Striking Improvement in Peroxidase Activity of Cytochrome c by Modulating Hydrophobicity of Surface‐Functionalized Gold Nanoparticles within Cationic Reverse Micelles

This work demonstrates a remarkable enhancement in the peroxidase activity of mitochondrial membrane protein cytochrome c (cyt c) by perturbing its tertiary structure in the presence of surface‐functionalised gold nanoparticles (GNPs) within cetyltrimethylammonium bromide (CTAB) reverse micelles. The loss in the tertiary structure of cyt c exposes its heme moiety (which is buried inside in the native globular form), which provides greater substrate (pyrogallol and H₂O₂) accessibility to the reactive heme residue. The surfactant shell of the CTAB reverse micelle in the presence of co‐surfactant (n‐hexanol) exerted higher crowding effects on the interfacially bound cyt c than similar anionic systems. The congested interface led to protein unfolding, which resulted in a 56‐fold higher peroxidase activity of cyt c than that in water. Further perturbation in the protein’s structure was achieved by doping amphiphile‐capped GNPs with varying hydrophobicities in the water pool of the reverse micelles. The hydrophobic moiety on the surface of the GNPs was directed towards the interfacial region, which induced major steric strain at the interface. Consequently, interaction of the protein with the hydrophobic domain of the amphiphile further disrupted its tertiary structure, which led to better opening up of the heme residue and, thereby, superior activity of the cyt c. The cyt c activity in the reverse micelles proportionately enhanced with an increase in the hydrophobicity of the GNP‐capping amphiphiles. A rigid cholesterol moiety as the hydrophobic end group of the GNP strikingly improved the cyt c activity by up to 200‐fold relative to that found in aqueous buffer. Fluorescence studies with both a tryptophan residue (Trp59) of the native protein and the sodium salt of fluorescein delineated the crucial role of the hydrophobicity of the GNP‐capping amphiphiles in improving the peroxidase activity of cyt c by unfolding its tertiary structure within the reverse micelles.     

Effect of dispersion on the diffusion zone in two-phase laminar flows in microchannels

Aim of the present work is to investigate the reaction–diffusion process of a two species system under laminar flow in a T-shaped microchannel. A zone formed at the interface between the aqueous solutions of these two species is affected by advection and diffusion. Through theoretical analyses and experimental results, the effect of dispersion has been shown to influence this diffusion zone. We have defined a parameter called effective diffusivity, to account for the dispersion effects and observed it to be a function of the channel Peclet number. In the limiting case of low Peclet number, this parameter is constant and turns out to be equal to the molecular diffusivity. We have also related effective diffusivity and the dispersion coefficient through scaling estimates.     

A useful scaffold based on acenaphthene exhibiting Cu2+ induced excimer fluorescence and sensing cyanide via Cu2+ displacement approach

A new simple organic scaffold based on acenaphthene 4 was designed and synthesized. The chromogenic and fluorogenic properties of 4 toward different metal ions and anions were investigated in H₂O/MeCN (8:2, v/v) solution. The probe 4 in the presence of Cu²⁺ exhibited strong static excimer emission at 507 nm along with a decrease in monomer emission at ～400 nm ratiometrically, attributed to a complexation through aldimine and amide groups of 4. Additionally, 4 upon interaction with different anions illustrated significant fluorescence enhancement with cyanide. However, interaction of complex, 4-Cu²⁺ with CN^? revealed fluorescence quenching attributed to formation of stable [Cu(CN)_x]^1?x species in the medium. A naked-eye sensitive fluorescent green color of solution was changed to blue. The mechanism of interaction between 4 and Cu²⁺ and sensing of cyanide through Cu²⁺ displacement approach was confirmed by the change in optical behaviors and ¹H NMR and ESI-MS spectral data analysis.     

Unraveling siRNA unzipping kinetics with graphene

Using all atom molecular dynamics simulations, we report spontaneous unzipping and strong binding of small interfering RNA (siRNA) on graphene. Our dispersion corrected density functional theory based calculations suggest that nucleosides of RNA have stronger attractive interactions with graphene as compared to DNA residues. These stronger interactions force the double stranded siRNA to spontaneously unzip and bind to the graphene surface. Unzipping always nucleates at one end of the siRNA and propagates to the other end after few base-pairs get unzipped. While both the ends get unzipped, the middle part remains in double stranded form because of torsional constraint. Unzipping probability distributions fitted to single exponential function give unzipping time (τ) of the order of few nanoseconds which decrease exponentially with temperature. From the temperature variation of unzipping time we estimate the energy barrier to unzipping.     

1,3-Dipolar Cycloadditions VI [1].Structure and Conformation of Cycloadducts from Reactions of C-Aryl-N-phenylnitrones with Substituted Cinnamic Acid Amides

Summary.  Studies on cycloadditions of C,N-diarylnitrones to cinnamic acid amides were carried out. The diastereoisomeric (I, II) and (in some cases) regioisomeric (III) cycloadducts obtained were characterized by spectroscopic and X-ray data. Conformational studies were carried out by molecular modelling. Received February 8, 2000. Accepted February 18, 2000     

Novel Polyurethane Gels: The Effect of Structure on Gelation

Novel polyurethane gels have been reported in common solvent like dimethyl formamide (DMF). Polyurethanes have been synthesized from diisocyanates, diols and rigid chain extenders. We have illustrated the influence of chemical structure of the chain extenders on gelation rate, thermal property and morphology of the gels in DMF. Gelation rate increases significantly with the rigidity of the chain extender. Introduction of more rigid chain extender molecules in polyurethane prepolymer enhanced the thermal stability of the pure polymer. On the contrary, the solvent retention power of the gels gradually decreases with increasing rigidity of chain extender presumably because of the poor dispersion/greater aggregation of the hard segments in the soft segment matrix. Morphology and formation of gelation have been discussed.     

Ligand-promoted palladium-catalyzed β-methylene C–H arylation of primary aldehydes

The transient directing group (TDG) strategy allowed long awaited access to the direct β-C(sp³)–H functionalization of unmasked aliphatic aldehydes via palladium catalysis. However, the current techniques are restricted to terminal methyl functionalization, limiting their structural scopes and applicability. Herein, we report the development of a direct Pd-catalyzed methylene β-C–H arylation of linear unmasked aldehydes by using 3-amino-3-methylbutanoic acid as a TDG and 2-pyridone as an external ligand. Density functional theory calculations provided insights into the reaction mechanism and shed light on the roles of the external and transient directing ligands in the catalytic transformation.

Aliphatic aldehydes are among the most common structural units in organic and medicinal chemistry research. Direct C–H functionalization has enabled efficient and site-selective derivatization of aliphatic aldehydes.

Simple aliphatic functional groups enrich the skeletal backbones of many natural products, pharmaceuticals, and other industrial materials, influencing the utility and applications of these substances and dictating their reactivity and synthetic modification pathways. Aliphatic aldehydes are some of the most ubiquitous structural units in organic materials.¹ Their relevance in nature and industry alike, combined with their reactivity and synthetic versatility, attracted much attention from the synthetic organic and medicinal chemistry communities over the years (Fig. 1).² Efficient means to the functionalization of these molecules have always been highly sought after.Open in a separate windowFig. 1Select aliphatic aldehyde-containing medicines and biologically active molecules.Traditionally, scientists have utilized the high reactivity of the aldehyde moiety in derivatizing a variety of functional groups by the means of red-ox and nucleophilic addition reactions. The resourceful moiety was also notoriously used to install functional groups at the α-position via condensation and substitution pathways.³ Although β-functionalization is just as robust, it has generally been more restrictive as it often requires the use of α,β-unsaturated aldehydes.^4,5 Hence, transition metal catalysis emerged as a powerful tool to access β-functionalization in saturated aldehydes.⁶ Most original examples of metal-catalyzed β-C–H functionalization of aliphatic aldehydes required the masking of aldehydes into better metal coordinating units since free unmasked aldehydes could not form stable intermediates with metals like palladium on their own.⁷ Although the masking of the aldehyde moiety into an oxime, for example, enabled the formation of stable 5-membered palladacycles, affording β-functionalized products, this system requires the installation of the directing group prior to the functionalization, as well as the subsequent unmasking upon the reaction completion, compromising the step economy and atom efficiency of the overall process.⁸ Besides, some masking and unmasking protocols might not be compatible with select substrates, especially ones rich in functional groups. As a result, the development of a one-step direct approach to the β-C–H functionalization of free aliphatic aldehydes was a demanding target for synthetic chemists.α-Amino acids have been demonstrated as effective transient directing groups (TDGs) in the remote functionalization of o-alkyl benzaldehydes and aliphatic ketones by the Yu group in 2016.⁹ Shortly after, our group disclosed the first report on the direct β-C–H arylation of aliphatic aldehydes using 3-aminopropanoic acid or 3-amino-3-methylbutanoic acid as a TDG.¹⁰ The TDG was found to play a similar role to that of the oxime directing group by binding to the substrate via reversible imine formation, upon which, it assists in the assembly of a stable palladacycle, effectively functionalizing the β-position.¹¹ Since the binding of the TDG is reversible and temporary, it is automatically removed upon functionalization, yielding an efficient and step-economic transformation. This work was succeeded by many other reports that expanded the reaction and the TDG scopes.^12–14 However, this system suffers from a significant restriction that demanded resolution; only substitution of methyl C–H bonds of linear aldehydes was made possible via this approach (Scheme 1a–e). The steric limitations caused by incorporating additional groups at the β-carbon proved to compromise the formation of the palladacycle intermediate, rendering the subsequent functionalization a difficult task.¹²Open in a separate windowScheme 1Pd-catalyzed β-C–H bond functionalization of aliphatic aldehydes enabled by transient directing groups.Encouraged by the recent surge in use of 2-pyridone ligands to stabilize palladacycle intermediates,^15,16 we have successfully developed the first example of TDG-enabled Pd-catalyzed methylene β-C–H arylation in primary aldehydes via the assistance of 2-pyridones as external ligands (Scheme 1f). The incorporation of 2-pyridones proved to lower the activation energy of the C–H bond cleavage, promoting the formation of the intermediate palladacycles even in the presence of relatively bulky β-substituents.¹⁷ This key advancement significantly broadens the structural scopes and applications of this process and promises future asymmetric possibilities, perhaps via the use of a chiral TDG or external ligand or both. Notably, a closely related work from Yu''s group was published at almost the same time.¹⁸We commenced our investigation of the reaction parameters by employing n-pentanal (1a) as an unbiased linear aldehyde and 4-iodoanisole (2a) in the presence of catalytic Pd(OAc)₂ and stoichiometric AgTFA, alongside 3-amino-3-methylbutanoic acid (TDG1) and 3-(trifluoromethyl)-5-nitropyridin-2-ol (L1) at 100 °C (ii) sources proved Pd(OAc)₂ to be the optimal catalyst, while Pd(TFA)₂, PdCl₂ and PdBr₂ provided only moderate yields (entries 10–12). Notably, a significantly lower yield was observed in the absence of the 2-pyridone ligand, and no desired product was isolated altogether in the absence of the TDG (entries 13 and 14). The incorporation of 15 mol% Pd catalyst was deemed necessary after only 55% yield of 3a was obtained when 10 mol% loading of Pd(OAc)₂ was instead used (entry 15).Optimization of reaction conditions^a

Entry	Pd source	L (mol%)	TDG1 (mol%)	Solvent (v/v, mL)	Yield (%)
1	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP	30
2	Pd(OAc)2	L1 (30)	TDG1 (40)	AcOH	<5
3	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP/AcOH (1 : 1)	28
4	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP/AcOH (9 : 1)	47
5	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP/AcOH (1 : 9)	<5
6	Pd(OAc)2	L1 (30)	TDG1 (60)	HFIP/AcOH (9 : 1)	50
7	Pd(OAc)2	L1 (30)	TDG1 (80)	HFIP/AcOH (9 : 1)	25
8	Pd(OAc)2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	70(68)b
9	Pd(OAc)2	L1 (75)	TDG1 (60)	HFIP/AcOH (9 : 1)	51
10	Pd(TFA)2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	60
11	PdCl2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	52
12	PdBr2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	54
13	Pd(OAc)2	—	TDG1 (60)	HFIP/AcOH (9 : 1)	9
14	Pd(OAc)2	L1 (60)	—	HFIP/AcOH (9 : 1)	0
15c	Pd(OAc)2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	55

Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd source (15 mol%), AgTFA (0.3 mmol), L1, TDG1, solvent (2.0 mL), 100 °C, 12 h. Yields are based on 1a, determined by ¹H-NMR using dibromomethane as an internal standard.^bIsolated yield.^cPd(OAc)₂ (10 mol%).To advance our optimization of the reaction conditions, a variety of 2-pyridones and TDGs were tested (Scheme 2). Originally, pyridine-2(1H)-one (L2) was examined as the external ligand, but it only yielded the product (3a) in 7% NMR yield. Similarly, other mono- and di-substituted 2-pyridone ligands (L3–L10) also produced low yields, fixating L1 as the optimal external ligand. Next, various α- and β-amino acids (TDG1–10) were evaluated, yet TDG1 persisted as the optimal transient directing group. These amino acid screening results also suggest that a [5,6]-bicyclic palladium species is likely the key intermediate in this protocol since only β-amino acids were found to provide appreciable yields, whereas α-amino acids failed to yield more than trace amounts of the product. The supremacy of TDG1 when compared to other β-amino acids is presumably due to the Thorpe–Ingold effect that perhaps helps facilitate the C–H bond cleavage and stabilize the [5,6]-bicyclic intermediate further.Open in a separate windowScheme 2Optimization of 2-pyridone ligands and transient directing groups.With the optimized reaction conditions in hand, substrate scope study of primary aliphatic aldehydes was subsequently carried out (Scheme 3). A variety of linear primary aliphatic aldehydes bearing different chain lengths provided the corresponding products 3a–e in good yields. Notably, relatively sterically hindered methylene C–H bonds were also functionalized effectively (3f and 3g). Additionally, 4-phenylbutanal gave rise to the desired product 3h in a highly site-selective manner, suggesting that functionalization of the methylene β-C–H bond is predominantly favored over the more labile benzylic C–H bond. It is noteworthy that the amide group was also well-tolerated and the desired product 3j was isolated in 60% yield. As expected, with n-propanal as the substrate, β-mono- (3k1) and β,β-disubstituted products (3k2) were isolated in 22% and 21% yields respectively. However, in the absence of the key external 2-pyridone ligand, β-monosubstituted product (3k1) was obtained exclusively, albeit with a low yield, indicating preference for functionalizing the β-C(sp³)–H bond of the methyl group over the benzylic methylene group.Open in a separate windowScheme 3Scope of primary aliphatic aldehydes. Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)₂ (15 mol%), AgTFA (0.3 mmol), L1 (60 mol%), TDG1 (60 mol%), HFIP (1.8 mL), HOAc (0.2 mL), 100 °C, 12 h. Isolated yields. ^aL1 (60 mol%) was absent and yields are given in parentheses.Next, substrate scope study on aryl iodides was surveyed (Scheme 4). Iodobenzenes bearing either an electron-donating or electron-withdrawing group at the para-, meta-, or ortho-position were all found compatible with our catalytic system (3l–3ah). Surprisingly, ortho-methyl- and fluoro-substituted aryl iodides afforded the products in only trace amounts. However, aryl iodide with ortho-methoxy group provided the desired product 3ac in a moderate yield. Notably, a distinctive electronic effect pattern was not observed in the process. It should be mentioned that arylated products bearing halogen, ester, and cyano groups could be readily converted to other molecules, which significantly improves the synthetic applicability of the process. Delightfully, aryl iodide-containing natural products like ketoprofen, fenchol and menthol were proven compatible, supplying the corresponding products in moderate yields. Unfortunately, (hetero)aryl iodides including 2-iodopyridine, 3-iodopyridine, 4-iodopyridine and 4-iodo-2-chloropyridine failed to produce the corresponding products. Although our protocol provides a novel and direct pathway to construct β-arylated primary aliphatic aldehydes, the yields of most examples are modest. The leading reasons for this compromise are the following: (1) aliphatic aldehydes are easily decomposed or oxidized to acids; (2) some of the prepared β-arylated aldehyde products may be further transformed into the corresponding α,β-unsaturated aldehydes.Open in a separate windowScheme 4Scope of aryl iodides. Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Pd(OAc)₂ (15 mol%), AgTFA (0.3 mmol), L1 (60 mol%), TDG1 (60 mol%), HFIP (1.8 mL), HOAc (0.2 mL), 100 °C, 12 h. Isolated yields.Density functional theory (DFT) calculations were performed to help investigate the reaction mechanism and to elucidate the role of the ligand in improving the reactivity (Fig. 2). The condensation of the aliphatic aldehyde 1a with the TDG to form imine-1a was found thermodynamically neutral (ΔG° = −0.1 kcal mol⁻¹). As a result, it was permissible to use imine-1a directly in the calculations. According to the calculations results, the precatalyst [Pd(OAc)₂]₃, a trimeric complex, initially experiences dissociation and ligand metathesis with imine-1a to generate the Pd(ii) intermediate IM1, which is thermodynamically favorable by 21.9 kcal mol⁻¹. Consequently, the deprotonated imine-1a couples to the bidentate ligand to form the stable six-membered chelate complex IM1. Therefore, IM1 is indeed the catalyst resting state and serves as the zero point to the energy profile. We have identified two competitive pathways for the Pd(ii)-catalyzed C–H activation starting from IM1, one of which incorporates L1 and another which does not. On the one hand, an acetate ligand substitutes one imine-1a chelator in IM1 to facilitate the subsequent C–H activation leading to IM2, which undergoes C(sp³)–H activation through concerted metalation-deprotonation (CMD) viaTS1 (ΔG^‡ = 37.4 kcal mol⁻¹). However, this kinetic barrier is thought to be too high to account for the catalytic activity at 100 °C. On the other hand, the chelate imine-1a could be replaced by two N-coordinated ligands (L1) leading to the Pd(ii) complex IM3. This process is endergonic by 6.4 kcal mol⁻¹. To allow the ensuing C–H activation, IM3 dissociates one ligand (L1) producing the active species IM4, which undergoes TS2 to cleave the β-C(sp³)–H bond and form the [5,6]-bicyclic Pd(ii) intermediate IM5. Although this step features an energy barrier of 31.2 kcal mol⁻¹, it is thought to be feasible under the experimental conditions (100 °C). Possessing similar coordination ability to that of pyridine, the ligand (L1) effectively stabilizes the Pd(ii) center in the C–H activation process, indicating that this step most likely involves a manageable kinetic barrier. This result explicates the origin of the ligand-enabled reactivity (TS2vs.TS1). Additionally, we considered the γ-C(sp³)–H activation pathway viaTS2′ which was found to have a barrier of 35.5 kcal mol⁻¹. The higher energy barrier of TS2′ compared to that of TS2 is attributed to its larger ring strain in the [6,6]-bicyclic Pd(ii) transition state, which reveals the motive for the site-selectivity. Reverting back to the supposed pathway, upon the formation of the bicyclic intermediate IM5, it undergoes ligand/substrate replacement to afford intermediate IM6, at which the Ar–I coordinates to the Pd(ii) center to enable oxidative addition viaTS3 (ΔG^‡ = 27.4 kcal mol⁻¹) leading to the five-coordinate Pd(iv) complex IM7. Undergoing direct C–C reductive elimination in IM7 would entail a barrier of 29.6 kcal mol⁻¹ (TS4). Alternatively, iodine abstraction by the silver(i) salt in IM7 is thermodynamically favorable and irreversible, yielding the Pd(iv) intermediate IM8 coordinated to a TFA ligand. Subsequently, C–C reductive coupling viaTS5 generates the Pd(ii) complex IM9 and concludes the arylation process. This step was found both kinetically facile (6.1 kcal mol⁻¹) and thermodynamically favorable (30.7 kcal mol⁻¹). Finally, IM9 reacts with imine-1avia metathesis to regenerate the palladium catalyst IM1 and release imine-3a in a highly exergonic step (21.0 kcal mol⁻¹). Ultimately, imine-3a undergoes hydrolysis to yield the aldehyde product 3a and to release the TDG.Open in a separate windowFig. 2Free energy profiles for the ligand-promoted Pd(ii)-catalyzed site-selective C–H activation and C–C bond formation, alongside the optimized structures of the C–H activation transition states TS1 and TS2 (selected bond distances are labelled in Å). Energies are relative to the complex IM1 and are mass-balanced.     

Noble-Noble Strong Union: Gold at Its Best to Make a Bond with a Noble Gas Atom

This Review presents the current status of the noble gas (Ng)-noble metal chemistry, which began in 1977 with the detection of AuNe⁺ through mass spectroscopy and then grew from 2000 onwards; currently, the field is in a somewhat matured state. On one side, modern quantum chemistry is very effective in providing important insights into the structure, stability, and barrier for the decomposition of Ng compounds and, as a result, a plethora of viable Ng compounds have been predicted. On the other hand. experimental achievement also goes beyond microscopic detection and characterization through spectroscopic techniques and crystal structures at ambient temperature; for example, (AuXe₄)²⁺(Sb₂F₁₁⁻)₂ have also been obtained. The bonding between two noble elements of the periodic table can even reach the covalent limit. The relativistic effect makes gold a very special candidate to form a strong bond with Ng in comparison to copper and silver. Insertion compounds, which are metastable in nature, depending on their kinetic stability, display an even more fascinating bonding situation. The degree of covalency in Ng–M (M=noble metal) bonds of insertion compounds is far larger than that in non-insertion compounds. In fact, in MNgCN (M=Cu, Ag, Au) molecules, the M−Ng and Ng−C bonds might be represented as classical 2c–2e σ bonds. Therefore, noble metals, particularly gold, provide the opportunity for experimental chemists to obtain sufficiently stable complexes with Ng at room temperature in order to characterize them by using experimental techniques and, with the intriguing bonding situation, to explore them with various computational tools from a theoretical perspective. This field is relatively young and, in the coming years, a lot of advancement is expected experimentally as well as theoretically.     

A two warehouse inventory model for deteriorating items with a linear trend in demand and shortages

In this paper, we develop a deterministic inventory model with two warehouses (one is the existing storage known as own warehouse (OW) and the other is hired on rental basis known as rented warehouse (RW). The model allows different levels of item deterioration in both warehouses. The demand rate is supposed to be a linear (increasing) function of time and the replenishment rate is infinite. The stock is transferred from RW to OW in continuous release pattern and the associated transportation cost is taken into account. Shortages in OW are allowed and excess demand is backlogged. For the general model, we give the equations for the optimal policy and cost function and we discuss some special cases. A numerical example is given to illustrate the solution procedure of the model. Finally, based on this example, we conduct a sensitivity analysis of the model.     

An efficient strategy for N-alkylation of benzimidazoles/imidazoles in SDS-aqueous basic medium and N-alkylation induced ring opening of benzimidazoles

A sustainable route for the N-1 alkylation of imidazole and benzimidazole derivatives has been developed under volatile organic solvent free condition in alkaline water-SDS system. Incorporation of SDS in the reaction medium enhances the reaction rate by suppressing the solubility issue that arises for different substrates. This method provides high yield of the alkylated product in a shorter reaction time. For reactive alkyl halides reaction proceeds at ambient temperature whereas in the cases of less reactive alkyl halides require 55–60?°C to complete alkylation process. N-alkylation induced ring opening of the heterocyclic ring in benzimidazole derivatives to multifunctional aromatic compounds were noticed at 60?°C when more than two equivalents of alkyl halide was used.