Β-keto Carboxylic Acids Research Articles

Computational insights into the binding modes, keto-enol tautomerization and stereo-electronically controlled decarboxylation of oxaloacetate in the active site of macrophomate synthase.

Oxaloacetic acid (OAA) is a β-ketocarboxylic acid, which plays an important role as an intermediate in some metabolic pathways, including the tricarboxylic acid cycle, gluconeogenesis and fatty acid biosynthesis. Animal studies have indicated that supplementing oxaloacetic acid shows an increase of lifespan and other substantial health benefits including mitochondrial DNA protection, and protection of retinal, neural and pancreatic tissues. Most of the chemical transformations of OAA in the metabolic pathways have been extensively studied; however, the understanding of decarboxylation of OAA at the atomic level is relatively lacking. Here, we carried out MD simulations and combined quantum mechanical/molecular mechanical (QM/MM) calculations as an example to systematically elucidate the binding modes, keto-enol tautomerization and decarboxylation of OAA in the active site of macrophomate synthase (MPS), which is a Mg(II)-dependent bifunctional enzyme that catalyzes both the decarboxylation of OAA and [4+2] cycloaddition of 2-pyrone with the decarboxylated intermediate of OAA (pyruvate enolate). On the basis of our calculations, it was found that the Mg2+-coordinated oxaloacetate may exist in enol forms and keto forms. The four keto forms can be transformed into each other by simply rotating the C2-C3 single bond, nevertheless, the keto-enol tautomerization strictly requires the assistance of pocket water molecules. In addition, the decarboxylation is stereo-electronically controlled, i.e., it is the relative orientation of the terminal carboxyl anion that determines the rate of decarboxylation. As such, the chemistry of oxaloacetate in the active site of MPS is complex. On one hand, the most stable binding mode (K-I) may undergo enol-keto tautomerization to isomerize to the enol form, which may further react with the second substrate; on the other hand, K-I may isomerize to another binding mode K-II to proceed decarboxylation to generate pyruvate enolate and CO2. Starting from K-I, the enol-keto tautomerization corresponds to a barrier of 16.2 kcal mol-1, whereas the decarboxylation is associated with an overall barrier of 19.7 kcal mol-1. These findings may provide useful information for understanding the chemistry of OAA and the catalysis of related enzymes, and they are basically in agreement with the available experimental kinetic data.

Exploration of Optical and Radiative Properties of Fluorinated β-keto Carboxylate Tb3+ Complexes Emanating Cool Green Light.

Tb3+ complexes with β-ketocarboxylic acid as main ligand and heterocyclic systems as auxiliary ligand were synthesized and analyzed to assess their prospective relevance as green light emitting material. The complexes were characterized via various spectroscopic techniques and were found to be stable up to ≈ 200 ℃. Photoluminescent (PL) investigation was performed to assess the emissive nature of complexes. Longest luminescence time of decay (1.34ms) and highest intrinsic quantum efficiency (63.05%) were fetched for complex T5. Color purity of complexes was found to be in range 97.1 - 99.8% which demonstrated the aptness of these complexes in green color display devices. NIR Absorption spectra were employed to evaluate Judd-Ofelt parameters to appraise the luminous performance and environment encircling Tb3+ ions. The JO parameters were found to follow the order: Ω2 > Ω4 > Ω6 and suggested the higher covalence character in complexes. Theoretical branching ratio in the range 65.32 - 72.68%, large stimulated emission cross section and narrow FWHM for 5D4 → 7F5 transition unlocked the relevance of these complexes as a green color laser media. Band gap and Urbach analysis were consummated via enforcing nonlinear curve fit function on absorption data. Two band gaps with values in between 2.02 - 2.93eV established the prospective use of complexes in photovoltaic devices. Energies of HOMO and LUMO were estimated employing geometrically optimized structures of complexes. Investigation of biological properties accomplished via antioxidant and antimicrobial assays which communicated their applicability in biomedical domain.

Designing of europium(III) complexes with β-keto carboxylic acid and nitrogen-containing secondary ligand possessing optoelectrical, Urbach energy and lasing properties

Designing of europium(III) complexes with β-keto carboxylic acid and nitrogen-containing secondary ligand possessing optoelectrical, Urbach energy and lasing properties

Study of Judd-Ofelt, Urbach energy and photosensitization process in luminescent Sm(III) complexes with heterocyclic ligands.

Six samarium (III) complexes were synthesised by employing the β-ketocarboxylic acid as main ligand and five N-donor systems as ancillary ligands through the environmentally safe liquid-assisted grinding method. Various characterisation techniques were employed to determine the structure of the complexes i.e. NMR, IR, XRD and SEM. Photoluminescent studies were carried out in solid as well as in solution form. In solid and solution form emission spectra show maximum intensity peak at 604 and 602nm, respectively, assigned to 4G5/2 → 6H7/2 transition which explains orange emission on UV excitation in complexes. CCT, CP, colorimetric parameters and quantum yield (relative and intrinsic) of the synthesized complexes were calculated. With the help of reflectance spectra, band gap and Urbach energy were determined. Lasing parameters were also calculated by employing FWHM values obtained from Gaussian fitting. Energy transfer study revealed the efficacious energy transfer from ligand to metal's emissive level. Further antimicrobial studies revealed higher activity in case of complexes in comparison to ligand.

Synthesis of 13 C and 2 H Labeled Vinyl Pyruvate and Hyperpolarization of Pyruvate.

The hyperpolarization of nuclear spins has enabled unique applications in chemistry, biophysics, and particularly metabolic imaging. Parahydrogen-induced polarization (PHIP) offers a fast and cost-efficient way of hyperpolarization. Nevertheless, PHIP lags behind dynamic nuclear polarization (DNP), which is already being evaluated in clinical studies. This shortcoming is mainly due to problems in the synthesis of the corresponding PHIP precursor molecules. The most widely used DNP tracer in clinical studies, particularly for the detection of prostate cancer, is 1-13 C-pyruvate. The ideal derivative for PHIP is the deuterated vinyl ester because the spin physics allows for 100 % polarization. Unfortunately, there is no efficient synthesis for vinyl esters of β-ketocarboxylic acids in general and pyruvate in particular. Here, we present an efficient new method for the preparation of vinyl esters, including 13 C labeled, fully deuterated vinyl pyruvate using a palladium-catalyzed procedure. Using 50 % enriched parahydrogen and mild reaction conditions, a 13 C polarization of 12 % was readily achieved; 36 % are expected with 100 % pH2 . Higher polarization values can be potentially achieved with optimized reaction conditions.

Judd-Ofelt, optical and photophysical analysis of β-ketocarboxylate Sm(III) complexes with N-donor aromatic system as secondary sensitizers

Reddish orange, Sm(III) complexes were synthesised by means of environmentally sustainable grinding method with β-keto carboxylic acid and heterocyclic aromatic systems. The photoluminescent studies revealed that 4G5/2 → 6H7/2 transition (608 nm) is responsible for the reddish orange emission of complexes when irradiated with UV light. Judd-Ofelt theory was applied to NIR absorption spectra to obtain three intensity parameters (Ω2, Ω4, Ω6) from oscillator strength. The higher Ω2 values obtained in complexes indicate greater covalence character. To assess luminescence performance, the radiative, nonradiative transition probability, radiative life time and intrinsic quantum yield were also evaluated. High quantum yield obtained for complexes signalises the superior luminescent behaviour. Exquisite color purity (89.8–96.2%) and CCT <3200 K establish these complexes as warm orange light source. The experimental data of absorption coefficient was fitted nonlinearly with Tauc's relation to obtain band gap energy. Two band gaps were reported in each complex hence the synthesised complexes can have materiality in solar cell and photovoltaic devices. The Urbach band tail width was also obtained through fitting with a new empirical relation which affirms the semiconducting properties of complexes. The investigation of antimicrobial and antioxidant properties of complexes ascertained the complexes as potent antibacterial and antioxidant agents.

Urbach and Judd-Ofelt analysis of crystalline samarium (III) complexes with β-ketocarboxylate and nitrogen donor secondary ligands

The scarlet Sm (III) complexes with eight coordination number, as favoured by EDAX and elemental analytical data, were synthesized with fluorinated β-keto carboxylic acid as primary ligand and neo, batho, phen, dmph, and bypy as secondary ligand. Binary and ternary complexes of Sm(III) ion [Sm(ligand)32H2O], [Sm(ligand)3secondary ligand] respectively were prepared by one-step grinding method. The complexes exhibit crystalline character, nanoparticle size and outstanding thermal stability, they also have high color purity and as warm orange light sources. In UV visible light, complexes display several characteristic emission transitions such as (4G5/2 → 6H5/2, 4G5/2 → 6H7/2 and 4G5/2 → 6H9/2) under the excitation of Sm (III) ion. The scarlet luminescence in UV domain is accredited to the 4G5/2 → 6H7/2 transition at 605 nm wavelength. The proton NMR and FT-IR data are reliable with coordination behavior of organic ligand and secondary ligand with Sm(III) ion. To understand the semiconducting nature, materiality in solar cell and photovoltaic devices with the help of HOMO- LUMO bandgap analysis and Urbach energy were examined. The calculated Judd-Ofelt parameter is a crucial aspect to describe the rigidity and symmetry of complexes. The anti-microbial investigation demonstrated that all complexes are practically applicable in bioassays.

Optical and photophysical portrayal of Sm3+ complexes possessing two band gaps for relevance in solar cells and photovoltaic devices

Octa-coordinated samarium (III) complexes were synthesised using a fluorinated β-keto carboxylic acid (L) as prime ligand and N-donor systems as auxillary ligands, by ecologically desirable grinding method. The photoluminescent properties were investigated in powder and solution form. The characteristic emission at ∼605 nm (solid state) and ∼599 (solution phase) relative to 4G5/2 → 6H7/2 transition is accountable for the bright vermillion color of complexes. Quantum yield and colorimetric parameters were obtained for solid and solution state. CCT and color purity value characterise these complexes as warm orange light source. Reflectance spectra of solid complexes were fitted nonlinearly to procure optical band gap and Urbach band tail width. Two band gaps were reported in each complex, hence can have materiality in solar cell and photovoltaic devices. The FWHM obtained for most emissive transition (4G5/2 → 6H7/2) is found to be comparable with Nd-doped fluorophosphates glass. Energy transfer pathway studied for all the synthesised complexes, affirmed the effective energy transfer from ligands to Sm3+ ion. Investigation of antimicrobial behaviour of complexes revealed either higher or similar activity with respect to the ligand.

Designing of emerald terbium (III) ions with β-ketocarboxylic acid and heterocyclic ancillary ligands for biological and optoelectronic applications.

A green and highly efficient grinding method was adopted to synthesize emerald terbium complexes with 1-cyclopropyl-6-fluro-4-oxo-7-piperazin-1-ylquinoline-3-carboxylic acid as the main organic ligand and 2,2'-bipyridyl, 1,10-phenanthroline, neocuproine, 5,6-dimethyl-1,10-phenanthroline and bathophenanthroline as ancillary ligands. Structural analysis of these complexes was executed via elemental, infrared and 1 H-nuclear magnetic resonance analysis, which confirmed that the ligand coordinated to the metal ion through β-ketone and hydroxyl groups of carboxylic acid. Thermal stability of these complexes was investigated by study of thermogravimetric/derivative thermogravimetric analysis. Photoluminescence properties were investigated by observing emission spectra (400-700 nm), excitation spectra (250-500 nm) and decay time curves for display devices. The emission spectra revealed that an intense peak at 545 nm was observed due to 5 D4 →7 F5 electronic transition, which is responsible for the emerald colour in synthesized complexes, under 353 nm ultraviolet light excitation. The energy band gap and refractive index were determined, which proclaimed the dormant applications of these complexes in semiconductors. Commission Internationale de l'éclairage colour coordinates confirmed that the emerald emission of these complexes lies in the green region. Furthermore, antioxidant, antimicrobial and antimalarial assays of these complexes were also investigated, which confirmed that these complexes are potent for antioxidant, antimicrobial and antimalarial activities.

Enantioselective decarboxylative protonation and deuteration of β-ketocarboxylic acids.

Enantioselective decarboxylative protonation of tetralone-derived β-ketocarboxylic acids was achieved with up to 89% enantiomeric excess (ee)-in the presence of a chiral primary amine catalyst. Furthermore, this method was applied to enantioselective deuteration to afford the corresponding α-deuterioketones with up to 88% ee.

Asymmetric Synthesis of Tertiary α -Hydroxyketones by Enantioselective Decarboxylative Chlorination and Subsequent Nucleophilic Substitution.

Chiral tertiary α-hydroxyketones were synthesized with high enantiopurity by asymmetric decarboxylative chlorination and subsequent nucleophilic substitution. We recently reported the asymmetric decarboxylative chlorination of β-ketocarboxylic acids in the presence of a chiral primary amine catalyst to obtain α-chloroketones with high enantiopurity. Here, we found that nucleophilic substitution of the resulting α-chloroketones with tetrabutylammonium hydroxide yielded the corresponding α-hydroxyketones without loss of enantiopurity. The reaction proceeded smoothly even at a tertiary carbon. The proposed method would be useful for the preparation of chiral tertiary alcohols.

Microwave-assisted green synthesis, antimicrobial activity, and drug-likeness of novel isoindolinone derivatives

An efficient and green microwave method has been developed for the synthesis of novel isoindolinone derivatives with good yields. The framework of these derivatives was constructed from β-ketocarboxylic acids, various primary amines, and 2-carboxybenzaldehyde via cetrimonium bromide salt-promoted multicomponent cascade of decarboxylation/lactamization reaction. This methodology features a simple, environmentally friendly approach, employing water as a green solvent and using a one-pot, three-component reaction. The synthesized compounds were evaluated for their antimicrobial activity in vitro against six microorganisms, namely Escherichia coli, Serratia, Staphylococcus aureus, Bacillus subtilis, Aspergillus niger, and Fusarium oxysporum. The results revealed that these derivatives have a significant antimicrobial activity. In addition, the drug-likeness of these derivatives has been evaluated.

Amine-Catalyzed Decarboxylative Aldol Reaction of β-Ketocarboxylic Acids with Trifluoropyruvates.

Decarboxylative aldol reaction of aliphatic carboxylic acids is a useful method for C–C bond formation because carboxylic acids are an easily available class of compounds. In this study, we found that the decarboxylative aldol reaction of tertiary β-ketocarboxylic acids and trifluoropyruvates proceeded smoothly to yield the corresponding aldol products in high yields and with high diastereoselectivity in the presence of a tertiary amine catalyst. In this reaction, we efficiently constructed a quaternary carbon center and an adjacent trifluoromethylated carbon center. This protocol was also extended to an enantioselective reaction with a chiral amine catalyst, and the desired product was obtained with up to 73% enantioselectivity.

Catalyst-Free Decarboxylative Fluorination of Tertiary β-Keto Carboxylic Acids

Decarboxylative fluorination of tertiary β-keto carboxylic ­acids was performed using an electrophilic fluorinating reagent. The reaction proceeded in the absence of a catalyst or base to yield the corresponding α-fluoroketones with tertiary fluorocarbons in good to high yields. Considering that the α-fluorination of asymmetrical ketones ­often causes problems with the regioselectivity between the α- and α′-positions, this method could be a good alternative to the α-fluorination of simple ketones for the synthesis of tertiary fluoroketones.

Rh(III)-Catalyzed Acceptorless Dehydrogenative Coupling of (Hetero)arenes with 2-Carboxyl Allylic Alcohols.

Rhodium(III)-catalyzed C-H activation of (hetero)arenes and redox-neutral coupling with 2-carboxyl allylic alcohols has been realized for the construction of β-aryl ketones. This reaction occurred efficiently at a relatively low catalyst loading via initial dehydrogenative alkylation to give a β-keto carboxylic acid, followed by decarboxylation.

Enantioselective decarboxylative chlorination of \u03b2-ketocarboxylic acids

Stereoselective halogenation is a highly useful organic transformation for multistep syntheses because the resulting chiral organohalides can serve as precursors for various medicinally relevant derivatives. Even though decarboxylative halogenation of aliphatic carboxylic acids is a useful and fundamental synthetic method for the preparation of a variety of organohalides, an enantioselective version of this reaction has not been reported. Here we report a highly enantioselective decarboxylative chlorination of β-ketocarboxylic acids to obtain α-chloroketones under mild organocatalytic conditions. The present method is also applicable for the enantioselective synthesis of tertiary α-chloroketones. The conversions of the resulting α-chloroketones into α-aminoketones and α-thio-substituted ketones via SN2 reactions at the tertiary carbon centres are also demonstrated. These results constitute an efficient approach for the synthesis of chiral organohalides and are expected to enhance the availability of enantiomerically enriched chiral compounds with heteroatom-substituted chiral stereogenic centres.

Reactivity of Ketyl and Acetyl Radicals from Direct Solar Actinic Photolysis of Aqueous Pyruvic Acid.

The variable composition of secondary organic aerosols (SOA) contributes to the large uncertainty for predicting radiative forcing. A better understanding of the reaction mechanisms leading to aerosol formation such as for the photochemical reaction of aqueous pyruvic acid (PA) at λ ≥ 305 nm can contribute to constrain these uncertainties. Herein, the photochemistry of aqueous PA (5-300 mM) continuously sparged with air is re-examined in the laboratory under comparable irradiance at 38° N at noon on a summer day. Several analytical methods are employed to monitor the time series of the reaction, including (1) the derivatization of carbonyl (C═O) functional groups with 2,4-dinitrophenylhydrazine (DNPH), (2) the separation of photoproducts by ultrahigh pressure liquid chromatography (UHPLC) and ion chromatography (IC) coupled to mass spectrometry (MS), (3) high resolution MS, (4) the assignment of 1H NMR and 13C gCOSY spectroscopic features, and (5) quantitative 1H NMR. The primary photoproducts are 2,3-dimethyltartaric acid and unstable 2-(1-carboxy-1-hydroxyethoxy)-2-methyl-3-oxobutanoic acid, a polyfunctional β-ketocarboxylic acid with eight carbons (C8) that quickly decarboxylates into 2-hydroxy-2-((3-oxobutan-2-yl)oxy)propanoic acid. Kinetic isotope effect studies performed for the first time for this system reveal the existence of tunneling during the initial loss of PA. Thus, the KIEs support a mechanism initiated by photoinduced proton coupled electron transfer (PCET). Measured reaction rates at variable initial [PA]0 were used to calculate the sum of the quantum yields for the products, which displays a hyperbolic dependence: ∑Φproduct = 1.99 [PA]0/(113.2 + [PA]0). The fast photochemical loss of aqueous PA with an estimated lifetime of 21.7 min is interpreted as a significant atmospheric sink for this species. The complexity of these aqueous phase pathways indicates that the solar photochemistry of an abundant α-ketocarboxylic acid can activate chemical processes for SOA formation.

Structural Determination of (-)-SCH 64874 and Hirsutellomycin by Semisynthesis.

The structure of a C2-symmetric epidithiodiketopiperazine alkaloid, SCH 64874, was determined by semisynthesis. The relative stereochemistry of the β-hydroxy carboxylic acid chain having three chiral centers was determined by comparison of the NMR data of the four possible diastereomeric β-hydroxy carboxylic acid fragments with those of SCH 64874. Condensation of the (-)-deacetylaranotin core with two enantiomeric β-hydroxy carboxylic acids revealed the relative stereochemistry of SCH 64874. The relative stereochemistry of the β-keto carboxylic acid chain of the analogous alkaloid hirsutellomycin was determined in a stepwise manner. The C4'-C6' syn relationships were predicted by comparing the NMR data of the corresponding ester fragments with that of hirsutellomycin. The relative stereochemistry of the whole molecule, including the epimerizable C2' stereocenter, was determined by introduction of four possible side chains into the bisdethiodi(methylthio)deacetylaranotin core. We found that the stereochemistry of C2' converged with that of the thermodynamically stable form influenced by the core structure.

Nickel-Catalyzed CO2 Rearrangement of Enol Metal Carbonates for the Efficient Synthesis of β-Ketocarboxylic Acids.

4-Methylene-1,3-dioxolan-2-ones underwent oxidative addition of a Ni0 catalyst in the presence of Me2 Al(OMe), followed by a coupling reaction with alkynes, to form δ,ϵ-unsaturated β-ketocarboxylic acids with high regio- and stereoselectivity. The reaction proceeds by [1,3] rearrangement of an enol metal carbonate intermediate and the formal reinsertion of CO2 .

Facile Synthesis of Spirocyclic Lactams from β-Keto Carboxylic Acids.

A facile synthesis of spirocyclic lactams starting from β-keto carboxylic acids via a one-pot cascade reaction involving a Curtius rearrangement and an intramolecular nucleophilic addition of the enol carbon to the isocyanate intermediate is reported. The same conditions have also been used for the generation of fused cyclic lactams with similar good yields. The synthetic value of this method has been demonstrated by efficient synthesis of tetracyclic spirolactam 8 and pentacyclic spirolactam 9.