Exocyclic Methylene Research Articles

Mono-, bi- and polynuclear complexes of diphenylmethane with Cr, Co and Ru. Synthesis and investigation by 1H, 13C and 17O NMR

Complexes of diphenylmethane (Ph2CH2): Ph2CH2Cr(CO)3 (1), Ph2CH2[Cr(CO)3]2 (2), Ph2CH2Co4 (CO)9 (3), Ph2CH2[Co4(CO)9]2 (4), Ph2CH2Cr(CO)3Co4(CO)9 (5) and Ph2CH2Ru6C(CO)14 (6) have been prepared and characterized by 1H and 13C-and17O-NMR spectroscopy. Strong shielding effects are caused by the metal valence electrons on the 1H- and 13C-NMR chemical shifts of aromatic protons and carbons in π-coordinated ring(s) diphenylmethane. Generally, the order of these shielding effects on the nuclei of the aromatic rings in 1H-NMR was Co4(CO)9 <Ru6C(CO)14 <Cr(CO)3 and in 13C-NMR Co4(CO)9<Cr(CO)3<Ru6C(CO)14. In addition, aromatic solvent exhibits an enhanced shielding effect on the 1H-NMR chemical shifts of the π-coordinated ring induced probably by aromatic solvent induced shifts (ASIS). The 1H-NMR chemical shifts of the exocyclic methylene protons are shielded or deshielded depending on the solvent, the metal and the degree of π-coordination. These findings can be explained by the varying conformational states adopted by the flexible ligand. The13C-NMR chemical shifts of the methylene carbon are generally shielded supporting the above explanation. This conformational flexibility can be of extreme importance in controlling the catalytic activity of these organometallic compounds. In chromium and heterobimetallic chromium cobalt derivatives1, 2 and5, 17O-NMR spectroscopy proved to have excellent sensitivity comparable with that of 13C-NMR. In cobalt clusters3 and4 no 17O-NMR lines were observed, which is probably because of strongly broadened 17O-NMR signals of carbonyls undergoing dynamic exchange. In the ruthenium cluster6 only one broad 17O-NMR line at 30°C was observed. An inverse relation between the 13C- and 17O-NMR chemical shifts of the carbonyl groups can be explained by the effect of π-backbonding.

Excited states and photochemical reactivity of fulvene. A theoretical study

Semiempirical and ab initio calculations including electron correlation have been carried out for the ground and excited states of fulvene. Vertical singlet and triplet excitation energies including several Rydberg transitions, which have been calculated using an extended basis set augmented with even tempered diffuse functions, are in good agreement with experiment. Spectroscopic minima were obtained for the 1A1(S2) and 3B2(T1) states of planar fulvene, and on the semiempirical level also for the 1A″(S1) state, which is only of Cs symmetry. Twisting of the exocyclic double bond was studied by means of correlation diagrams as well as by calculating potential energy hypersurfaces. At 90° twist all stationary points are identified as transition states at the ab initio level, while two minima (S0 and S2) and one transition state (T1) result from the semiempirical calculations. Taking into account pyramidalization of the exocyclic methylene group yields a minimum for the T1 state and a conical intersection of the S1 and S0 states, which is not identical with the one that is to be expected for a critically heterosymmetric biradicaloid. The photochemistry of fulvene is being discussed in the light of the present results.

Molecular modeling of the conformational and sodium ion binding properties of the oligosaccharide component of ganglioside GM1.

The receptor-like recognition behavior of the GM1 ganglioside has been examined theoretically in terms of conformational and binding properties. Modeling was conducted at two limiting conditions of dielectric constant in order to determine sensitivity to scaling of coulombic interactions. A systematic conformational search of the GM1 oligosaccharide in the absence of explicit solvent molecules indicates that there are many inherently low energy conformational states. Up to 39 conformers were found with energies within 5 kcal/mole of the observed lowest energy conformer. Using a dielectric constant of 80, a systematic search of sodium binding sites on GM1 identified 37 sites where a positively charged group might bind, while at least 12 sites were identified using a dielectric constant of 1. Notably important binding sites include pockets formed by the proximity of glycosidic (O1), sugar ring (O5), and exocyclic methylene hydroxyl (OH6) oxygens on the sugars. The oxygens of acetyl groups attached to sugars also contribute to the binding. Direct coordination with the carboxylate of sialic acid is not a prerequisite for cationic binding. The large number of conformational states and binding sites for the GM1 oligosaccharide are paradoxical to the specific recognition behavior of the molecule. This paradox can be explained in terms of bridging ligands, which are found from molecular dynamics to be capable of stabilizing molecular conformation.

Evidence from 18O Exchange Studies for an Exocyclic Methylene Intermediate in the Reaction Catalyzed by T4 Deoxycytidylate Hydroxymethylase

18O exchange experiments were designed to identify the final intermediate in the catalytic mechanism of bacteriophage T4 deoxycytidylate (dCMP) hydroxymethylase (CH). CH catalyzes the formation of 5-(hydroxymethyl)-dCMP (HmdCMP) from dCMP and methylenetetrahydrofolate (CH2-THF). CH resembles thymidylate synthase (TS), an enzyme of known three-dimensional structure, in both amino acid sequence and the reaction catalyzed. The final intermediate in the reaction catalyzed by TS or CH has been proposed to be the nucleotide with an exocyclic 5-methylene group covalently linked to the enzyme. This intermediate is then hydrated to HmdCMP (by CH) or reduced to deoxythymidylate (by TS). We report here that CH catalyzes the incorporation of 18O from solvent water into the product, HmdCMP, in the presence of tetrahydrofolate (THF). The cause of this exchange is a reverse reaction followed by a resynthesis. CH also catalyzes the exchange of 18O from solvent water into HmdCMP in the absence of exogenous THF and in the presence of THF analogues that lack N-5. N-5 is the nitrogen that is likely to be bound to the methylene as it is transferred to dCMP. A CH variant that lacks the nucleophilic Cys 148 is incapable of promoting these 18O exchange reactions. The THF analogues lacking N-5 do not promote a CH-catalyzed reverse reaction. Rather, we propose that the CH-catalyzed 18O exchange reaction promoted by these THF analogues occurs via 5-methylene-dCMP linked to the enzyme through Cys 148. We conclude here that enzyme-bound 5-methylene-dCMP is the final intermediate during catalysis by CH, as has also been proposed for TS and dUMP.

Synthesis of spiro-substituted 1,3-oxazines by a new sequence leading to spiroheterocycles

The target compounds, i.e. 1,3-oxazines which are spiro-substituted in position 6 by a piperidine moiety, are derived from 1-oxa-3,9-diaza-spiro[5.5]undecane, a novel heterocyclic parent system. They were all approached by the following three-step sequence: 1,3-dipolar cycloadditions of nitrile oxides and nitrones to piperidines bearing an exocyclic methylene group gave the corresponding spiro-substituted oxazole derivatives3. In a consecutive step these were cleaved by hydrogenolysis to γ-amino-alcohols4, which in a final step were recyclized by insertions of a C1-unit to yield the target structures5–10: thus ade facto ring-extension of spiro-oxazoles to spiro-oxazines was accomplished.

Efficient Preparation of Novel Exocyclic Methylene Derivatives of Qinghaosu (Artemisinin) as Potential Antimalarial Agents

Abstract Two new exocyclic methylene derivatives 4 and 6 of Qinghaosu (1) a potent antimalarial, have been prepared by a facile and convenient one step synthetic route.

2,6-Bis[(4-methyl-1-piperazinyl)methyl]-4-nitrophenol

In the title compound, C 18 H 29 N 5 O 3 , each piperazine ring assumes a «perfect chair» conformation with the exocyclic methyl group in an equatorial position. The nitro group makes a dihedral angle of 5.5 (1) o with the mean plane of the phenyl ring. Best planes through the four non-N atoms of each of the two piperazine rings make a dihedral angle of 29.9 (1) o with one another

ChemInform Abstract: A Palladium Way to Exocyclic Methylene by Formal Antithermodynamic Isomerization of an Endocyclic Double Bond to an Exo Position.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Alkaline Hydrolysis of Cefotaxime. A HPLC and 1H nmR Study

A kinetic study on the alkaline hydrolysis of cefotaxime at pH 10.5 and 37°C has been carried out by using HPLC and 1HnmR. The main resulting degradation products have been isolated and identified. These include, apart from the well-known deacetylcefo- taxime, the exocyclic methylene derivative, the 7-epimer of cefotaxime and the 7-epimer of deacetylcefotaxime. The kinetic constants involved in the process have been determined and according to the experimental results the attack of the hydroxyl group on the ester function bonded to the 3’-carbon is the fastest step in the proposed kinetic scheme. It should be emphasized that the base-catalyzed epimerization of the hydrogen at the 7 position clearly depends on the presence of a good electron-withdrawing group at C(3’). On the other hand, no hydrolysis of the amide at position 7 was detected.

Stereospecific assignment of exocyclic methylene protons in panose by 13C‐filtered 1D TOCSY

AbstractThe C‐6‐methylene protons in the internal glucosyl unit of panose, D‐Glc‐α(1 → 6)‐D‐Glc‐α(1 → 4)‐D‐Glc(α,β), were stereospecifically assigned. The assignment strategy involved the measurement of the long‐range 3J(C‐4, H‐6R) and 3J(C‐4,H‐6S) coupling constants for this residue in panose, with natural 13C isotope abundance, using a newly designed 13C‐filtered 1D TOCSY experiment.

Synthesis and some conversions of 4-aryl-6-methyl-2-methoxy(phenyl)-5-nitro-1,4-dihydropyrimidines

The reaction of 1-arylidene-1-nitropropan-2-ones with O-methylisourea (or benzamidine) in the presence of aluminum oxide gave 4-aryl-6-methyl-2-methoxy(phenyl)-5-nitro-1,4-dihydropyrimidines. It was shown that the reactions of the compounds synthesized with electrophilic agents proceed at the exocyclic methyl group, as well as at the N(1), N(3), and C(5) atoms of the 1,4-dihydropyrimidine fragment of the molecule.

Tests of a model for promoter recognition by T7 RNA polymerase: thymine methyl group contacts.

The DNA-dependent RNA polymerase from bacteriophage T7 is highly specific for a 17 base promoter sequence. Interactions between T7 RNA polymerase and its promoter DNA have been probed using modified oligonucleotides and a steady-state kinetic assay. The incorporation of deoxyuridine in place of thymidine at individual sites in the promoter sequence results in the replacement of an exocyclic methyl group by hydrogen (effectively removing the thymine methyl). This substitution has been placed individually at each of the thymines in the T7 consensus promoter. Many of these substitutions do not affect binding or catalysis; however, the thymine methyl group at position-6 is critical to recognition. The kinetic parameter Km increases approximately 10-fold while kcat is only slightly affected, suggesting that this thymine methyl is critical to binding specificity, but not to the kinetics of initiation. Two methyl groups near the start site on the template strand (at positions -1 and -3) also contribute to promoter specificity, while nearby methyl groups on the nontemplate strand do not. The implications of these results are discussed with respect to recent models for promoter binding.

Research on 4H-3,1-benzoxazines. 9. 2-Alkyl(aryl, furyl)-4H-3,1-benzoxazinium perchlorates and their transformations

A new method was developed for obtaining 4,4-diphenyl-4H-3,1-benzoxazinium Perchlorates by acylation of o-aminophenyldiphenylcarbinol with organic acids in the presence of perchloric acid. Weak CH acidity of the exocyclic methyl group of the corresponding perchlorate was observed.

Synthesis and Molecular Structure of Heterocycles Containing two Phosphorus(V) Centers Bridged by Two‐Coordinate Phosphorus and Arsenic

Abstract1,1‐Bis[(diphenylphosphanyl)methyl]ethene (3) reacts with PCl3 or AsCl3 in the presence of SnCl2 as a reducing agent to form cationic heterocycles in which the two newly generated phosphonium centers are bridged by two‐coordinate, negatively charged phosphorus (4a) or arsenic (4b) centers. Hexachlorostannate(IV) dianions function as counterions to these heterocycles, in which the exocyclic methylene group is retained. By treatment of 4a with a base a rearrangement is induced which includes a proton migration from an endo‐to the exocyclic CH2 group to give 5‐methyl‐1,1,3,3‐tetraphenyl‐1λ5,2λ3,3λ51‐triphosphinine (5), a novel 1,2,3‐triphosphabenzene species. The reaction of the arsenic compound 4b with base did not yield the corresponding arsa‐diphosphabenzene, but gave only decomposition products. Compound 4b · 0.5 CH3CN has been studied by X‐ray crystallography. The six‐membered heterocycle shows a chair conformation with an arsenic atom solely coordinated by two phosphorus atoms at roughly equal distances with a sharp angle P – As – P of only 93.0(1)°.

Chemically modified field-effect transistors; potentiometric Ag+ selectivity of PVC membranes based on macrocyclic thioethers

A chemically modified field-effect transistor (CHEMFET) with satisfactory Ag+ selectivity is described. The potentiometric Ag+ selectivities of CHEMFETs with plasticized PVC membranes based on macrocyclic thioethers have been determined. All the macrocyclic thioethers tested showed silver response and a selectivity towards Ag + and Hg2+ versus other interfering cations. The highest Ag+ selectivity was obtained for a 14-membered cyclic tetrathioether with an exocyclic methylene group.

The structure of ajabicine, a novel diterpenoid alkaloid from Delphinium ajacis

The structure of ajabicine, a novel diterpenoid alkaloid from Delphinium ajacis, has been established as 1. This is the first diterpenoid alkaloid bearing a C-14 exocyclic methylene group.

A Palladium Way to Exocyclic Methylene by Formal Anti-thermodynamic Isomerization of an Endocyclic Double Bond to an Exo Position

Exocyclic methylene group is prepared by the palladium-catalyzed hydrogenolysis of endocyclic allylic formates. Endocyclic double bonds of allylic sulfones and allylic nitro compounds are isomerized to exo position by the palladium-catalyzed hydrogenolysis with triethylammonium formate.

The syntheses of 1R- and 1S-5-methylenylcamphor and their epoxidation by cytochrome P-450-CAM

The syntheses of 1R- and 1S-5-methylenylcamphor, camphor analogues in which the two methylene hydrogens at C-5 have been replaced with an exocyclic methylene group, are described. The stereospecific epoxidations of both olefins by Pseudomonas putida cytochrome P450-CAM to give the exo-epoxides are reported. The turnover rates for the epoxidation of the 1R and 1S olefins are ten- and three-fold slower, respectively, than the rates of hydroxylation of 1R- and 1S-camphor.

Substituted Benzamides with Conformationally Restricted Side Chains. 3. Azabicyclo[x.y.0] derivatives as gastric prokinetic agents.

The effect of alteration of ring size, introduction of alternative substituents and insertion of an exocyclic methylene group on the gastric prokinetic and dopamine antagonist activity of azabicyclic benzamides related to the serotonin 5-HT 4 agonist. BRL 20627 (2) is described.

Identification of a cysteinyl adduct of oxidized 3-methylindole from goat lung and human liver microsomal proteins.

3-Methylindole is a selective pneumotoxin that is oxidized by cytochrome P-450 enzymes to a reactive intermediate. 3-Methyleneidolenine, a methylene imine electrophile, is the postulated reactive intermediate, and it binds to proteins, a reaction that probably initiates the pneumotoxicity of 3-methylindole. Thioether adducts of this electrophile are formed with glutathione in vitro, but the identity of the adducted electrophile with amino acid residues of microsomal proteins had not previously been determined. 3-Methylindole was incubated with NADPH and goat lung or human liver microsomal proteins, and the proteins were hydrolyzed. 3-(Cystein-S-ylmethyl)indole was isolated and identified as the major amino acid adduct of 3-methyleneindolenine, demonstrating that cysteine thiols preferentially attack the exocyclic methylene position and result in a covalently (thioether) attached 3-methylindole residue to these pulmonary and hepatic proteins. These results demonstrate that the putative methylene imine intermediate is indeed the active electrophile that binds to proteins and presumably initiates the toxic events.