Phenyl- and cyclopentylimino derivatization for double bond location in unsaturated C<Subscript>37</Subscript>-C<Subscript>40</Subscript> alkenones by GC-MS

A method for the identification of double bond locations in polyunsaturated long chain alkenones adapted to nanogram amounts as currently analyzed by gas chromatography coupled to mass spectrometry (GC-MS) has been developed. The method is based on interpretation of the electron impact mass spectra of the imino derivatives of the carbonyl groups using either cyclopentyl or phenyl substitutents. Other complementary derivatization methods such as elaidization and hydrogenation have also been used for structural characterization of these compounds. This application has led to the identification of a novel homologous series of di-, tri-, and tetraunsaturated ketones with carbon number chain lengths between 37 and 40 in coastal hypersaline sediments. The novel series identified shows a distribution in which the double bond position between different homologs is established by reference to the distance from the carbonyl group whereas the previously known alkenones were constituted by unsaturated homologs with double bonds located at defined distances of the terminal methyl. This difference points out to a dissimilar, but still unknown, biogenic precursor of these novel alkenones.     

Characterization of unusual alkenones and alkyl alkenoates by electron ionization gas chromatography/mass spectrometry

Unusual long-chain, diunsaturated alkenones and alkyl alkenoates exhibiting double bonds separated by three methylene units instead of the more usual five were characterized by electron ionization (EI) gas chromatography/mass spectrometry. In a first step, the positions of the double bonds of these compounds (isolated from Holocene Black Sea sediments) were confirmed after OsO4 treatment and silylation. Mass spectra of the resulting tetratrimethylsilyloxy derivatives allowed unambiguous determination of the positions of unsaturations. The EI mass spectra of the non-derivatized compounds were then compared with those of the alkenones and alkyl alkenoates having double bonds separated by five methylene units. Specific fragment ions resulting from gamma-H rearrangements were found to be prominent in EI mass spectra of these unusual 'Black Sea' diunsaturated alkenones and alkyl alkenoates. These fragment ions can be used to characterize these compounds in natural samples without the need for laborious derivatization treatments.     

Non-catalytic liquid phase oxidation of alkenes with nitrous oxide. 1. Oxidation of cyclohexene to cyclohexanone

A very efficient way of alkenes oxidation to carbonyl compounds is discovered. It is based on remarkable ability of nitrous oxide to interact directly with the double C=C bonds of liquid alkene and to transfer its oxygen, without catalyst aid, to unsaturated carbon atom with nearly 100% selectivity. This oxidation method can be applied to a wide range of organic compounds including aliphatic, cyclic, heterocyclic alkenes and their numerous derivatives.     

Derivatization procedures for the detection of beta(2)-agonists by gas chromatographic/mass spectrometric analysis

An evaluation of derivatization procedures for the detection of beta(2)-agonists is presented. The study was performed with the beta(2)-agonists bambuterol, clenbuterol, fenoterol, formoterol, salbutamol, salmeterol and terbutaline. Different derivatizating agents were employed, aiming to obtain derivatives with high selectivity to be used in the gas chromatographic/mass spectrometric analysis of beta(2)-agonists in biological samples. Trimethylsilylation was compared with different agents and the role of some catalysts was evaluated. Acylation, combined trimethylsilylation and acylation, and the formation of cyclic methylboronates were also studied. Sterical hindrance caused by different substituents at the nitrogen atom of the beta-ethanolamine lateral chain of beta(2)-agonist molecules is mainly responsible for differences in the abundances of the derivatives obtained. The use of catalysts produces an increase in the derivatization yield, especially for compounds with low steric hindrance (substituents with primary and secondary carbon atoms). The formation of trimethylsilyl (TMS) ethers is not influenced by structural molecular differences when only hydroxy groups are involved in derivatization. Combined trimethylsilylation and acylation showed that compounds with a secondary carbon atom linked to the nitrogen atom form mainly N-TFA-O-TMS derivatives, with a small amount of N-TMS-O-TMS derivatives. Compounds with tert-butyl substituents at the amino group (bambuterol, salbutamol and terbutaline) formed O-TMS derivatives as the main products, although a limited amount of trifluoroacylation at the nitrogen atom also occurred. Cyclic methylboronates were formed with bambuterol, clenbuterol, formoterol, salbutamol and salmeterol. Owing to hydroxy substituents in unsuitable positions for ring formation, this procedure was not effective for fenoterol and terbutaline. Mass spectra of different derivatives and tentative fragmentation profiles are also shown. For screening purpose (e.g. sports drug testing), derivatization with MSTFA or BSTFA alone is recommended as a comprehensive derivatization technique for beta(2)-agonists owing to minimal by-product formation; formation of cyclic methylboronates can be useful for confirmation purposes. Detection limits were obtained for the TMS and cyclic methylboronate derivatives using the derivatizing reagents MSTFA and trimethylboroxine, respectively. For most of the compounds, lower detection limits were found for the TMS derivatives.     

Trends in structure–toxicity relationships for carbonyl-containing α,β-unsaturated compounds

Using toxicity data for 30 aliphatic polarized α,β-unsaturated derivatives of esters, aldehydes, and ketones, a series of six structure–toxicity relationships were evaluated. The structure feature of all assessed compounds, an acetylenic or olefinic moiety conjugated to a carbonyl group, is inherently electrophilic and conveys the capacity to exhibit enhanced toxicity. However, the toxic potency of α,β-unsaturated carbonyl compounds is dependent on the specific molecular structure with several trends being observed. Specific observations include: (1) between homologues, the acetylenic-substituted derivative was more toxic than the corresponding olefinic-substituted one, respectively; (2) between olefinic-homologues, terminal vinyl-substituted derivative was more toxic than the internal vinylene-substituted one; (3) within α,β-unsaturated ketones, methyl substitution on the vinyl carbon atoms reduces toxicity with methyl-substitution on the carbon atom farthest from the carbonyl group exhibiting the greater inhibition; (4) between α,β-unsaturated carbonyl compounds with the carbon–carbon double bond on the end of the molecule (vinyl ketones) and those with carbon–oxygen double bonds on the end of the molecule (aldehydes), the ketones are more toxic than the aldehydes; (5) between homologues of α,β-unsaturated esters, those with additional unsaturated moieties (allyl, propargyl, or vinyl groups) were more toxic than homologues having relevant unsaturated moieties (propyl or ethyl groups); (6) between α,β-unsaturated carbonyl compounds with different shaped alkyl-groups (i.e. different degrees of branching), homologues with straight-chain hydrocarbon moieties were more toxic than those with branched groups.     

Intramolecularly hydrogen-bonded 3-phenacyl-lH-pyrido[3,4-b]-pyrazin-2-one and 2-Phenacyl-4H-pyrido[3,4-b]pyrazin-3-one

Twelve phenacyl derivatives of 1H-pyrido[3,4-b]pyrazin-2-ones and 4H-pyrido[3,4-b]pyrazin-3-ones have been synthesized. In these compounds, C = N double bonds at the 3 and 4 positions in the former compounds and those at the 1 and 2 positions in the latter compounds migrate onto the side chains to form phenacyli-dene structures. These migrations are facilitated by chelation between side chain carbonyl and the proton attached to the ring nitrogen atom which was generated by the migration. All the hydrogen-bonded structures appear to be stable as shown by their ir spectra in the crystalline state, and by their ¹H nmr spectra in solution.     

Syntheses of Cyclopropylcarbonyl Compounds

There are three important direct routes to cyclopropylcarbonyl compounds: 1. Cyclization of chains of three carbon atoms, the first or third of which is adjacent to a carbonyl or potential carbonyl carbon atom (this type includes syntheses by intramolecular alkylation of γ-halogeno ketones or related compounds in alkaline media); 2. insertion of a methylene group or substituted methylene group into the olefinic double bond of an α,β-unsaturated carbonyl compound; and 3. introduction of an acetonyl group into the double bond of an olefin. However, cyclopropylcarbonyl compounds can also be obtained from 1,2-epoxycyclobutane and 2-bromocyclobutanone derivatives by ring contraction. Another possibility is the dehalogenation of α,α-bis(bromomethyl) cycloalkanones. This review concludes with a discussion of these little known routes and of a particularly suitable method which involves the reaction of methylene iodide, a Zn? Cu couple, and α,β-unsaturated ketones.     

Addition of organometallic compounds to tin-containing cyclic ketones. Remote stereocontrol induced by the stannyl group

The addition of organometallic reagents to cyclic ketones bearing stannyl groups at an appropriate distance to the carbonyl group occurs with a high level of stereocontrol, giving alcohols resulting from attack of the nucleophile syn to the tin center. This remarkable remote control is a consequence of the anchoring of the organometallic reagent by the tin and carbonyl groups. The degree of selectivity observed depends on the spatial distance between the carbonyl group and the tin center. (Z)-beta-Stannylvinyl ketones (Sn/CO separation: 5 bonds) react with organolithium reagents, showing a high degree of stereocontrol. On the contrary, the analogous ketones with E stereochemistry do not show selectivity at all. In the case of beta-stannyl ketones (Sn/CO separation: 3 bonds), the long distance between the tin center and the carbonyl group does not favor selective addition except when allyllithium derivatives are used. A chelation-controlled pathway assisted by the three-carbon chain of the allyl anion, which compensates the distance between tin and carbonyl groups, has been proposed. The selectivity found for ketones 34-36 (Sn/CO separation: 4 bonds) depends on their structure and varies with the hybridization of the carbon atom linked to the trialkyltin group. Deuterium labeling experiments as well as ab initio molecular-orbital analysis support the mechanistic hypothesis of an intramolecular delivery. Grignard reagents are less selective than organolithium compounds.     

Trends in structure-toxicity relationships for carbonyl-containing alpha,beta-unsaturated compounds

Using toxicity data for 30 aliphatic polarized alpha,beta-unsaturated derivatives of esters, aldehydes, and ketones, a series of six structure-toxicity relationships were evaluated. The structure feature of all assessed compounds, an acetylenic or olefinic moiety conjugated to a carbonyl group, is inherently electrophilic and conveys the capacity to exhibit enhanced toxicity. However, the toxic potency of alpha,beta-unsaturated carbonyl compounds is dependent on the specific molecular structure with several trends being observed. Specific observations include: (1) between homologues, the acetylenic-substituted derivative was more toxic than the corresponding olefinic-substituted one, respectively; (2) between olefinic-homologues, terminal vinyl-substituted derivative was more toxic than the internal vinylene-substituted one; (3) within alpha,beta-unsaturated ketones, methyl substitution on the vinyl carbon atoms reduces toxicity with methyl-substitution on the carbon atom farthest from the carbonyl group exhibiting the greater inhibition; (4) between alpha,beta-unsaturated carbonyl compounds with the carbon-carbon double bond on the end of the molecule (vinyl ketones) and those with carbon-oxygen double bonds on the end of the molecule (aldehydes), the ketones are more toxic than the aldehydes; (5) between homologues of alpha,beta-unsaturated esters, those with additional unsaturated moieties (allyl, propargyl, or vinyl groups) were more toxic than homologues having relevant unsaturated moieties (propyl or ethyl groups); (6) between alpha,beta-unsaturated carbonyl compounds with different shaped alkyl-groups (i.e. different degrees of branching), homologues with straight-chain hydrocarbon moieties were more toxic than those with branched groups.     

New synthesis of multi-substituted α-chlorocyclobutanones from 1-chloro-3-cyanoalkyl p-tolyl sulfoxides by 4-Exo-Dig nucleophilic ring closure of magnesium carbenoids to nitrile group as the key reaction

1-Chloro-3-cyanoalkyl p-tolyl sulfoxides were easily prepared from 1-chlorovinyl p-tolyl sulfoxides, which were synthesized from carbonyl compounds and chloromethyl p-tolyl sulfoxide, with lithium α-cyano carbanion of acetonitrile derivatives in good yields. Treatment of these sulfoxides with i-PrMgCl resulted in the formation of multi-substituted α-chlorocyclobutanones in good to high yields via the 4-Exo-Dig nucleophilic ring closure of the generated magnesium carbenoid intermediates to the nitrile group. This procedure provides a new and good way for the synthesis of multi-substituted α-chlorocyclobutanones from carbonyl compounds and substituted acetonitriles with formation of three carbon–carbon bonds in relatively short steps.     

Referees for Volumes 1–2

For toxicological-based structure–activity relationships to advance, will require a better understanding of molecular reactivity. A rapid and inexpensive spectrophotometric assay for determining the reactive to glutathione (GSH) was developed and used to determine GSH reactivity (react_GSH) data for 21 aliphatic derivatives of esters, ketones and aldehydes. From these data, a series of structure–activity relationships were evaluated. The structure feature associated with react_GSH was an acetylenic or olefinic moiety conjugated to a carbonyl group (i.e. polarized α,β-unsaturation). This structure conveys the capacity to undergo a covalent interaction with the thiol group of cysteine (i.e. Michael- addition). Quantitatively react_GSH of the α,β-unsaturated carbonyl compounds is reliant upon the specific molecular structure with several tendencies observed. Specifically, it was noted that for α,β-unsaturated carbonyl compounds: (1) the acetylenic-substituted derivatives were more reactive than the corresponding olefinic-substituted ones; (2) terminal vinyl-substituted derivatives was more reactive than the internal vinylene-substituted ones; (3) methyl substitution on the vinyl carbon atoms diminishes reactivity and methyl-substitution on the carbon atom farthest from the carbonyl group causes a larger reduction; (4) derivatives with carbon–carbon double bond on the end of the molecule (i.e. vinyl ketone) were more reactive than one with the carbon–oxygen bond at the end of the molecule (i.e. aldehyde) and (5) the ester with an additional unsaturated vinyl groups were more reactive than the derivative having an unsaturated ethyl group.     

Synthesis of [59]fullerenones through peroxide-mediated stepwise cleavage of fullerene skeleton bonds and X-ray structures of their water-encapsulated open-cage complexes

Fullerene skeleton modification has been investigated through selective cleavage of the fullerene carbon-carbon bonds under mild conditions. Several cage-opened fullerene derivatives including three [59]fullerenones with an 18-membered-ring orifice and one [59]fullerenone with a 19-membered-ring orifice have been prepared starting from the fullerene mixed peroxide 1, C60(OOtBu)6. The prepositioned tert-butyl peroxy groups in 1 serve as excellent oxygen sources for formation of hydroxyl and carbonyl groups. The cage-opening reactions were initiated by photoinduced homolysis of the tBu-O bond, followed by sequential ring expansion steps. A key step of the ring expansion reactions is the oxidation of adjacent fullerene hydroxyl and amino groups by diacetoxyliodobenzene (DIB). Aminolysis of a cage-opened fullerene derivative containing an anhydride moiety resulted in multiple bond cleavage in one step. A domino mechanism was proposed for this reaction. Decarboxylation led to elimination of one carbon atom from the C60 cage and formation of [59]fullerenones. The cage-opened [59]fullerenones were found to encapsulate water under mild conditions. All compounds were characterized by spectroscopic data. Single-crystal structures were also obtained for five skeleton-modified derivatives including two water-encapsulated fulleroids.     

Structure-activity relationships for reactivity of carbonyl-containing compounds with glutathione

For toxicological-based structure-activity relationships to advance, will require a better understanding of molecular reactivity. A rapid and inexpensive spectrophotometric assay for determining the reactive to glutathione (GSH) was developed and used to determine GSH reactivity (reactGSH) data for 21 aliphatic derivatives of esters, ketones and aldehydes. From these data, a series of structure-activity relationships were evaluated. The structure feature associated with reactGSH was an acetylenic or olefinic moiety conjugated to a carbonyl group (i.e. polarized alpha,beta-unsaturation). This structure conveys the capacity to undergo a covalent interaction with the thiol group of cysteine (i.e. Michael- addition). Quantitatively reactGSH of the alpha,beta-unsaturated carbonyl compounds is reliant upon the specific molecular structure with several tendencies observed. Specifically, it was noted that for alpha,beta-unsaturated carbonyl compounds: (1) the acetylenic-substituted derivatives were more reactive than the corresponding olefinic-substituted ones; (2) terminal vinyl-substituted derivatives was more reactive than the internal vinylene-substituted ones; (3) methyl substitution on the vinyl carbon atoms diminishes reactivity and methyl-substitution on the carbon atom farthest from the carbonyl group causes a larger reduction; (4) derivatives with carbon-carbon double bond on the end of the molecule (i.e. vinyl ketone) were more reactive than one with the carbon-oxygen bond at the end of the molecule (i.e. aldehyde) and (5) the ester with an additional unsaturated vinyl groups were more reactive than the derivative having an unsaturated ethyl group.     

Reactivity of pyrrol-2-ones. (review)

Published data on the chemical transformations of pyrrol-2-ones are reviewed and analyzed. The extensive synthetic possibilities of compounds containing a pyrrolone ring in the synthesis of various heterocyclic compounds with complex structures are demonstrated. The reactions are arranged according to the reaction centers of the pyrrol-2-ones: The methylene unit, the C=C double bond, the electron-deficient carbon atom of the carbonyl group.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1443–1463, October, 2004.     

Tunable delocalization of unpaired electrons of nitroxide radicals for sickle-cell disease drug improvements

Hydroxyurea is a drug recently approved to treat sickle cell diseases. Hydroxyurea benefits the patients by increasing the level of fetal hemoglobin via a nitroxide radical pathway. Here, we report an unpaired-electron-delocalization approach to tune the stability of nitroxide radicals. In this approach, the substitution by an unsaturated alkyl group containing conjugated C=C double bonds for the hydrogen on the nitrogen atom attached to the hydroxyl of hydroxyurea can significantly increase its ability to generate nitroxide radical. Furthermore, the increase can be remarkably enhanced by increasing the number of conjugated C=C double bonds. For a hydroxyurea derivative that contains two conjugated C=C double bonds, the reaction rate to generate its radical is 118 times faster than that of hydroxyurea, and for a hydroxyurea derivative containing 20 conjugated C=C double bonds, the reaction rate to form its radical is 238 times faster than that of hydroxyurea. For this reason, hydroxyurea derivatives with conjugated C=C double bonds may constitute new potential drugs for the treatment of sickle-cell diseases.     

Ligand properties of aromatic azines: C-H activation, metal induced disproportionation and catalytic C-C coupling reactions

The reaction of aromatic azines with Fe₂(CO)₉ yields dinuclear iron carbonyl cluster compounds as the main products. The formation of these compounds may be rationalized by a C-H activation reaction at the aromatic substituent in ortho position with respect to the exocyclic C-N double bond followed by an intramolecular shift of the corresponding hydrogen atom toward the former imine carbon atom. The second imine function of the ligand does not react. Additional products arise from the metal induced disproportionation of the azine into a primary imine and a nitrile. So also one of the imine C-H bonds may be activated during the reaction. Depending on the aromatic substituent of the azine ligands iron carbonyl complexes of the disproportionation products are isolated and characterized by X-ray crystallography. C-C coupling reactions catalyzed by Ru₃(CO)₁₂ result in the formation of ortho-substituted azines. In addition, ortho-substituted nitriles are identified as side-products showing that the metal induced disproportionation reaction also takes place under catalytic conditions.     

Mass spectra of N-substituted cantharidinimides

The mass spectra of a series of N-substituted cantharidinimides were examined. The feature of this series compounds is a sequential double hydrogen transfer from the oxabicycloheptane unit to either the carbonyl group of the succinimide unit or the nitrogen atom of the pyridyl or thiazolyl substituent through space. The ability of the N-substituent to accept a hydrogen atom possibly leads to the different fragmentation pathway.     

New possibilities of dimethylformamide dimethylacetal as a derivatization agent for gas chromatography/mass spectrometry analysis

It is shown that the use of dimethylformamide dimethylacetal for the derivatization of analytes in gas chromatography/mass spectrometry cannot be restricted by the known conversion of carboxylic acids, phenols, and thiols into their methyl esters (ethers), as well as by the conversion of non-volatile amino acids (and C-amino compounds of other classes) into their dimethylaminomethylene derivatives. The application of this reagent to the derivatization of hydrazine derivatives and volatile carbonyl-containing analytes is considered. In the last case, the reaction proceeds selectively via CH₂ and/or CH₃ groups in the α-position to the carbonyl fragment. The principal predestination of the derivatization of such analytes is their characterization by differences of gas-chromatographic retention indices (ΔRI) of reaction products and initial substrates. The ranges of variation of such increments, ΔRI, appeared to be different for different subgroups of carbonyl compounds; this allowed us to determine their structures more precisely. The mass spectra of C-dimethylaminomethylene derivatives of some carbonyl compounds, preferably 2-substituted 1-methyl- and 1-aryl-3-(dimethylamino) prop-2-en-1-ones, revealed intense [M–17] peaks. The appearance of these signals can be explained by the migration of a hydrogen atom and the formation of [М–ОН]⁺ ions.     

Molecular orbital analysis of the XPS spectra of PMDA-ODA polymide and its polyamic acid precursor

The calculated carbon 1s (C1s) core energy-level positions of PMDA-ODA polymide and of its polyamic acid precursor are compared with the level positions inferred from XPS measurements. For the polyamic acid, calculation and experiment both yield a difference of approximately 1 eV between the carboxylic acid and the amide carbonyl C1s level positions. The difference in shape between the main C1s XPS peaks of the polyamic acid and polyimide is shown to be related to the difference in C1s core energy-level shifts of the carbon atoms composing the benzene ring adjacent to the amide or imide group. The planar imide or PMDA structure apparently yields larger core level shifts for these atoms. We have previously designated these atoms as “imide carbon atoms” (C-Im) to distinguish them from the aromatic carbon atoms (C-C) of the ODA part of the polymeric repeat unit. Comparison of the carbonyl XPS band intensities with the main peak intensities for the polyamic acid, as well as for the polyimide, suggests that there is a carbonyl deficiency at the surface of both of these materials.