Reduction Of Acetophenone Research Articles

A Modified Green Star Area (MoGSA) and software to assess greenness of reactions in the chemistry laboratories.

The environmental and health impacts of chemical processes have been a growing concern, leading to the establishment of Green Chemistry principles. Introducing new metrics for the assessment of methods' greenness is crucial to evaluate the exerted efforts to conserve the environment. In this work, we introduce a Modified Green Star Area (MoGSA) and software to assess the greenness of chemical reactions in laboratory settings. MoGSA refines the traditional Green Star Area Index (GSAI) by allowing users to selectively apply specific principles of Green Chemistry based on their relevance to the chemical process being evaluated. This approach addresses the limitations of GSAI, which often lacks clear boundaries between green and non-green practices and does not account for the varying applicability of the 12 Green Chemistry principles across different contexts. Through comparative case studies on catalytic stereoselective reduction of acetophenone, MoGSA demonstrates its utility in providing a more refined and flexible assessment, enhancing both educational and industrial applications of sustainable chemical practices. The software is available as an open source at https://bit.ly/MOGSA.

Pickering Emulsion Promoted Interfacial Sequential Chemo-Biocatalytic Reaction for the Synthesis of Chiral Alcohols from Styrene.

Chemo-biocatalytic cascades have emerged as a promising approach in the realm of advanced synthesis. However, reconciling the incompatible reaction conditions among distinct catalytic species presents a significant challenge. Herein, we introduce an innovative solution using an emulsion system stabilized by Janus silica nanoparticles, which serve as a bridge for both chemo-catalysts and biocatalysts at the interface. The chemo-catalyst is securely anchored within a hydrophobic polymer matrix, ensuring its residence in an organic environment. Meanwhile, the negatively charged E. coli cells containing enzymes are attracted to the aqueous phase at the interface, facilitating their optimal positioning. We demonstrate the efficacy of this system through a two-step cascade reaction. Initially, the oxidation of styrene to acetophenone using palladium as a chemocatalyst achieves a 6-fold increase in yield compared to the control system. Subsequently, the reduction of achiral acetophenone to its chiral alcohol derivative presents a 17-fold yield enhancement relative to that of the control reaction. Importantly, our system exhibits versatility, accommodating a wide range of substrates for both individual and sequential reactions. This work not only validates the concept but also paves the way for the integration of chemo- and biocatalysts in the synthesis of a broader array of high-value chemical compounds.

New metallophthalocyanine (M: Ni(II) and Fe(II)) complexes as efficient catalysts for transfer hydrogenation of various ketones

Hydrogen transfer reduction methods are attracting increasing attention from synthetic chemists in view of their operational simplicity. Therefore, the novel Ni(II) and Fe(II) tetra substituted metallophthalocyanines containing resorcinol and guaiacol groups were synthesized using microwave irradiation and characterized via elemental analysis, UV-Vis and FT-IR spectroscopy, and TGA. The comparison of the catalytic features of phthalocyanine based on metals is discussed in detail. These phthalocyanine-complexes were tested in transfer hydrogenation (TH) of ketones in the existence of KOH, utilizing 2-propanol as a hydrogen source. Examination of different carbonyl substrates revealed that Nickel (II) phthalocyanine, (Ni2) complex was a remarkable catalyst for the catalytic reduction of acetophenones (1.0 mol % of catalyst, 99 % conversion). Furthermore, we have discovered that the catalytic characteristics of this class of molecules are significantly influenced by both steric and electronic variables.

Mechanistic Insights of the Ir‐bipyridonate Catalyzed Aqueous Methanol Dehydrogenation and Transfer Dehydrogenation to Acetophenone: Experimental and DFT Study

AbstractThe mechanisms of the Cp*IrIII(bpyOO)‐catalyzed (bpyOO=bidentate (NN) doubly deprotonated 2,2′‐bipyridine‐6,6′‐diol) acceptorless methanol dehydrogenation and acetophenone transfer hydrogenation by methanol under basic conditions have been explored by the combination of 1H NMR, kinetics, and DFT computational studies. During dehydrogenation of methanol and of its dehydrogenated derivatives, the presence of two iridium hydride species (anionic [Cp*Ir(bpyOO)H]−, C* and neutral [Cp*Ir(bpyOOH)H], D*), which interconvert depending on pH, was detected. The DFT studies on a Cp model system highlighted three interrelated catalytic cycles of methanol, formaldehyde and formic acid dehydrogenation, all leading to the same hydride intermediates C and D. The dehydrogenation of methanol prefers a direct β‐hydride transfer pathway from the methoxide ion to Ir, rather than the classical β‐hydride elimination pathway from a coordinated methoxide ligand, but an alternative bifunctional H+/H− transfer with involvement of a ligand O atom may become competitive at lower pH. The transfer hydrogenation of acetophenone using methanol as hydrogen source features species C* as resting state, with the acetophenone reduction being rate‐determining and following the reverse pathway of methanol oxidation, with a first‐order acetophenone decay and a kinetic isotope effect of 2.36±0.09.

Optically Pure Calixarenyl Phosphine via Stereospecific Alkylation on Evans' Oxazolidinone Moiety.

A convenient protocol for the synthesis of 25,26,27-tribenzoyl-28-[((S)-1-diphenylphos- phanyl-propan-2-yl)oxy]-calix[4]arene via stereospecific methylation on Evans' oxazolidinone moiety was reported. According to the 13C NMR analysis of this phosphine, the calix[4]arene skeleton adopted a 1,3-alternate conformation. The latter conformation of the macrocycle and the (S)-chirality of the carbon atom bearing the methyl substituent were confirmed by a single-crystal X-ray diffraction study. After coordination of the phosphinated ligand to the dimeric [RuCl2(p-cymene)]2 organometallic precursor, the resulting arene-ruthenium complex was tested in the asymmetric reduction of acetophenone and alcohol was obtained with modest enantiomeric excess.

Catalytic performance of Noyori–Ikariya-type ruthenium complex with tethered syn-ULTAM ligand for the asymmetric transfer hydrogenation of ketones

The ruthenium complex of the tethered syn-ULTAM ligand, i.e. syn-3-(α-aminobenzyl)-benzo-γ-sultam, has been evaluated for the asymmetric transfer hydrogenation (ATH) of a variety of ketones in formic acid/triethylamine mixture. Its performance was similar to the established Noyori–Ikariya-type catalysts for the reduction of benzo-fused cyclic ketones, but the enantioselectivity for the reduction of acetophenone was only moderate. The syn-ULTAM-based catalyst was particularly efficient and enantioselective for ATH of the sterically demanding α,α-disubstituted ketones. Moreover, we report a divergent ATH of 2-phenyl-1,3-indandione to either cis-2-phenyl-1-indanol, or cis,trans-2-phenyl-1,3-indandiol.

Half-sandwich Ni(II) complexes bearing enantiopure bidentate NHC-carboxylate ligands: efficient catalysts for the hydrosilylative reduction of acetophenones.

Chiral nickel complexes containing NHC-carboxylate chelate ligands derived from the (S)-isomeric form of amino acids have been synthesised from the corresponding imidazolium salt and nickelocene. The presence of the carboxylate on the N-side arm of the heterocycle results in the competing formation of mixtures of mono- and bis-NHC complexes (i.e., [Ni(η5-Cp)(κ2-C,O-NHC)] and [Ni(κ2-C,O-NHC)2]), both of which retain the (S)-configuration of the stereogenic center and which can be separated by chromatography. Both the 18e- and 16e- complexes are found to be very stable and cannot be interconverted. The composition of the resulting mixtures depends mainly on the entity of the amino acid residue and, of more practical interest, on the reaction conditions. Thus, microwave heating and MeCN as a solvent favor the formation of the half-sandwich nickel complexes, rather than the bis-NHC compounds. Some of the [Ni(η5-Cp)(κ2-C,O-NHC)] complexes turn out to be among the best nickel catalysts for the hydrosilylative reduction of p-acetophenones described to date, although without chiral induction, in the absence of activating additives and under mild catalytic conditions.

Design of a gold nanoparticles site in an engineered lipase: an artificial metalloenzyme with enantioselective reductase-like activity.

The conjugation of gold complexes with proteins has proved to be interesting and effective in obtaining artificial metalloenzymes as catalysts with improved properties such as higher stability, activity and selectivity. However, the design and precise regulation of their structure as protein nanostructured forms level remains a challenge. Here, we have designed and constructed a gold nanoparticles-enzyme bioconjugate, by tailoring the in situ formation of gold nanoparticles (AuNPs) at two specific sites on the structure of an alkalophilic lipase from Geobacillus thermocatenulatus (GTL). For this purpose, two genetically modified variants of GTL were created by inserting a unique cysteine residue into the catalytic active site by replacing the active serine (GTL-114) and into the lid site (GTL-193). The enzyme, after a first protein-gold coordination, induced the in situ formation of AuNPs, generating a homogeneous artificial enzyme. The size and morphology of the nanoparticles in the AuNPs-enzyme conjugate have been controlled by specific pH conditions in synthesis and the specific protein region where they are formed. Reductase activity of all of them was confirmed in the hydrogenation of nitroarenes in aqueous media. The protein area seemed to be key for the AuNPs, with the best TOF values obtained for the bioconjugates with AuNPs in the lid site. Finally, the protein environment and the asymmetric properties of the AuNPs were tested in the reduction of acetophenone to 1-phenylethanol in aqueous medium at room temperature. A high reductive conversion and an enantiomeric excess of up to 39% towards (R)-1-phenylethanol was found using Au-Mt@GTL-114 pH 10 as a catalyst. Moderate enantioselectivity towards the opposite isomer was also observed using the Au-Mt@GTL-193 pH 10 conjugate.

Vigna radiata (mung) as superior natural biobased catalyst for asymmetric reduction of prochiral acetophenone

Asymmetric reduction of prochiral ketone via biocatalysis is one of the most promising and straight forward routes to prepare optically active alcohols. In this work, whole cells of Vigna radiata (also called mung) catalyzed enantioselective reduction of prochiral aromatic ketones was investigated. Effects of various parameters such as co-substrate, temperature, cell loading, substrate concentration on conversion and enantioselectivity were studied in a systematic manner by using acetophenone as the model compound. Glucose was found to be the most effective co-substrate for co-factor regeneration among different co-substrates employed. Whole cells of mung have shown excellent thermostability and high substrate tolerance (up to 200 mM). Under optimum conditions, maximum conversion of 93.44% and enantioselectivity of 98.92% were obtained in 9 h. Good conversion and enantioselectivity were observed with various substituted aromatic ketones. This is a cheap, clean, and eco-friendly process for preparation of chiral secondary alcohols compared to chemical processes.

Two anti‐Prelog NAD‐Dependent Alcohol Dehydrogenases with Broad Substrate Scope and Excellent Enantioselectivity

AbstractEnantiomerically pure alcohols are important to produce active pharmaceutical ingredients, agrochemicals and fine chemicals. Herein, we explored the substrate scope and chemo‐ and enantioselectivity of two NAD‐dependent anti‐Prelog alcohol dehydrogenases from Candida maris (Cm‐ADH) and Pichia finlandica (Pf‐ADH) in the asymmetric reduction of ketones. The ADHs were tested for the reduction of acetophenone with NADH that was recycled using a formate dehydrogenase and sodium formate. Cm‐ADH and Pf‐ADH performed best at 30 °C and at around pH 7 and pH 6, respectively. Pf‐ADH operated well at 50 mM acetophenone concentration, while Cm‐ADH was limited to 10 mM. Regarding the substrate scope, linear‐chain alkyl ketones were efficiently reduced (up to 98 % conversion), while branched and cyclic ketones gave lower conversions (up to 60 %). Aryl‐aliphatic ketones showed variable levels of conversion (<1–79 %), while α,β‐unsaturated and heteroaromatic ketones exhibited good to excellent conversions. In most of the cases, the enantiomeric excess was >99 %. Aliphatic and aryl‐aliphatic aldehydes were converted with up to >99 % conversion. A scale‐up experiment with Pf‐ADH using acetophenone as substrate led to 73 % isolated yield and >99 % ee (R).This work contributes to filling the gap in biocatalytic asymmetric synthesis of chiral alcohols by introducing two NAD‐dependent ADHs with anti‐Prelog selectivity.

Stereoselective Bioreduction of Acetophenone to (R)-1-Phenylethanol by Bacillus thuringiensis

Abstract: Optically pure alcohols have a pivotal synthetic role, being key intermediates for numerous pharmaceutical agents. Therefore, the synthesis of optically pure alcohols is now becoming a foremost research field in both academia and industries. Herein, Bacillus thuringiensis has been described for the first time for the bioreduction of acetophenone to 1-phenylethanol. Five incubated bacillus species and a consortium were investigated for the reduction of acetophenone. Among them, Bacillus thuringiensis (growing cells) exhibited >99% conversion efficiency of acetophenone (40 mM). The biocatalyst produced (R)-1-phenyl ethanol with excellent stereoselection (99%) at pH 7.5 after 24 h reaction intervals. To enhance the solubility of substrate and cofactor regeneration, isopropanol (10% v/v) was found to be effective among different tested cosolvents. The biocatalyst displayed excellent stereoselectivity and provided R-enantiomer with 99% enantiomeric excess.

Enzyme-Compatible Core-Shell Nanoreactor for in Situ H2 -Driven NAD(P)H Regeneration.

The regeneration of the reduced form cofactor NAD(P)H is essential for the extra-cellular application of bio-reduction, which necessitates not only the development of efficient artificial NAD(P)H regeneration catalytic system but also its well compatibility with the cascade enzymatic reduction system. In this work, we reported the preparation of a metal nanoparticle (NP) and metal complex integrated core-shell nanoreactor for H2 -driven NAD(P)H regeneration through the immobilization of a Rh complex on Ni/TiO2 surface via a bipyridine contained 3D porous organic polymer (POP). In comparison with the corresponding single component metal NPs and the immobilized Rh complex, the integrated catalyst presented simultaneously enhanced activity and selectivity in NAD(P)H regeneration thanks to the rapid spillover of activated H species from metal NPs to Rh complex. In addition, the size-sieving effect of POP precluded the direct interaction of enzyme and Rh complex confined in the pores, enabling the success coupling of core-shell nanoreactor and aldehyde ketone reductase (AKR) for chemoenzymatic reduction of acetophenone to (R)-1-phenylethan-1-ol. This work provides a strategy for the rational manipulation of multicomponent cooperation catalysis.

Enzyme‐Compatible Core‐Shell Nanoreactor for in Situ H2‐Driven NAD(P)H Regeneration

AbstractThe regeneration of the reduced form cofactor NAD(P)H is essential for the extra‐cellular application of bio‐reduction, which necessitates not only the development of efficient artificial NAD(P)H regeneration catalytic system but also its well compatibility with the cascade enzymatic reduction system. In this work, we reported the preparation of a metal nanoparticle (NP) and metal complex integrated core‐shell nanoreactor for H2‐driven NAD(P)H regeneration through the immobilization of a Rh complex on Ni/TiO2 surface via a bipyridine contained 3D porous organic polymer (POP). In comparison with the corresponding single component metal NPs and the immobilized Rh complex, the integrated catalyst presented simultaneously enhanced activity and selectivity in NAD(P)H regeneration thanks to the rapid spillover of activated H species from metal NPs to Rh complex. In addition, the size‐sieving effect of POP precluded the direct interaction of enzyme and Rh complex confined in the pores, enabling the success coupling of core‐shell nanoreactor and aldehyde ketone reductase (AKR) for chemoenzymatic reduction of acetophenone to (R)‐1‐phenylethan‐1‐ol. This work provides a strategy for the rational manipulation of multicomponent cooperation catalysis.

Regioselective cycloruthenation of N‐(benzylidene)benzylamines: Enantiopure catalysts for transfer hydrogenation

The reaction between N‐(benzylidene)benzylamines (p‐RC6H4CH=NCH2C6H5; R = Cl, H, NO2, F, OMe), [RuCl2(η6‐p‐cymene)]2 and potassium acetate has cleanly furnished the corresponding cycloruthenated complexes C1–C5. The process is completely regioselective, with the formation in all cases of the endo‐derivative, independently of the substituent of the aromatic ring. The five‐membered endo‐metallacycles C6 and C7 can also be obtained from the enantiopure imines (RC)‐p‐RC6H4CH=NCHMeC10H7 (R = Cl, H, respectively) working under similar conditions. The crystal structures of the seven metallated compounds have been determined by X‐ray diffraction. These complexes are active as catalyst precursors for the reduction of acetophenone and benzophenone by transfer hydrogenation. An enantiomeric excess of up to 77% at room temperature has been obtained with the complex C7 in the reduction of acetophenone.

Active and stable alcohol dehydrogenase-assembled hydrogels via synergistic bridging of triazoles and metal ions

Biocatalysis is increasingly replacing traditional methods of manufacturing fine chemicals due to its green, mild, and highly selective nature, but biocatalysts, such as enzymes, are generally costly, fragile, and difficult to recycle. Immobilization provides protection for the enzyme and enables its convenient reuse, which makes immobilized enzymes promising heterogeneous biocatalysts; however, their industrial applications are limited by the low specific activity and poor stability. Herein, we report a feasible strategy utilizing the synergistic bridging of triazoles and metal ions to induce the formation of porous enzyme-assembled hydrogels with increased activity. The catalytic efficiency of the prepared enzyme-assembled hydrogels toward acetophenone reduction is 6.3 times higher than that of the free enzyme, and the reusability is confirmed by the high residual catalytic activity after 12 cycles of use. A near-atomic resolution (2.1 Å) structure of the hydrogel enzyme is successfully analyzed via cryogenic electron microscopy, which indicates a structure–property relationship for the enhanced performance. In addition, the possible mechanism of gel formation is elucidated, revealing the indispensability of triazoles and metal ions, which guides the use of two other enzymes to prepare enzyme-assembled hydrogels capable of good reusability. The described strategy can pave the way for the development of practical catalytic biomaterials and immobilized biocatalysts.

RuCl2(DPEphos)(N-N)] (DPEphos = bis[(2-diphenylphosphino)phenyl]ether; N-N = 2-aminomethylpyridine or ethylenediamine): synthesis, characterization and transfer hydrogenation of aryl-ketones

The complexes trans/cis-[RuCl2(DPEphos)(ampy)] (trans – 1a; cis – 1b) and trans/cis-[RuCl2(DPEphos)(en)] (trans – 2a; cis – 2b) were obtained from the reactions of mer-[RuCl2(DPEphos)(PPh3)] (PPh3 = triphenylphosphine) with the corresponding amine in CH2Cl2. The isomer 1a was observed in situ when the reaction was carried out at r.t.; isolation leads to mixtures with 1b, while the latter was isolated when the reaction was performed under reflux. On the other hand, trans-[RuCl2(DPEphos)(en)] (2a) was obtained at r.t., in good yield and the cis-isomer 2b was observed when the reaction was carried out under reflux or when a CH2Cl2 solution of 2a is exposed to ambient light, but 2b was not isolated in pure form even under reflux for one week. Cyclic voltammetry studies revealed the presence of one reversible process with E1/2 0.57 and 0.40 V for 1b and 2a, respectively. Both 1b and 2a were used as pre-catalysts for reduction of acetophenone and p-substituted acetophenones (F–, Me– and MeO–) in transfer-hydrogenation conditions (isopropanol, 82 °C, and pre-catalyst:KOH:acetophenones in molar ratio 1:20:500 and/or 1:20:1000) showing conversions of 93–99% and TOF values up to 4.2 104 h−1.

Robust and efficient transfer hydrogenation of carbonyl compounds catalyzed by NN-Mn(I) complexes.

A series of manganese(I) carbonyl complexes bearing structurally related NN- and NNN-chelating ligands have been synthesized and assessed as catalysts for transfer hydrogenation (TH). Notably, the NN-systems based on N-R functionalized 5,6,7,8-tetrahydroquinoline-8-amines, proved the most effective in the manganese-promoted conversion of acetophenone to 1-phenylethanol. In particular, the N-isopropyl derivative, Mn1, when conducted in combination with t-BuONa, was the standout performer mediating not only the reduction of acetophenone but also a range of carbonyl substrates including (hetero)aromatic-, aliphatic- and cycloalkyl-containing ketones and aldehydes with especially high values of TON (up to 17 200; TOF of 3550 h-1). These findings, obtained through a systematic variation of the N-R group of the NN ligand, are consistent with an outer-sphere mechanism for the hydrogen transfer. As a more general point, this Mn-based catalytic TH protocol offers an attractive and sustainable alternative for producing alcoholic products from carbonyl substrates.

Enhancing Acetophenone Tolerance of Anti-Prelog Short-Chain Dehydrogenase/Reductase EbSDR8 Using a Whole-Cell Catalyst by Directed Evolution

The short-chain dehydrogenase/reductase (SDR) from Empedobacter brevis ZJUY-1401 (EbSDR8, GenBank: ALZ42979.1) is a promising biocatalyst for the reduction of acetophenone to (R)-1-phenylethanol, but its industrial application is restricted by its insufficient tolerance to acetophenone. In this paper, we developed a chromogenic reaction-based high-throughput screening method and employed directed evolution to enhance the acetophenone tolerance of EbSDR8. The resulting variant, M190V, showed 74.8% improvement over the wild-type in specific activity when catalyzing the reduction of 200 mM acetophenone. Kinetic analysis revealed a 70% enhancement in its catalytic efficiency (kcat/Km). Molecular docking was conducted to reveal the possible mechanism behind the improved acetophenone tolerance, and the result implied that the M190V mutation is conducive to the binding and release of coenzyme. Aside from the improved catalytic performance when dealing with a high concentration of acetophenone, other features of M190V, such as a broad pH range (6.0 to 10.5), low optimal cosubstrate concentration (1% isopropanol), and a temperature optimum close to that of E. coli cells (35 °C), also contribute to its practical application as a whole-cell catalyst. In this study, we first designed a directed evolution means to engineer the enzyme and obtained the positive variant which has a high activity under high concentrations of acetophenone. After that, we optimized the catalytic performance of the variant to adapt to industrial applications.

Hydrogenation of imines catalyzed by ruthenium(II) complexes containing phosphorus-nitrogen ligands via hydrogen transfer reaction

This work describes the synthesis and characterization of Ru(II) compounds with general formula cis-Cl- cis-P cis-N- RuCl2(PN)2 (where PN represents a heterobidentate PN-donor chelated ligand) and their application as catalysts in the reduction of acetophenone and imines hydrogenation via hydrogen transfer reaction using 2-propanol as the hydrogen source. Single crystal diffraction analysis for all synthesized ruthenium complexes shows non-regular octahedral coordination around the metal. All the synthesized Ru(II) complexes achieved high conversions and turnover frequencies in hydrogen transfer reaction to acetophenone (830 h−1) and imine hydrogenation (760 h−1 for N-benzylideneaniline). The complex (dichloro bis-(8-(diphenylphosphino)quinoline)ruthenium(II)) (RuL2) achieved high conversion in imine hydrogenation, while the complex(dichloro bis-(N-(diphenylphosphino)pyridin-2-amine)ruthenium(II)) (RuL3) showed high conversion in acetophenone reduction. It was found that the electronic, structural, and steric properties of the ligands could influence catalytic performance.

The crystal structure of the S154Y mutant carbonyl reductase from Leifsonia xyli explains enhanced activity for 3,5-bis(trifluoromethyl)acetophenone reduction

Carbonyl reductase from Leifsonia xyli (LXCAR, UniProtKB - T2FLN4) can stereoselectively catalyze the reduction of 3,5-bis(trifluoromethyl)acetophenone (BTAP) to its corresponding alcohol, (R)-[3,5-bis(trifluoromethyl)phenyl]ethanol ((R)-BTPE), which is a valuable chiral intermediate for the synthesis of antiemetic drugs, Aprepitant and Fosaprepitant. Moreover, this protein was found to have a broad spectrum of substrate specificity and can asymmetrically catalyze the reduction of a variety of ketones and keto esters. Even though molecular modelling of this protein was done by Wang et al. (2014), a crystal structure has not yet obtained. In this study, a single mutant, S154Y, which was shown to have higher catalytic activity toward BTAP than that of the wild type, was overexpressed in Escherichia coli BL21 (DE3), purified, and crystallized. The crystal structure of LXCAR-S154Y explains how the mutant enzyme can work with BTAP more efficiently than wild type carbonyl reductase. Furthermore, the structure explains why LXCAR-S154Y can use either NADH or NADPH efficiently as a cofactor, as well as elucidates a proton relay system present in the enzyme.