Reaction Of Malonaldehyde Research Articles

Vilsmeier-Haack reagent: A facile synthesis of 2-(4-chloro-3,3-dimethyl-7-phenoxyindolin-2-ylidene)malonaldehyde and transformation into different heterocyclic compounds

Article history: Received March 20, 2013 Received in Revised form July 7, 2013 Accepted 28 July 2013 Available online 30 July 2013 2-(5-Chloro-2-phenoxyphenyl)hydrazine was converted to corresponding 3H-indole by Fischer method utilizing the isopropyl methyl ketone in acetic acid. The reaction of 3H-indole with Vilsmeier-Haack reagent furnished aminomethylene malonaldehyde in excellent yield while the reactions of malonaldehyde with hydrazine, arylhydrazines, amines, cyanoacetamide and hydroxylamine hydrochloride, led to the corresponding pyrazole derivatives, enamines, cyanopyridone, and cyanoacetamide derivatives respectively. © 2013 Growing Science Ltd. All rights reserved.

ChemInform Abstract: Reaction of Malonaldehyde with Nucleic Acid. Part 4. Formation of Pyrimido(1,2-a)purin-10(3H)-one Nucleoside by Thermal Decomposition of Diastereomers Containing Oxadiazabicyclononene Residues Linked to Guanosine.

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Reactions Of Malonaldehyde And Acetaldehyde With Calf Thymus Dna: Formation Of Conjugate Adducts

Our previous work has shown that treatment of nucleosides with malonaldehyde simultaneously with acetaldehyde affords stable conjugate adducts. In the present study we demonstrate that conjugate adducts are also formed in calf thymus DNA when incubated with the aldehydes. The adducts were identified in the DNA hydrolysates by their positive ion electrospray MS/MS spectra, by coelution with the 2′-deoxynucleoside standards, and, in the case of adducts exhibiting fluorescent properties, also by LC using a fluorescence detector. In the hydrolysates of double-stranded DNA (ds DNA), two deoxyguanosine and two deoxyadenosine conjugate adducts were detected and in single-stranded DNA (ss DNA) also, the deoxycytidine conjugate adduct was observed. The guanine base was the major target for the malonaldehyde-acetaldehyde conjugates and 2′-deoxyguanosine adducts were produced in ds DNA at levels of 100–500 adducts/105 nucleotides (0.7–3 nmol/mg DNA).

A Hamilton–Jacobi type equation for computing minimum potential energy paths

A new method for computing minimum-energy reaction paths is presented. Unlike existing approaches (e.g. intrinsic reaction coordinate methods), our approach works for any reactant configuration: the structure of the transition state, reactive intermediates and product will be determined by the algorithm, and so need not be known beforehand. The method we have developed is based on solving a Hamilton–Jacobi type equation. Specifically, we introduce a speed function so that the ‘first arrival times’ from the Hamilton–Jacobi equation correspond to least-potentials. Then, adopting a back-tracing method, we can use the first arrival times to determine the minimum-energy path between any classically allowed molecular conformation and the initial (reactant) conformation. The method is illustrated by applying it to six different systems: (1) a model system with four different minima in the potential energy surface, (2) a model Muller–Brown potential, (3) the isomerization reaction of malonaldehyde using a fitting potential energy surface, (4) a model Minyaev–Quapp potential representative of con- and dis-rotations of two BH2 groups in the BH2–CH2–BH2 molecule, (5) the F + H2→FH + H reaction and (6) the H + FH → HF + H reaction. Our results demonstrate that the proposed method represents a robust alternative to existing techniques for finding chemical reaction paths.

Formation of Conjugate Adducts in the Reactions of Malonaldehyde−Acetaldehyde and Malonaldehyde−Formaldehyde with Guanosine

The reactions of guanosine with malonaldehyde in buffered aqueous solutions in the presence of acetaldehyde or formaldehyde were studied. The reaction mixtures were analyzed by RP-HPLC. Two adducts were formed in the reaction of malonaldehyde and acetaldehyde and one in the reaction of malonaldehyde and formaldehyde. The products were isolated and purified by preparative C-18 chromatography and structurally characterized by UV absorbance, 1H NMR, and 13C NMR spectroscopy and mass spectrometry. The adducts formed in the reaction of malonaldehyde and acetaldehyde were identified as 7-(2,2-diformyl-1-methylethyl)-3-(beta-D-ribofuranosyl)pyrimido[1,2-a]-purin-10(3H)-one (M2AA-Guo I) and 2-(3,5-diformyl-4-methyl-1,4-dihydro-1-pyridyl)-9-(beta-D-ribofuranosyl)-purin-6(9H)-one (M2AA-Guo II). In the reaction of malonaldehyde and formaldehyde, the major product was identified as 7-formyl-3-(beta-D-ribofuranosyl)pyrimido[1,2-a]purin-10(8H)-one (M1FA-Guo). The highest yields of M2AA-Guo I and M2AA-Guo II, 7 and 2 mol %, respectively, were obtained in the reaction performed at pH 7.4 and 37 degrees C for 6 days, while M1FA-Guo was produced at a yield of 0.3 mol % after 3 days of reaction at pH 7.4 and 37 degrees C. The products are formed by reactions of malonaldehyde-acetaldehyde and malonaldehyde-formaldehyde condensation products with guanosine and are analogous to the previously identified condensation products formed with adenosine, cytidine, and proteins.

Identification of a novel fluorescent adduct formed in the reaction of malonaldehyde with adenosine

Malonaldehyde was reacted with adenosine in aqueous solution at acidic conditions and the reaction mixtures were analysed by HPLC. Four major product peaks were observed in the chromatogram recorded by the UV detector at 320 nm. Two of the peaks could be deduced to the previously characterised malonaldehyde–adenosine reaction product 9-(β- d-ribofuranosyl)-6-(5,7-diformyl-2 H-3,6-dihydro-2,6-methano-1,3-oxazocin-3-yl)purine (M 3A) and to the ribose analogue of the 2′-deoxy adduct 9-(2′-deoxy-β- d-ribofuranosyl)-6-(3,5-diformyl-4-methyl-1,4-dihydro-1-pyridyl)purine (M 2AA-dA). The two other peaks were due to previously uncharacterised adducts. Upon isolation of these adduct peaks it was found that the peaks are interconverted to each other, one adduct peak dominating over the other one. On the basis of data recorded by UV, fluorescence and 1H NMR spectroscopy, and mass spectrometry, the structure of the major adduct could be determined as 9-(β- d-ribofuranosyl)-6-(3,5-diformyl-4-etanal-1,4-dihydro-1-pyridyl)purine (3M-A). The adduct is most likely formed by reaction of adenosine with a malonaldehyde condensation product consisting of three units of malonaldehyde. The highest yield of 3M-A was obtained in the reaction performed at pH 4.6 and 80 °C for 75 h. The minor form of the interconverting peaks could not be characterised on the basis of the spectral data. However, it is concluded that the minor peak most likely represents the hydrated form of 3M-A. Since these adducts are formed only in trace amounts at neutral pH and 37 °C and the formation requires high amounts of malonaldehyde, it is likely that the adducts are not formed in DNA in vivo and thus not contribute to the malonaldehyde genotoxicity.

Reaction Paths of Keto−Enol Tautomerization of β-Diketones

Density functional theory calculations were conducted on the title reactions with water molecules. Malonaldehyde, acetylacetone, and malonic acid were adopted as reactants. A reaction of malonaldehyde and (2 + 2) water molecules was found to proceed by a small (ca. 7 kcal/mol) activation energy. Two are reactant and two are catalyst molecules, respectively. The intramolecular hydrogen bond in the enol form is disrupted by the intermolecular one. Tautomerization transition-state geometries for acetylacetone and malonic acid are similar to that of malonaldehyde. Without the enhanced reactivity of water hydrogen-bond networks, tautomerization reactions undergo large activation energies. Various reaction models of (malonaldehyde)n (n = 2, 3, and 4) have given the energetic result. The keto−enol tautomerization has an analogy with the bimolecular nucleophilic elimination (E2) mechanism.

Energy density analysis (EDA) of cis, trans-enol isomerization in malonaldehyde, tropolone and 9-hydroxyphenalenone

We have recently proposed an energy density analysis (EDA) that partitions the total energy of a molecular system into atomic energy densities. In this study, the EDA is applied to cis, trans-enol isomerization reactions of malonaldehyde, tropolone and 9-hydroxyphenalenone. Energy density changes in the reactions are shown to be closely related to the formation and breaking of the chemical bonds. By analyzing the energy density changes, we can find the reason why the hydrogen atom moves through the out-of-plane pathway instead of the in-plane pathway.

Identification of conjugate adducts formed in the reactions of malonaldehyde-acetaldehyde and malonaldehyde-formaldehyde with cytidine.

Malonaldehyde was reacted with cytidine in buffered aqueous solutions in the presence of acetaldehyde or formaldehyde. The reaction mixtures were analyzed by HPLC, and the products were isolated by preparative C18 chromatography and structurally characterized by UV absorbance, fluorescence emission, (1)H and (13)C NMR spectroscopy, and mass spectrometry. The major adducts formed in the reaction of malonaldehyde and acetaldehyde were identified as 7-(beta-D-ribofuranosyl)-4-methyl-6-oxo-6,7-dihydro-4H-pyrimido[1,6-a]pyrimidine-3-carbaldehyde (M(1)AA-Cyd) and 1-(beta-D-ribofuranosyl)-4-(3,5-diformyl-4-methyl-1,4-dihydro-1-pyridyl)pyrimidine (M(2)AA-Cyd). In the reaction of malonaldehyde and formaldehyde, the major product was identified as 7-(beta-D-ribofuranosyl)-6-oxo-6,7-dihydro-4H-pyrimido[1,6-a]pyrimidine-3-carbaldehyde (M(1)FA-Cyd). The highest yields of M(1)AA-Cyd and M(2)AA-Cyd, 3.2 and 0.5 mol %, respectively, were obtained in the reaction performed at pH 4.6 and 37 degrees C for 8 days, while M(1)FA-Cyd was produced at a yield of 0.3 mol % after 3 days of reaction at pH 4.0 and 37 degrees C. The products consist of units derived from malonaldehyde and acetaldehyde (M(1)AA-Cyd and M(2)AA-Cyd) or from malonaldehyde and formaldehyde (M(1)FA-Cyd), and are thus further examples of nucleoside modifications containing structural elements derived from aldehyde condensation reactions. Trace amounts of the adducts may be formed at physiological conditions and may be involved in the mutagenicity of the studied aldehydes.

Reaction of mucochloric and mucobromic acids with adenosine and cytidine: formation of chloro- and bromopropenal derivatives.

Mucochloric (MCA) and mucobromic acid (MBA)--bacterial mutagens and water disinfection byproducts--were reacted with adenosine, cytidine, and guanosine in N,N-dimethylformamide (DMF). In the MCA reaction with adenosine and cytidine and in the MBA reaction with adenosine one major product was formed. In the reactions of MBA with cytidine and in the reactions of MCA and MBA with guanosine only trace levels of products could be detected, and these were not further characterized. The products from the adenosine and cytidine reactions were isolated by preparative chromatography on octadecylsilane columns and structurally characterized by UV absorbance, 1H and 13C NMR spectroscopy, and mass spectrometry. The products were identified as 3-(N6-adenosinyl)-2-chloro-2-propenal (MClA), 3-(N6-adenosinyl)-2-bromo-2-propenal (MBrA), and 3-(N4-cytidinyl)-2-chloro-2-propenal (MClC). The yields of MClA, MBrA, and MClC were 19, 4 and 7 mol %, respectively. These halopropenal derivatives were formed also in reactions carried out in aqueous solutions at pH 7.4 and 37 degrees C at low yields, about 5 x 10(-3)%. The mechanism of formation of the halopropenal derivatives and of the previously identified etheno and ethenocarbaldehyde derivatives was elucidated by reacting 13C-3 labeled MCA with adenosine in DMF and in water. The location of the labeled carbon in the products was determined from the 13 C NMR spectra. It was concluded that the halopropenal derivatives were formed by mechanisms that differ completely from the one responsible for the formation of the propenal adducts (M1A and M1C) previously reported to be formed in reactions of malonaldehyde with adenosine and cytidine.

Reaction of Malonaldehyde with Adenosine. Formation of a Novel Adduct Containing a Dioxazatricycloundecene Residue in the Base-pairing Region

Abstract Reaction of malonaldehyde with adenosine at pH 4.5 gave three major adducts including a novel one containing diastereomeric dioxazatricycloundecene residue, formed by addition of three malonaldehyde units.

Interactions of sulfanilamide and 2-thiobarbituric acid with malonaldehyde: structure of adducts and implications in determination of oxidative state of nitrite-cured meats

Reaction of malonaldehyde (MA) with 2-thiobarbituric acid (TBA) in model systems resulted in the formation of the typical pink adduct (TMT) with absorption minima at 278, 372, and 532 nm. Reactions of MA with sulfanilamide (SA) produced a bright yellow adduct (SMS) with absorption minima at 256, 332, and 396 nm. Addition of TBA to the MA-SA system resulted in the disappearance of the characteristic absorption bands of SMS and the appearance of the characteristic absorption bands of TBA-MA as well as a new band at 472 nm

Determination of malonaldehyde-modified 2'-deoxyguanosine-3'-monophosphate and DNA by 32P-postlabelling.

The 32P-postlabelling assay was used to determine adducts arising upon the reaction of malonaldehyde with 2'-deoxyguanosine-3'-monophosphate. The adducts formed were isolated, structurally characterized and identified as 3-(2-deoxy-beta-D-erythro-pentafuranosyl)pyrimido[1,2-alpha] purin-10(3H)-one. The kinetics of phosphorylation by T4 polynucleotide kinase was studied using 500 fmol of the synthesized standard and found to reach its maximum after 1 h of incubation. A 60% labelling efficiency was obtained at low concentrations of substrate. The adducted substrate was detected at the sub-femtomolar level. Sensitivity of the adducts towards nuclease P1 3'-dephosphorylation was also tested. The same adduct could be detected from calf thymus DNA that had been reacted in vitro with malonaldehyde, and in DNA isolated from mice treated with [14C]malonaldehyde. DNA adducts formed in vitro were isolated after enzymatic digestion to mononucleotides followed by HPLC fractionation or nuclease P1 digestion of normal nucleotides. A combination of the two procedures proved to be the method of choice for the isolation of the malonaldehyde-DNA adducts formed in vivo prior to applying the 32P-postlabelling assay.

Reaction of malonaldehyde with nucleic acid. IV. Formation of pyrimido(1,2-a)purin-10(3H)-one nucleoside by thermal decomposition of diastereomers containing oxadiazabicyclononene residues linked to guanosine.

The reaction of 1, 1, 3, 3-tetraethoxypropane with guanosine under strongly acidic conditions resulted in the formation of diastereomeric oxadiazabicyclononene residues linked to guanine base. The diastereomers were decomposed by heat, giving changed pyrimido[1, 2-a]purin-10(3H)-one nucleoside (3) in a good yield. A convenient method for the preparation of 3, which includes the thermal decomposition process of the diastereomers, was developed.

Mechanism of horseradish peroxidase-catalyzed oxidation of malonaldehyde

The mechanism of malonaldehyde oxidation by horseradish peroxidase in the presence of manganese(II) and acetate was investigated. Our results show that an apparent oxygenase behavior demonstrated by peroxidase in this system can be explained in terms of normal peroxidase activity. A free radical is generated from the reaction of malonaldehyde with compounds I and II of peroxidase; this radical is scavenged by dissolved molecular oxygen to give the appearance of peroxidase acting as an oxygenase. Oxygen consumption, absorbance spectra, and kinetic results show that the reaction is initiated by autoxidation of malonaldehyde to give a free radical. The radical reacts with oxygen and through the action of manganese(II), a peroxide is generated. This peroxide drives the peroxidase cycle to generate more free radicals which propagate the oxygen consumption reaction.

Comparison of Fluorescence Characteristics of Products of Peroxidation of Membrane Phospholipids with Those of Products Derived from Reaction of Malonaldehyde with Glycine as a Model of Lipofuscin Fluorescent Substances

The fluorescence characteristics of product (I), formed during the lipid peroxidation of rat liver phosphatidylcholine liposomes containing glycine, and fluorescent product (II), derived from the reaction of malonaldehyde with glycine, were examined to elucidate the mechanism of fluorescent chromophore formation. Fluorescent product (I) had a fluorescence emission maximum at 430 nm when excited at 360 nm; its fluorescence intensity decreases in alkaline medium, but is restored by readjustment of pH to neutrality. In contrast, fluorescent product (II) exhibited an emission maximum at 458 nm, and the fluorescence was quenched at acidic pH. The fluorescent substances formed during the lipid peroxidation of hemoglobin-free human erythrocyte ghost membranes had similar fluorescence characteristics to product (I). Gel filtration experiments showed that molecular size of fluorescent product (I) was larger than that of fluorescent product (II). The thiobarbituric acid-reactive substances released from peroxidizing liposomal phospholipids had a larger molecular size than malonaldehyde, and produced little or no fluorescence with glycine. It is concluded that the precursor of the fluorescent product formed during the lipid peroxidation of membrane phospholipids differs from malonaldehyde. The mechanism of the formation of blue emitting fluorescent material, believed to be a component of lipofuscin, seems to involve peroxidized phospholipids of the membrane.

Determination of malonaldehyde in oxidized lipids by the Hantzsch fluorometric method

Malonaldehyde is a secondary product formed during lipid oxidation. We developed a sensitive and reliable Hantzsch fluorometric method for determination of malonaldehyde in oxidized lipids. The principle of the method is based on the formation of highly fluorescent 1,4-dimethyl-1,4-dihydropyridine-3,5-dicarbaldehyde MI by reaction of malonaldehyde, methylamine, and acetaldehyde under neutral conditions. Compound MI formed could be estimated by high-performance liquid chromatography. Free malonaldehyde, that liberated under neutral conditions (labile forms) and that liberated by acid pretreatment (acid labile forms), could be determined by use of the calibration curves of MI versus malonaldehyde sodium salt. Oxidized methyl linoleate with a peroxide value of 1600 neq/mg contained 0.95 (free and labile) and 1.3 nmol (acid labile) malonaldehyde/mg, oxidized sardine oil with a peroxide value of 640 neq/mg contained 1.1 (free and labile) and 3.0 nmol (acid labile) malonaldehyde/mg, and the lipid fraction of oxidized rat liver microsomes contained less than 0.2 (free and labile) and 0.8 nmol (acid labile) malonaldehyde/mg. The malonaldehyde contents were much lower than those obtained by traditional 2-thiobarbituric acid test. It appears likely that the malonaldehyde contents, both free and labile, and acid labile forms, in oxidized lipids are too low to be taken into account.

Structure and properties of the thiobarbituric acid–malonaldehyde chromogen

An X-ray crystallographic study supported by 1H n.m.r. provides unequivocal evidence that the chromogen formed from the reaction of malonaldehyde with 4,6-dihydroxy-2-mercaptopyrimidine (thiobarbituric acid) is the highly stable delocalised anion (2) from 5,5′-(propane-1,3-diylidene)bis-(2-thioxopyrimidine-4,6-dione).

Fluorometric determination of malonaldehyde in oxidized lipids.

Malonaldehyde contents in oxidized lipid samples were determined fluorometrically by applying the reaction reported by Sawicki et al. (Anal. Chem., 35, 199 (1963)). This assay is based on the reaction of malonaldehyde with ethyl p-aminobenzoate in an acidic medium, followed by treatment with alkaline dimethylformamide to afford fluorescence. Time course studies of the malonaldehyde contents in methyl linoleate, soybean oil and sesame oil oxidized by the active oxygen method showed that the contents increased and subsequently decreased with increasing oxidation time. The malonaldehyde contents were always lower than those estimated by means of the thiobarbituric acid method.

Butylated hydroxytoluene addition improves the thiobarbituric acid assay for malonaldehyde from chicken plasma fat.

Samples of plasma lipid were tested for autoxidation during the heating step of the thiobarbituric acid (TBA) assay for malonaldehyde. Butylated hydroxytoluene (BHT) was used to quench sample autoxidation during the assay, and 25 ppm BHT was found effective in eliminating autoxidation in fresh plasma fat. At this concentration, BHT does not interfere with the reaction of malonaldehyde with TBA. Depending on fat concentration, absorbance at 532 nm was 2-5 times higher when samples were assayed without BHT compared to identical samples with 25 ppm BHT addition. It is concluded that BHT addition to the TBA assay before the heating step improves the reliability of the assay by eliminating autoxidation which may generate the majority of oxidative products measured in TBA assays lacking antioxidant protection.