Monoadduct Formation Research Articles

Reactivity of Open-Shell Metallofullerene Anions: Synthesis, Crystal Structures, and Electrochemical Properties of Benzylated Gd@C2v-C82

The reactivity of the open-shell Gd@C2v-C82 with different charge states towards benzyl bromide was investigated. [Gd@C2v-C82]3− exhibited enhanced activity relative to Gd@C2v-C82 and [Gd@C2v-C82]−. The structural characterizations, including MALDI-TOF MS, UV-vis-NIR, and single crystal X-ray diffraction, indicate the formation of isomeric benzyl monoadducts of Gd@C2v-C82. All three monoadducts contain 1:1 mirror-symmetric enantiomers. Additionally, the addition of the benzyl group and its specific position result in distinct electrochemical behavior of the products compared to the parent Gd@C2v-C82. Theoretical studies demonstrate that only [Gd@C2v-C82]3− has a HOMO energy level that matches well with the LUMO energy level of the PhCH2 radical, providing a rationalization for the observed significantly different reactivity.

Relative contributions of endogenous and exogenous formaldehyde to formation of deoxyguanosine monoadducts and DNA-protein crosslink adducts of DNA in rat nasal mucosa.

Understanding the dose-response for formaldehyde-induced nasal cancer in rats is complicated by (1) the uneven distribution of inhaled formaldehyde across the interior surface of the nasal cavity and, (2) the presence of endogenous formaldehyde (endoF) in the nasal mucosa. In this work, we used computational fluid dynamics (CFD) modeling to predict flux of inhaled (exogenous) formaldehyde (exogF) from air into tissue at the specific locations where DNA adducts were measured. Experimental work has identified DNA-protein crosslink (DPX) adducts due to exogF and deoxyguanosine (DG) adducts due to both exogF and endoF. These adducts can be considered biomarkers of exposure for effects of endoF and exogF on DNA that may be part of the mechanism of tumor formation. We describe a computational model linking CFD-predicted flux of formaldehyde from air into tissue, and the intracellular production of endoF, with the formation of DPX and DG adducts. We assumed that, like exogF, endoF can produce DPX. The model accurately reproduces exogDPX, exogDG, and endoDG data after inhalation from 0.7 to 15 ppm. The dose-dependent concentrations of exogDPX and exogDG are predicted to exceed the concentrations of their endogenous counterparts at about 2 and 6 ppm exogF, respectively. At all concentrations examined, the concentrations of endoDPX and exogDPX were predicted to be at least 10-fold higher than that of their DG counterparts. The modeled dose-dependent concentrations of these adducts are suitable to be used together with data on the dose-dependence of cell proliferation to conduct quantitative modeling of formaldehyde-induced rat nasal carcinogenicity.

Proliferating Stem Cells are Acutely Affected by DNA Damage Induced by Sulfur Mustard.

Sulfur mustard (SM), a chemical warfare agent, can form adducts with DNA, RNA, and proteins. Reactions with DNA lead to the formation of both DNA monoadducts and interstrand cross-links, resulting in DNA damage, and is an important component of SM toxicity. Our previous in vivo studies indicated that dividing cells such as hematopoietic stem cells and intestinal villi stem cells seemed to have increased sensitivity to SM. Therefore, to compare the sensitivity of somatic and stem cells to SM and to investigate the mechanism of SM cytotoxicity, we isolated human foreskin fibroblasts, reprogrammed them into pluripotent stem cells, and then compared the DNA damage repair pathways involved upon SM treatment. Our results indicated that proliferating stem cells were more sensitive to SM-induced DNA damage, and the damage mainly comprised single-stranded breaks. Furthermore, the pathways involved in DNA repair in stem cells and somatic cells were different.

Regioselective Synthesis, Crystallographic Characterization, and Electrochemical Properties of Pyrazole- and Pyrrole-Ring-Fused Derivatives of Y2 @C3v (8)-C82.

Chemical modification of endohedral metallofullerenes (EMFs) is an efficient strategy to realize their ultimate applications in many fields. Herein, we report the highly regioselective and quantitative mono-formation of pyrazole- and pyrrole-ring-fused derivatives of the prototypical di-EMF Y2 @C3v (8)-C82 , that is, Y2 @C3v (8)-C82 (C13 N2 H10 ) and Y2 @C3v (8)-C82 (C9 NH11 ), from the respective 1,3-dipolar reactions with either diphenylnitrilimine or N-benzylazomethine ylide, without the formation of any bis- or multi-adducts. Crystallographic results unambiguously reveal that only one [6,6]-bond out of the twenty-five different types of nonequivalent C-C bonds of Y2 @C3v (8)-C82 is involved in the 1,3-dipolar reactions. Our theoretical results rationalize that the remarkably high regioselectivity and the quantitative formation of mono-adducts are direct results from the anisotropic distribution of π-electron density on the C3v (8)-C82 cage and the local strain of the cage carbon atoms as well. Interestingly, electrochemical and theoretical studies demonstrate that the reversibility of the redox processes, in particular the reversibility of the reductive processes of Y2 @C3v (8)-C82 , has been markedly altered upon exohedral functionalization, but the oxidative process was less influenced, indicating that the oxidation is mainly influenced by the internal Y2 cluster, whereas the reduction is primarily associated with the fullerene cage. The pyrazole and pyrrole-fused derivatives may find potential applications as organic photovoltaic materials and biological reagents.

Reactions between N-Heterocyclic Carbene and Lutetium–Metallofullerenes: High Regioselectivity Directed by Electronic Effect in Addition to Steric Hindrance

The Lewis acid-base pairing reaction between strained N-heterocyclic carbene (NHC) and endohedral metallofullerenes (EMFs) is an efficient strategy to obtain stable derivatives in a highly regioselective manner. Herein, we report an in-depth study on the reactions between 3-dimesityl-1 H-imidazol-3-ium-2-ide (1) and three different EMFs, namely, Lu3N@ Ih(7)-C80, Lu2@ C3 v(8)-C82, and Lu2@ C2 v(9)-C82, respectively. Only one monoadduct is obtained for each EMF under certain conditions, demonstrating surprisingly high regioselectivity and exclusive formation of monoadducts. X-ray results of the derivatives of Lu3N@C80 reveal that an epoxide adduct (2a) with a specific [6,6,6]-carbon atom of the C80 cage singly bonded to the normal carbene center (C2) of the NHC is obtained under ambient condition, whereas a pure argon atmosphere gives 2b with an abnormal C5-bonding structure. In contrast, the derivatives of Lu2@C82 (3 and 4) are both normal C2-bonding [5,6,6]-adducts without oxygen addition, even though air is involved in the reaction. Our theoretical results confirm that the remarkably high regioselectivity and the quantitative formation of monoadducts are direct result from the distributions of molecular orbital and electrostatic potential on the cage surfaces in addition to the previously assumed steric hindrance between the fullerene cage and the NHC moiety.

Reactivity Enhancement of a Zerovalent Diboron Compound by Desymmetrization.

The desymmetrization of the cyclic (alkyl)(amino)carbene-supported diboracumulene B2(cAACMe)2 (cAACMe = 1-(2,6-diisopropylphenyl)-3,3,5,5-tetramethylpyrrolidin-2-ylidene) by monoadduct formation with IMeMe (1,3-dimethylimidazol-2-ylidene) yields the zerovalent sp-sp2 diboron compound B2(cAACMe)2(IMeMe), which provides a versatile platform for the synthesis of novel symmetrical and unsymmetrical zerovalent sp2-sp2 diboron compounds by adduct formation with IMeMe and CO, respectively. Furthermore, B2(cAACMe)2(IMeMe) displays enhanced reactivity compared to its symmetrical precursor, undergoing spontaneous intramolecular C-H activation and facile twofold hydrogenation, the latter resulting in B-B bond cleavage and the formation of the mixed-base parent borylene (cAACMe)(IMeMe)BH.

Lewis Acid-Base Adducts of Sc2C2@C3v(8)-C82/N-Heterocyclic Carbene: Toward Isomerically Pure Metallofullerene Derivatives.

The addition of a bulky N-heterocyclic carbene (NHC) to Sc2C2@C3v(8)-C82 affords two monoadducts (2a and 2b) quantitatively and regioselectively, representing the first examples of Lewis acid-base pairs of metal carbide cluster fullerenes. 2b is likely a kinetically favorable labile product that cannot be isolated from the solution. The crystallographic results of 2a unambiguously demonstrate that one polarized C-C single bond is formed between the normal carbene site C2N of the NHC and a specific [5,6,6]-carbon atom out of 17 types of nonequivalent cage carbon atoms of Sc2C2@C3v(8)-C82. Theoretical calculations demonstrate that the high regioselectivity, the unexpected addition pattern, and the quantitative formation of monoadducts are synergistic results from the cage geometry and electron distribution on the cage.

Formation of Perfluoroalkyl Fullerene Alkylphosphonic Acid Self-Assembled Monolayers on Aluminum Oxide

The possibility of fabricating self-assembled monolayers (SAMs) from alkylphosphonic acids functionalized with trifluoromethyl derivatives of C60 on a metal oxide surface has been demonstrated in this work. Using several trifluoromethylfullerenes (TMFs) of different compositions and isomeric structures, we explored their relative reactivities in the Bingel-Hirsch cycloaddition reactions with 11-(diethoxyphosphoryl)undecyl methyl malonate for the first time. Only two isomers of C60(CF3)10 showed fairly selective monoadduct formation, whereas compounds with lower CF3 content showed no selectivity. Converting the phosphonic ester into a phosphonic acid moiety enabled the successful formation of self-assembled monolayers of the TMF-alkylphosphonic acid on aluminum oxide surfaces. Comparison with analogous SAMs made with underivatized C60 showed that TMFs form more hydrophobic surfaces.

Photosensitivity to Triflusal: Formation of a Photoadduct with Ubiquitin Demonstrated by Photophysical and Proteomic Techniques.

Triflusal is a platelet aggregation inhibitor chemically related to acetylsalicylic acid, which is used for the prevention and/or treatment of vascular thromboembolisms, which acts as a prodrug. Actually, after oral administration it is absorbed primarily in the small intestine, binds to plasma proteins (99%) and is rapidly biotransformed in the liver into its deacetylated active metabolite 2-hydroxy-4-trifluoromethylbenzoic acid (HTB). In healthy humans, the half-life of triflusal is ca. 0.5 h, whereas for HTB it is ca. 35 h. From a pharmacological point of view, it is interesting to note that HTB is itself highly active as a platelet anti-aggregant agent. Indeed, studies on the clinical profile of both drug and metabolite have shown no significant differences between them. It has been evidenced that HTB displays ability to induce photoallergy in humans. This phenomenon involves a cell-mediated immune response, which is initiated by covalent binding of a light-activated photosensitizer (or a species derived therefrom) to a protein. In this context, small proteins like ubiquitin could be appropriate models for investigating covalent binding by means of MS/MS and peptide fingerprint analysis. In previous work, it was shown that HTB forms covalent photoadducts with isolated lysine. Interestingly, ubiquitin contains seven lysine residues that could be modified by a similar reaction. With this background, the aim of the present work is to explore adduct formation between the triflusal metabolite and ubiquitin as model protein upon sunlight irradiation, combining proteomic and photophysical (fluorescence and laser flash photolysis) techniques. Photophysical and proteomic analysis demonstrates monoadduct formation as the major outcome of the reaction. Interestingly, addition can take place at any of the ε-amino groups of the lysine residues of the protein and involves replacement of the trifluoromethyl moiety with a new amide function. This process can in principle occur with other trifluoroaromatic compounds and may be responsible for the appearance of undesired photoallergic side effects.

Unusual Example of Chelate Ring Opening upon Coordination of the 9-Ethylguanine Nucleobase to [Pt(di-(6-methyl-2-picolyl)amine)Cl]Cl.

Anticancer-active monofunctional Pt(II) complexes have bulky carrier ligands and bind to G residues in DNA, causing structural distortions. To gain fundamental chemical information on such monofunctional adducts, we assessed the 9-ethylguanine (9-EtG) adducts formed by [Pt(N(H)6,6'-Me2dpa)Cl]Cl (N(H)6,6'-Me2dpa = di-(6-methyl-2-picolyl)amine). 9-EtG added to [Pt(N(H)6,6'-Me2dpa)Cl]Cl to form not only the expected [Pt(N(H)6,6'-Me2dpa)(9-EtG)](2+) monoadduct having syn and anti conformers but also a [Pt(N(H)6,6'-Me2dpa)(9-EtG)2](2+) bisadduct consisting of ΛHT and ΔHT conformers (HT = head-to-tail). For both adducts, the two conformers exist as a dynamic equilibrium mixture. Concomitant with formation of the bisadduct, the binding mode of the N(H)6,6'-Me2dpa ligand converts from tridentate to bidentate. A Pt(II)-bound 6-methyl-2-picolyl chain and the secondary amine constitute the bidentate chelate ring. The other 6-methyl-2-picolyl chain is dangling. The secondary nitrogen is an asymmetric center, and each conformer exists as a racemic mixture of two enantiomers. For a given configuration at the secondary amine of the [Pt(N(H)6,6'-Me2dpa)(9-EtG)2](2+) adduct, the more abundant HT conformer can form a hydrogen bond between the NH of the bidentate ligand and the cis 9-EtG O6. [Pt(N(H)6,6'-Me2dpa)Cl]Cl forms the monoadduct in ∼1/20 the time for its parent, [Pt(N(H)dpa)Cl]Cl (N(H)dpa = di(2-picolyl)amine), which exhibited typical behavior in forming only a monoadduct. We attribute the unusual new findings for [Pt(N(H)6,6'-Me2dpa)Cl]Cl to Pt-N bond weakening induced by the steric bulk of 6/6'-Me groups. We hypothesize that undetectable intermediates with a dangling 6-methyl-2-picolyl chain facilitate both rapid monoadduct formation and also bisadduct formation. Consistent with the intermediacy of such species with a dangling chain, addition of HCl to a [Pt(N(H)6,6'-Me2dpa)Cl]Cl solution readily produced a dichloro complex with the N(H)6,6'-Me2dpa chelate ligand in the bidentate mode, whereas HCl addition had no effect on [Pt(N(H)dpa)Cl]Cl.

Atom transfer radical addition (ATRA) catalyzed by copper complexes with N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) ligand

Synthesis, characterization, electrochemical studies and ATRA activity of copper complexes with N,N,N′,N′-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN) ligand in the presence of ascorbic acid as a reducing agent were reported. [CuII(TPEN′)Br][Br] (TPEN′ denotes tetracoordinated ligand) catalyst showed a very low activity in ATRA of CBr4 to 1-octene, methyl methacrylate, methyl acrylate and styrene in methanol, which is a typical solvent used for ATRA reactions employing ascorbic acid. On the contrary, the yields and stereoselectivity towards monoadduct formation were dramatically increased in slightly polar but aprotic acetone. Based on molecular structures of isolated [CuII(TPEN)][BPh4] and [CuII(TPEN′)Br][Br] complexes, as well as UV–Vis and cyclic voltammetry studies, an equilibrium was proposed involving inactive [CuII(TPEN)]2+ and ATRP active [CuII(TPEN′)Br]+ cations The halidophilicity of the bromide-based deactivating complex ([CuII(TPEN′)Br][Br]) decreased approximately 750 times upon changing the solvent from acetone (KBr = 3000 ± 230) to methanol (KBr = 4.1 ± 0.1), explaining poor catalytic activity in methanol. In acetone, [CuII(TPEN′)Br][Br] complex was nearly as active in ATRA reactions employing ascorbic acid as previously reported [CuII(TPMA)Br][Br].

A guanine-ethylthioethyl-glutathione adduct as a major DNA lesion in the skin and in organs of mice exposed to sulfur mustard

Sulfur mustard (SM) is an old chemical warfare but it remains a threat to both militaries and civilians. SM mainly targets skin, eyes and lungs and diffuses to internal organs. At the molecular level, SM is able to damage DNA through the formation of monoadducts and biadduct. Glutathione (GSH) is another critical target of SM in cells since it is part of the detoxification mechanism against alkylating agents. In the present work, we investigated whether SM could form covalent bonds simultaneously with a DNA base and the sulfhydryl group of GSH. The expected guanine adduct, S-[2-(N7-guanyl)-ethylthioethyl]-glutathione (N7Gua-ETE-GSH), was synthesized and detected in several tissues of SKH-1 mice exposed to 60mg/kg of SM in the dorsal-lumbar region. N7Gua-ETE-GSH was detected in all organs studied, except in the liver. The tissue exhibiting the highest levels of N7Gua-ETE-GSH was skin, followed by brain, lungs, kidneys and spleen. N7Gua-ETE-GSH was detected in skin, brain and lungs as long as two weeks after exposure. The persistence was less in other organs. The observation of the formation of N7Gua-ETE-GSH in vivo confirms the variety of damages induced by SM in DNA. It also provides another example of the formation of DNA adducts involving glutathione following in vivo exposure to bifunctional alkylating compounds.

Reaction mechanism of Ru(II) piano-stool complexes: umbrella sampling QM/MM MD study.

Biologically relevant interactions of piano-stool ruthenium(II) complexes with ds-DNA are studied in this article by hybrid quantum mechanics-molecular mechanics (QM/MM) computational technique. The whole reaction mechanism is divided into three phases: (i) hydration of the [Ru(II) (η(6) -benzene)(en)Cl](+) complex, (ii) monoadduct formation between the resulting aqua-Ru(II) complex and N7 position of one of the guanines in the ds-DNA oligomer, and (iii) formation of the intrastrand Ru(II) bridge (cross-link) between two adjacent guanines. Free energy profiles of all the reactions are explored by QM/MM MD umbrella sampling approach where the Ru(II) complex and two guanines represent a quantum core, which is described by density functional theory methods. The combined QM/MM scheme is realized by our own software, which was developed to couple several quantum chemical programs (in this study Gaussian 09) and Amber 11 package. Calculated free energy barriers of the both ruthenium hydration and Ru(II)-N7(G) DNA binding process are in good agreement with experimentally measured rate constants. Then, this method was used to study the possibility of cross-link formation. One feasible pathway leading to Ru(II) guanine-guanine cross-link with synchronous releasing of the benzene ligand is predicted. The cross-linking is an exergonic process with the energy barrier lower than for the monoadduct reaction of Ru(II) complex with ds-DNA.

DNA damage in internal organs after cutaneous exposure to sulphur mustard

Sulphur mustard (SM) is a chemical warfare agent that attacks mainly skin, eye and lungs. Due to its lipophilic properties, SM is also able to diffuse through the skin and reach internal organs. DNA represents one of the most critical molecular targets of this powerful alkylating agent which modifies DNA structure by forming monoadducts and biadducts. These DNA lesions are involved in the acute toxicity of SM as well as its long-term carcinogenicity. In the present work we studied the formation and persistence of guanine and adenine monoadducts and guanine biadducts in the DNA of brain, lungs, kidneys, spleen, and liver of SKH-1 mice cutaneously exposed to 2, 6 and 60mg/kg of SM. SM-DNA adducts were detected in all studied organs, except in liver at the two lowest doses. Brain and lungs were the organs with the highest level of SM-DNA adducts, followed by kidney, spleen and liver. Monitoring the level of adducts for three weeks after cutaneous exposure showed that the lifetime of adducts were not the same in all organs, lungs being the organ with the longest persistence. Diffusion from skin to internal organs was much more efficient at the highest compared to the lowest dose investigated as the result of the loss of the skin barrier function. These data provide novel information on the distribution of SM in tissues following cutaneous exposures and indicate that brain is an important target.

ChemInform Abstract: Stereoselective Synthesis of (E)‐(2‐Bromovinyl)tellurium Tribromide.

There are a few published data on reactions of tellurium tetrabromide with acetylenes [1, 2]. The addition of TeBr4 to phenylacetylene and hept-1-yne was reported to give bis(2-bromo-2-phenylvinyl)tellurium dibromide and bis(2-bromohept-1-en-1-yl)tellurium dibromide in 89 and 70% yield, respectively, as mixtures of Z and E isomers, the former prevailing [1]. We have developed an efficient procedure for the synthesis of E,E-bis(2-bromovinyl)tellurium dibromide in 96% yield by reaction of tellurium tetrabromide with acetylene [2]. The reaction was carried out in chlorooform under an acetylene pressure of 12–14 atm at 40–70°C. The addition of tellurium tetrachloride to acetylene, depending on the conditions, led to the formation of both bisand monoadducts, E,E-bis(2-chlorovinyl) tellurium dichloride and E-(2-chlorovinyl)tellurium trichloride [3]. Unlike vinyltellurium trichlorides, vinyltellurium tribromides have not been reported previously. Z isomers [1, 4, 5]. We detected no possible Z-configured product in the reaction of tellurium tetrabromide with acetylene. The process was stereoselective anti-addition. Presumably, the reaction involves formation of three-membered cyclic tellurirenium intermediate, as in electrophilic anti-addition of sulfenyl and selenenyl halides to triple C≡C bond through thiirenium and selenirenium cations [6]. It is known that compounds containing a 2-bromovinyltellanyl group are used in stereoselective syntheses of alkenes via consecutive replacement of bromine and tellurium atoms by organic groups in cross-coupling reactions [4]. To conclude, we have developed an efficient procedure for the stereoselective synthesis of (E)-2-bromovinyltellurium tribromide (I) which is promising as intermediate product and building block for organic synthesis and is the first representative of previously unknown vinyltellurium tribromides. (E)-2-Bromovinyltellurium tribromide (I). Light grey powder which darkens on heating to 60–64°C and begins to decompose. H NMR spectrum, δ, ppm: 7.56 d and 7.92 d (1H each, J = 13.5 Hz). C NMR spectrum, δC, ppm: 120.04 (CHBr), 137.72 (TeCH). Found, %: C 4.88; H 0.38; Br 68.02; Te 27.45. C2H2Br4Te. Calculated, %: C 5.08; H 0.43; Br 67.54; Te 26.96. The H and C NMR spectra were recorded on a Bruker DPX-400 spectrometer at 400.13 and 100.61 MHz, respectively, using DMSO-d6 as solvent and hexamethyldisiloxane as internal reference. This study was performed in the framework of the Basic Research Program of the Russian Academy of ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 9, pp. 1397–1398. © Pleiades Publishing, Ltd., 2013. Original Russian Text © M.V. Musalova, V.A. Potapov, M.V. Musalov, S.V. Amosova, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 9, pp. 1413–1414.

Chemical Properties of Divalent Metallofullerenes Yb@D 3h(1)-C74 and Yb@C 2(13)-C84

Endohedral metallofullerenes (EMFs) encapsulating divalent metal ions have rarely been studied because of their low production yields. We report here for the first time the chemical understanding of two typical divalent EMFs, i.e. Yb@D3h-C74 and Yb@C2(13)-C84 with a disilirane reagent (1), which has shown great success in probing the chemical reactivity of EMFs encapsulating a variety of metallic cores. It was surprising to find that Yb@D3h(1)-C74 reacted with 1 neither thermally nor photochemically under normal conditions, showing an unusually low reactivity. However, monoadduct formation was achieved by laser-irradiation of their mixtures during the mass spectroscopic measurement. Accordingly, the thermal and photochemical reactions of Yb@C2(13)-C84 with 1 were conducted under harsher conditions and monoadduct formation was confirmed by both chromatographic and mass spectroscopic studies. The relatively low reactivity of these divalent EMFs compared with that of the corresponding trivalent analogues is attributed to their more negative first reduction potentials, as well as their close-shell electronic configurations, presenting new insights into the templating effect of the internal metal ion on the chemical properties of the cage carbons of EMFs.

Computational Studies of 1,3-Dipolar [3 + 2]-Cycloaddition Reactions of Fullerene-C60 with Nitrones

Solubility of fullerene-C60 improves with functionalization. 1,3-dipolar [3+2]-cycloaddition reactions of fullerene-C60 with substituted nitrones, a versatile method for fullerene functionalization, were investigated at the MO6/6-31G*//PM3 level of theory to elucidate the effect of electron-releasing (-CH3, -CH2CH3, -CH2CH2CH3, C6H5CH2) substituents and electronwithdrawing substituents (-F, -Cl, -Br, -NC, and -NO2) on the energetics of the reaction; the regio- and stereo-selectivity of the mono- and bis-addition of nitrones; and global reactivity descriptors of the molecular systems to rationalize and predict their chemical reactivity and site selectivity. The results show that electron-withdrawing groups on the nitrones increase the activation barrier of the reaction whereas electron-donating groups decrease the activation barriers. However, electron-withdrawing groups on the nitrones result in more stable products compared to the electron-donating groups. It was found that the reactions with electron-donating substituents on the nitrone are normal electron demand reactions, with C60 as the dipolarophile and the substituted nitrones as the dipoles while the reactions with electron-withdrawing substituents on the nitrones are inverse electron demand reactions. The chemical hardness values show greater positive values for adducts with electron-withdrawing substituents on the nitrone and smaller negative values for adducts with electron-donating substituents on the nitrone, confirming the trend that larger activation barriers accompany reactions with electron-withdrawing substituents on the nitrone while electron-donating substituents lower activation barriers. The activation barriers of the second nitrone addition (bisadduct formation) were found to be lower than the barriers for the first nitrone addition (monoadduct formation). Stereo-chemically, syn-bisaddition was found to be thermodynamically and kinetically stable favoured over anti-bisaddition. Electron donating and electron-withdrawing substituents have a marked effect on the energetics of the reaction.

Stereoselective synthesis of (E)-(2-bromovinyl)tellurium tribromide

There are a few published data on reactions of tellurium tetrabromide with acetylenes [1, 2]. The addition of TeBr4 to phenylacetylene and hept-1-yne was reported to give bis(2-bromo-2-phenylvinyl)tellurium dibromide and bis(2-bromohept-1-en-1-yl)tellurium dibromide in 89 and 70% yield, respectively, as mixtures of Z and E isomers, the former prevailing [1]. We have developed an efficient procedure for the synthesis of E,E-bis(2-bromovinyl)tellurium dibromide in 96% yield by reaction of tellurium tetrabromide with acetylene [2]. The reaction was carried out in chlorooform under an acetylene pressure of 12–14 atm at 40–70°C. The addition of tellurium tetrachloride to acetylene, depending on the conditions, led to the formation of both bisand monoadducts, E,E-bis(2-chlorovinyl) tellurium dichloride and E-(2-chlorovinyl)tellurium trichloride [3]. Unlike vinyltellurium trichlorides, vinyltellurium tribromides have not been reported previously. Z isomers [1, 4, 5]. We detected no possible Z-configured product in the reaction of tellurium tetrabromide with acetylene. The process was stereoselective anti-addition. Presumably, the reaction involves formation of three-membered cyclic tellurirenium intermediate, as in electrophilic anti-addition of sulfenyl and selenenyl halides to triple C≡C bond through thiirenium and selenirenium cations [6]. It is known that compounds containing a 2-bromovinyltellanyl group are used in stereoselective syntheses of alkenes via consecutive replacement of bromine and tellurium atoms by organic groups in cross-coupling reactions [4]. To conclude, we have developed an efficient procedure for the stereoselective synthesis of (E)-2-bromovinyltellurium tribromide (I) which is promising as intermediate product and building block for organic synthesis and is the first representative of previously unknown vinyltellurium tribromides. (E)-2-Bromovinyltellurium tribromide (I). Light grey powder which darkens on heating to 60–64°C and begins to decompose. H NMR spectrum, δ, ppm: 7.56 d and 7.92 d (1H each, J = 13.5 Hz). C NMR spectrum, δC, ppm: 120.04 (CHBr), 137.72 (TeCH). Found, %: C 4.88; H 0.38; Br 68.02; Te 27.45. C2H2Br4Te. Calculated, %: C 5.08; H 0.43; Br 67.54; Te 26.96. The H and C NMR spectra were recorded on a Bruker DPX-400 spectrometer at 400.13 and 100.61 MHz, respectively, using DMSO-d6 as solvent and hexamethyldisiloxane as internal reference. This study was performed in the framework of the Basic Research Program of the Russian Academy of ISSN 1070-4280, Russian Journal of Organic Chemistry, 2013, Vol. 49, No. 9, pp. 1397–1398. © Pleiades Publishing, Ltd., 2013. Original Russian Text © M.V. Musalova, V.A. Potapov, M.V. Musalov, S.V. Amosova, 2013, published in Zhurnal Organicheskoi Khimii, 2013, Vol. 49, No. 9, pp. 1413–1414.

Mechanism of the cis-[Pt(1R,2R-DACH)(H2O)2]2+ Intrastrand Binding to the Double-Stranded (pGpG)·(CpC) Dinucleotide in Aqueous Solution: A Computational DFT Study

A mechanism of the intrastrand 1,2-cross-link formation between the double-stranded pGpG·CpC dinucleotide (ds(pGpG)) and fully aquated oxaliplatin cis-[Pt(DACH)(H2O)2](2+) (DACH = cyclohexane-1R,2R-diamine) is presented. All structures of the reaction pathways including the transition states (TSs) were fully optimized in water solvent using DFT methodology with dispersion corrections. Both 5' → 3' and 3' → 5' binding directions were considered. In the first step there is a slight kinetic preference for 5'-guanine (5'G) monoadduct formation with an activation Gibbs free energy of 18.7 kcal/mol since the N7 center of the 5'G base is fully exposed to the solvent. On the other hand, the N7 atom of 3'-guanine (3'G) is sterically shielded by 5'G. The lowest energy path for formation of the 3'G monoadduct with an activation barrier of 19.3 kcal/mol is connected with a disruption of the 'DNA-like' structure of ds(pGpG). Monoadduct formation is the rate-determining process. The second step, chelate formation, is kinetically preferred in the 3' → 5' direction. The whole process of the platination is exergonic by up to -18.8 kcal/mol. Structural changes of ds(pGpG), charge transfer effects, and the influence of platination on the G·C base pair interaction strengths are also discussed in detail.

Characterization of Model Peptide Adducts with Reactive Metabolites of Naphthalene by Mass Spectrometry

Naphthalene is a volatile polycyclic aromatic hydrocarbon generated during combustion and is a ubiquitous chemical in the environment. Short term exposures of rodents to air concentrations less than the current OSHA standard yielded necrotic lesions in the airways and nasal epithelium of the mouse, and in the nasal epithelium of the rat. The cytotoxic effects of naphthalene have been correlated with the formation of covalent protein adducts after the generation of reactive metabolites, but there is little information about the specific sites of adduction or on the amino acid targets of these metabolites. To better understand the chemical species produced when naphthalene metabolites react with proteins and peptides, we studied the formation and structure of the resulting adducts from the incubation of model peptides with naphthalene epoxide, naphthalene diol epoxide, 1,2-naphthoquinone, and 1,4-naphthoquinone using high resolution mass spectrometry. Identification of the binding sites, relative rates of depletion of the unadducted peptide, and selectivity of binding to amino acid residues were determined. Adduction occurred on the cysteine, lysine, and histidine residues, and on the N-terminus. Monoadduct formation occurred in 39 of the 48 reactions. In reactions with the naphthoquinones, diadducts were observed, and in one case, a triadduct was detected. The results from this model peptide study will assist in data interpretation from ongoing work to detect peptide adducts in vivo as markers of biologic effect.