Correction: Nano N-TiO2 mediated selective photocatalytic synthesis of quinaldines from nitrobenzenes

Correction for ‘Nano N-TiO₂ mediated selective photocatalytic synthesis of quinaldines from nitrobenzenes’ by Kaliyamoorthy Selvam et al., RSC Adv., 2012, 2, 2848–2855, DOI: 10.1039/C2RA01178F.

The authors regret omitting citations of their related papers in Journal of Molecular Catalysis A: Chemical and Applied Catalysis A: General: ‘Cost effective one-pot photocatalytic synthesis of quinaldines from nitroarenes by silver loaded TiO₂’ (DOI: 10.1016/j.molcata.2011.09.014)¹ and ‘Mesoporous nitrogen doped nano titania—A green photocatalyst for the effective reductive cleavage of azoxybenzenes to amines or 2-phenyl indazoles in methanol’ (DOI: 10.1016/j.apcata.2011.11.011).² The citations should have appeared in the following places as ref. 36 (ref. 1, in the reference list here) and ref. 37 (ref. 2, in the reference list here):In the sentence starting on line 5 of paragraph 5 in the introduction:‘Photocatalytic synthesis of quinolone derivatives from nitrobenzene using TiO₂, metal doped TiO₂ and others had been reported earlier.^1,23–25’At the end of Section 3.12 with the addition of the following sentence:‘This catalyst was also found to be effective for the reductive cleavage of azoxybenzenes to amines or 2-phenyl indazoles in methanol.²’The authors regret that it was not clear in the original article that the bare TiO₂ and N-TiO₂ characterisation data had been reproduced from their related Journal of Molecular Catalysis A: Chemical, Applied Catalysis A: General and Catalysis Communications papers.^1–3 Although the Catalysis Communications article was cited as ref. 25 (ref. 3, in the reference list here) in the original article, it was not made clear that some of the data was reproduced from this article. The appropriate figure captions have been updated to reflect this.Fig. 2: Diffuse reflectance spectra of (a) bare TiO₂, (b) N-TiO₂ and (c) TiO₂-P25. The bare TiO₂ data in Fig. 2a have been reproduced with permission from ref. 1. Copyright 2011 Elsevier. The N-TiO₂ data in Fig. 2b have been reproduced with permission from ref. 2. Copyright 2012 Elsevier.Fig. 3: Photoluminescence spectra of (a) bare TiO₂, (b) TiO₂-P25 and (c) N-TiO₂. The bare TiO₂ data in Fig. 3a have been reproduced with permission from ref. 1. Copyright 2011 Elsevier. The N-TiO₂ data in Fig. 3c have been reproduced with permission from ref. 2. Copyright 2012 Elsevier.Fig. 4: HR-TEM analysis: (a and b) images at two different regions of N-TiO₂, (c) SAED pattern of N-TiO₂, (d) lattice fringes of N-TiO₂ and (e) particle size distribution of N-TiO₂. Fig. 4 has been entirely reproduced with permission from ref. 2. Copyright 2012 Elsevier.Fig. 5: X-ray photoelectron spectra of N-TiO₂: (a) survey spectrum, (b) Ti 2p peak, (c) O 1s peak, (d) N 1s peak and (e) C peak. Fig. 5 has been entirely reproduced with permission from ref. 2. Copyright 2012 Elsevier.Fig. 6: (a) N₂ adsorption–desorption isotherms of N-TiO₂ and (b) its pore size distribution. Fig. 6 has been entirely reproduced with permission from ref. 2. Copyright 2012 Elsevier.Fig. 8: GC-MS chromatograms at different reaction times for the photocatalytic conversion of nitrobenzene with N-TiO₂. Fig. 8 has been entirely reproduced with permission from ref. 3. Copyright 2011 Elsevier.The authors also wish to remove Fig. 1 from the original article due to similarities between two of the spectra and the raw data no longer being available. This does not affect the conclusions as the presence of nitrogen was confirmed by other techniques.The authors also wish to clarify the differences between this RSC Advances paper and the Journal of Molecular Catalysis A: Chemical, Applied Catalysis A: General and Catalysis Communications papers.^1–3 The Journal of Molecular Catalysis A: Chemical paper discusses the photocatalytic synthesis of quinaldines from nitroarenes by silver loaded TiO₂.¹ The Applied Catalysis A: General paper reports the reductive cleavage of azoxybenzenes to amines or 2-phenyl indazoles using mesoporous nitrogen doped nano titania.² The Catalysis Communications paper, ref. 25 in the original article, discusses the synthesis of quinaldines from nitroarenes with gold loaded TiO₂ nanoparticles.³ The original RSC Advances paper discusses the catalytic ability of N-TiO₂ in the synthesis of quinaldines from nitrobenzenes. In each paper, either a different catalyst was used or a different synthetic reaction was investigated.     

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.     

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.     

Organocatalytic sulfa-Michael/aldol cascade: constructing functionalized 2,5-dihydrothiophenes bearing a quaternary carbon stereocenter

A practical sulfa-Michael/aldol cascade reaction of 1,4-dithiane-2,5-diol and α-aryl-β-nitroacrylates has been developed, which allows efficient access to functionalized 2,5-dihydrothiophenes bearing a quaternary carbon stereocenter in moderate to good yields with high enantioselectivities.

A sulfa-Michael/aldol cascade reaction of 1,4-dithiane-2,5-diol and α-aryl-β-nitroacrylate has been developed, which allows access to 2,5-dihydrothiophenes bearing a quaternary carbon center in moderate to good yields with high enantioselectivities.

Among the various classes of heterocycles, members of the thiophene family have received particular attention from the chemical community because of their widespread occurrence as ubiquitous motifs in natural products, pharmaceuticals, agrochemicals as well as materials.¹ In this context, the 2,5-dihydrothiophene ring is a common structural feature of many bioactive compounds and a potential intermediate for various synthetic applications.² Over the decades, only a few examples of the assembly of optically active 2,5-dihydrothiophenes have been documented.³ For instance, the Spino^3b group successfully prepared non-racemic dihydrothiophenes using an efficient chiral auxiliary. The first gold-catalyzed cycloisomerization of α-hydroxyallenes to 2,5-dihydrothiophenes was reported by Krause^3c and co-workers. Then in 2010, the Xu^3e group developed a highly stereoselective domino thia-Michael/aldol reaction between 1,4-dithiane-2,5-diol and α,β-unsaturated aldehyde catalyzed by a chiral diphenylprolino TMS ether, which provided a new avenue for the synthesis of functionalized 2,5-dihydrothiophenes.Quaternary carbon stereocenters are often contained in natural products and pharmaceuticals.⁴ Compared with the chiral pool synthesis,⁵ the procedure of chiral materials or catalysts to construct such sterically congested stereogenic centers is more challenging because of the difficulty of orbital overlap.⁶ To date, a lot of progresses have been made in the construction of chiral quaternary carbon centers in cyclic compounds,⁷ which are greatly accelerated by the advancement of transition metal catalysis,⁸ and organocatalysis,⁹ including methods beyond radical initiation.¹⁰ However, only few examples are about the construction of a quaternary carbon in 2,5-dihydrothiophene ring.¹¹ Inspired by the previous work of the Xu group,^3e we describe herein an elegant organocatalytic asymmetric cascade sulfa-Michael/aldol reaction, providing a convenient way for the synthesis of 2,5-dihydrothiophenes bearing a chiral quaternary cabon center.     

TEMPORAL EVOLUTION AND PREDICTORS OF SUBJECTIVE COGNITIVE COMPLAINTS UP TO 4 YEARS AFTER STROKE

ObjectiveTo examine the temporal evolution of subjective cognitive complaints in the long-term after stroke, and to identify predictors of long-term subjective cognitive complaints.MethodsProspective cohort study including 395 stroke patients. Subjective cognitive complaints were assessed at 2 months, 6 months and 4 years post-stroke, using the Checklist for Cognitive and Emotional consequences following stroke (CLCE-24). The temporal evolution of subjective cognitive complaints was described using multilevel growth modelling. Associations between CLCE-24 cognition score at 4 years post-stroke and baseline characteristics, depression, anxiety, cognitive test performance, and adaptive and maladaptive psychological factors were examined. Significant predictors were entered in a multivariate multilevel model.ResultsA significant increase in subjective cognitive complaints from 2 months up to 4 years (mean 3.7 years, standard deviation (SD) 0.6 years) post-stroke was observed (p≤0.001). Two months post-stroke, 76% of patients reported at least one cognitive complaint, 72% at 6 months, and 89% at 4 years post-stroke. A higher level of subjective cognitive complaints at 2 months and lower scores on adaptive and maladaptive psychological factors were significant independent predictors of a higher level of subjective cognitive complaints at 4 years post-stroke.ConclusionPost-stroke subjective cognitive complaints increase over time and can be predicted by the extent of subjective cognitive complaints and the presence of adaptive and maladaptive psychological factors in the early phases after stroke.LAY ABSTRACTMany people suffer a stroke in the brain leading to consequences in different areas of functioning. Complaints in the domain of thinking (memory, attention, planning and organization) are frequent post-stroke. This study investigated the occurrence and type of complaints experienced in the first years after a stroke. The study found that these complaints increase over time. Longterm complaints are found in those people who already have problems early after stroke.Key words: stroke, rehabilitation, cognition, cognitive complaints

Subjective cognitive complaints (SCC) are common after stroke, with prevalence rates varying between 28.6% (1) and 90.2%, (2), depending on stroke characteristics, time since stroke, SCC definitions and the instruments used. The most commonly reported complaints are mental slowness (in 46–80% of patients) and difficulties in concentration and memory (in 38–68% and 38–94% of patients, respectively) (3). Previous cross-sectional studies showed that SCC are present in both the early stages after stroke (1–6 months after stroke) (4–6), and in the long-term (> 1 year after stroke) (1, 7, 8). To date only a few studies have examined the temporal evolution of SCC. Tinson & Lincoln observed an increase in SCC between 1 and 7 months post-stroke (n = 95) (9). The authors used the Everyday Memory Questionnaire (10), focusing on memory-related complaints. Wilz & Barskova also found an increase in SCC over time after stroke (3 vs 15 months post-stroke, n = 81) (11). SCC were measured with the Patient Competency Rating Scale cognition subscale (12). Van Rijsbergen et al., who used the Checklist for Cognitive and Emotional consequences following stroke (CLCE-24) (13), recently found that SCC remained stable between 3 and 12 months after stroke (n = 155) (14). Long-term results on the course of post-stroke SCC are lacking. Since SCC were found to be independently related to lower quality of life in patients with mild cognitive impairment (15), and patients with subarachnoid haemorrhage (16), it is important to assess SCC after stroke. Furthermore, earlier research showed that SCC were most strongly associated with participation after stroke, compared with cognitive tests in a neuropsychological test battery, and the Montreal Cognitive Assessment (MoCA) (17, 18). Hence, in order to improve participation and integration in society after stroke, it is important to take the patients’ perspective into account, rather than only determining objective cognitive measures.The presence and severity of SCC is expected to be a direct reflection of the presence and severity of cognitive deficits. However, previous studies investigating the relationship between SCC and cognitive performance in stroke patients have shown conflicting results (1–4, 7, 8, 13, 19, 20). Other factors have shown to be related to SCC, in particular psychological factors, such as depressive symptoms (2, 4, 6, 7, 21), anxiety (21, 22), perceived stress (14), personality traits (7, 22), and coping style (23). To date, only one study on SCC used a longitudinal design (14), which prevents conclusions on the temporal evolution of SCC in stroke patients in the long term. Since more stroke patients survive, recover well and are discharged home nowadays, it is important to address predictors of SCC in the early phases after stroke, in order to identify patients who need more intensive monitoring at follow-up. Once identified, it is possible to investigate whether the patients will benefit from more focused rehabilitation programmes.The aim of this longitudinal study was to examine the temporal evolution of SCC, from 2 months until 4 years post-stroke. Furthermore, the study assessed which factors are predictive of SCC at 4 years post-stroke, taking into account demographic and stroke-related characteristics at baseline, and cognitive deficits and psychological factors measured at 2 months post-stroke.     

Synthesis of novel 1,2,4-thiadiazinane 1,1-dioxides via three component SuFEx type reaction

Herein, we report the preparation of 1,2,4-thiadiazinane 1,1-dioxides from reaction of β-aminoethane sulfonamides with dichloromethane, dibromomethane and formaldehyde as methylene donors. The β-aminoethane sulfonamides were obtained through sequential Michael addition of amines to α,β-unsaturated ethenesulfonyl fluorides followed by further DBU mediated sulfur(vi) fluoride exchange (SuFEx) reaction with amines at the S–F bond.

Herein, we report the preparation of 1,2,4-thiadiazinane 1,1-dioxides from reaction of β-aminoethane sulfonamides with dichloromethane, dibromomethane and formaldehyde as methylene donors.

The 1,2,4-thiadiazinane 1,1-dioxide motif can be found in many biologically active compounds for vastly different medical conditions. For example, verubecestat (1) has been in phase III clinical trials as a β-amyloid precursor protein cleaving enzyme (BACE 1) inhibitor to treat moderate and prodromal Alzheimer''s disease.¹ Ribizzi et al. have shown that taurolidine (2) displays cytotoxic activity against certain human tumour cells,² but primarily it is used as an antibacterial agent.³ In addition, benzothiadiazines (3) are patented as ATP-sensitive potassium channel modulators for the treatment of respiratory, central nervous, and endocrine system disorders.⁴ 1,2,4-Thiadiazinane 1,1-dioxides of this type may be formed by various methods;^5–13 most closely related to the present work is the [2 + 2 + 2] sulfa Staudinger cycloaddition of sulfonylchlorides and imines, in which case β-sultams may also be formed through the corresponding [2 + 2] cycloaddition.^14,15 α,β-Unsaturated sulfonyl fluorides 4 are so far rarely encountered as starting materials for organic synthesis.^16–18 The literature on this reagent describe it as a connector molecule,¹⁹ and a warhead in chemical biology.^20–22 There are only four publications that, so far, have reported the use of α,β-unsaturated sulfonyl fluoride based compounds as starting materials in organic synthesis.^23–26 Based on our earlier experience with the reactivity of aryl α,β-unsaturated sulfonyl fluoride towards various amine nucleophiles¹⁷ (Scheme 1), we hypothesized that an α,β-unsaturated sulfonyl fluoride of type 4 can possibly be explored for the synthesis of thiadiazinanes. This hypothesis was based on observation of low amounts of the six-membered product was formed along with the major β-sultam product 5 when p-nitrophenylethenesulfonyl fluoride was subjected to excess methyl amine in methylene chloride as a solvent and triethylamine as additional base at room temperature (Scheme 1).Open in a separate windowScheme 1Formation of 1,2,4-thiadiazinane 1,1-dioxides, along with β-sultams, when aryl ethenesulfonyl fluorides are subjected to large excess of primary amines in DCM as solvent and DBU as catalyst.The reactivity of dichloromethane (DCM) as a methylene donor was unfamiliar to us at the time, but a literature survey quickly revealed that organic solvents (DMF,²⁷ DMSO,^28–30 CHCl₃ (ref. 31 and 32) and CH₂Cl₂ (ref. 33 and 34)) have proved to be more than solvents. DCM has indeed been reported to act as a bis-electrophilic methylene donor in the presence of strong bases and nucleophiles³³ (e.g. carboxylic acids,³⁵ thiols,³⁶ amines, etc.). DCM may also form hydrochloride salts,³⁷ aminals,³⁸ and quaternary salts³⁹ when reacted with tertiary and secondary amines. These reactions were reviewed by Mills et al.⁴⁰ and the kinetics of the reaction of DCM with pyridine was documented by Rudine et al.⁴¹ Liu and co-workers reported formation of methylene-bridged 3,3′-bis-(oxazolidin-2-one) through reaction of oxazolidin-2-ones with DCM and sodium hydride.⁴² Cui et al. reported the synthesis of bispidine with the utilisation of DCM as a C1 unit.⁴³ Dipyrrolidylmethane CH₂(pyr)₂ and dipiperidylmethane, CH₂(pip)₂ were synthesized via the condensation of the secondary amine precursors and DCM at room temperature in the absence of light.⁴⁴ Another reaction of amines with methylene chloride yielded aminals rapidly.⁴⁵ Matsumoto et al. reported the reaction of DCM with ketones or esters in the presence of secondary amines at high pressure whereby DCM was used as methylene bridge in forming both C–C and C–N bonds.⁴⁶ Zhang and co-workers also published the formation of simultaneous carbon–carbon bond and carbon-nitrogen bonds whereby DCM acted as a synthon in the presence of 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and a copper catalyst.⁴⁷     

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     

Nano-Fe3O4@walnut shell/Cu(ii) as a highly effective environmentally friendly catalyst for the one-pot pseudo three-component synthesis of 1,3-oxazine derivatives under solvent-free conditions

Fe₃O₄@walnut shell/Cu(ii) as an eco-friendly bio-based magnetic nano-catalyst was prepared by adding CuCl₂ to Fe₃O₄@walnut shell in alkaline medium. A series of 2-aryl/alkyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines were synthesized by the one-pot pseudo three-component reaction of β-naphthol, formaldehyde and various amines using nano-Fe₃O₄@walnut shell/Cu(ii) at 60 °C under solvent-free conditions. The catalyst was removed from the reaction mixture by an external magnet and was reusable several times without any considerable loss of its activity. This protocol has several advantages such as excellent yields, short reaction times, clean and convenient procedure, easy work-up and use of an eco-friendly catalyst.

Fe₃O₄@walnut shell/Cu(ii) as an eco-friendly bio-based magnetic nano-catalyst was prepared by adding CuCl₂ to Fe₃O₄@walnut shell in alkaline medium.

Biopolymers, especially cellulose and its derivatives, have some unparalleled properties, which make them attractive alternatives for ordinary organic or inorganic supports for catalytic applications.¹ Cellulose is the most abundant natural material in the world and it can play an important role as a biocompatible, renewable resource and biodegradable polymer containing OH groups.² Walnut shell is a natural, cheap, and readily available source of cellulose. Fe₃O₄ nanoparticles are coated with various materials such as surfactants,³ polymers,^4,5 silica,⁶ cellulose⁷ and carbon⁸ to form core–shell structures. Magnetic nanoparticles as heterogeneous supports have many advantages such as high dispersion in reaction media and easy recovery by an external magnet.⁹ Cu(ii) as a safe and ecofriendly cation is a good Lewis acid and can activate the carbonyl group for nucleophilic addition reactions.¹⁰1,3-Oxazines moiety has gained great attention from many organic and pharmaceutical chemists due to their broad range of biological activities such as anticancer,¹¹ anti-bacterial,¹² anti-tumor¹³ and anti-Parkinson''s disease.¹⁴Owing to the biological importance of benzo-fused 1,3-oxazines, various methods have been developed for the synthesis of these compounds. Some shown protocols for the synthesis of various 2-aryl/alkyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazines via a Mannich type condensation between a 2-naphthol, formaldehyde and a primary amine were reported. This protocol has been catalyzed by KAl(SO₄)₂·12H₂O (alum),¹⁵ ZrOCl₂,¹⁶ polyethylene glycol (PEG),¹⁷ thiamine hydrochloride (VB₁)¹⁸ and CCl₃COOH.¹⁹ Other methods of synthesis of oxazines are aza-acetalizations of aromatic aldehydes with 2-(N-substituted aminomethyl) phenols in the presence of an acid as catalyst²⁰ and electrooxidative cyclization of hydroxyamino compounds.²¹However, some of these catalysts have limitations such as inefficient separation of the catalyst from reaction mixtures, unrecyclable and environmental limitations. Therefore, the development of green and clean methodology for the preparation of 2-aryl/alkyl-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine derivatives is still an interesting challenge.Herein, we wish to report the preparation of Fe₃O₄@nano-walnut shell/Cu(ii) as a new and bio-based magnetic nanocatalyst and its using for one-pot synthesis of 1,3-oxazine derivatives via condensation of β-naphthol, primary amine and formaldehyde.     

Creating de novo peptide-based bioactivities: from assembly to origami

DNA origami has created complex structures of various spatial dimensions. However, their versatility in terms of function is limited due to the lower number of the intrinsic building blocks, i.e. nucleotides, compared with the number of amino acids. Therefore, protein origami has been proposed and demonstrated to precisely fabricate artificial functional nanostructures. Despite their hierarchical folded structures, chain-like peptides and DNA share obvious similarities in both structures and properties, especially in terms of chain hybridization; therefore, replacing DNA with peptides to create bioactivities not only has high theoretical feasibility but also provides a new bottom-up synthetic strategy. However, designing functionalities with tens to hundreds of peptide chains using the similar principle of DNA origami has not been reported, although the origami strategy holds great potential to generate more complex bioactivities. In this perspective review, we have reviewed the recent progress in and highlighted the advantages of peptide assembly and origami on the orientation of artificially created bioactivities. With the great potential of peptide origami, we appeal to develop user-friendly softwares in combination with artificial intelligence.

Chain-like peptides and DNA share obvious similarities in terms of chain hybridization; thus, replacing DNA with peptides to create bioactivities not only has high theoretical feasibility but also provides a new bottom-up synthetic strategy.

In cells, peptides form versatile nanostructures with different bioactivities through self-assembly and co-assembly. Proteins such as collagen,¹ actin² and the peptides/proteins that are associated with amyloid diseases³ can self-assemble into fibrous structures. Helicase⁴ and nuclease⁵ are naturally ring-shaped structures. TMV capsid protein,⁶ α-hemolysin,⁷ and the Bacillus anthracis protective antigen⁸ are tubular structures. Citrate synthase,⁹ lysyl oxidase,¹⁰ RecR proteins,¹¹ ribonucleotide reductase I,¹² and hydrolase CS2 ¹³ can self-assemble into the lariat structures. Transferrin,¹⁴ vault protein,¹⁵ clathrin,¹⁶ chaperonin,¹⁷ and the capsids of viruses¹⁸ can form cage structures. These ordered nanostructures formed by the peptide assembly play essential roles in life.One of the ultimate goals of synthetic biology is to create artificial cells, and assembly is an important approach. DNA origami has been used to create versatile nanostructures since its origin¹⁹ and proof-of-concept reports²⁰ published by Seeman and coworkers. The nanostructures from DNA origami can act as scaffolds to synthesize inorganic particles or units to conduct multi-component and multi-functional assembly. Recently, de novo designed proteins have been investigated in various fields such as catalysis,²¹ energy (i.e., light harvesting²²), medicine (i.e., vaccine R&D,²³ gene and drug delivery²⁴), and environmental science (i.e., water treatment²⁵). Related review papers have been published by Guang et al.²⁶ and Yan et al.²⁷ However, the current artificial protein design is normally folded from one to a few long single-peptide chains (as the subunits of tertiary/quaternary structures), and designing complex artificial nanostructures with tens to hundreds of peptide chains using the similar principle of DNA origami (Fig. 1) has not been reported yet.Open in a separate windowFig. 1Peptide assembly with the principle of DNA origami. All amino acids are blocks for peptide assembly, and short peptide sequences can be designed as complementary pairs similar to base pairs (A T, G C) for peptide origami. Peptide sequences containing such complementary pairs can further assemble into nanostructures.     

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.     

ASSOCIATION BETWEEN PRE-STROKE PHYSICAL ACTIVITY AND MOBILITY AND WALKING ABILITY IN THE EARLY SUBACUTE PHASE: A REGISTRY-BASED STUDY

ObjectiveTo investigate associations between prestroke physical activity and mobility, walking ability, and self-perceived upper extremity function during stroke unit care.DesignA longitudinal, registry-based study with a consecutively collected cohort.Subjects/patientsA total of 1,092 adults with stroke admitted to 3 Swedish stroke units between 2017 and 2018.MethodsLogistic mixed effects regression models were performed to investigate associations (adjusted for age and sex). Pre-stroke physical activity was assessed with Saltin-Grimby Physical Activity Level Scale on admission. Mobility, walking ability, and self-perceived upper extremity function were assessed at admission and discharge from the stroke units and compared between pre-stroke physically active (45%) and inactive (55%) groups.ResultsAll groups of patients showed improvements in mobility (p < 0.001), walking ability (p < 0.001), and upper extremity function (p < 0.001). The changes over time tended to differ between the physically inactive and active groups for mobility (p < 0.062) and walking ability (p < 0.056), but the differences were not significant.ConclusionPre-stroke physically active people showed a tendency to be more independent in physical functioning early after stroke. Regardless of prestroke physical activity, all patients showed improvements in mobility, walking ability, and self-perceived upper extremity function during inpatient care.LAY ABSTRACTTo be physically active prior to a stroke may improve the post-stroke recovery process. Therefore, we hypothesized that pre-stroke physical activity might reduce the consequences of a stroke. This study investigated associations between pre-stroke physical activity and post-stroke recovery of mobility, walking ability, and arm and hand function. A total of 1,092 patients were examined; 44% were women, 89% had ischaemic stroke, and 55% were physically inactive before the stroke. All patients showed improvements during care at the stroke units, regardless of their previous physical activity level. At hospital discharge, 71% of patients showed independent mobility, 68% could walk independently, and 55% reported self-perceived arm and hand impairments. Patients with higher pre-stroke physical activity levels had a tendency of being more independent in mobility and walking compared with inactive patients. However, the frequencies of self-perceived arm and hand impairments were similar between the physically active and physically inactive groups. To be physically active prior to a stroke may improve the post-stroke recovery process.Key words: prestroke, stroke, exercise, physical activity, mobility, transfers, walking, upper extremity

The number of people living with the consequences of a stroke has increased over time (1), which has substantially increased the global burden of adult disability (2). The overall goal of stroke rehabilitation is to regain independence (2), but it has been shown that 43% have remaining disability one month after stroke, and 39% after 5 years (3). Recovery can be defined as an improvement over time, evaluated as the return to pre-stroke functions and activities, or alternatively, evaluated in terms of the underlying mechanisms (4). Agreed definitions of phases in stroke recovery are acute (1–7 days), early (7 days to 3 months), and late (3–6 months) subacute, and chronic (more than 6 months) (4). Improvements mainly occur in the early subacute phase after a stroke (4), and care at a stroke unit is important for positive outcomes (5). Stroke-unit care and rehabilitation increases the probability that patients will survive, return to their own homes, and regain independence (5) at one year post-stroke (6). In stroke rehabilitation research, stroke-related impairments (sensorimotor deficiencies, quality of life, and global disability) should be evaluated with measures capturing mobility, walking, and motor function (7). According to the International Classification of Functioning, Disability, and Health (ICF) (8), mobility and walking ability are categorized as “activities and participation”, and upper extremity (UE) function is included in the category of “body structures”.Pre-stroke physical activity may promote neuroprotective mechanisms, such as angiogenesis, and neuroplasticity, in both human and animal subjects (9). This could contribute to better motor function, and motor recovery (9). Previous studies have shown that physical activity could reduce the risk of stroke by 25–30% (10). Physical activity is defined as any bodily movement produced by skeletal muscles that requires energy expenditure (11). Different types of physical activity can be categorized as occupational, sports, conditioning, household, or other activities (11). Exercise, which is a subcategory of physical activity, is planned, structured, and repetitive, and its purpose is to improve or maintain physical fitness (11). Pre-stroke physical activity was previously related to a reduction in the size of a cerebral infarction (12), less severe acute stroke symptoms (12–15), less post-stroke disability (12, 15, 16), and improved performance in activities of daily living (ADL) (15, 17, 18). Previous studies on disability after stroke often included a mobility assessment, but, typically, mobility was not measured separately from other abilities. Moreover, few studies have focused on associations between pre-stroke physical activity and post-stroke physical functioning (19) (i.e. mobility, walking ability, and UE function). However, 3 small studies showed that pre-stroke physical activity was positively related to post-stroke improvements in balance, walking speed (17), independent gait (20), and walking frequency (21). No studies have investigated the association between pre-stroke physical activity and UE function. Overall, little evidence is available on associations between pre-stroke physical activity and different post-stroke consequences, and the published results are conflicting (19, 22). The current study aimed to investigate associations between pre-stroke physical activity and post-stroke mobility, walking ability, and self-perceived UE function during inpatient stroke unit care.     

Nanozyme-based catalytic theranostics

Nanozymes, a type of nanomaterial with intrinsic enzyme-like activities, have emerged as a promising tool for disease theranostics. As a type of artificial enzyme mimic, nanozymes can overcome the shortcomings of natural enzymes, including high cost, low stability, and difficulty in storage when they are used in disease diagnosis. Moreover, the multi-enzymatic activity of nanozymes can regulate the level of reactive oxygen species (ROS) in various cells. For example, superoxide dismutase (SOD) and catalase (CAT) activity can be used to scavenge ROS, and peroxidase (POD) and oxidase (OXD) activity can be used to generate ROS. In this review, we summarize recent progress on the strategies and applications of nanozyme-based disease theranostics. In addition, we address the opportunities and challenges of nanozyme-based catalytic theranostics in the near future.

With its diverse physical–chemical properties and highly efficient enzyme-like activities, nanozymes have been widely used in various theranostics.

A nanozyme is a type of nanomaterial (1–100 nm) with enzyme-like activities.^1,2 It can catalyze the reaction of enzyme substrates under physiological conditions, and it has similar catalytic efficiency and enzymatic abilities to natural enzymes. Our previous work found that Fe₃O₄ nanoparticles (NPs) possess an intrinsic peroxidase (POD)-like activity.³ Since then, numerous nanomaterials have been discovered to have POD-, catalase (CAT)-, superoxide dismutase (SOD)-, or oxidase (OXD)-like catalytic activities.⁴ A nanozyme may have more than one type of catalytic activity.⁵ Nowadays, more than 540 nanozymes from 49 elements have been reported from 350 laboratories in 30 countries.^6,7 Among these, iron oxide nanoparticles,⁸ CeO₂,⁹ graphene oxide,¹⁰ carbon nanozymes¹¹ and gold nanoparticles¹² are widely studied and applied.Nanozymes can simulate the catalytic processes of natural enzymes and regulate the redox level of cells, especially on reactive oxygen species (ROS). ROS are intermediate products which emerge in the process of oxygen metabolism, mainly including superoxide anion (O₂˙⁻), hydroxyl radical (·OH), and hydrogen peroxide (H₂O₂).¹³ An abnormal rise in ROS level will destroy the homeostasis of redox in vivo and cause oxidative stress. Nanozymes typically exhibit multiple enzymatic activities. On the one hand, the catalase and superoxide dismutase activity of nanozymes are mainly used to regulate the intracellular ROS level, which plays an important role in protecting cells. On the other hand, the oxidase and peroxidase activity of nanozymes induce ROS production and promote apoptosis, such as in cancer cells.With advantages such as high catalytic efficiency, high stability, biosafety, low cost and easy preparation,¹⁴ nanozymes have been widely used in industrial, medical, and biological fields and in environmental remediation.^2,15,16 Currently, a variety of nanozyme-based biomedical applications have been extensively explored, including biosensors,¹⁷in vitro texts,¹⁸ and antimicrobial¹⁹ and disease treatments, such as cancer therapy, bone marrow therapy and wound healing.²⁰ Here, we summarize the biomedical applications of nanozymes in vivo, as well as addressing the opportunities and challenges of nanozyme-based catalytic disease theranostics in the near future.     

Yield stress fluids and fundamental particle statistics

Yield stress in complex fluids is described by resorting to fundamental statistical mechanics for clusters with different particle occupancy numbers. Probability distribution functions are determined for canonical ensembles of volumes displaced at the incipient motion in three representative states (single, double, and multiple occupancies). The statistical average points out an effective solid fraction by which the yield stress behavior is satisfactorily described in a number of aqueous (Si₃N₄, Ca₃(PO₄)₂, ZrO₂, and TiO₂) and non-aqueous (Al₂O₃/decalin and MWCNT/PC) disperse systems. Interestingly, the only two model coefficients (maximum packing fraction and stiffness parameter) turn out to be correlated with the relevant suspension quantities. The latter relates linearly with (Young’s and bulk) mechanical moduli, whereas the former, once represented versus the Hamaker constant of two particles in a medium, returns a good linear extrapolation of the packing fraction for the simple cubic cell, here recovered within a relative error ≈ 1.3%.

Yield stress in complex fluids is described by resorting to fundamental statistical mechanics for clusters with different particle occupancy numbers.

Yield stress fluids form a particular state of matter,¹ displaying non-linear and novel visco-plasto-elastic flow dynamics upon different boundary conditions. As their name says, they don’t flow until a certain load, the so-called yield stress (or point, τ₀), is applied. This value may be generally interpreted as a shear stress threshold for the breakage of interparticle connectivity.² Furthermore, as it initiates motion in the system, it is connected to mechanical inertia³ and particle settling, i.e. it is a terse summary of buoyancy, dynamic pressure, weight, viscous and yield stress resistances.⁴ For prototype systems such as colloids dispersed in a liquid, yield points sensibly depend on the mechanism by which the solid phase tends to interact or aggregate.^5–8 The macroscopic constitutive equations they obey, such as the Herschel–Bulkley model, were shown to correspond, over a four-decade range of shear rates, to the local rheological response.⁹From the side of an experimenter, however, unambiguously defining a yield stress may not always be straightforward. It can be affected by the experimental procedure adopted, always considering a measurement or some extrapolation technique with the limit of zero shear. Conversely, unyielded domains may be defined by areas where the shear stress second invariant falls below the yield value, plus some small semi-heuristic constant.¹⁰ In addition, theoretically, the meaning of notions like τ₀ and rheological yielding were questioned to be only qualitative or even to stand for an apparent quantity.¹¹ The dependence they generally show on timescales characteristic of the applied (mechanical) disturbance, also suggested an intimate relationship¹² between yield stress and dispersion thixotropy.¹³ On the other hand, assigning a hydrodynamic or mechanical state below the yield point to a material that is not flowing seems not to be scientifically sound. Experimental values are normally obtained by extrapolation of limited data, whereas careful measurements below the yield point would actually imply that flow takes place.¹⁴At any rate, the analysis of properly defined τ₀ concepts forms the subject of interesting investigations and is still a powerful tool in many applications, including macromolecular suspensions,¹⁵ gels, colloidal gels and organogels,^16–18 foams, emulsions and soft glassy materials.¹⁹ It allows for effective comparisons between the resistances which fluids initially oppose to the shear perturbation, somehow specifying a measure of the particle aggregation states taking place in a given dispersant. Electrorheological materials, for instance, exhibit a transition from liquid-like to solid-like behaviors, which is often examined by a yield stress investigation upon a given fluid model (e.g. the Bingham model or the Casson model).^20,21 The combination of yield stress measurements with AFM techniques can be used to well-characterize the nature of weak particle attractions and surface forces at nN scales.⁸ Further issues of a more geometrical nature, which naturally connect to τ₀, are rheological percolation²² and its differences from other connectivity phenomena, such as the onset of electric²³ or elastic percolation.^24,25 In granular fluids, it relates with the theory of jammed states,²⁶ originally pioneered by Edwards.²⁷In nanoscience as well, the stability control and characterization in single and mixed dispersions or melts is an important and complex step.^28,29 Carbon nanotube suspensions,³⁰ for example, can be prepared in association with other molecular systems, like surfactants and polymers^31–33 or by (either covalent or non-covalent) functionalization of their walls with reactive groups, which increases the chemical affinity with dispersing agents.³⁴ As a consequence of large molecular aspect ratios and significant van der Waals’s attractions, the nanotube aggregation is highly enhanced, giving rise to strongly anisotropic systems of crystalline ropes and entangled network bundles, which are difficult to exfoliate, suspend or even characterize.³⁵ Stable CNT dispersions of controlled molecular mass may also exhibit polymeric behavior, and be quantitatively studied by equations taken from the well-established science of macromolecules.^36,37This paper puts forward a basic approach, mostly focused on equilibrium arguments, to devise a yield stress law connected with particle statistics. By conjecturing an ensemble of effective volumes ‘displaced’ at the incipient state of motion, a statistical mechanics picture of τ₀ is proposed. This affords a phenomenological hypothesis that can be developed with reasonable simplicity. The derived relations are applied to typical disperse systems in colloid science and soft matter, such as aqueous and nonaqueous suspensions of ceramic/metal oxides and nanoparticles.     

Comment on “Incipient plasticity of diamond during nanoindentation” by C. Xu,C. Liu and H. Wang,RSC Advances, 2017, 7, 36093

A recent molecular dynamics simulation study on nanoindentation of diamond carried out by Xu et al.¹ has reported observation of the presence of a controversial hexagonal lonsdaleite phase of carbon in the indentation area. In this comment, we question the reported observation and attribute this anomaly to shortcomings of the long range bond order potential (LCBOP) employed in the nanoindentation study.

A recent molecular dynamics simulation study on nanoindentation of diamond carried out by Xu et al. has reported observation of the presence of a controversial hexagonal lonsdaleite phase of carbon in the indentation area.

In 1967, lonsdaleite (a material named in honour of an Irish crytallographer Ms. Kathleen Lonsdale) was first proposed to be a hexagonal lattice structure allotrope of carbon that rivals cubic diamond in hardness.³ Controversy exists concerning the physical existence of lonsdaleite. Recently, evidence suggesting the physical existence of lonsdaleite was obtained from X-ray diffraction data of pyrolytic graphite subjected to laser shock compression at pressures higher than 170 GPa.⁴ This evidence arguing that lonsdaleite is a thermodynamic phase by itself has recently been questioned.⁵ Based on X-ray diffraction patterns,⁶ it is suggested that lonsdaleite is merely a faulted and twinned (stacking disordered) cubic diamond structure. Theoretical ab initio results⁷ indicate that the cohesive energy difference per atom between the diamond and lonsdaleite phases is about 51.7 meV.⁷Absence of a matured theoretical understanding and sufficient data are why the lonsdaleite phase of carbon is generally not considered in the construction of material constitutive models, particularly interatomic potential functions or force-fields needed for molecular dynamics simulations. An interatomic potential function is usually parameterised and fitted for a given set of phases of the material, but none of the currently available potentials captures the mechanical, structural and energetic aspects of all phases of carbon.⁸ It is well known that each potential function has its own characteristic advantages and weaknesses, and whether it is applicable or not to a given problem is governed by a range of factors. Only in rare cases and typically by chance a potential may work to describe a phase for which it was not originally fitted. For instance, the analytical bond order potential (ABOP) of Erhart and Albe has been found to best describe the most recently identified phase of penta-graphene⁹ whilst the EDIP potential was reported most appropriate for simulating amorphous carbons.¹⁰Ideally, MD simulation studies of contact loading processes like nanometric cutting or nanoindentation require a potential to be highly transferable as the material undergoes extreme conditions of stress. For an interatomic potential to correctly reproduce changes in the microstructure or predict phase transitions during contact loading, it is necessary (but generally not sufficient) that the potential function correctly reproduces the cohesive energy of the involved phases of the material, particularly because the incipient plasticity in early stages of wear may occur either due to atom-by-atom attrition, diffusion, or bond breaking.The above considerations motivated us to examine a series of potentials for carbon proposed in the literature, including the LCBOP function² employed in the study of Xu et al.,¹ to see how closely they describe the cohesive energy difference between cubic and hexagonal phases of carbon. We performed molecular statics calculations at zero pressure to determine the cohesive energies of the diamond and lonsdaleite phases of carbon. Our results shown in 11 of the reactive empirical bond-order (REBO) potential^12,13 predicting energy differences between the diamond and hexagonal phases of carbon that are close to the ab initio energy difference.⁷ From this, it can be concluded that the occurrence of lonsdaleite observed in the study of Xu et al.¹ may be an artefact of the employed LCBOP potential and is likely to have resulted from the underestimation of the structural energy difference. This renders the significance of the reported transformation process questionable.Differences in the cohesive energy per atom between diamond and lonsdaleite phases

INCREASED SATELLITE CELL APOPTOSIS IN VASTUS LATERALIS MUSCLE AFTER ANTERIOR CRUCIATE LIGAMENT RECONSTRUCTION

ObjectiveRecovery of the quadriceps femoris muscle after anterior ligament reconstruction is impaired. The aim of this study was to investigate satellite cell content and function of the vastus lateralis muscle after anterior ligament reconstruction.MethodsBiopsies were obtained from the vastus lateralis muscle of 16 recreational athletes immediately before and again 12 weeks after anterior ligament reconstruction. Total satellite cell number (Pax7⁺), activated (Pax7⁺/MyoD⁺), differentiating (Pax7^–/MyoD⁺), and apoptotic (Pax7⁺/TUNEL⁺) satellite cells, myofibers expressing myosin heavy chain (MHC) I and II, and neonatal MHC (MHCneo) were determined immunohistochemically.ResultsAfter anterior ligament reconstruction, the number of apoptotic satellite cells was significantly (p = 0.019) increased, concomitant with a significant (p < 0.001) decrease in total satellite cell number, with no change in activated and differentiating satellite cell number. MHCneo⁺ myofibers tended towards an increase.CONCLUSIONSatellite cell apoptosis and the reduction in the satellite cell pool might provide an explanation for prolonged quadriceps muscle atrophy after anterior ligament reconstruction.LAY ABSTRACTProtracted muscle atrophy is common after anterior ligament reconstruction, even if athletes adhere to a structured rehabilitation programme. Satellite cells, the stem cells of skeletal muscle, play an important role in recovery of an atrophied muscle. Exercise can activate satellite cells, induce their proliferation, and probably also differentiation of these stem cells. The current study evaluated satellite cell content and function in biopsies from the vastus lateralis muscle of 16 recreational athletes immediately before and 12 weeks after anterior ligament reconstruction. After anterior ligament reconstruction, an increased number of satellite cells showed signs of apoptosis (cell death). Furthermore, total satellite cell number was decreased, with no change in the numbers of activated and differentiating satellite cells. The number of regenerating myofibers expressing neonatal myosin tended to increase. In conclusion, satellite cell apoptosis and the reduced satellite cell number might provide an explanation for the impaired muscle recovery after anterior ligament reconstruction.Key words: satellite cells, apoptosis, muscle regeneration, developmental myosin heavy chain, muscular atrophy, quadriceps muscle

Protracted atrophy and weakness of the quadriceps muscle are common after anterior cruciate ligament (ACL) injury and/or anterior cruciate ligament reconstruction (ACL-R), even if the patients undergo guided rehabilitation programmes (1–4). Muscle recovery is compromised due to negative changes in the knee extensor muscles, most likely due to impaired neuromuscular function (5), post-surgery inflammation (6) and immobilization (7). After ACL injury, fibrogenic alterations were observed in biopsies obtained from the vastus lateralis muscle of the injured leg (8, 9). Satellite cell (SC) abundance was also reduced compared with biopsies taken from the vastus lateralis muscle of the uninjured leg (8, 10). Furthermore, there was a surprising lack of increase in SC number after regular rehabilitation training (10), as well as after 12 weeks of supervised quadriceps strength training during rehabilitation after ACL-R (3).SCs play an important role in skeletal muscle growth and regeneration (11, 12). Increases in SC number occur after 11–12 weeks of quadriceps strength training in healthy subjects (13–15). The role of SCs in atrophy of human skeletal muscle, however, has scarcely been investigated. In the very few studies on the role of SCs in atrophy of human skeletal muscle (8, 10, 16), loss of SCs with atrophy is not a consistent finding. However, there is some evidence that a particularly severe atrophic environment, as is found, for example, after severe burn injury, has a negative impact on SC number and SC function and can induce SC apoptosis (17). With regard to findings in animal studies, it has been hypothesized that muscle wasting in old age (sarcopaenia) could at least partly be explained by SC dysfunction with increased SC apoptosis due to chronic low-grade systemic inflammation (18). The significantly reduced SC number in biopsies from the vastus lateralis muscle after ACL injury (8, 10) and the lack of increase in SC number after resumption of muscular training after ACL-R (3, 10) suggest that ACL injury and/or ACL-R with quadriceps tendon or semitendinosus tendon autografts, respectively, might generate a severe atrophic environment with negative effects on SC number and function.The primary aim of this study was to further investigate the effects of ACL-R on SCs and to determine whether the previously described reduction in SC number might be due to SC apoptosis. The study analysed muscle biopsies from the vastus lateralis muscle of recreational athletes immediately before ACL surgery and again after 12 weeks of early rehabilitation.     

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.     

EFFECTS OF VIRTUAL REALITY-BASED NECK-SPECIFIC SENSORIMOTORTRAINING IN PATIENTS WITH CHRONIC NECK PAIN: A RANDOMIZED CONTROLLED PILOT TRIAL

ObjectiveTo evaluate the effects of neck-specific sensorimotor training using a virtual reality device compared with 2 standard rehabilitation programmes: with, and without general sensorimotor training, in patients with non-traumatic chronic neck pain.DesignPilot randomized control study.Patients and methodsA total of 51 participants were randomly assigned to 1 of 3 groups: 1: control group; 2: sensorimotor group; 3: virtual reality group. All 3 groups received the clinic’s standard rehabilitation programme. Group 2 also received “general sensorimotor training” in the form of group therapy, for a total of 120 min. Group 3 received additional virtual reality-based “neck-specific sensorimotor training” for a total of 120 min. Participants’ neck pain, headaches, active cervical range of motion, and Neck Disability Index were determined before and after 3 weeks of intervention.ResultsCompared with the control group, the virtual reality group showed significant (p < 0.05) advantages in relief of headaches, and active cervical range of motion in flexion and extension. Compared with the sensorimotor group, the virtual reality group showed significant improvements in cervical extension.ConclusionVirtual reality-based sensorimotor training may increase the effects of a standard rehabilitation programme for patients with non-traumatic chronic neck pain, especially active cervical range of motion in extension.LAY ABSTRACTThe aim of this study was to evaluate the effectiveness of neck-specific coordination training using a virtual reality device, in comparison with general coordination training and a standard exercise programme as part of inpatient rehabilitation for patients with chronic neck pain. Pain, disability and mobility of the neck were determined before and after 3 weeks of training intervention in 51 patients. The virtual reality training group exhibited greater effects in relief of headaches, and bending the neck forwards and backwards compared with the standard exercise group, and an increased ability to bend the neck backwards compared with the coordination training group. The results suggest that neck-specific coordination training using a virtual reality device increases the benefits of standard inpatient rehabilitation in patients with chronic neck pain, particularly in bending the neck backwards.Key words: neck pain, rehabilitation, virtual reality, kinematics

Neck pain is a widespread problem; 60–80% of individuals develop neck pain during their life-time, with 30–50% of the general population reporting neck pain annually (1–3). Many patients experience neck pain as a complex biopsychosocial disorder, with problematic physical and psychological symptoms (3), such as reduced cervical range of motion, headaches, lack of concentration, emotional and cognitive disorders (4, 5). Aside from the decreased quality of life, these complaints are a major cause of inability to work (6, 7) and lead to considerable economic damage (8). Hence, the demand for an effective treatment is indisputable.According to a recently published review (9), the strongest treatment effects for neck pain are those associated with exercise. However, the evidence for this claim is only of moderate quality. Since there is no data available at present to show that any one form of exercise is evidentially more effective than another, multimodal care is concordantly recommended by leading experts (3, 9).Sensorimotor training methods are a current trend in exercise therapy, and for the first time they take into account the special function of the neck, by including connections between the perceptions of sensory organs located in the head and neck muscles (10–14). Alterations of sensorimotor control have been identified in many patients with neck pain, and are thought to play an important role in the aetiology and maintenance of associated disorders (14, 15).To date, there are only a few sensorimotor training concepts that have been specially developed for the neck region. Initial studies found that patients undergoing these training methods experienced reduced neck pain, as well as improvements in cervical range of motion, self-reported disability, and general health (11, 13, 14, 16). However, a systematic review from 2014 (17) revealed very little evidence for eye-neck coordination and proprioceptive exercises. Furthermore, a randomized controlled trial (RCT) found that neck coordination exercises did not produce a larger effect than strength training and massages (18).Application of a virtual reality (VR) device is a novel and promising option for training cervical kinematics (10, 12, 19). In theory, this technique provides several advantages: distracting attention and therefore reducing pain and kinesiophobia (20, 21), engaging and motivating physical activities, and improving the effectiveness of exercise (22, 23).To date, only one RCT has compared the effects of VR-based training with conventional kinematic training using laser beams in patients with chronic neck pain (12). The VR group exhibited significant improvements in motion velocity, pain intensity, health status, and accuracy of neck motion.Due to the conflicting evidence and lack of research, there is a need for more studies that consider the effectiveness of VR-based sensorimotor training concepts, especially in combination with other effective therapeutic exercises or as part of individually tailored programmes (12).The aim of this study was therefore to evaluate the effects of neck-specific sensorimotor training using a VR device, in comparison with standard rehabilitation programmes, both with and without general sensorimotor training, in patients with non-traumatic chronic neck pain.     

A universal strategy to continuously tune the properties of materials through internal strain

We proposed a universal strategy to continuously and precisely tune the properties of materials. Atoms or molecules would be inserted into a nano tuner, which is a nano container with inwalls linked by molecular springs. Interactions between core materials and nanocontainers can be precisely and continuously tuned by changing the types and amount of molecular springs. The fact is that most properties of atoms or molecules depend on their environments. This strategy can be applied universally to numerous materials. It could raise the performances of many materials significantly, even up to their theoretical limits.

We proposed a universal strategy to continuously and precisely tune the properties of materials.

Energy and materials are the bases for the survival and development of human society. Researches on related topics, such as transistors,¹ photovoltaics,^2,3 photodetection,⁴ thermoelectricity,⁵ electroluminescence,⁶ catalysis,⁷ lithium batteries,⁸ hydrogen storage,⁹ superconductivity,¹⁰ magnetic materials,¹¹ target drugs¹² and so on, are extremely important. Although lots of progress have been made, there is still much room for improvement.For example, the power conversion efficiency (PCE) of a photovoltaic cell under the standard radiation condition of the global air mass 1.5 (AM 1.5G) spectrum has a theoretical limit of 87% (concentrator cell).³ However, the highest record of PCE was 47% of 6-junction III–V tandem cells (concentrator cell) up to now.¹³ It is important to raise the PCE of photovoltaic cells high enough at a low cost for the future energy requirement of mankind. The key to getting high PCE is to synthesize a range of materials with high carrier mobilities and different energy gaps (the energy gap distribution or optical absorption bands should be narrow), covering the entire solar spectrum. The former mentioned 6-junction tandem cell has 140 materials with different energy gaps as photo absorption materials, electron transport materials and hole transport materials. Metal–organic chemical vapor deposition (MOCVD), the key technology to manufacture quality inorganic materials, is a high energy-consuming, high environment polluting, expensive and complex method. Besides, due to the limited variety of suitable chemical materials, these very high-cost cells may be already close to the limit of traditional material-based photovoltaic cells. The nano tuner-modified technology will raise PCEs of photovoltaic cells to the theoretical limit at a much lower cost.     

Water wettability of graphene: interplay between the interfacial water structure and the electronic structure

Wetting phenomena are ubiquitous and impact a wide range of applications. Simulations so far have largely relied on classical potentials. Here, we report the development of an approach that combines density-functional theory (DFT)-based calculations with classical wetting theory that allows practical but sufficiently accurate determination of the water contact angle (WCA). As a benchmark, we apply the approach to the graphene and graphite surfaces that recently received considerable attention. The results agree with and elucidate the experimental data. For metal-supported graphene where electronic interactions play a major role, we demonstrate that doping of graphene by the metal substrate significantly alters the wettability. In addition to theory, we report new experimental measurements of the WCA and the force of adhesion that corroborate the theoretical results. We demonstrate a correlation between the force of adhesion and WCA, and the use of the atomic force microscope (AFM) technique as an alternative measure for wettability at the nanoscale. The present work not only provides a detailed understanding of the wettability of graphene, including the role of electrons, but also sets the stage for studying the wettability alteration mechanism when sufficiently accurate force fields may not be available.

Wettability of graphene is characterized from first principles.

Wetting phenomena are ubiquitous in a variety of practical issues, including adhesion,¹ friction,² interfacial thermal conductance (Kapitza conductance),^3,4 to name just a few. Graphene has emerged as an important material for applications where water wettability plays a major role, e.g., as a lubricant,⁵ small-molecule gas sensor,^6,7 desalination membrane,^8,9 protective coating from electrochemical degradation,¹⁰ promotive coating for dropwise condensation,¹¹etc. Among these applications, to wet or not to wet is the key problem.^12,13 More recently, doping-induced tunable wettability was reported for graphene.^14,15Interactions between the wetting liquid and the solid it rests on are responsible for the wetting properties of a surface. The binding energy of individual molecules on the solid surface, obtained by quantum-mechanical calculations, has at times been used as an indicator of wettability.^14,16 A better indicator, however, is the water contact angle (WCA), an experimentally easily accessible parameter that characterizes macroscopically a surface''s wettability by water.^17,18 Large WCA, >90°, signifies hydrophobic behavior, whereas small WCA, <90°, signifies hydrophilic behavior. The past few years have witnessed increasing efforts to understand the wetting mechanism of graphitic carbon surfaces. Theoretical calculations of WCAs of graphitic carbon surfaces have so far been done primarily using classical potentials, by constructing an analytical interaction potential between water and the solid surface based on interatomic Lennard-Jones potentials^19–21 or classical molecular dynamics (CMD) simulations.^19,22–29 In those pioneering studies with the work-of-adhesion approach, one first computes the work of adhesion of a water slab on a surface and then employs the Young-Dupré equation that relates the work of adhesion to the WCA.^19,25–28 Alternatively, CMD can be sued to measures the shape of a water droplet on a surface and extract the WCA.^22–24Though these approaches have provided significant insights into wetting behavior,^19,22–28 they depend on the availability of reliable classical potentials. The construction of such potentials becomes a difficult task when many atomic species are present. For example, the interplay between ions such as Ca²⁺, Mg²⁺, SO₄²⁻, Na⁺ and Cl⁻ in saline water and calcite (CaCO₃) surfaces is responsible for the wettability alteration for oil recovery.^30,31 There are also cases, e.g., monolayers on metallic substrates, where explicit electron doping effects may play a major role, requiring electronic-structure calculations. While density functional theory (DFT) is the method of choice for predictive, atomic-scale calculations of interactions at the solid–water interface, the major difficulty lies in the limited time and length scales achievable by quantum MD (QMD) simulations.³² So far there exists only one report of QMD simulations of water nanodroplets, on graphene and hexagonal boron nitride monolayers.³³In this paper, we adopt the method based on the work of adhesion and the Young-Dupré equation, and employ an approximation that allows practical but sufficiently accurate DFT-based determination of the WCA. Benchmark calculations confirm that graphitic carbon surfaces are nonpolar and intrinsically hydrophilic, with their wettability determined by the dispersive interaction. The WCA gradually decreases with increasing number of graphene layers N, while a monolayer of adsorbed hydrocarbons is sufficient to render graphene hydrophobic, complementing similar results obtained using classical potentials.^20,21,25,34 In the presence of a metal substrate, electronic structure comes into play and electron doping of the graphene sheet by the metal substrate alters the wettability of graphene. We report new WCA and AFM (atomic force microscopy) measurements for Cu-supported monolayer and multilayer graphene that further corroborate the theoretical results. Finally, we demonstrate a correlation between the force of adhesion and WCA, and the use of the AFM technique as an alternative measure for wettability at the nanoscopic scale.