Chemistry Of Aldehydes Research Articles

The Chemistry of Aldehydes and Ketones in the Synthesis of Heterocycles - Historical Reactions with a New and Green Perspective

Abstract: The reactivity of aldehydes and ketones carries great potential for multicomponent heterocyclizations. These reactions are convergent and highly versatile in the development of synthetic methodologies for compound families, displaying variations in substituents in their structures. Therefore, they have been regarded as an important tool in the field of Green Chemistry. Furthermore, they prove to be very useful in studies of biological activity, where small structural modifications can result in significant differences. Many heterocyclizations date back to the mid-19th and early 20th centuries. In this review, we aim to demonstrate, through some of these reactions, their continuously growing potential and improvements concerning synthetic development. Additionally, we present the original studies as reported, enabling us to appreciate the evolution of chemical representations over the years until reaching the standardization we have today.

Reactive aldehyde chemistry explains the missing source of hydroxyl radicals

Hydroxyl radicals (OH) determine the tropospheric self-cleansing capacity, thus regulating air quality and climate. However, the state-of-the-art mechanisms still underestimate OH at low nitrogen oxide and high volatile organic compound regimes even considering the latest isoprene chemistry. Here we propose that the reactive aldehyde chemistry, especially the autoxidation of carbonyl organic peroxy radicals (R(CO)O2) derived from higher aldehydes, is a noteworthy OH regeneration mechanism that overwhelms the contribution of the isoprene autoxidation, the latter has been proved to largely contribute to the missing OH source under high isoprene condition. As diagnosed by the quantum chemical calculations, the R(CO)O2 radicals undergo fast H-migration to produce unsaturated hydroperoxyl-carbonyls that generate OH through rapid photolysis. This chemistry could explain almost all unknown OH sources in areas rich in both natural and anthropogenic emissions in the warm seasons, and may increasingly impact the global self-cleansing capacity in a future low nitrogen oxide society under carbon neutrality scenarios.

A detailed high-pressure oxidation study of n-pentanal

Oxidation of n-pentanal is studied in a jet-stirred reactor at 10 atm for four dilute mixtures with equivalence ratios 0.3, 0.5, 1 and 2 and between 500–1150 K. A detailed kinetic sub-mechanism is developed and used along with the mechanisms representing the oxidation of two branched isomers of pentanal, namely 2- and 3-methylbutanal. At all conditions, n-pentanal showed a strong low-temperature reactivity and an NTC region. Among the experimentally observed species, ones related to the low-temperature oxidation of n-butyl radicals can be found, consolidating the importance of the (N-1) alkyl radicals in aldehyde chemistry. The kinetic mechanism showed good agreement against the data as well as other speciation data at atmospheric pressure from literature. The present data are also compared to previous similar studies on the oxidation of C3–C5 aldehydes in the same JSR and where n-pentanal shows the highest global reactivity.

Aldol Polymerization to Construct Half-Fused Semiconducting Polymers

Conventional conjugated polymer synthesis involves costly transition-metal catalysts and even toxic reagents, causing serious environmental challenges around the world. The comonomer linkages of semiconducting polymers are mostly single bonds; charge delocalization and transport have been hindered due to rotation around these single bonds, leading to energetic and conformational disorders. Here, we have developed a novel programmable half-fused polymer library by introducing aldehyde chemistry to promote a very simple and cheap Lewis acid-mediated aldol condensation that affords conjugated polymers with continuous double bonds and single bonds as the linkages between the polymer repeat units, maintaining a coplanar conjugated backbone to eliminate rotation owing to the intramolecular noncovalent interactions. In addition, this innovative concept not only shows an excellent substrate generality but also affords unprecedented polymers with unique properties, allowing us to change the variable conjugated length and side-chain engineering of the backbone to modulate the optoelectronic properties and tune the delocalization of frontier molecular orbitals. These polymers also exhibit very high number-averaged molecular weights (Mn) while showing good solution processability, which makes them applicable as high-performance thin-film transistor materials with reduced conformational disorder. Herein, our results demonstrate that the half-fused design strategy can effectively extend the scope of semiconducting polymers. The low synthetic complexity can be utilized to design organic electronic materials for large-scale production and commercialization.

An experimental and kinetic modelling study of n-C4C6 aldehydes oxidation in a jet-stirred reactor

Abstract In recent years a few experimental and kinetic modelling studies have been devoted to the understanding of the oxidation chemistry of aldehydes, because of their importance as intermediate and product species in alkane and biofuel oxidation. In this work, new jet-stirred reactor experimental data are presented for n-butanal and n-pentanal, extending the availability of targets for kinetic model validation. Consistently with previous detailed measurements on n-hexanal oxidation, experiments have been carried out for both fuels over the temperature range 475–1100 K, at a residence time of 2 s, pressure of 106.7 kPa, inlet fuel mole fraction of 0.005 and at three equivalence ratios (ϕ = 0. 5, 1 and 2). A recently published literature model by Pelucchi et al. was used to interpret these experiments. The assumption according to which most of the Cn aldehyde reactivity is controlled by the low-temperature branching pathways of the Cn-1 alkyl radical, allows good agreement between experiments and model in terms of fuel conversion and for most of the detected species. The systematic and comparative analysis here presented for C4 C6 linear aldehydes further constrains the general rate rules, applicable to the description of higher molecular weight aldehydes, which can be produced from heavier alcohols (n-pentanol, n-hexanol etc.) and fossil fuel oxidation.

Green chemistry of aldehydes and tertiary phosphines in organic and organophosphorus syntheses

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Single molecule study of samarium oxide nanoparticles as a purely heterogeneous catalyst for one-pot aldehyde chemistry

Heterogeneous catalysis holds distinct advantages over homogeneous catalysis; however, it is only truly advantageous if unaffected by metal ion leaching or in situ formation of a soluble catalytically active species.

Reactivity of aldehydes at the air–water interface. Insights from molecular dynamics simulations and ab initio calculations

Understanding the influence of solute-solvent interactions on chemical reactivity has been a subject of intense research in the last few decades. Theoretical studies have focused on bulk solvation phenomena and a variety of models and methods have been developed that are now widely used by both theoreticians and experimentalists. Much less attention has been paid, however, to processes that occur at liquid interfaces despite the important role such interfaces play in chemistry and biology. In this study, we have carried out sequential molecular dynamics simulations and quantum mechanical calculations to analyse the influence of the air-water interface on the reactivity of formaldehyde, acetaldehyde and benzaldehyde, three simple aldehydes of atmospheric interest. The calculated free-energy profiles exhibit a minimum at the interface, where the average reactivity indices may display large solvation effects. The study emphasizes the role of solvation dynamics, which are responsible for large fluctuations of some molecular properties. We also show that the photolysis rate constant of benzaldehyde in the range 290-308 nm increases by one order of magnitude at the surface of a water droplet, from 2.7 × 10(-5) s(-1) in the gas phase to 2.8 × 10(-4) s(-1) at the air-water interface, and we discuss the potential impact of this result on the chemistry of the troposphere. Experimental data in this domain are still scarce and computer simulations like those presented in this work may provide some insights that can be useful to design new experiments.

Phenyl amide linker improves the pharmacokinetics and pharmacodynamics of N-terminally mono-PEGylated human growth hormone.

Human growth hormone (hGH) suffers from a short plasma half-life of ∼15 min, necessitating frequent injections to maintain its physiological effect. PEGylation, conjugation of polyethylene glycol (PEG), is an effective strategy to prolong the plasma half-life of hGH. However, PEGylation can significantly decrease the bioactivity of hGH. Thus, a new PEGylation approach is desired to improve the pharmacokinetics (PK) and pharmacodynamics (PD) of the PEGylated hGH. In the present study, two N-terminally mono-PEGylated hGHs were prepared using aldehyde chemistry. Phenyl amide and ethyl moieties were used as the linkers between PEG and hGH, respectively. The hydrodynamic volume, proteolytic sensitivity, and immunogenicity of the PEGylated hGH with phenyl amide linker (hGH-phenyl-PEG) were lower than those of the one with propyl linker (hGH-prop-PEG). In addition, hGH-phenyl-PEG showed a higher in vitro bioactivity and better PK and PD than hGH-prop-PEG. The better PK of hGH-phenyl-PEG was mainly due to its lower proteolytic sensitivity and low immunogenicity. The better PD of hGH-phenyl-PEG was mainly due to its higher in vitro bioactivity. Thus, the phenyl amide linker can improve the overall pharmacological profiles of the PEGylated hGH. Our study is expected to advance the development of long-acting protein biotherapeutics with high therapeutic efficacy.

Adsorption Studies Of Acetaldehyde On TiO2 Nanosurface

The present work deals with the adsorption of acetaldehyde, one of the most harmful volatile organic compounds (VOCs), on the TiO2 anatase nanosurface. The research was undertaken due to environmental concerns, as the TiO2 nanosurface serves as an excellent catalyst for the adsorption and decomposition of VOCs. The chemistry of aldehydes on metal oxides is complex and elaborate, as it can result in a variety of reactions, such as selective oxidation, alcohols disproportionation, etherification and reductive coupling to higher olefins. The structural properties of the various nanosurfaces were first examined and finally adsorption studies were made on the (TiO2)17 cluster, as it shows least reconstruction and offers all kinds of coordination sites for the study. It is found that a myriad of different adsorption products are formed on the TiO2 nanosurface, depending upon the coordination site. The low coordination (3c) sites are highly reactive and form stronger bonds with the acetaldehyde molecule, whereas adsorption at the four coordination site leads to the reconstruction of the nanosurface. Acetaldehyde chemisorbs onto the surface producing zwitterionic four-membered rings, in which the carbonyl C=O bond is considerably weakened, or it adsorbs on the TiO2 surface in a H-bridge bonded form. The most feasible mode of adsorption on the TiO2 nanosurface is found to be methyl hydrogen migration resulting in the formation of [CH2-C(H)O] species, which may further undergo transformation by β-aldolization to yield crotonaldehyde and butane. Other products investigated in this work include oxidation to acetate and reduction to ethoxy species. The results obtained in this work can be of significant help in deciding the fate of reaction of acetaldehyde on the TiO2 nanosurface, and using it for decomposition of acetaldehyde to benign products.

Tuning drug release from smart microgel–hydrogel composites via cross-linking

Soft nanocomposite hydrogels consisting of thermoresponsive microgels physically entrapped or covalently cross-linked to a non-thermoresponsive hydrogel are synthesized and tested for their capacity to facilitate long-term drug release of a small molecule drug. Copolymer microgels based on N-isopropylacrylamide and acrylic acid were synthesized that exhibited ionic affinity for binding to bupivacaine, a cationic local anesthetic. These microgels were subsequently physically entrapped within an in situ-gelling carbohydrate-based hydrogel network cross-linked via hydrazide–aldehyde chemistry; alternately, hydrazide-functionalized microgels were prepared that covalently cross-linked to the bulk hydrogel phase. Both the overall rate of drug release and the magnitude of the burst release were significantly decreased when microgels were restricted from undergoing a phase transition between the preparation temperature of the nanocomposite (25°C) and the test temperature (37°C), whether deswelling was inhibited by increasing the cross-link density within the microgel itself or by cross-linking the microgel to the bulk hydrogel network. This result facilitates facile tuning of soft nanocomposite drug delivery systems to achieve targeted drug release kinetics.

Will the real culprit of heterograft valve calcification please stand up?

Sinha and colleagues1Sinha P. Zurakowski D. Kumar T.K. He D. Rossi C. Jonas R.A. Effects of glutaraldehyde concentration, pretreatment time, and type of tissue (porcine versus bovine) on postimplantation calcification.J Thorac Cardiovasc Surg. 2012; 143: 224-227Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar are not the first to implicate glutaraldehyde as a culprit for tissue valve calcification. Although they are to be commended for their careful methods and the suggestion that glutaraldehyde concentration and exposure times appear to correlate with the degree of calcification, they unfortunately failed to reach far enough back into the literature to recognize that most of their questions had already been answered by others.2Fishbein M.C. Levy R.J. Ferrans V.J. Dearden L.C. Nashef A. Goodman A.P. et al.Calcifications of cardiac valve bioprostheses. Biochemical, histologic, and ultrastructural observations in a subcutaneous implantation model system.J Thorac Cardiovasc Surg. 1982; 83: 602-609PubMed Google Scholar A closer look at the literature might also have led these researchers to arrive at a different conclusion; that is, calcific degeneration of heterograft tissues is primarily an immunologic phenomenon. Alain Carpentier and his wife Sophie, a biochemist, are given credit for the introduction of aldehyde chemistry to the modern manufacture of heterograft tissue valves.3Carpentier A. From valvular xenograft to valvular bioprosthesis (1965-1977).Med Instrum. 1977; 11: 98-101PubMed Google Scholar At the time, they did not advance an argument that aldehyde preservation rendered heterograft tissues nonimmunogenic. That perception belongs to perspicacious marketing departments within the tissue valve industry. The observation that calcific degeneration of heterograft valves is an age-related phenomenon was an early and important clue to the problem of tissue valve durability.4Dunn J.M. Porcine valve durability in children.Ann Thorac Surg. 1981; 32: 357-368Abstract Full Text PDF PubMed Scopus (84) Google Scholar These issues notwithstanding, the Carpentiers’ discovery had already spawned the multibillion dollar industry of heterograft tissue heart valves. More than 30 years ago, Salgaller and Bajpai5Salgaller M.L. Bajpai P.K. Immunogenicity of glutaraldehyde-treated bovine pericardial tissue xenografts in rabbits.J Biomed Mater Res. 1985; 19: 1-12Crossref PubMed Scopus (27) Google Scholar detected both cellular and humoral immune responses to glutaraldehyde-treated and untreated bovine pericardium. Their data provided the first real proof that glutaraldehyde-preserved heterograft tissues are not biologically inert and remain antigenic. The association between a smoldering immune response and tissue valve durability was never widely recognized, however, and glutaraldehyde continued to be the presumed cause of heterograft calcification, leading researchers and companies to search for new tissue treatments designed to retard calcification. Love and associates6Love J.W. Calvin J.H. Phelan R.F. Love C.S. Rapid intraoperative fabrication of an autologous tissue heart valve: a new technique.in: Bodnar E. Yacoub M. Proceedings of the Third International Symposium on Cardiac Bioprostheses. Yorke Medical, New York1986: 691-698Google Scholar first described the successful use of autologous pericardium briefly treated in 0.6% glutaraldehyde for use as a stent-mounted valve replacement. Since this introduction, multiple investigators have reported wide success with the use of autologous pericardium briefly treated in 0.6% glutaraldehyde for the replacement of semilunar heart valves7Chan K.M. Rahman-Haley S. Mittal T.K. Gavino J.A. Dreyfus G.D. Truly stentless autologous pericardial aortic valve replacement: an alternative to standard aortic valve replacement.J Thorac Cardiovasc Surg. 2011; 141: 276-283Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar and the repair of damaged and shortened mitral valve leaflets.8Chauvaud S. Jebara V. Chachques J.C. el Asmar B. Mihaileanu S. Perier P. et al.Valve extension with glutaraldehyde-preserved autologous pericardium. Results in mitral valve repair.J Thorac Cardiovasc Surg. 1991; 102: 171-178PubMed Google Scholar All these techniques have proved durable, and in none of the published experiences, including those with pediatric or very young patients, has calcific degeneration been considered a limitation. The more than 20-year clinical experience with autologous pericardium briefly immersed in glutaraldehyde and used for valve reconstruction should finally dispel any perception that aldehydes are directly responsible for calcific degeneration of tissue valves. Effects of glutaraldehyde concentration, pretreatment time, and type of tissue (porcine versus bovine) on postimplantation calcificationThe Journal of Thoracic and Cardiovascular SurgeryVol. 143Issue 1PreviewOur objective was to evaluate the effects of glutaraldehyde (GA) concentration, time of pretreatment, and type of tissue (porcine vs bovine) on quantitative and qualitative postimplant calcification of tissues. Full-Text PDF Reply to the EditorThe Journal of Thoracic and Cardiovascular SurgeryVol. 144Issue 1PreviewWe thank Mr Love for responding to our article1 and for emphasizing the importance of immune mechanisms in heterograft calcification. We are in agreement that aldehyde treatment is just one of several factors that can exacerbate calcification of implanted tissues. In the clinical setting of pediatric cardiac surgery, where autologous pericardium is often used and immune mechanisms are presumably not so important, however, it is the factor that can be most readily modified. Unfortunately, our animal model was not suited to autologous pericardium implantation. Full-Text PDF

Competing Mechanistic Channels in the Oxidation of Aldehydes by Ozone

The reaction of ozone with aldehydes has been studied intermittently for over 100 years, but its mechanism remains uncertain. Experimental results support two reaction channels: radical abstraction of the acyl hydrogen and addition to form a five-membered ring tetroxolane. We have studied the aldehyde-ozone reaction by DFT and CCSD(T) calculations. CCSD(T)/6-311+G(d,p)//M05-2X)/6-311+G(d,p) calculations predict two competitive pathways for the oxidation of formaldehyde by ozone. Abstraction of the acyl hydrogen by ozone has a barrier of 16.2 kcal/mol, leading to a radical pair, which can combine to form a hydrotrioxide; this species may subsequently decompose to a carboxylic acid and singlet oxygen. In the second reaction channel, addition of ozone to the carbonyl is stepwise, with barriers of 19.1 and 23.0 kcal/mol, leading to a five-membered ring tetroxolane intermediate. This process may be reversible, consistent with earlier observations of isotopic exchange. The two channels connect by an intramolecular hydrogen abstraction. Ring opening of the tetroxolane by an alternate O-O bond cleavage, followed by spin inversion in the resulting diradical intermediate, can give a carbonyl oxide plus (3)O(2). It is also possible that reaction of triplet oxygen with carbonyl oxides can produce ozone by the reverse route. These two stepwise reaction channels, hydrogen abstraction and addition to the C=O bond, explain much of what has been observed in the long history of ozone-aldehyde chemistry. Known reaction rates and the substantial barriers to both channels support an earlier conclusion that aldehyde oxidation by ozone is too slow to be of importance in atmospheric chemistry.

Synthesis of Multifunctional Polyvinylsaccharide Containing Controllable Amounts of Biospecific Ligands

In the present study, the attempt to synthesize a multibiofunctional polymeric vector to be used for construction of composite scaffolds for bone tissue engineering has been undertaken. The polymers based on 2-deoxy-2-methacrylamido- d-glucose were functionalized by a growth factor (BMP-2), GRGDSP peptide, and poly( l-lysine) using aldehyde chemistry. The covalent modification process was quantitatively studied, and a polymer conjugate containing all these ligands was formed. In addition, the impacts of coupled ligands toward the adsorption of polymers on the commercial mineral macroporous matrix Sponceram used in cell culture applications were studied.

Intramolecular and intermolecular Schmidt reactions of alkyl azides with aldehydes

Despite recent advances in the use of alkyl azides in ring expansion reactions of ketones, there has been little work done on the corresponding chemistry of aldehydes. In the present study, the Lewis acid-promoted reactions of alkyl azides with aldehydes were studied in both intermolecular and intramolecular contexts. The intramolecular reactions of azidoalkyl aldehydes in which the azide and carbonyl groups were separated by 2–5 carbons were examined. Although the examples having the shortest tether failed (3-azidopropanals), each of the other systems gave good yields of either NH-substituted lactams (resulting from hydride migration in the initially formed azidohydrin adduct) or formamides (alkyl migration). The product formed was dependent on the chain length of the starting azido aldehyde. The intermolecular reactions were less efficient, requiring TiCl 4 promotion for even moderate yields, and in each case gave mixtures of products resulting from hydride and alkyl migration.

An efficient synthesis of achiral and chiral 1,2,4-triazolium salts: bench stable precursors for N-heterocyclic carbenes.

[reaction: see text] The promising utility of triazolyl N-heterocyclic carbene catalysts in umpolung aldehyde chemistry requires a straightforward reliable synthesis from readily available materials. Herein, we describe the synthesis of a variety of triazolyl N-heterocyclic carbene precursors. The reactions commence from commercially available amino acids and proceed in 44-68% overall yields. The N-heterocyclic salts are air-stable crystalline solids that can be stored with no special precaution and can generate the active catalyst when treated with an appropriate base.

A novel DNA microarray system for analysis of limited forensic evidence material

The ability to match a genetic profile from an evidence material with genetic profiles of suspects makes an important contribution to the traditional criminal investigations. Furthermore, the possibility of analyzing very small amounts of DNA found at the scene of a crime has greatly influenced forensic analysis. Today mitochondrial DNA analysis is widely used on biological samples of limited amounts because of the high copy number of mtDNA. However, its discriminating power is not as high as its analysis of nuclear DNA, wherefore a method that combines mitochondrial and nuclear markers would be a powerful tool to reduce the probability of DNA identity by chance for limited DNA samples. Analysis of DNA from material of bad quality and small amounts is also often time-consuming and difficult to perform. In order to increase the discrimination power and reduce the turnaround time in analysis of samples with minute DNA amounts, we have developed a one-color microarray-based SNP detection system. The system relies on minisequencing in solution prior to hybridization to universal tagarrays. The minisequencing reaction is based on the extension of a tagged primer with a chain terminating fluorescent dideoxynucleotide at the position to be interrogated. Our one-color system detects C and T polymorphisms in separate multiplex reactions with the fluorophore TAMRA coupled to the respective dideoxynucleotide. The extended primers are hybridized through its complementary tag sequence on the array and positive signals are detected by a confocal laser scanner (Scan Array 5000, Packard BioScience). The tagarrays are produced with an in-house robotic workstation (GMS 417 Arrayer, SDS) using silylated slides with aldehyde chemistry. In order to maintain a high sensitivity even for analysis of the nuclear markers, the PCR systems have been designed to amplify very short fragments.

Use of thiazolidine-mediated ligation for site specific biotinylation of mouse EGF for biosensor immobilisation

Biosensors provide a sophisticated and discriminating means of probing biomolecular interactions. Specific ligands such as peptides and proteins can be immobilized onto sensor surfaces by a number of means including covalent attachment via amine, thiol or aldehyde chemistry, capture via biotin-avidin interaction or the use of specific tags. We have devised a simple chemoselective ligation method to selectively conjugate an anchoring functionality onto N-terminal serine or threonine residues of peptides and proteins allowing them to be immobilised onto the sensor surface in a defined orientation. It is based on the specific reaction of the 1,2-aminothiol of cysteine with an aldehyde under acidic conditions to form a stable thiazolidine product. The carbonyl precursors are derived from the 1,2-aminoalcohols of Ser or Thr that can be selectively and rapidly converted to the aldehyde form by periodate oxidation. Biotinylation of the aldehyde is then achieved via simple conjugation with a novel water-soluble dipeptide that contains a lysine residue bearing an Ne-cysteine-derived 1,2-aminothiol and an Nα-biotin moiety. Use of this method allowed selective biotinylation of a native form of murine EGF (mEGF2-53) that has an N-terminal serine residue. This derivative was then immobilised onto a streptavidin biosensor surface, and the resultant surface activity compared with those obtained by immobilising recombinant human EGF or the soluble extracellular domain of the EGF receptor (sEGFR1-621) using amine coupling (NHS/EDC) chemistry. The surface recognised the recombinant sEGFR with a similar K D to that of human EGF immobilised using NHS/EDC chemistry, or if the receptor was immobilised and murine EGF injected.

Post-photoaffinity labeling modification using aldehyde chemistry to produce a fluorescent lectin toward saccharide-biosensors

A new method to construct a fluorescent saccharide biosensor based on a lectin protein is successfully proposed using post-photoaffinity labeling modification coupled to aldehyde chemistry.

The interactions of oxygen with aldehydes on the Pd(111) surface

Oxygen atoms alter the characteristic chemistry of aldehydes on transition metal surfaces in a variety of ways. The most dramatic effect of oxygen on the Pd(111) surface was to shift the principal reaction pathway of C 1C 3 aldehydes from decarbonylation on the clean surface to carboxylate formation on the (2 × 2)O surface. This shift actually involves several different roles played by surface oxygen, including alteration of the preferred binding state of aldehydes from η 2 to η 1, and nucleophilic oxidation of adsorbed aldehydes to form carboxylates. Oxygen adatoms also influence the thermal stabilities and reaction selectivities of carboxylates, both by lateral interactions and by scavenging adsorbed hydrogen atoms which would otherwise hydrogenate carboxylates carboxylic acids. Oxygen adatoms also initiated formaldehyde polymerization on the Pd(111) surface, but no polymerization of the higher aldehydes was observed. The multiple roles played by oxygen serve to illustrate some of the difficulties in oxidation catalysis by noble metals.