Simple Carbonyl Research Articles

Ketyl Radical Enabled Synthesis of Oxetanes

AbstractOxetanes, 4-membered oxygen-containing heterocycles, were identified to have pharmaceutical applications after the discovery of the chemotherapeutic drug taxol (Paclitaxel) and its analogues. Furthermore, oxetanes have been identified as bioisosteres for several common functional groups and are present in a number of natural products. However, oxetanes are one of the least common oxygen-containing heterocycles in active pharmaceutical ingredients on the market, which can be attributed, in part, due to challenges with their synthesis. Previous strategies rely on nucleophilic substitutions or [2+2]-cycloadditions, but are limited by the stepwise buildup of starting material and limitations in scope resulting from requirements for activated substrates. To address these limitations, we envisioned activating simple carbonyls to their corresponding α-oxy iodides to promote ketyl radical formation. These radicals can then undergo atom-transfer radical addition with alkenes followed by one-pot nucleophilic substitution to produce oxetanes. Herein, we present a proof-of-principle of this strategy in which fluoroalkyl carbonyls are successfully converted into the corresponding fluoroalkyl oxetanes.

A Review of Synthetic Application of Homogeneous, Heterogenised‐Homogeneous, and Microwave‐Assisted Catalytic Carbonylation of Selected Substrates

AbstractCatalytic carbonylation has gained a lot of interest over the past 20 years. It produced various pharmaceuticals, agrochemicals, and intermediates that can made through this process. The carbonylation process is the most straightforward method to insert CO into any organic substrate using a simple carbonyl source, i. e., CO gas. Apart from gaseous CO, many techniques have devised for producing CO in situ using surrogates such as HCOOH, DMF, Formic acid, Phenyl Formate, Oxalic acid, and Chloroform. Several carbonylation methods, such as aminocarbonylation, alkoxycarbonylation, double carbonylation, and oxidative carbonylation, provide viable and appealing substitutes for conventional synthetic methods on a commercial or laboratory scale. Many recent studies focus on catalyst‐product separation, catalyst recoverability, and reusability in these reactions. Therefore, advancements in using different approaches, such as supported liquid phase catalysis and biphasic catalysis, to anchor homogeneous catalysts are becoming increasingly important. These carbonylation methods are easy to use, cost‐effective, and do not require ligands. They also produce excellent yields of the products necessary. Using phosphine ligands has drawbacks, including high work‐up costs, laborious work‐up techniques, and sensitivity to air and moisture. Several phosphine‐free carbonylation pathways offer affordable and straightforward ways to accomplish these changes without phosphine ligands. This review summarizes the synthetic application of homogeneous and immobilized catalysts in producing carboxylic acid derivatives and heterocycles that have medicinal properties.

Temperature-Dependent Kinetics of the Reactions of the Criegee Intermediate CH2OO with Hydroxyketones.

Though there is a growing body of literature on the kinetics of CIs with simple carbonyls, CI reactions with functionalized carbonyls such as hydroxyketones remain unexplored. In this work, the temperature-dependent kinetics of the reactions of CH2OO with two hydroxyketones, hydroxyacetone (AcOH) and 4-hydroxy-2-butanone (4H2B), have been studied using a laser flash photolysis transient absorption spectroscopy technique and complementary quantum chemistry calculations. Bimolecular rate constants were determined from CH2OO loss rates observed under pseudo-first-order conditions across the temperature range 275-335 K. Arrhenius plots were linear and yielded T-dependent bimolecular rate constants: kAcOH(T) = (4.3 ± 1.7) × 10-15 exp[(1630 ± 120)/T] and k4H2B(T) = (3.5 ± 2.6) × 10-15 exp[(1700 ± 200)/T]. Both reactions show negative temperature dependences and overall very similar rate constants. Stationary points on the reaction energy surfaces were characterized using the composite CBS-QB3 method. Transition states were identified for both 1,3-dipolar cycloaddition reactions across the carbonyl and 1,2-insertion/addition at the hydroxyl group. The free-energy barriers for the latter reaction pathways are higher by ∼4-5 kcal mol-1, and their contributions are presumed to be negligible for both AcOH and 4H2B. The cycloaddition reactions are highly exothermic and form cyclic secondary ozonides that are the typical primary products of Criegee intermediate reactions with carbonyl compounds. The reactivity of the hydroxyketones toward CH2OO appears to be similar to that of acetaldehyde, which can be rationalized by consideration of the energies of the frontier molecular orbitals involved in the cycloaddition. The CH2OO + hydroxyketone reactions are likely too slow to be of significance in the atmosphere, except at very low temperatures.

Olefination of aldehydes with alpha-halo redox-active esters

A simple and practical decarboxylative carbonyl olefination is described. This procedure explores the application of α-halo NHPI redox-active esters in organic chemistry.

Assessment of atmospheric levels of carbonyls in an urban environment of Argentina

It is well-documented that carbonyl compounds have adverse effects on human health. On the other hand, these oxygenated volatile organic compounds (OVOCs) are precursors of secondary pollutants such as tropospheric ozone or peroxy acetyl nitrate (PAN). In particular, formaldehyde, the simplest carbonyl, is the most abundant carbonyl in the air generated from the degradation of most volatile organic compounds (VOCs). This work presents for the first time the characterization and determination of levels of carbonyl compounds by passive monitoring performed from April–December 2021 in the city of Córdoba, Argentina, the second most populated Mediterranean city located in the center of the country. Annual concentrations, considering the 11 carbonyls measured, were in the range of 0.13–8.75 μgm−3. Formaldehyde and acetaldehyde were the carbonyls detected in the highest annual average concentrations of 4.44 ± 1.75 μgm−3 and 3.85 ± 1.44 μgm−3, respectively. These carbonyls represent a contribution of around 40–57% on total carbonyls measured. Statistical analysis to determine significant differences and Pearson correlations with the meteorological parameters were performed. Spring and summer were found to be the seasons with the highest carbonyl concentration linked to forest fire episodes, especially in springtime. The values for the C1/C2 and C2/C3 ratios showed that sources of carbonyl formation are anthropogenic. In addition, the prop-Equiv concentration was determined, where formaldehyde and acetaldehyde were the main producers of tropospheric ozone. The ozone formation potential (OFP) showed that spring and summer are the seasons where carbonyls contribute to the formation of tropospheric ozone.This study represents a first approach of the carbonyl concentration in the city and of the influence of meteorological parameters on the behavior of carbonyls.

Aldehydes as O-Nucleophiles in Cobalt Hydride Hydrogen Atom Transfer Catalysis: Overriding the Innate Somophilicity

In metal hydride-catalyzed alkene hydrofunctionalization reactions via hydrogen atom transfer, simple carbonyl groups have been well-recognized as good somophiles at the carbon for C-C bond formation. Here we report an alternative pathway exploring the carbonyl as an O-nucleophile to make new C-O bonds during the CoH-catalyzed oxidative cyclization of alkenyl aldehydes. This reaction provides a rapid, mild, modular, and stereoselective (up to >20:1) entry to saturated O-heterocycles via nucleophilic trapping of an in situ-formed oxocarbenium intermediate. The key to overriding the carbonyl's innate somophilicity was found to be promoting the formation of organocobalt species and suppressing the radical exchange.

α-Amination of Carbonyl Compounds by Using Hypervalent Iodine-Based Aminating Reagents Containing a Transferable (Diarylmethylene)amino Group.

Hypervalent iodine-based aminating reagents containing a transferable (diarylmethylene)amino group can be used for the α-amination of simple carbonyl compounds such as esters, amides, and ketones in the presence of a lithium base. The (diarylmethylene)amino groups of the products can be readily modified, thus providing access to primary amines and diarylmethylamines. The developed method features transition-metal-free conditions and a simple one-pot procedure without the need to prepare enolate equivalents separately, thus offering a general and practical approach to the synthesis of a wide variety of α-amino carbonyl compounds. Experimental mechanistic investigations indicate that this amination proceeds through a unique radical coupling of an α-carbonyl radical with an iminyl radical; they are generated through a single-electron transfer between a lithium enolate and the hypervalent iodine reagent.

Chromium-catalyzed transfer hydrogenation of aromatic aldehydes facilitated by a simple metal carbonyl complex

We communicate a simple method for the transfer hydrogenation of aromatic aldehydes in i-PrOH effected by the cost-effective and easy-to-handle [Cr(CO)6]. The reactions are readily carried in Ar-flushed tubes without further need of special equipment. Functional groups are widely tolerated and, if desired, the catalytic transformations can be further promoted through the addition of trimethylamine N-oxide (TMAO). This paves the way for processing thermo-labile substrates under mild reaction conditions. In addition, the introduced method is suitable for the deuteration of benzyl alcohol derivatives.

Merging Carbonyl Addition with Photocatalysis.

The carbonyl group stands as a fundamental scaffold and plays a ubiquitous role in synthetically important chemical reactions in both academic and industrial contexts. Venerable transformations, including the aldol reaction, Grignard reaction, Wittig reaction, and Nozaki-Hiyama-Kishi reaction, constitute a vast and empowering synthetic arsenal. Notwithstanding, two-electron mechanisms inherently confine the breadth of accessible reactivity and topological patterns.Fostered by the rapid development of photoredox catalysis, combing well-entrenched carbonyl addition and radicals can harness several unique and increasingly sustainable transformations. In particular, unusual carbon-carbon and carbon-heteroatom disconnections, which are out of reach of two-electron carbonyl chemistry, can be conceived. To meet this end, a novel strategy toward the utilization of simple carbonyl compounds as intermolecular radical acceptors was developed. The reaction is enabled by visible-light photoredox-initiated hole catalysis. In situ Brønsted acid activation of the carbonyl moiety prevents β-scission from occurring. Furthermore, this regioselective alkyl radical addition reaction obviates the use of metals, ligands, or additives, thus offering a high degree of atom economy under mild conditions. On the basis of the same concept and the work of Schindler and co-workers, carbonyl-olefin cross-metathesis, induced by visible light, has also been achieved, leveraging a radical Prins-elimination sequence.Recently, dual chromium and photoredox catalysis has been developed by us and Kanai, offering a complementary approach to the revered Nozaki-Hiyama-Kishi reaction. Leveraging the intertwined synergy between light and metal, several radical-to-polar crossover transformations toward eminent molecular motifs have been developed. Reactions such as the redox-neutral allylation of aldehydes and radical carbonyl alkylation can harvest the power of light and enable the use of catalytic chromium metal. Overall, exquisite levels of diastereoselectivity can be enforced via highly compact transition states. Other examples, such as the dialkylation of 1,3-dienes and radical carbonyl propargylation portray the versatile combination of radicals and carbonyl addition in multicomponent coupling endeavors. Highly valuable motifs, which commonly occur in complex drug and natural product architectures, can now be accessed in a single operational step. Going beyond carbonyl addition, seminal contributions from Fagnoni and MacMillan preconized photocatalytic HAT-based acyl radical formation as a key aldehyde valorization strategy. Our group articulated this concept, leveraging carboxy radicals as hydrogen atom abstractors in high regio- and chemoselective carbonyl alkynylation and aldehyde trifluoromethylthiolation.This Account, in addition to the narrative of our group and others' contributions at the interface between carbonyl addition and radical-based photochemistry, aims to provide core guiding foundations toward novel disruptive synthetic developments. We envisage that extending radical-to-polar crossovers beyond Nozaki-Hiyama-Kishi manifolds, taming less-activated carbonyls, leveraging multicomponent processes, and merging single electron steps with energy-transfer events will propel eminent breakthroughs in the near future.

Performance evaluation and mechanism analysis of halotolerant bacterial strains and cerium oxide nanoparticle to degrade Benzo[a]pyrene

The key source for Benzo[a]pyrene (B[a]P) and various other Polyaromatic hydrocarbon (PAH) is partial ignition of crude oil, and several other by-products of petroleum and its components. Moreover, industries that utilises coal and further when coal is burnt during various natural and anthropogenic activities also leads B[a]P to cause great threat to the environment by getting mixed in the air. The PAH compounds are highly enduring, bio-toxic, cytotoxic, and cancerous. The aqua-phobic property of these hydrocarbons makes these stable and unreactive. Among various other environments marine environment is under great threat due to various anthropogenic activities like an oil leak accidents and industrial emission, specifically from factories. Due to the rapidly varying industrial trends the harmful pollutants get released into the saline and hypersaline environment. Thus, it is the need of the hour to find a way to degrade these toxic chemicals in the environment. Many physicochemical techniques to remediate B[a]P include chemical oxidation, photo-dissociation, burning, landfilling, volatilisation, and adsorption. The by-products from all the techniques cause severe harm to the environment. Here we describe the Benzo[a]pyrene degradation by employing two techniques, first through biodegradation and second using cerium oxide nanoparticles synthesised employing sol gel method. This current work aims to compare the degradation of B[a]P using both bacterial cocultures (Biological) and CeO2 nanoparticle (Chemical method). Mechanism of Biodegradation of B[a]P is proposed to take place by the hydroxylation through oxidation of aromatic ring, tracked by cis-dihydrodiol intermediates formation, finally resulting in cleavage to simple alcohols, carbonyl compounds, phenolics and carboxylic acids. The interpretation of the Mass spectrum also revealed some non-reported low molecular weight compounds like cyclopentadienyl, cyclobutadienyl cations, diacetylene and DHP, along with O-Cresol, Benzaldehyde, Benzoic acid, Naphthalene, Naphthol, Diacetylene and Dihydropyran. On comparing with biodegradation, the degradation using cerium oxide nanoparticles gave many simple, and fewer toxic by-products. • Halotolerant B[a]P degrading bacterial strains were isolated from marine environment. • Strains were screened and optimised for enhanced degradation of B[a]P. • Synthesis (citrate–nitrate sol–gel route) & characterisation of CeO 2 nanoparticles. • Degradation of benzo[a]pyrene of CeO 2 NP in the visible light. • Comparative study on bio and CeO 2 nanoparticle B[a]P degradation.

Theoretical study of the effect of water clusters on the enol content of acetone as a model for understanding the effect of water on enolization reaction

The enolization of simple carbonyl compounds is a key reaction for many chemical and biochemical processes. Numerous theoretical and experimental studies have been done to probe aspects of the mechanism of this reaction. In this work, the effect of small water clusters, (H2O)n, n = 1–9, on the enol content of acetone has been investigated by using density functional theory calculations at the M06 level of theory in the gas and solution phases. The calculations indicated that the formation of hydrogen-bonded assemblies between water clusters and both tautomers of acetone affect the enolization reaction. Among them, the trimeric water cluster has the highest binding energy difference (ΔEb) in the solution phase and greatly shifts the equilibrium in the favor of the enol form. The results also show that under this condition, the enol content of acetone increased with decreasing polarity of the solvent. The practical conclusion of this study is that the enol content of carbonyl compounds can be maximized only by addition of a defined amount of water.

Organocatalyzed Oxa-Diels–Alder Reactions: Recent Progress

AbstractThe oxa-Diels–Alder reaction is a straightforward, atom-economical process for the construction of six-membered oxacycles, which are privileged structures due to their very common occurrence in several pharmaceuticals and natural products. As with many other asymmetric transformations, organocatalysis provides an elegant pathway to their synthesis via [4+2] annulation under mild reaction conditions. The oxa-Diels–Alder reaction utilizes either an α,β-unsaturated carbonyl as an oxa-diene with a suitable dienophile or a simple carbonyl as a dienophile with other dienes. A range of organocatalysts has been explored in the past decade to execute this strategy. The catalysts induce stereoselectivities via two basic reactivities: (1) The formation of chiral intermediates, or (2) selectively activating suitable reactants via a transition state. The present short review compiles organocatalyzed asymmetric oxa-Diels–Alder reactions published over the last ten years, along with detailed discussions on mechanistic approaches.1 Introduction2 Catalysis through Covalent Activation2.1 N-Heterocyclic Carbenes2.2 Amines2.3 Isothiourea Catalysis2.4 Phosphines3 Catalysis through Non-Covalent Activation3.1 Bifunctional Amines3.2 Brønsted Acids3.3 Guanidines4 Multicatalysis through Both Covalent and Non-Covalent Activation5 Conclusion

Towards an Understanding of Halide Interactions with the Carbonyl-Containing Molecule CH3 CHO.

The anion photoelectron spectra of Cl- ⋅⋅⋅CD3 CDO, Cl- ⋅⋅⋅(CD3 CDO)2 , Br- ⋅⋅⋅CH3 CHO, and I- ⋅⋅⋅CH3 CHO are presented with electron stabilisation energies of 0.55, 0.93, 0.48, and 0.40 eV, respectively. Optimised geometries of the singly solvated species featured the halide appended to the CH3 CHO molecule in-line with the electropositive portion of the C=O bond and having binding energies between 45 and 52 kJ mol-1 . The doubly solvated Cl- ⋅⋅⋅(CH3 CHO)2 species features asymmetric solvation upon the addition of a second CH3 CHO molecule. Theoretical detachment energies were found to be in excellent agreement with experiment, with comparisons drawn between other halide complexes with simple carbonyl molecules.

Carbonyl Desaturation: Where Does Catalysis Stand?

There is a strong parallel between simple alcohol oxidation and carbonyl desaturation from both strategic and tactical vantage points. As they both seek to extract hydrogen from an organic substrate, they are deceptively simple looking transformations that have been addressed over the past 70+ years through stoichiometric means. The past decade has seen an intensifying level of interest in rendering both of these simple reactions catalytic. In this Perspective, recent advances from the past 5 years are highlighted featuring both transition-metal-catalyzed and metal-free approaches to carbonyl desaturation. Through a historical overview and a detailed look at each of these new developments, we seek to address the question of in what context a catalytic strategy emerges as ideal.

A single benzene fluorescent probe for efficient formaldehyde sensing in living cells using glutathione as an amplifier

Formaldehyde (FA), a simple reactive carbonyl molecule, is endogenously produced in the cell at various physiological condition. At elevated level, FA causes severe cell toxicity as well as damage in macromolecules such proteins and DNA. For detecting FA in living cell, we identify a small but effective fluorescent turn on probe comprising single benzene-based orothophenylenediamine compound. Further study reveals that carboxylic group in orothophenylenediamine plays the important role in enhancing fluorescent signal than another electron withdrawing group. It is even interesting to observe the occurrence of fluorescent enhancement in glutathione (GSH) environment which is generally abundant in every cell. Our probe enables to detect FA over other bio-analytes efficiently with limit of detection of 123 nM and 355-fold of enhancement in cellular mimicking conditions. Moreover, this probe could be useful in discriminating cell that has high concentration of FA as well as GSH.

(Carbonyl)oxyalkyl linker-based amino acid prodrugs of the HIV-1 protease inhibitor atazanavir that enhance oral bioavailability and plasma trough concentration

We describe the design, synthesis and pharmacokinetic (PK) evaluation of a series of amino acid-based prodrugs of the HIV-1 protease inhibitor atazanavir (1) derivatized on the pharmacophoric secondary alcohol using a (carbonyl)oxyalkyl linker. Prodrugs of 1 incorporating simple (carbonyl)oxyalkyl-based linkers and a primary amine in the promoiety were found to exhibit low chemical stability. However, chemical stability was improved by modifying the primary amine moiety to a tertiary amine, resulting in a 2-fold enhancement of exposure in rats following oral dosing compared to dosing of the parent drug 1. Further refinement of the linker resulted in the discovery of 22 as a prodrug that delivered the parent 1 to rat plasma with a 5-fold higher AUC and 67-fold higher C24 when compared to oral administration of the parent drug. The PK profile of 22 indicated that plasma levels of this prodrug were higher than that of the parent, providing a more sustained release of 1 invivo.

Application of High-Resolution Mass Spectrometry and a Theoretical Model to the Quantification of Multifunctional Carbonyls and Organic Acids in e-Cigarette Aerosol.

Electronic (e-) cigarette aerosol (particle and gas) is a complex mixture of chemicals, of which the profile is highly dependent on device operating parameters and e-liquid flavor formulation. The thermal degradation of the e-liquid solvents propylene glycol and glycerol often generates multifunctional carbonyls that are challenging to quantify because of unavailability of standards. We developed a theoretical method to calculate the relative electrospray ionization sensitivities of hydrazones of organic acids and carbonyls with 2,4-dinitrophenylhydrazine based on their gas-phase basicities (ΔGdeprotonation). This method enabled quantification by high-performance liquid chromatography-high-resolution mass spectrometry HPLC-HRMS in the absence of chemical standards. Accurate mass and tandem multistage MS (MSn) were used for structure identification of vaping products. We quantified five simple carbonyls, six hydroxycarbonyls, four dicarbonyls, three acids, and one phenolic carbonyl in the e-cigarette aerosol with Classic Tobacco flavor. Our results suggest that hydroxycarbonyls, such as hydroxyacetone, lactaldehyde, and dihydroxyacetone can be significant components in e-cigarette aerosols but have received less attention in the literature and have poorly understood health effects. The data support the radical-mediated e-liquid thermal degradation scheme that has been previously proposed and emphasize the need for more research on the chemistry and toxicology of the complex product formation in e-cigarette aerosols.

Simple manganese carbonyl catalyzed hydrogenation of quinolines and imines

Manganese-catalyzed hydrogenation of unsaturated molecules has made tremendous progresses recently benefiting from non-innocent pincer or bidentate ligands for manganese. Herein, we describe the hydrogenation of quinolines and imines catalyzed by simple manganese carbonyls, Mn2(CO)10 or MnBr(CO)5, thus eliminating the prerequisite pincer-type or bidentate ligands.

Analysis of e-liquids for electronic cigarettes using GC-IMS/MS with headspace sampling

Electronic cigarettes (e-cigarettes) are continuously increasing in popularity due to being considered healthier compared with traditional cigarettes. Based on the European directive 2014/40/EU [1] the German legislation restricts the usage of potential harmful substances in these tobacco related products [2,3]. The aim of this work was to establish a method for the detection and quantification of selected substances covered by the above regulation. For this purpose, one-of-a-kind gas chromatograph with ion mobility spectrometer (GC-IMS) was used. Instrument was parallelly coupled with conventional chromatograph equipped with quadrupole mass spectrometer (GC-MS). Headspace (HS) was used as a sample preparation technique.During initial tests both systems were correlated by using a mixture of simple carbonyl compounds. The identification of the selected analytes was performed by mass spectrometry and calibration curves for the quantification were recorded. For all tested substances the limit of detection (LOD) and limit of quantification (LOQ) were determined. The LOD ranges are from 8 to 70 μg/L, the LOQ are from 25 to 200 μg/L. For testing the usability of the developed method 20 samples of commercially available refills for e-cigarettes (e-liquids), produced in Germany and Poland, were analyzed. Substances listed in the directive were found in all samples. In two of them an according to the regulations forbidden substance (estragole) was detected.

Keto–Enol Tautomerization as a First Step in Hydrogenation of Carbonyl Compounds

Keto–enol tautomerization of carbonyl compounds to their enol form is theoretically predicted to enable a low-barrier pathway for hydrogenation of normally very stable C═O bond. In the scope of this anticipated mechanism, the reaction can proceed via two consecutive steps, including the formation of enol followed by an H insertion into the enolic C═C bond, and exhibits a lower activation barrier than the direct H insertion into the carbonyl group. Here, we present an experimental study on atomistic level details of hydrogenation of a simple carbonyl compound acetophenone over Pt(111) providing experimental evidence that keto–enol tautomerization plays a crucial role in this reaction. By employing a combination of spectroscopic and imaging techniques, we show that acetophenone forms ketone–enol dimers, in which the normally unstable form of enol is stabilized by H-bonding with the carbonyl group of the neighboring acetophenone molecule. These ketone–enol dimers can attach an H atom to form a reaction inter...