Synthesis Of Carboxylic Acids Research Articles

Heterogeneous Catalyst–Microbiome Hybrids for Efficient CO-Driven C6 Carboxylic Acid Synthesis via Metabolic Pathway Manipulation

Heterogeneous Catalyst–Microbiome Hybrids for Efficient CO-Driven C6 Carboxylic Acid Synthesis via Metabolic Pathway Manipulation

Photocatalytic C–H Carboxylation of 1,3-Dicarbonyl Compounds with Carbon Dioxide Promoted by Nickel(II)-Sensitized α-Fe2O3 Nanoparticles

Insertion of carbon dioxide into C–H bonds under mild conditions is an industrially important yet highly challenging task. In the present study, we report the synthesis of an efficient photocatalyst consisting of a Ni(bpy)3Cl2 sensitizer supported on α-Fe2O3 nanoparticles for the CO2 insertion into C–H bonds, particularly carboxylation of 1,3-dicarbonyl compounds like acetyl acetone, methyl acetoacetate, and ethyl acetoacetate with CO2 under visible light irradiation using carbon tetrachloride as a solvent. The carboxylation of these compounds afforded the predominant formation of a single isomeric acid as confirmed by 13C NMR spectroscopy. Based on the computational studies, a possible reaction mechanism suggested the generation of CO2 radical anions at the conduction band of α-Fe2O3 through single electron transfer mediated by the nickel(II) complex that coupled with acetyl acetone cation radicals at the valence band of α-Fe2O3 to give the corresponding carboxylic acid. The protocol described in the present study presents a light-assisted approach and a low-cost material for the synthesis of carboxylic acids utilizing CO2 under mild reaction conditions.

Features of the synthesis of pentaerythritol esters and carboxylic acids of aliphatic isomeric structure

Objectives. Due to their structures, pentaerythritol esters have a number of appealing properties such as high viscosity index when used as oils and excellent compatibility with polyvinyl chloride when used as plasticizers. For the production of pentaerythritol and carboxylic acids, natural gas can be used as a feedstock, which implies a strategic development of the petrochemical industry, a decrease in the amount of gas used for combustion, and its applications for the production of chemical products.Methods. The synthesis process was conducted in a self-catalysis mode with excess acids in a molar ratio of 8:1 and in the presence of a solvent (toluene) of ~30% per reaction mass. This ensures a uniform distillation of the reaction water at a constant temperature of 100–110 °C, a decrease in the side reaction products, and an increase in process selectivity. The products from the reaction mass were isolated by vacuum distillation, and identification of all the synthesized tetraesters was performed by chromatography–mass spectrometry analysis.Results. This work proposes options for optimizing the conditions of the thermal esterification of pentaerythritol with isomeric monocarboxylic acids (isobutyric, isovaleric, pivalic, and 2-ethylhexanoic acids) that have different reactivities due to their structures. Methods for isolating tetraesters of pentaerythritol and corresponding acids have been developed. The characteristics of the main series of ions of tetraesters of pentaerythritol and aliphatic isomeric acids C4–C8 in the mass spectra were obtained.Conclusions. The yields of tetraesters were at 95%–96% of the theoretical value, and product purity was >99.6%. The resulting target products (tetraesters) were characterized by relative color stability, where the maximum degree of color after cleaning was less than 20 units according to Hazen (180 units for tetra-2-ethylhexnoate), which corresponds to the standards in GOST 29131-91 (ISO 2211-73). The esterification rates were compared, and it was shown that the quantitative yields of isomeric tetraesters at 100–110 °C were achieved in 12–15 h for isobutyric and isovaleric acids, 25–27 h for 2-ethyl-hexanoic acid, and ~40 h for pivalic acid.

Boryl Radical Activation of Benzylic C-OH Bond: Cross-Electrophile Coupling of Free Alcohols and CO2 via Photoredox Catalysis.

A new strategy for the direct cleavage of the C(sp3)-OH bond has been developed via activation of free alcohols with neutral diphenyl boryl radical generated from sodium tetraphenylborate under mild visible light photoredox conditions. This strategy has been verified by cross-electrophile coupling of free alcohols and carbon dioxide for the synthesis of carboxylic acids. Direct transformation of a range of primary, secondary, and tertiary benzyl alcohols to acids has been achieved. Control experiments and computational studies indicate that activation of alcohols with neutral boryl radical undergoes homolysis of the C(sp3)-OH bond, generating alkyl radicals. After reducing the alkyl radical into carbon anion under photoredox conditions, the following carboxylation with CO2 affords the coupling product.

Solvent-promoted and acid- controlled selectivity oxidation of 5-hydroxymethylfurfural over metal-free TEMPO catalyst

Achieving efficient metal-free synthesis of 2,5-diformylfuran and 2,5-furandicarboxylic acid is always a challenge. In this manuscript, the selective oxidation of 5-hydroxymethylfurfural was achieved by using TEMPO system in t-BuOH solvent with the suitable acid promoters. And t-BuOH was considered to be a suitable solvent due to its excellent stability, oxidation promotion and solubility for intermediates. Remarkably, 90% and 83% yield of DFF and FDCA can be obtained with acetic acid and phosphoric acid, respectively. Additionally, the role of acid additives was discussed in detail and the hydration degree of aldehyde intermediates was considered to be key to controlling the selectivity of this reaction. The isolated yield of 2,5-diformylfuran and 2,5-furandicarboxylic acid were 82% and 78% through the scale-up oxidation, respectively. This approach may be a promising alternative to traditional oxidations for the synthesis of carboxylic acids.

Autoxidation of Formaldehyde with Oxygen-A Comparison of Reaction Channels.

The autoxidation of formaldehyde through initiation by triplet oxygen is studied via two initial steps: (1) H-atom abstraction and (2) 3O2 addition reaction. The reaction energy profiles show that the reactions are thermodynamically and kinetically demanding. A comparison of the pathways of these initial reactions and the search for a less energy-demanding pathway is presented. The presence of a Brønsted acid has no effect on the energetics of the reaction, while the presence of a single water molecule catalyst enhances the initial reactions. The H-atom abstraction reaction from formaldehyde results in formyl and hydroperoxy radicals. These radicals on further reaction with the second equivalent of 3O2 lead to a CO + 2HO2 product channel. The 3O2 addition reaction to formaldehyde results in a triplet biradical intermediate which further leads to performic acid, the precursor in the synthesis of carboxylic acids from aldehydes. In the presence of water molecules, performic acid is formed in a single kinetic step, and this leads to a CO2 + OH + HO2 product channel upon subsequent reaction with 3O2 in a thermodynamically favorable reaction. The results show that the less established 3O2 addition reaction to aldehydes is a viable route for autoxidation in the absence of purpose-built initiators, in addition to the well-established H-atom abstraction route.

Design and synthesis of novel spirocyclic carboxylic acids as potent and orally bioavailable DGAT1 inhibitors and their biological evaluation

A series of novel spirocyclic DGAT1 inhibitors containing the oxadiazole motif were designed and synthesized for biological evaluation. Several compounds exhibited potent diacylglycerol acyltransferase 1 (DGAT1) inhibitory activity. Optimization of the series led to the identification of five lead compounds 8, 9, 10, 11 and 12 that showed excellent in-vitro activity with IC50 values ranging from 7 to 20 nM against human DGAT1. All compounds demonstrated good druggability as well as microsomal stability and safety profiles such as hERG and CYP. Compound 12 significantly reduced plasma triglyceride levels in-vivo in the mouse model of acute lipid challenge. Significant reduction in plasma TG excursion was observed, thus indicating DGAT1 inhibition in-vivo.

Synthesis and evaluation of functional carboxylic acid based poly(εCL-st-αCOOHεCL)-b-PEG-b-poly(εCL-st-αCOOHεCL) copolymers for neodymium and cerium complexation

Original carboxylic acid-based copolymers have been developed for the complexation of actinides. For such purpose, ring-opening copolymerizations of α-benzyl carboxylate-ε-caprolactone (BzCL) and ε-caprolactone (εCL) have been carried out with poly(ethylene glycol) (PEG) as macro-initiator and tin(II) octanoate, as catalyst, to afford poly(εCL-st-αBzεCL)-b-PEG-b-poly(εCL-st-αBzεCL) (PB) copolymers. Three different εCL/BzCL ratios were targeted (90/10, 75/25 and 50/50), leading to PB10%, PB25% and PB50%, respectively. Then, hydrogenation of the prepared copolymers allowed the deprotection of benzyl esters to carboxylic acids groups, leading to poly(εCL-st-αCOOHεCL)-b-PEG-b-poly(εCL-st-αCOOHεCL) copolymers (PA10%, PA25% and PA50%). All materials were fully characterized by 1H NMR, 13C NMR and size exclusion chromatography. Experimental ratios were found to be close from theoretical ones as equal to 92/08, 75/25, and 60/40. Molecular weight was the same for all copolymers (4000 g.mol−1). Complexing properties of the different copolymers were studied by Isothermal Titration Calorimetry (ITC) with neodymium (Nd(III)) and cerium (Ce(III)), used as actinide surrogates. ITC enabled the determination of the full thermodynamic profile (ΔG, ΔH, TΔS, Ka, and stoichiometry). The results showed that PA25% was the polymer with the highest sorption capacity (13.6 mg.g−1 for Nd(III) and 13.7 mg.g−1 for Ce(III)) and the highest binding constant (8500 M−1 and 5500 M−1 for Nd(III) and Ce(III), respectively). This demonstrated that by increasing the amount of complexing carboxylic acid functions, the complexing capacity did not necessarily increase as well, reaching a maximum with PA25%. In a more general manner, all developed copolymers are very promising for cation complexation.

Catalytic asymmetric synthesis of α-stereogenic carboxylic acids: recent advances.

Chiral carboxylic acids bearing an α-stereogenic center constitute the backbone of many natural products and therapeutic reagents as well as privileged chiral ligands and catalysts. Hence, it is not surprising that a large number of elegant catalytic asymmetric strategies have been developed toward the efficient synthesis of α-chiral carboxylic acids, such as α-hydroxy acids and α-amino acids. In this review, the recent advances in asymmetric synthesis of α-stereogenic free carboxylic acids via organocatalysis and transition metal catalysis are summarized (mainly from 2010 to 2020). The content is organized by the reaction type of the carboxyl source involved, including asymmetric functionalization of substituted carboxylic acids, cyclic anhydrides, α-keto acids, substituted α,β-unsaturated acids and so on. We hope that this review will motivate further interest in catalytic asymmetric synthesis of chiral α-substituted carboxylic acids.

Modular synthesis of α-arylated carboxylic acids, esters and amides via photocatalyzed triple C–F bond cleavage of methyltrifluorides

α-Arylated carboxylic acids, esters and amides are widespread motifs in bioactive molecules and important building blocks in chemical synthesis. Thus, straightforward and rapid access to such structures is highly desirable. Here we report an organophotocatalytic multicomponent synthesis of α-arylated carboxylic acids, esters and amides from exhaustive defluorination of α-trifluoromethyl alkenes in the presence of alkyltrifluoroborates, water and nitrogen/oxygen nucleophiles. This operationally simple strategy features a unified access to functionally diverse α-arylated carboxylic acids, esters, and primary, secondary, and tertiary amides through backbone assembly from simple starting materials enabled by consecutive C–F bond functionalization at room temperature. Preliminary mechanistic investigations reveal that the reaction operates through a radical-triggered three-step cascade process, which involves distinct mechanisms for each defluorinative functionalization of the C–F bond.

Preparation of glycosyl carboxylic acids via stereoselective synthesis and oxidative cleavage of C-vinyl glycosides.

We have developed an improved cyanide-free strategy for the synthesis of glycosyl carboxylic acids, employing stereoselective C-vinyl glycosylation and oxidative cleavage of C-vinyl glycosides as key steps. Compared to our previous work, the amount of NaIO4 required for the oxidative cleavage step is reduced significantly from 18 equivalents to 4.5 equivalents. This modification not only is advantageous in terms of operation and costs but also avoids the over-oxidation problem, thus greatly expanding the substrate scope, which is evidenced by the fact that 10 out of 21 glycosyl carboxylic acids synthesized are undocumented. With differently O5-protected furanosyl acids in hand, we demonstrate that an electron-rich protecting group is beneficial for the decarboxylative arylation of furanosyl carboxylic acids. This represents a rare example of protecting groups affecting the reaction efficiency in radical C-glycosylation. As C-vinyl glycosides can be prepared stereoselectively and the oxidative step is stereoretentive, the approach provides an effective means to access 1,2-trans or 1,2-cis glycosyl acids, which would be a valuable alternative to the cyanide-based synthesis of glycosyl carboxylic acids.

Synthesis of carboxylic acids via the hydrocarboxylation of alcohols with CO2 and H2

Alcohols with different chain lengths can react with CO2 and H2 to produce C1-elongated carboxylic acids using an Ir catalyst.

Synthesis of Carboxylic Acids from Benzamide Precursors Using Nickel Catalysis

Synthesis of Carboxylic Acids from Benzamide Precursors Using Nickel Catalysis

Characterization and immobilization of Pycnoporus cinnabarinus carboxylic acid reductase, PcCAR2

Carboxylic acid reductases (CARs) are well-known for their eminent selective one-step synthesis of carboxylic acids to aldehydes. To date, however, few CARs have been identified and characterized, especially from fungal sources. In this study, the CAR from the white rot fungus Pycnoporus cinnabarinus (PcCAR2) was expressed in Escherichia coli. PcCAR2′s biochemical properties were explored in vitro after purification, revealing a melting temperature of 53 °C, while the reaction temperature optimum was at 35 °C. In the tested buffers, the enzyme showed a pH optimum of 6.0 and notably, a similar activity up to pH 7.5. PcCAR2 was immobilized to explore its potential as a recyclable biocatalyst. PcCAR2 showed no critical loss of activity after six cycles, with an average conversion to benzaldehyde of more than 85% per cycle. Immobilization yield and efficiency were 82% and 76%, respectively, on Ni-sepharose. Overall, our findings contribute to the characterization of a thermotolerant fungal CAR, and established a more sustainable use of the valuable biocatalyst.

Synthesis of higher carboxylic acids via reaction of polyols with CO2 and H2

Synthesis of value-added chemicals from biomass-derived polyols and CO 2 is of great importance. Herein we report a strategy to produce higher carboxylic acids by the reaction of polyol, CO 2 , and H 2 . The reaction can be efficiently accelerated by Rh catalyst in a binary solvent of ionic liquid (1-butyl-3-methylimidazolium iodide) and water, where cheap and nontoxic I 2 was used as a promoter. The reaction can occur at above 100°C. At optimal conditions, the yield of the carboxylic acids was as high as 86.4%. The catalytic mechanism is proposed based on a series of control experiments. Interestingly, the polyol could be effectively transformed into olefin intermediate at metal-free and mild conditions, which was the key to the success of this strategy. The peculiar solvent effect was also favorable to the reaction. In addition, the catalytic system was adaptable to various polyol substrates. • Higher carboxylic acids are effectively produced from polyol, CO 2 , and H 2 • The Rh/I 2 catalyst may accelerate the reaction in the ionic liquid/water solvent • The polyol is transformed into the olefin intermediate at metal-free condition • Various polyols and simulated crude glycerol could be applied as substrates The accumulation of CO 2 in the environment and the over-reliance on dwindling fossil fuel may cause disastrous consequences. In mitigating these challenges, chemical utilization of CO 2 and biomass-derived polyols have aroused extensive interest among scientists all over the world. As a clean reductant, H 2 can be produced from water by renewable energy, such as wind, hydro, and solar energy. Higher carboxylic acids are basic and very useful chemicals. Synthesis of higher carboxylic acids from CO 2 usually needs expensive or air/water-sensitive substrates, such as organometallic reagents, organic halides, and/or unsaturated hydrocarbons. In addition, metallic reducing agents and/or silanes are often needed to drive the reactions. In this report, we developed a method to efficiently produce higher carboxylic acids via reaction of CO 2 , biomass-derived polyols, and H 2 . The catalytic system was recyclable and may apply to various polyols and simulated crude glycerol. Higher carboxylic acids are efficiently synthesized by the reaction of biomass-derived polyols, CO 2 , and H 2 accelerated by a Rh catalyst with cheap and nontoxic I 2 promoter in a binary solvent of 1-butyl-3-methylimidazolium iodide and water. The catalytic system may apply to various polyol substrates and simulated crude glycerol.

Visible-Light Photoredox-Catalyzed Carboxylation of Activated C(sp3)─O Bonds with CO2

The photocatalytic carboxylation with CO2 has emerged as an efficient way to afford valuable aliphatic carboxylic acids. However, the difficultly available starting materials, limited substrate scope, and/or the use of high loading of transition-metal catalysts hamper their wide application. In contrast, alcohols and derivatives, which are environmentally benign and readily available in nature and industry, have rarely been investigated in such a process. Herein, we report a visible-light photoredox-catalyzed carboxylation of activated C(sp3)─O bonds with CO2 under mild and transition-metal-free conditions. A variety of benzyl alcohols and derivatives, bearing primary, secondary, and more challenging tertiary C(sp3)─O bonds, undergo carboxylation with CO2, generating valuable aryl acetic acids, such as ibuprofen, naproxen, fenoprofen, and flurbiprofen, with broad substrate scope and good functional group tolerance. Moreover, this strategy is also applicable to other carboxylates of α-hydroxyl amides, esters, and nitriles, as well as allyl alcohols, representing a practical method for aliphatic carboxylic acid synthesis.

Implementation of Synthetic Pathways to Foster Microbe-Based Production of Non-Naturally Occurring Carboxylic Acids and Derivatives.

Microbially produced carboxylic acids (CAs) are considered key players in the implementation of more sustainable industrial processes due to their potential to replace a set of oil-derived commodity chemicals. Most CAs are intermediates of microbial central carbon metabolism, and therefore, a biochemical production pathway is described and can be transferred to a host of choice to enable/improve production at an industrial scale. However, for some CAs, the implementation of this approach is difficult, either because they do not occur naturally (as is the case for levulinic acid) or because the described production pathway cannot be easily ported (as it is the case for adipic, muconic or glucaric acids). Synthetic biology has been reshaping the range of molecules that can be produced by microbial cells by setting new-to-nature pathways that leverage on enzyme arrangements not observed in vivo, often in association with the use of substrates that are not enzymes’ natural ones. In this review, we provide an overview of how the establishment of synthetic pathways, assisted by computational tools for metabolic retrobiosynthesis, has been applied to the field of CA production. The translation of these efforts in bridging the gap between the synthesis of CAs and of their more interesting derivatives, often themselves non-naturally occurring molecules, is also reviewed using as case studies the production of methacrylic, methylmethacrylic and poly-lactic acids.

Gram-scale synthesis of carboxylic acids via catalytic acceptorless dehydrogenative coupling of alcohols and hydroxides at an ultralow Ru loading

Acceptorless dehydrogenative coupling (ADC) of alcohols and water/hydroxides is an emergent and graceful approach to produce carboxylic acids. Therefore, it is of high demand to develop active and practical catalysts/catalytic systems for this attractive transformation. Herein, we designed and fabricated a series of cyclometallated N-heterocyclic carbene-Ru (NHC-Ru) complexes via ligand tuning of [Ru-1], the superior complex in our previous work. Gratifyingly, gram-scale synthesis of carboxylic acids was efficiently enabled at an ultralow Ru loading (62.5 ppm) in open air. Moreover, effects of distinct ancillary NHC ligands and other parameters on this catalytic process were thoroughly studied, while further systematic studies were carried out to provide rationales for the activity trend of [Ru-1]-[Ru-7]. Finally, determination of quantitative green metrics illustrated that the present work exhibited superiority over representative literature reports. Hopefully, this study could provide valuable input for researchers who are engaging in metal-catalyzed ADC reactions.

Enantioselective Synthesis of Chiral Carboxylic Acids from Alkynes and Formic Acid by Nickel-Catalyzed Cascade Reactions: Facile Synthesis of Profens.

We report a stereoselective conversion of terminal alkynes to α-chiral carboxylic acids using a nickel-catalyzed domino hydrocarboxylation-transfer hydrogenation reaction. A simple nickel/BenzP* catalyst displayed high activity in both steps of regioselective hydrocarboxylation of alkynes and subsequent asymmetric transfer hydrogenation. The reaction was successfully applied in enantioselective preparation of three nonsteroidal anti-inflammatory profens (>90 % ees) and the chiral fragment of AZD2716.

Enantioselective Synthesis of Chiral Carboxylic Acids from Alkynes and Formic Acid by Nickel‐Catalyzed Cascade Reactions: Facile Synthesis of Profens

AbstractWe report a stereoselective conversion of terminal alkynes to α‐chiral carboxylic acids using a nickel‐catalyzed domino hydrocarboxylation‐transfer hydrogenation reaction. A simple nickel/BenzP* catalyst displayed high activity in both steps of regioselective hydrocarboxylation of alkynes and subsequent asymmetric transfer hydrogenation. The reaction was successfully applied in enantioselective preparation of three nonsteroidal anti‐inflammatory profens (>90 % ees) and the chiral fragment of AZD2716.