Carbonyl-containing Molecules Research Articles

Carbonylation Reactions at Carbon-Centered Radicals with an Adjacent Heteroatom.

Heteroatoms are essential to living organisms and present in almost all molecules with medicinal usage. The catalytic functionalization at the carbon-centered radical with an adjacent heteroatom provides an effective way to value added moiety while retaining the unique physicochemical and pharmacological properties of heteroatoms, which can promote the development of pharmaceutical and fine chemical production. Carbonylative transformation was discovered nearly a century ago which is an efficient method for the synthesis of carbonyl-containing molecules with potent applications in both industry and academia. Despite numerous advances in new reaction development, carbonylative transformation involving adjacent heteroatom carbon radical remain a subject that deserves to be discussed. In this minireview, we systematically summarized and discussed the recent advances in carbonylative transformations involving carbon-centered radicals with an adjacent heteroatom, including oxygen (O), nitrogen (N), phosphorus (P), silicon (Si), sulfur (S), boron (B), fluorine (F), and chlorine (Cl). The related reaction mechanism was also discussed.

Copper-Catalyzed Carbonylation Reactions: A Personal Account

AbstractCarbonylation reactions have been widely used to construct carbonyl-containing molecules or carbon enhancement reactions, which are mostly catalyzed by noble metals (Pd, Rh, Ru, Ir). In this review, we introduce the copper-catalyzed carbonylation reactions that have been developed in our group. Diverse reactions have been developed using various substrates, including the carbonylation of C–H activated alkanes, the difunctionalization of unsaturated C–C bonds, and the carbonylation of alkyl halides via the radical pathway.1 Introduction2 Cu-Catalyzed Carbonylation of C(sp 3)–H Bonds3 Cu-Catalyzed Carbonylative Difunctionalization of Unsaturated Bonds4 Cu–X (H or B) Mediated Acylation of Unsaturated Bonds with Electrophiles5 Cu–X (H or B) Mediated Carbonylation of Unsaturated Bonds6 Cu-Catalyzed Carbonylation of Alkyl Halides7 Other Types of Copper-Catalyzed Carbonylation Reactions8 Conclusion and Outlook

Pd-catalyzed CO-free double carbonylation for the synthesis of 1,4-ketoesters with Mo(CO)6 as the carbonyl source.

An unprecedented Pd-catalyzed CO-free double carbonylation using Mo(CO)6 as a safe carbonyl source for the efficient synthesis of 1,4-ketoesters in an atom- and step-economic manner has been developed. The current method features operational safety, a wide substrate range, good functional group compatibility and easy scale-up. The application of carbonylation using a safe carbonyl source for the synthesis of biologically and synthetically useful carbonyl-containing molecules is underway in our lab.

Excited-State Dynamics during Primary C-I Homolysis in Acetyl Iodide Revealed by Ultrafast Core-Level Spectroscopy.

In typical carbonyl-containing molecules, bond dissociation events follow initial excitation to nπC═O* states. However, in acetyl iodide, the iodine atom gives rise to electronic states with mixed nπC═O* and nσC-I* character, leading to complex excited-state dynamics, ultimately resulting in dissociation. Using ultrafast extreme ultraviolet (XUV) transient absorption spectroscopy and quantum chemical calculations, we present an investigation of the primary photodissociation dynamics of acetyl iodide via time-resolved spectroscopy of core-to-valence transitions of the I atom after 266 nm excitation. The probed I 4d-to-valence transitions show features that evolve on sub-100-fs time scales, reporting on excited-state wavepacket evolution during dissociation. These features subsequently evolve to yield spectral signatures corresponding to free iodine atoms in their spin-orbit ground and excited states with a branching ratio of 1.1:1 following dissociation of the C-I bond. Calculations of the valence excitation spectrum via equation-of-motion coupled cluster with single and double substitutions (EOM-CCSD) show that initial excited states are of spin-mixed character. From the initially pumped spin-mixed state, we use a combination of time-dependent density functional theory (TDDFT)-driven nonadiabatic ab initio molecular dynamics and EOM-CCSD calculations of the N4,5 edge to reveal a sharp inflection point in the transient XUV signal that corresponds to rapid C-I homolysis. By examining the molecular orbitals involved in the core-level excitations at and around this inflection point, we are able to piece together a detailed picture of C-I bond photolysis in which d → σ* transitions give way to d → p excitations as the bond dissociates. We also report theoretical predictions of short-lived, weak 4d → 5d transitions in acetyl iodide, validated by weak bleaching in the experimental transient XUV spectra. This joint experimental-theoretical effort has thus unraveled the detailed electronic structure and dynamics of a strongly spin-orbit coupled system.

Tuning solvent electrostatic environment of amide carbonyls as prototypical peptide backbones

Interactions of amide linkages in the peptide backbone with solvent play key roles in the folding and stability of proteins. The strength of these effects can be quantitatively characterized in terms of solvent electric fields on the peptide, a useful framework that has been applied to understand various non-covalent solvent-solute interactions. We demonstrate how the solvent-induced electric field on carbonyl-containing molecules, including peptides, can be experimentally measured using the vibrational Stark effect (VSE).

Untargeted detection of the carbonyl metabolome by chemical derivatization and liquid chromatography-tandem mass spectrometry in precursor ion scan mode: Elucidation of COVID-19 severity biomarkers

Metabolomics (both targeted and untargeted) has become the gold standard in biomarker discovery. Whereas targeted approaches only provide information for the selected markers, thus hampering the determination of out-of-the-box markers, the common bottleneck of untargeted metabolomics is the identification of detected biomarkers. In this study, we developed a strategy based on derivatization and LC-MS/MS detection in a precursor ion scan for the untargeted determination of a specific part of the metabolome (carbonyl-containing metabolites). The usefulness of this guided metabolomics approach has been demonstrated by elucidating carbonyl-containing biomarkers of COVID-19 severity. First, the LC-MS/MS behavior of 63 model compounds after O-benzylhydroxylamine derivatization was studied. A precursor ion scan of m/z 91 was selected as a suitable approach for the untargeted detection of carbonyl-containing metabolites. The method was able to detect ≈300 potential carbonyl-containing molecules in plasma, including mono-/di-/tricarbonylic compounds with satisfactory intra-day and inter-day repeatability and RSDs commonly <15%. Additionally, the semiquantitative nature of the precursor ion scan method was confirmed by comparison with a fully validated targeted method. The application of the guided metabolomics method to COVID-19 plasma samples revealed the presence of four potential COVID-19 severity biomarkers. Based on their LC-MS/MS behavior, these biomarkers were elucidated as 2-hydroxybutyrate, 2,3-dihydroxybutyrate, 2-oxobutyrate and 2-hydroxy-3-methylbutyrate. Their structures were confirmed by comparison with reference materials. The alterations of these biomarkers with COVID-19 severity were confirmed by a target analysis of a larger set of samples. Our results confirm that guided metabolomics is an alternative approach for the untargeted detection of selected families of metabolites; this approach can accelerate their elucidation and provide new perspectives for the establishment of health/disease biomarkers.

Recent advances in Cu-catalyzed carbonylation with CO

Transition metal-catalyzed carbonylation has emerged as a powerful and versatile strategy for the efficient construction of complicated carbonyl-containing molecules from simple chemical feedstocks in the past decades.

Two transition-metal-modified Nb/W mixed-addendum polyoxometalates for visible-light-mediated aerobic benzylic C–H oxidations

The visible-light-induced selective oxidation of ubiquitous C–H bonds into valuable C=O bonds under aerobic conditions is one of the most attractive approaches for the construction of carbonyl-containing molecules. In this work, two transition metal-containing Nb/W mixed-addendum POMs dimers with the formula of K2Na2H5[(Fe(H2O)4)3(P2W15Nb3O62)2]·24H2O (POM[Fe]) and K2Na3H4[(Cr(H2O)4)3(P2W15Nb3O62)2]·32H2O (POM[Cr]) have been synthesized and characterized by various analytical and spectral techniques. POM[Fe] was proved to be an efficient photocatalyst for benzylic C–H oxidation under visible light and using oxygen as an oxidant to produce the corresponding carbonyl complex in good yields. A plausible mechanism involving superoxide radical was proposed for the catalytic reaction. POM[Fe] showed good reusability in the recycling experiments. IR spectroscopy and XRD analysis indicate that POM[Fe] can retain its integrity after catalysis.

DMF as CO Surrogate in Carbonylation Reactions: Principles and Application to the Synthesis of Heterocycles

Transition metal-catalyzed carbonylation reactions have emerged as one of the most relevant synthetic approaches for the preparation of carbonyl-containing molecules. The most commonly used protocol for the insertion of a carbonyl moiety is the use of carbon monoxide (CO) but, due to its toxic and explosive nature, this process is not suitable at an industrial scale. More recently, the chemistry of CO surrogates has received large attention as a way to use less expensive and more environmentally friendly methods. Among the various CO surrogates, N,N-dimethylformamide (DMF) has been paid greater attention due to its low cost and easy availability. This mini-review gives appealing insights into the application of DMF as a CO surrogate in metal-catalyzed carbonylations; in particular, in the first part we will give a general state of the art of these reactions for the preparation of carbonyl-containing molecules; then, we will take into account all the various synthetic approaches for the metal-catalyzed carbonylative synthesis of heterocycles using DMF as a CO surrogate. Each protocol has been discussed critically in order to screen the best synthetic method and to offer perspective on trends and future directions in this field.

Machine Learning for Functional Group Identification in Vibrational Spectroscopy: A Pedagogical Lab for Undergraduate Chemistry Students

Techniques from the branch of artificial intelligence known as machine learning (ML) have been applied to a wide range of problems in chemistry. Nonetheless, there are very few examples of pedagogical activities to introduce ML to chemistry students in the chemistry education literature. Here we report a computational activity that introduces undergraduate physical chemistry students to ML in the context of vibrational spectroscopy. In the first part of the activity, students use ML binary classification algorithms to distinguish between carbonyl-containing and noncarbonyl-containing molecules on the basis of their infrared absorption spectra. In the second part of the activity, students test modifications to this basic analysis including different analysis parameters, different ML algorithms, and different test data sets. In a final extension of the activity, students implement a multiclass classification to predict whether carbonyl-containing molecules contain a ketone, a carboxylic acid, or another carbonyl group. This activity is designed to introduce students both to the basic workflow of a ML classification analysis and to some of the ways in which ML analyses can fail. We provide a comprehensive handout for the activity, including theoretical background and a detailed protocol, as well as data sets and code to implement the exercise in Python or Mathematica. This activity is designed as a standalone exercise for physical chemistry lab classes but can also be integrated with courses or modules on vibrational spectroscopy and computational chemistry. On the basis of student surveys, we conclude that this activity was successful in introducing students to applications of ML in chemistry.

Caveat when using ADC(2) for studying the photochemistry of carbonyl-containing molecules.

Several electronic-structure methods are available to study the photochemistry and photophysics of organic molecules. Among them, ADC(2) stands as a sweet spot between computational efficiency and accuracy. As a result, ADC(2) has recently seen its number of applications booming, in particular to unravel the deactivation pathways and photodynamics of organic molecules. Despite this growing success, we demonstrate here that care has to be taken when studying the nonradiative pathways of carbonyl-containing molecules, as ADC(2) appears to suffer from a systematic flaw.

Gem-Diol-Type Intermediate in the Activation of a Ketone on Sn-β Zeolite as Studied by Solid-State NMR Spectroscopy.

Lewis acid zeolites have found increasing application in the field of biomass conversion, in which the selective transformation of carbonyl-containing molecules is of particular importance due to their relevance in organic synthesis. Mechanistic insight into the activation of carbonyl groups on Lewis acid sites is challenging and critical for the understanding of the catalytic process, which requires the identification of reaction intermediates. Here we report the observation of a stable surface gem-diol-type species in the activation of acetone on Sn-β zeolite. 13 C, 119 Sn, and 13 C-119 Sn double-resonance NMR spectroscopic studies demonstrate that only the open Sn site ((SiO)3 Sn-OH) on Sn-β is responsible for the formation of the surface species. 13 C MAS NMR experiments together with density functional theory calculations suggest that the gem-diol-type species exhibits high reactivity and can serve as an active intermediate in the Meerwein-Ponndorf-Verley-Oppenauer (MPVO) reaction of acetone with cyclohexanol. The gem-diol-type species offers an energy-preferable pathway for the direct carbon-to-carbon hydrogen transfer between ketone and alcohol. The results provide new insights into the transformation of carbonyl-containing molecules catalyzed by Lewis acid zeolites.

β-Hydroxy-Stabilized Boron-Nitrogen Heterocycles Enable Rapid and Efficient C-Terminal Protein Modification.

Bioorthogonal chemistry has enabled the development of bioconjugates in physiological environments while averting interference from endogenous biomolecules. Reactions between carbonyl-containing molecules and alkoxyamines or hydrazines have experienced a resurgence in popularity in bioorthogonal chemistry owing to advances that allow the reactions to occur under physiological conditions. In particular, ortho-carbonyl-substituted phenylboronic acids (CO-PBAs) exhibit greatly accelerated rates of hydrazone and oxime formation via intramolecular Lewis acid catalysis. Unfortunately, the rate of the reverse reaction is also increased, yielding a kinetically less stable bioconjugate. When the substrate is a hydrazine derivative, an intramolecular reaction between the boronic acid and the hydrazone can lead to the formation of a heterocycle containing a boron-nitrogen bond. We have shown previously that α-amino hydrazides undergo rapid reaction with CO-PBAs to form highly stable, tricyclic products, and that this reaction is orthogonal to the popular azide-alkyne and tetrazine-alkene reactions. In this work, we explore a series of heteroatom-substituted hydrazides for their ability to form tricyclic products with two CO-PBAs, 2-formylphenylboronic acid (2fPBA), and 2-acetylphenylboronic acid (AcPBA). In particular, highly stable products were formed using β-hydroxy hydrazides and 2fPBA. C-Terminal β-hydroxy hydrazide proteins are available using conventional biochemical methods, which alleviates one of the difficulties with applications of bioorthogonal chemical reactions: site-specific incorporation of a reactive group into the biomolecular target. Using sortase-mediated ligation (SML), C-terminal threonine and serine hydrazides were appended to a model eGFP protein in high yield. Subsequent labeling with 2fPBA functionalized probes could be performed quickly and quantitatively at neutral pH using micromolar concentrations of reactants. The SML process was applied directly to an expressed protein in cellular extract, and the C-terminal modified target protein was selectively immobilized using 2fPBA-agarose. Elution from the agarose yielded a highly pure protein that retained the hydrazide functionality. This strategy should be generally applicable for rapid, efficient site-specific protein labeling, protein immobilization, and preparation of highly pure functionalized proteins.

2-Hydroxyacyl-CoA lyase catalyzes acyloin condensation for one-carbon bioconversion.

Despite the potential of biotechnological processes for one-carbon (C1) bioconversion, efficient biocatalysts required for their implementation are yet to be developed. To address intrinsic limitations of native C1 biocatalysts, here we report that 2-hydroxyacyl CoA lyase (HACL), an enzyme involved in mammalian α-oxidation, catalyzes the ligation of carbonyl-containing molecules of different chain lengths with formyl-coenzyme A (CoA) to produce C1-elongated 2-hydroxyacyl-CoAs. We discovered and characterized a prokaryotic variant of HACL and identified critical residues for this newfound activity, including those supporting the hypothesized thiamine pyrophosphate-dependent acyloin condensation mechanism. The use of formyl-CoA as a C1 donor provides kinetic advantages and enables C1 bioconversion to multi-carbon products, demonstrated here by engineering an Escherichia coli whole-cell biotransformation system for the synthesis of glycolate and 2-hydroxyisobutyrate from formaldehyde and formaldehyde plus acetone, respectively. Our work establishes a new approach for C1 bioconversion and the potential for HACL-based pathways to support synthetic methylotrophy.

Catalyst systems for the clean synthesis of nitrogen-containing fine chemicals based on the building and transformation of carbonyl-containing molecules

The clean synthesis of nitrogen-containing fine chemicals with wide applications in organic and pharmaceutical chemistry has attracted lots of attention. Meanwhile, the sustainable development for chemical industry is based on the clean conversion of fossil resource derived basic chemicals such as hydrocarbon, alcohols, CO, CO2 and amines. Therefore, it is very important to synthesize the nitrogen-containing fine chemicals by the effective and clean conversion of fossil resource derived basic chemicals. The synthesis of nitrogen-containing fine chemicals via building, activation and transformation of carbonyl-containing molecules is an effective way to realize it. The key point is to establish a highly active catalyst system for building and transformation of carbonyl-containing molecules. Our group has focused on the clean synthesis of the nitrogen-containing fine chemicals based on the building and transformation of carbonyl-containing molecules since 2008. Here, the main progress from our group in the catalytic amination based on the activation and conversion of C1 carbonyl molecules, the building of the intermediate containing carbonyl, and the establishment of the catalytic system bridging homogeneous and heterogeneous catalysis based on a catalytic cycle between C=O and CH–OH has been summarized.

Coenzyme A, protein CoAlation and redox regulation in mammalian cells.

In a diverse family of cellular cofactors, coenzyme A (CoA) has a unique design to function in various biochemical processes. The presence of a highly reactive thiol group and a nucleotide moiety offers a diversity of chemical reactions and regulatory interactions. CoA employs them to activate carbonyl-containing molecules and to produce various thioester derivatives (e.g. acetyl CoA, malonyl CoA and 3-hydroxy-3-methylglutaryl CoA), which have well-established roles in cellular metabolism, production of neurotransmitters and the regulation of gene expression. A novel unconventional function of CoA in redox regulation, involving covalent attachment of this coenzyme to cellular proteins in response to oxidative and metabolic stress, has been recently discovered and termed protein CoAlation (S-thiolation by CoA or CoAthiolation). A diverse range of proteins was found to be CoAlated in mammalian cells and tissues under various experimental conditions. Protein CoAlation alters the molecular mass, charge and activity of modified proteins, and prevents them from irreversible sulfhydryl overoxidation. This review highlights the role of a key metabolic integrator CoA in redox regulation in mammalian cells and provides a perspective of the current status and future directions of the emerging field of protein CoAlation.

Chemically and electrochemically catalysed conversion of CO2 to CO with follow-up utilization to value-added chemicals

Carbon dioxide is ubiquitous and a vital molecule for maintaining life on our planet. However, the ever-increasing emission of anthropogenic CO2 into our atmosphere has provoked dramatic climate changes. In principle, CO2 could represent an important one-carbon building block for the chemical industry, yet its high thermodynamic and kinetic stability has limited its applicability to only a handful of industrial applications. On the other hand, carbon monoxide represents a more versatile reagent applied in many industrial transformations. Here we review the different methods for converting CO2 to CO with specific focus on the reverse water gas shift reaction, main element reductants, and electrochemical protocols applying homogeneous and heterogeneous catalysts. Particular emphasis is given to synthetic methods that couple the deoxygenation step with a follow-up carbonylation step for the synthesis of carbonyl-containing molecules, thus avoiding the need to handle or store this toxic but highly synthetically useful diatomic gas. CO is a vital building block in organic synthesis but, due to its toxicity, storage and transport can be problematic. This review focuses on the methods — both chemical and electrochemical — for the in situ generation of CO from CO2, and its subsequent incorporation into chemicals through catalytic means.

Characterization of the Clostridium difficile volatile metabolome using comprehensive two-dimensional gas chromatography time-of-flight mass spectrometry.

Clostridium difficile is a bacterial pathogen capable of causing life-threatening infections of the gastrointestinal tract characterized by severe diarrhea. Exposure to certain classes of antibiotics, advanced age, and prolonged hospitalizations are known risk factors for infection by this organism. Anecdotally, healthcare providers have reported that they can smell C. difficile infections in their patients, and several studies have suggested that there may indeed be an olfactory signal associated with C. difficile-associated diarrhea. In this study, we sought to characterize the volatile molecules produced by an epidemic strain of C. difficile (R20291) using headspace solid-phase microextraction (HS-SPME) followed by two-dimensional gas chromatography time-of-flight mass spectrometry (GC×GC-TOFMS). We report on a set of 77 volatile compounds, of which 59 have not previously been associated with C. difficile growth in vitro. Amongst these reported compounds, we detect both straight-chain and branched-chain carboxylic acids, as well as p-cresol, which have been the primary foci of C. difficile volatile metabolomic studies to-date. We additionally report on novel sulfur-containing and carbonyl-containing molecules that have not previously been reported for C. difficile. With the identification of these novel C. difficile-associated volatile compounds, we demonstrate the superior resolution and sensitivity of GC×GC-TOFMS relative to traditional GC-MS.

An Organic Flow Cathode for Flexible Lithium-Organic Redox Flow Batteries

Organic electrode materials have been considered as promising candidate for large-scale electrochemical energy storage systems (EES) due to low cost, safety, and even biomass orientation. Among various organic materials, the carbonyl-containing molecules have been highlighted to achieve high-performance redox couples with stable and reversible redox reactions. Recently, the Aziz’s group proposed an aqueous-type organic-inorganic redox flow battery using 9,10-antraquinone-2,7-disulphonic acid and bromine, which demonstrated high power density of 0.6 W cm− 2 at 1.3 A cm− 2 with stable capacity retention. However, the system has an intrinsic limitation on the operating potential below 1.5 V like other aqueous redox flow battery systems based on all-vanadium or zinc/bromine, which only allow a narrow selection for new redox-active species. Non-aqueous electrolyte systems appear to be a good choice for high-energy redox battery systems, which can provide higher operating potential (>2 V) and energy density. The researchers in Pacific Northwest National Laboratory (PNNL) studied the state-of-the-art non-aqueous lithium hybrid redox flow battery using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) and ferrocene compound as liquid cathode materials in order to attain high energy density and cell voltage. As for the organic cathode materials, various quinone-based organic materials have been widely studied for lithium ion batteries due to their abundant active sites and fast electron and ionic transfer kinetics. Due to low electrical conductivities of organic electrode materials, large amount of conductive materials and binders is added for the slurry coating process to assemble the coin-cell type batteries. Moreover, the dissolution of quinone based molecules into electrolyte places additional obstacles. Thus, current research has been focused on suppressing these issues in aprotic electrolytes. Interestingly, the synthesis of organic molecule with high solubility is one of the major research topics in the redox battery system. Thus, such features associated with solubility issues can make our tube-type redox batteries a novel flexible energy storage system. The construction of liquid type electrodes could be a new approach for the development of organic-based redox batteries including a novel flexible energy storage system. Herein, we report the first demonstration of liquid type flexible batteries. In addition the structure dependent electrochemical performances of two polycyclic quinone derivatives, 5,12-naphthacenequinone (NAQ) and 1,2-nenzanthraquinone (BAQ), will be studied. This constitutional isomers as liquid cathode materials can reversibly uptake two lithium ions in liquid phase after dissolving in tetraethylene glycol dimethyl ether (TEGDME) containing 1.3 M lithium bis(trifluoromethane sulfonyl) imide salt (LiTFSI). Importantly, BAQ with an asymmetric structure presented higher redox potential during charging and discharging steps than NAQ, showing two pronounced voltage plateaus with stable cycling performance. Tube-type redox batteries using the organic redox-active materials that dissolved in aprotic electrolyte can be easily scale-up and flexible. And the architecture injected with BAQ showed reliable mechanical flexibility under in-situ bending test of 50 mm min− 1, showing energy efficiency of ~80% and coulombic efficiency of ~99.5%.

Tetrel, chalcogen, and CH⋅⋅O hydrogen bonds in complexes pairing carbonyl-containing molecules with 1, 2, and 3 molecules of CO2.

The complexes formed by H2CO, CH3CHO, and (CH3)2CO with 1, 2, and 3 molecules of CO2 are studied by ab initio calculations. Three different types of heterodimers are observed, most containing a tetrel bond to the C atom of CO2, and some supplemented by a CH⋅⋅O H-bond. One type of heterodimer is stabilized by an anti-parallel arrangement of the C=O bonds of the two molecules. The binding energies are enhanced by methyl substitution on the carbonyl, and vary between 2.4 and 3.5 kcal/mol. Natural bond orbital analysis identifies a prime source of interaction as charge transfer into the π*(CO) antibonding orbital. Heterotrimers and tetramers carry over many of the geometrical and bonding features of the binary complexes, but also introduce O⋅⋅O chalcogen bonds. These larger complexes exhibit only small amounts of cooperativity.