Maximum Turnover Number Research Articles

Half-sandwich Iridium(III) complexes with triphenylamine-substituted dipyridine frameworks and bioactivity applications

Nine half-sandwich IrIII complexes [(η5-Cpx)Ir(NˆN)Cl]PF6, where Cpx is Cp* or its phenyl Cpxph or biphenyl Cpxbiph derivative and NˆN is a triphenylamine (TPA)-substituted bipyridyl ligand, were synthesized and characterized. MTT assay revealed that the complexes show potent antitumor activity with IC50 values of 1.2–36.3 μM against A549 lung cancer cells. The IrIII complexes bound to BSA and oxidized NADH to NAD+, leading to production of H2O2 (maximum turnover number, 37.9), which plays an important role in regulating cell apoptosis. Confocal microscopy showed that the complexes could target lysosomes effectively in cells with a high Pearson's colocalization coefficient (∼0.5) and followed an energy-dependent cellular uptake mechanism.

Superior Cascade Ring-Opening/Ring-Closing Metathesis Polymerization and Multiple Olefin Metathesis Polymerization: Enhancing the Driving Force for Successful Polymerization of Challenging Monomers.

Recently, our group successfully developed two new polymerization methodologies for monomers containing two cycloalkene moieties. These polymerization methods yielded well-defined polymers via a combination of ring-opening and ring-closing metathesis (cascade polymerization) or ring-opening, ring-closing, and cross-metathesis (multiple olefin metathesis polymerization (MOMP)) using a second monomer. However, cascade polymerization had some limitations such as low polymerization efficiency (maximum turnover number (TON) of 250) and narrow monomer scope. Furthermore, one-shot MOMP also showed a very narrow monomer scope because of certain undesired side reactions. To overcome these problems, we designed various new monomers containing cyclopentene and even more challenging ring-strain-free cyclohexene moieties, so that polymerization would produce a thermodynamically favored six-membered-ring backbone repeat unit. With this enhanced driving force for polymerization, these new monomers successfully underwent cascade polymerization with a high polymerization efficiency, leading to a maximum TON of 1940 and maximum number-average molecular weight ( Mn) of 343 kDa. Lastly, one-shot MOMP, which uses all three types of metathesis transformations in a single step, was possible with these monomers and gave highly A,B-alternating copolymers with high selectivity as well. This was possible because the newly designed monomers with the appropriate thermodynamic and kinetic preferences suppressed undesired polymerization pathways and reduced defects in the polymer microstructures. In short, we present our strategies for achieving superior cascade polymerization and MOMP using these new monomers.

Direct synthesis of 2,5-diformylfuran from carbohydrates via carbonizing polyoxometalate based mesoporous poly(ionic liquid)

A promising atom-effective heterogeneous catalyst derived from the partial carbonization of polyoxometalate based mesoporous poly(ionic liquid) was constructed for the direct (one-pot and one-step) conversion of carbohydrates into 2,5-diformylfuran (DFF). The carbon precursor was synthesized through the free radical copolymerization of carboxylic acid functional ionic liquid and divinyl benzene, followed by the ion-exchange with heteropolyacid H5PMo10V2O40 to introduce heteropolyanions. Partial carbonization dramatically enhanced the acid and oxidation properties, rendering the greatly strengthened activity in both the degradation of fructose into 5-hydroxymethylfurfural (HMF) and oxidation of HMF into DFF. As a result, the catalyst exhibited remarkable performance in the direct synthesis of DFF from fructose in a one-pot and one-step reaction, offering a high yield of 87.3% and a maximum turnover number (TON) of 77.7. The catalyst was facilely recovered and reused without apparent deactivation. The one-pot and one-step conversion of glucose into DFF reached the highest yield of 51.2% so far. Other carbohydrates such as inulin and sucrose were also effectively transformed into DFF, displaying good substrate compatibility.

Surface Engineering of a Supported PdAg Catalyst for Hydrogenation of CO2 to Formic Acid: Elucidating the Active Pd Atoms in Alloy Nanoparticles.

The hydrogenation of carbon dioxide (CO2) to formic acid (FA; HCOOH), a renewable hydrogen storage material, is a promising means of realizing an economical CO2-mediated hydrogen energy cycle. The development of reliable heterogeneous catalysts is an urgent yet challenging task associated with such systems, although precise catalytic site design protocols are still lacking. In the present study, we demonstrate that PdAg alloy nanoparticles (NPs) supported on TiO2 promote the efficient selective hydrogenation of CO2 to give FA even under mild reaction conditions (2.0 MPa, 100 °C). Specimens made using surface engineering with atomic precision reveal a strong correlation between increased catalytic activity and decreased electron density of active Pd atoms resulting from a synergistic effect of alloying with Ag atoms. The isolated and electronically promoted surface-exposed Pd atoms in Pd@Ag alloy NPs exhibit a maximum turnover number of 14 839 based on the quantity of surface Pd atoms, which represents a more than 10-fold increase compared to the activity of monometallic Pd/TiO2. Kinetic and density functional theory (DFT) calculations show that the attack on the C atom in HCO3- by a dissociated H atom over an active Pd site is the rate-determining step during this reaction, and this step is boosted by PdAg alloy NPs having a low Pd/Ag ratio.

Dyad Sensitizer of Chlorophyll with Indoline Dye for Panchromatic Photocatalytic Hydrogen Evolution

Photocatalytic H2 evolution under a wide visible spectral range is a challenging issue. In this work, we report the synthesis of a novel organic dyad consisting of an indoline–rhodanine π-conjugation with a strong absorption in the green region and a chlorophyll derivative with intense absorbance in the purple and red regions. This synthetic dyad (Dyad) was employed as a photosensitizer in the TiO2-based system for photocatalytic H2 evolution with Pt as the assisting catalyst and ascorbic acid (AA) as the sacrificial reagent. The Dyad-sensitized Pt/TiO2 photocatalyst exhibited a maximum turnover number (TON) of 1044 after 6 h of continuous light irradiation (λ > 400 nm). In comparison, under the same conditions, the TONs of photocatalytic systems based on sole counterpart chlorophyll (Chl) or indoline dye (Ind) were merely 267 or 301, respectively. Moreover, the apparent quantum yield of Dyad/Pt/TiO2 (1.27%) is much higher than those of Chl/Pt/TiO2 (0.37%) and Ind/Pt/TiO2 (0.20%) under 420 nm monochromati...

Electrocatalytic and Photocatalytic Reduction of CO2 to CO by Cobalt(II) Tripodal Complexes: Low Overpotentials, High Efficiency and Selectivity

The reduction of carbon dioxide (CO2 ) has been considered as an approach to mitigate global warming and to provide renewable carbon-based fuels. Rational design of efficient, selective, and inexpensive catalysts with low overpotentials is urgently desired. In this study, four cobalt(II) tripodal complexes are tested as catalysts for CO2 reduction to CO in a MeCN/H2 O (4:1 v/v) solution. The replacement of pyridyl groups in the ligands with less basic quinolinyl groups greatly reduces the required overpotential for CO2 -to-CO conversion down to 200-380 mV. Benefitting from the low overpotentials, a photocatalyst system for CO2 -to-CO conversion is successfully constructed, with an maximum turnover number (TON) of 10 650±750, a turnover frequency (TOF) of 1150±80 h-1 , and almost 100 % selectivity to CO. These outstanding catalytic performances are further elucidated by DFT calculations.

Platinum Complexes with Chelating Acyclic Aminocarbene Ligands Work as Catalysts for Hydrosilylation of Alkynes.

This work describes the preparation of a series of platinum–aminocarbene complexes [PtCl{C(N=Ca(C6R2R3R4R5CONb))=N(H)R1}(CNR1)]a–b (8–19, 65–75% isolated yield) via the reaction of cis-[PtCl2(CNR1)2] (R1 = Cy 1, t-Bu 2, Xyl 3, 2-Cl-6-MeC6H34) with 3-iminoisoindolin-1-ones HN=Ca(C6R2R3R4R5CONbH) (R2–R5 = H 5; R3 = Me, R2, R4, R5 = H 6; R3, R4 = Cl, R2, R5 = H 7). New complexes 17–19 were characterized by elemental analyses (C, H, N), ESI+-MS, Fourier transform infrared spectroscopy (FT-IR), one-dimensional (1H, 13C{1H}), and two-dimensional (1H,1H correlation spectroscopy (COSY), 1H,13C heteronuclear multiple quantum correlation (HMQC)/1H,13C heteronuclear single quantum coherence (HSQC), 1H,13C heteronuclear multiple bond correlation (HMBC)) NMR spectroscopy, and authenticity of known species 8–16 was confirmed by FT-IR and 1H and 13C{1H} NMR. Complexes 8–19 were assessed as catalysts for hydrosilylation of terminal alkynes with hydrosilanes to give vinyl silanes, and complex [PtCl{C(N=Ca(C6H3(5-Me)CONb))=N(H)(2-Cl-6-MeC6H3)}{CN(2-Cl-6-MeC6H3)}]a−b (18) showed the highest catalytic activity. The catalytic system proposed operates at 80–100 °C for 4–6 h in toluene and with catalyst loading of 0.1 mol %, enabling the reaction of a number of terminal alkynes (PhC≡CH, t-BuC≡CH, and 4-(t-Bu)C6H4C≡CH) with hydrosilanes (Et3SiH, Pr3SiH, i-Pr3SiH, and PhMe2SiH). Target vinyl silanes were prepared in 48–95% yields (as a mixture of α/β isomers) and with maximum turnover number of 8.4 × 103. Hydrosilylation of internal alkynes (PhC≡CPh, Me(CH2)2C≡C(CH2)2Me, and PhC≡CMe) with hydrosilanes (Et3SiH, PhMe2SiH) led to the corresponding trisubstituted silylated alkenes in 86–94% yields. Initial observations on the mechanism of the catalytic action of platinum–ADC catalysts 8–19 suggested a molecular catalytic cycle.

Ruthenium-hydrotalcite (Ru-HT) as an effective heterogeneous catalyst for the selective hydrogenation of CO2 to formic acid

The reaction containing CO2 and H2 has been investigated for the hydrogenation of CO2 to formic acid using ruthenium hydrotalcite (Ru-HT) catalyst. Ruthenium salt was introduced to the synthesis of hydrotalcite as an active metal center to develop ruthenium based heterogeneous catalyst. Hydrotalcite not only acted as a support for the active metal but also acted as a soft solid base avoiding the use of the liquid base, which is normally required under homogeneous conditions for the formation of formic acid from the hydrogenation of CO2. Reaction temperatures were in the range of 40–100 °C, total pressure 10–100 bar with an ideal 1:1 ratio of pCO2:pH2. The maximum Turnover Number (TON) of 11389 was obtained for the formic acid formation under the optimized conditions at 60 °C temperature and 60 bar total pressure, using a mixture of methanol:water as a solvent (5:1, v/v). Ru-HT catalyst was synthesised and thorougly characterized by FT-IR, PXRD, SEM-EDX and surface area analysis. The catalyst was effectively recycled up to 7 times without any loss in catalytic activity.

Application of a Water‐Soluble Matrix‐Stabilized Palladium Nanoparticle Catalyst for Photocatalytic Hydrogen Generation with High Activity and Stability

AbstractPd@(BiPy‐PEG‐OMe) is a catalyst comprised of palladium nanoparticles (Pd‐NPs) stabilized and made water soluble by 2,2′‐bipyridine‐end‐functionalized polyethylene glycol monomethyl ether (BiPy‐PEG‐OMe). The catalyst has been used in the past for nitrile hydrogenation. In this work, we prove that it is also very active for photocatalytic hydrogen generation, which might be true for more catalysts of its kind and therefore worthy of further investigation. Using the inexpensive photosensitizer Eosin Y, high turnover numbers (TONs) of over 4 500 were achieved for the evolution of molecular hydrogen from pure water under visible‐light irradiation. Replacing Eosin Y, which showed only a short lifetime under experimental conditions (i.e. a few hours), by a novel osmium‐based metal complex, which is also characterized by its crystal structure, the longevity of the system can be boosted to over one and a half months with a maximum TON of 1 500. Combining excellent yield and stability is a clear goal for further research.

Characterizing Isozymes of Chlorite Dismutase for Water Treatment.

This work investigated the potential for biocatalytic degradation of micropollutants, focusing on chlorine oxyanions as model contaminants, by mining biology to identify promising biocatalysts. Existing isozymes of chlorite dismutase (Cld) were characterized with respect to parameters relevant to this high volume, low-value product application: kinetic parameters, resistance to catalytic inactivation, and stability. Maximum reaction velocities (Vmax) were typically on the order of 104 μmol min-1 (μmol heme)-1. Substrate affinity (Km) values were on the order of 100 μM, except for the Cld from Candidatus Nitrospira defluvii (NdCld), which showed a significantly lower affinity for chlorite. NdCld also had the highest susceptibility to catalytic inactivation. In contrast, the Cld from Ideonella dechloratans was least susceptible to catalytic inactivation, with a maximum turnover number of approximately 150,000, more than sevenfold higher than other tested isozymes. Under non-reactive conditions, Cld was quite stable, retaining over 50% of activity after 30 days, and most samples retained activity even after 90–100 days. Overall, Cld from I. dechloratans was the most promising candidate for environmental applications, having high affinity and activity, a relatively low propensity for catalytic inactivation, and excellent stability.

Titania/lignin hybrid materials as a novel support for α-amylase immobilization: A comprehensive study

α-Amylase from Aspergillus oryzae was immobilized via covalent bonds and by physical interactions on a synthesized titania/lignin novel hybrid support. A temperature of 5°C, a pH of 7.0, an initial enzyme solution concentration of 3.0mg/mL and a 3h process duration were found to be optimal for the highest activity of the immobilized enzyme. Moreover, the effect of temperature, pH, storage time and repeated catalytic cycles on the activity of free and immobilized enzyme was examined. Bound α–amylase showed enhanced thermal and chemical stability, and its reusability was also improved. Immobilized α-amylase retained over 80% of its initial activity when stored for 30days at 4°C. Kinetic parameters of the free and immobilized biocatalyst were calculated and compared. The maximum reaction rate (Vmax) and turnover number (kcat) were slightly lower for the immobilized enzyme than for the free enzyme. It should be clearly stated that this work presents a useful protocol to produce stable and active immobilized α–amylase onto titania/lignin hybrid which may also be applied to immobilization of other enzymes.

Amphiphilic Mesoporous Poly(Ionic Liquid) Immobilized Heteropolyanions Towards the Efficient Heterogeneous Epoxidation of Alkenes with Stoichiometric Hydrogen Peroxide

AbstractNew mesoporous poly(ionic liquid)s (MPILs) that feature a pure polycationic framework and tunable hydrophobicity were synthesized through the free‐radical polymerization of alkyl‐functionalized ionic liquids (ILs) and bisvinylimidazolium salt. Phosphotungstic (PW) anions were immobilized firmly on these MPILs with a high dispersion and density. The obtained catalyst was effective in the epoxidation of cis‐cyclooctene with stoichiometric hydrogen peroxide (H2O2) to give a high yield (>98 %) and a remarkable H2O2 efficiency (>98 %). The maximum turnover number and turnover frequency was 2375 and 685 h−1, respectively. The catalyst can be recovered easily by filtration and reused with stable activity. Other alkenes can be converted with high yields. The extraordinary performance was attributed to the pure ionic porous framework with an enhanced hydrophobicity that not only provides strong cation–anion interactions towards the stable immobilized PW anions with a high dispersion but also enables the strong affinity of the catalyst with both the substrate and oxidant.

New insights into the alkoxycarbonylation of propargyl alcohol

The challenging carbonylation of propargyl alcohol is effectively catalyzed by Pd(OAc)2 in combination with diphenyl-(6-methyl-pyridin-2-yl)phosphine and methanesulfonic acid. In dichloroethane at 20–50°C, the reaction affords with almost complete regioselectivity alkyl 2-(hydroxymethyl)acrylates. Turnover frequency numbers (TOF) of up to 450h−1 can be achieved working at 50°C, while a maximum turnover number (TON) of about 730 is obtained at 30°C. The catalyst longevity is limited because the carbonylation product reacts with the phosphorus atom of the ligand to give a quaternary phosphonium salt. This reaction leads to deactivation of the catalyst and eventually to palladium black formation.

Direct aerobic oxidative homocoupling of benzene to biphenyl over functional porous organic polymer supported atomically dispersed palladium catalyst

Synthesis of biphenyl directly from the oxidative coupling of benzene with O2 as the sole oxident is an atom-efficiency and environmental-friendly route, which is however unattainable as yet due to the most inert nature of sp2 CH bond in benzene ring, especailly for recyclable heterogeneous catalysis. In this work, single atomic dispersed palladium(II)-porous organic polymer (POP) catalyst with a high loading (>2wt%) was constructed by anchoring Pd(II) species on the task-specifically designed POP support tethered with carboxyl acid and sulfonic acid groups. It exhibited efficient activity in the heterogeneous aerobic oxidative coupling of benzene with O2, giving the highest biphenyl yield of 26.1% so far. The high electrophilicity of thus anchored single atomic Pd(II) species is demonstrated, endowing the unprecedentedly maximum turnover number (TON) of 487 and turnover frequency (TOF) of 352h−1 that expletively exceeds 15 and 88 times of previous heterogeneous catalyst. The catalyst can be facilely recycled and reused, and readily extendable to the conversion of other nonactivated arenes into corresponding biaryls. The designing strategy of POP materials developed in the study may provide a platform towards stable single atomic dispersed noble metal species with desirable electrophilicity as efficient catalysts for more sustainable CC formation-involved organic transformations.

Photochemical Water Oxidation Using {PMo12O40@Mo72Fe30}n Based Soft Oxometalate

Finding an alternative energy resource which can produce clean energy at a low cost is one of the major concerns of our times. The conversion of light energy into chemical energy is one key step forward in the direction. With that end in view photochemical water oxidation to produce oxygen plays a crucial role. In the present paper we have synthesized a soft oxometalate {PMo[Formula: see text]O[Formula: see text]@Mo[Formula: see text]Fe[Formula: see text]}n(1) from its well-known precursor polyoxometalate constituent [Muller et al., Chem. Commun. 1, 657 (2001)]. It is known that in the matter of catalysis, high surface area, possibility of heterogenization, recoverability makes soft oxometalates (SOMs) attractive as catalytic materials. Here we exploit such advantages of SOMs. The SOM based material acts as an active catalyst for photochemical water oxidation reaction with a maximum turnover number of 20256 and turnover frequency of 24.11[Formula: see text]min[Formula: see text]. The catalyst material is stable under photochemical reaction conditions and therefore can be reused for multiple photo catalytic water oxidation reaction cycles.

Synthesis, crystal structures of oxovanadium(V) complexes with hydrazone ligands and their catalytic performance for the styrene oxidation

Four new oxovanadium(V) complexes, [VO(aha)L1] (1), [VO(aha)L2] (2), [VO(aha)L3] (3), and [VO(aha)L4]·EtOH (4) (Haha=acetohydroxamic acid, H2L1=4-nitrophenyl 2-(2-hydroxybenzylidene)hydrazinecarboxylate, H2L2=N′-(2-hydroxylbenzylidene)-4-methoxybenzohydrazide, H2L3=N′-(2-hydroxylbenzylidene)-4-methylbenzohydrazide, HL4=N′-(5-bromo-2-hydroxybenzylidene)-3-methyl benzohydrazide), have been prepared and structurally characterized by physico-chemical methods and X-ray diffraction. The V atoms in the complexes are in octahedral coordination, with the three donor atoms of the hydrazone ligand and the deprotonated hydroxyl O atom of the aha ligand defining the equatorial plane, and with the carbonyl O atom of the aha ligand and one oxo O atom occupying the axial positions. Crystal structures of the complexes are stabilized by hydrogen bonds. In addition, the catalytic performances for the peroxidative oxidation (with hydrogen peroxide) of complexes 1–4 and their starting materials VO(acac)2 were studied by the reaction of styrene (St) to benzaldehyde (BzA) (the maximum total turnover number is 667) under the mild conditions.

Oxidation of Alkanes by Periodate Using a MnV Nitrido Complex as Catalyst.

The design of catalytic systems that can selectively oxidize unactivated C-H bonds under mild conditions is a challenge to chemists. We report here that the manganese(V) nitrido complex [MnV (N)(CN)4 ]2- is a highly efficient catalyst for the oxidation of alkanes by periodate (IO4- ) at ambient conditions. Excellent yields of alcohols and ketones (>95 %) are obtained with a maximum turnover number (TON) of 3000.

Process development for oxidations of hydrophobic compounds applying cytochrome P450 monooxygenases in-vitro

Cytochrome P450 monooxygenases are a unique family of enzymes that are able to catalyze regio- and stereospecific oxidations for a broad substrate range. However, due to limited enzyme activities and stabilities, hydrophobicity of substrates, as well as the necessity of a continuous electron and oxygen supply the implementation of P450s for industrial processes remains challenging. Aim of this study was to point out key aspects for the development of an efficient synthesis concept for cytochrome P450 catalyzed oxidations. In order to regenerate the natural cofactor NADPH, a glucose dehydrogenase was applied. The low water soluble terpene α-ionone was used as substrate for the model reaction system. The studies reveal that an addition of surfactants in combination with low volumetric amounts of co-solvent can significantly increase substrate availability and reaction rates. Furthermore, these additives facilitated a reliable sampling procedure during the process. Another key factor for the process design was the oxygen supply. Based on various investigations, a bubble-aerated stirred tank reactor in batch mode represents a promising reactor concept for P450 oxidations. Main restriction of the investigated reaction system was the low process stability of the P450 monooxygenase, characterized by maximum total turnover numbers of ∼4100molα‐ionone/molP450.

Dominant form of cationic peroxidase from sorghum roots

A dominant form of cationic peroxidase (PO-2) was isolated from sorghum (Sorghum bicolor L. Moench) roots and purified to electrophoretically homogeneous state. The enzyme is a monomer with mol wt of 49.7 kD. The optimum pH and the main catalytic constants (KM, V max, k cat) were determined for oxidation of the main substrates including Н2О2, 2,2'-azino-bis(3-ethylbenzthiazoline-6-sulfonate) (ABTS), 2,7-diaminofluorene, syringaldazine, 2,6-dimethoxyphenol, and o-dianisidine. The KM values increased in the sequence: H2O2 < 2,7-diaminofluorene < ABTS < o-dianisidine, whereas the maximum turnover number (93.9 s–1) was found for 2,7-diaminofluorene. Based on the analysis of molecular and catalytic properties of the enzyme, it was proven that PO-2 is a typical cationic plant peroxidase. Polycyclic aromatic hydrocarbons (phenanthrene, anthracene, fluorene), 2,2'-diphenic acid, and Ni ions had no significant influence on the activity of PO-2. The enzyme was inhibited by p-aminobenzoic acid, NaN3, 1-naphthol, 9,10-anthraquinone, and 9,10-phenanthrenequinone. In the presence of NaN3, 1-naphthol, and 9,10-phenanthrenequinone, a mixed competitive/noncompetitive type of inhibition was noted. The peroxidase PO-2 was found to oxidize synthetic anthraquinone dyes, phenanthrene, and some oxygenated derivatives of polycyclic aromatic hydrocarbons (9-phenanthrol; 1-naphthol; and 1-hydroxy-2-naphthoic, salicylic, and 2,2'-diphenic acids), which indirectly confirms the coupled plant–microbial metabolism of these compounds in the root zone of sorghum. The results indicate that 9,10-phenanthrenequinone and 2,2'-diphenic acid are the products of peroxidase-catalyzed oxidation of 9-phenanthrol.

Photocatalytic Reduction of Carbon Dioxide to CO and HCO2H Using fac-Mn(CN)(bpy)(CO)3.

Studies are reported regarding the use of Mn(CN)(bpy)(CO)3 (1) as a catalyst for CO2 reduction employing [Ru(dmb)3](2+) as a photosensitizer in mixtures of dry N,N-dimethylformamide-triethanolamine (N,N-DMF-TEOA) or acetonitrile-TEOA (MeCN-TEOA) with 1-benzyl-1,4-dihydronicotinamide as a sacrificial reductant. Irradiation with 470 nm light for up to 15 h yields both CO and HCO2H with maximum turnover numbers (TONs) as high as 21 and 127, respectively, with product preference dependent on the solvent. Further data suggests that upon single electron reduction this catalyst avoids the formation of a Mn-Mn dimer and instead undergoes a disproportionation reaction, which requires 2 equiv of [Mn(CN)(bpy)(CO)3](•-) to generate 1 equiv each of the active catalyst [Mn(bpy)(CO)3](-) and the starting compound 1. Additional characterization by cyclic voltammetry (CV) and infrared spectroelectrochemistry (IR-SEC) indicates that the stability of the singly reduced [Mn(CN)(bpy)(CO)3](•-) differs slightly in the N,N-DMF-TEOA solvent system compared to the MeCN-TEOA system. This contributes to the observed selectivities for HCO2H vs CO production.