based FDA-approved multi-drug resistant anti-tuberculosis drug, Delamanid and anti-leishmanial lead candidate VL-2098.

Imidazoles are present in a wide variety of biologically relevant molecules exhibiting diverse pharmaceutical properties. Specifically, nitroimidazole containing compounds are active therapeutic agents against a wide variety of protozoan, bacterial (anaerobic) and leishmanial infections of humans and animals.¹ The notable examples of drugs are fexindazole,² metronidazole,³ benznidazole,⁴ tinidazole,⁵etc. Nitroimidazole was also well explored in the area of tuberculosis (TB) drug discovery (the structure of nitroimidazole containing drugs and lead compounds shown in Fig. 1).^6–9 CGI-17341 (I, developed by Ciba-Geigy, India) represents one of the very earliest outcomes but was not continued because of mutagenicity.⁶ Continued efforts to overcome the mutagenic liability led to the discovery of Delamanid (II, OPC-67683, a blockbuster against multi-drug resistant-TB, approved in 2014 by the EU)⁷ and Pretomanid^8a (III, PA-824, against multi-drug-resistant-MTB, approved in 2019 by the USFDA).¹⁰ Our involvement in the area of the TB drug discovery program and nitroimidazole chemistry^8b,c motivated us to develop a new concise and improved strategy towards the synthesis of Delamanid. The first synthesis of Delamanid was done by Tsubouchi et al. in 2004 (Otsuka Pharmaceutical Ltd. WO2004033463A1) which involved 16 steps (details shown in Fig. S1 of ESI^†).^11,12 The synthesis involves protection–deprotection strategy and made the process lengthy. Later on, in 2011, Otsuka had developed another concise route for Delamanid with improved yield (upper half of Fig. 2, details shown in Fig. S2 of ESI^†). This method involved the Sharpless epoxidation of 2-methyl allylalcohol followed by ring opening with 4-bromophenol. Then coupling with 4(4-trifluoromethoxy phenyl)piperidine fragment under palladium catalyzed conditions, which in turn was synthesized in 2–5 steps.¹³ Considering the importance of Delamanid, It could be better if more concise route was developed. In this regard, here we devised a route which involves sequential addition of fragments which not only avoid protection and deprotection but also provides the advantages of avoidance of dry conditions and costly intermediates. The lower half of Fig. 2 represents the strategy of the present method used for the synthesis of Delamanid, which involve the sequential coupling with following cascade viz., allylation, selective N-arylation, Mitsunobu ether formation, Sharpless dihydroxylation, epoxidation, ring opening and cyclization using inexpensive and easily available starting materials.Open in a separate windowFig. 1Nitroimidazole containing drugs and leads.Open in a separate windowFig. 2Previous and current approaches.The present synthesis started with 2-methylallyl chloride as first starting material and its selection is because of following reasons (i) as protecting group, (ii) inexpensive (33$ per 100 mL, Sigma) in comparison to 2-methylallyl alcohol (766$ per 100 mL, Sigma) which is used in earlier reported method and (iii) provide double bond functionality to generate epoxide via Sharpless dihydroxylation approach, which operates under open atmosphere conditions and avoids the anhydrous and dry environment as required for Sharpless epoxidation, used in the previous reported methods.^7,11b,12