Formation,preservation, and cleavage of the disulfide bond by vanadium

Reaction of the disulfide [HpicanS](2) (HpicanS is the carboxamide based on picolinate (pic) and o-mercaptoaniline (anS); the [] brackets are used to denote disulfides) with [VOCl(2)(thf)(2)] leads to reductive scission of the disulfide bond and formation of the mixed-valence (V(IV)/V(V)) complex anion [(OVpicanS)(2)mu-O](-) (1), with the dianionic ligand coordinating through the pyridine-N atom, the deprotonated amide-N atom, and thiophenolate-S atom. Reductive cleavage of the SbondS bond is also observed as [VCl(2)(tmeda)(2)] (tmeda=tetramethylethylenediamine) is treated with the disulfides [HsalanS](2) or [HvananS](2) (HsalanS and HvananS are the Schiff bases formed between o-mercaptoaniline and salicylaldehyde (Hsal) or vanillin (Hvan), respectively), yielding the V(III) complexes [VCl(tmeda)(salanS)] (2 a), or [VCl(tmeda)(vananS)] (2 b). The disulfide bond remains intact in the aerial reaction between [HsalanS](2) and [VCl(3)(thf)(3)] to yield the V(V) complex [VOCl[salanS](2)] (3), where (salanS)(2-) coordinates through the two phenolate and one of the imine functions. The S-S bond is also preserved as [VO(van)(2)] or [VO(nap)(2)] (Hnap=2-hydroxynaphthalene-1-carbaldehyde) is treated with bis(2-aminophenyl)disulfide, [anS](2), a reaction which is accompanied by condensation of the aldehyde and the diamine, and complexation of the resulting bis(Schiff bases) [HvananS](2) or [HnapanS](2) to form the complexes [VO[vananS](2)] (4 a) or [VO[napanS](2)] (4 b). In 4 a and 4 b, the phenolate and imine functions, and presumably also one of the disulfide-S atoms, coordinate to V(IV). 2-Mercaptophenyl-2'-pyridinecarboxamide (H(2)picanS) retains its identity in the presence of V(III); reaction between [VCl(3)(thf)(3)] and H(2)picanS yields [V[picanS](2)](-) (5). The dithiophenolate 2,6-bis(mercaptophenylthio)dimethylpyridine (6 a) is oxidized, mediated by VO(2+), to the bis(disulfide) octathiadiaza-cyclo-hexaeicosane 6 b. The relevance of these reactions for the speciation of vanadium under physiological conditions is addressed. [HNEt(3)]-1.0.5 NEt(3,) 3.3 CH(2)Cl(2), [HsalanS](2), [HNEt(3)]-5, and 6 b.4 THF have been characterized by X-ray diffraction analysis.     

Kinetic measurements on single-molecule disulfide bond cleavage

We use single-molecule force clamp spectroscopy (SMFCS) to explore the reactivity of tris(2-carboxyethyl)phosphine (TCEP), 1, 4-dl-dithiothreitol (DTT) and hydrosulfide anion (HS(-)) on disulfide bonds within a mechanically stretched polypeptide. The single-bond level bimolecular nucleophilic substitution (S(N)2) events are recorded at a series of precisely controlled temperatures so that the Arrhenius kinetic parameters, that is, the height of the activation energy barrier (E(a)) and the attempting frequency (A) of the chemical reactions, can be determined. The values of A are typically at the order of 10(7) M(-1) s(-1), which is far lower than that predicted by the transition-state theory, in which A is given by k(B)T/h and around 10(12) M(-1) s(-1) at room temperature. Furthermore, E(a) is derived to be 30-40 kJ/mol, which can be lowered by ～6-8% with every 100 pN mechanical force applied. The correlation of the A and E(a) with the molecular structures reveals that the relative magnitude of these two parameters cannot be simply judged from the size of the molecule or the nucleophilicity of the attacking atom. The comparison of the influences on the reaction rate induced by force and temperature indicates an equivalent accelerating effect by every 50 pN or 10 K increment, giving for the first time the relationship between mechanical and thermal effects on a single-molecule S(N)2 chemical reaction.     

Penicillamine disulfide (PNS) and alkaline cations

D-penicillamine disulfide (PNS) shows protolytic properties and is able to form complexes with cations, because it has two aminic groups and two carboxylic groups. The four protonation constants of its deprotonated species were determined by means of electromotive force (e.m.f.) measurements of a galvanic cell involving a glass electrode at 25 degrees C and in a constant ionic medium constituted by N(CH3)4Cl 3.00 or 1.00 mol dm-3. At 25 degrees C and in 3.00 mol dm-3 N(CH3)4Cl as ionic medium, equilibria taking place between PNS and lithium, sodium and potassium ions were investigated. Experimental data, again obtained from e.m.f. measurements, were explained by assuming the formation of species of the type MH2PNS ed M2H2PNS, where M indicates a cation. Stability constants for each proposed species were calculated. A comparison with cystine is discussed.     

Preparation and alkaline cleavage of 4H-imidazole N-oxides

Heating 1-acyloxy-5,5-dimethyl-3-imidazoline 3-oxides in vacuo gives derivatives of 4H-imidazole 1-oxides. The reaction of the latter with alkalis is accompanied by ring opening and the formation of oximes of-acylamino ketones.Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1241–1245, September, 1972.     

Synthesis of trialkyl-gallium and -indium adducts of tetramethyldiphosphine

Trimethyl- and triethyl-gallium and -indium reacted with tetramethyldiphosphine to form 2/1 addition compounds. Characterization studies have included elemental analyses, molecular weight measurements, infrared, NMR, and mass spectra. In addition, vapor pressure measurements have been carried out between 50 and 100°. Attempts to isolate and identify 1/1 compounds were inconclusive.     

Mechanism of SN2 disulfide bond cleavage by phosphorus nucleophiles. Implications for biochemical disulfide reducing agents

The B3LYP variant of DFT has been used to study the mechanism of S-S bond scission in dimethyl disulfide by a phosphorus nucleophile, trimethylphospine (TMP). The reaction is highly endothermic in the gas phase and requires significant external stabilization of the charged products. DFT calculations (B3LYP) were performed with explicit (water molecules added) and implicit solvent corrections (COSMO model). The transition structures for this SN2 displacement reaction in a number of model systems have been located and fully characterized. The reaction barriers calculated with different approaches for different systems are quite close (around 11 kcal/mol). Remarkably, the calculations suggest that the reaction is almost barrierless with respect to the preorganized reaction complex and that most of the activation energy is required to rearrange the disulfide and TMP to its most effective orientation for the SMe group transfer way. Different reactivities of different phosphorus nucleophiles were suggested to be the result of steric effects, as manifested largely by varying amounts of hindrance to solvation of the initial product phosphonium ion. These data indicate that the gas-phase addition of a phosphine to the disulfide moiety will most likely form a phosphonium cation-thiolate anion salt, in the presence of four or more water molecules, that provide sufficient H-bonding stabilization to allow displacement of the thiolate anion, a normal uncomplicated SN2 transition state is to be expected.     

Formation of stable radicals during the reduction of fluoranil in alkaline alcoholic solutions

The magnetic-resonance parameters of a stable radical formed under anaerobic conditions during the reduction of fluoranil in alkaline alcohols were measured by the EPR, ENDOR and electron spin echo methods. It was concluded that a tetraethoxy-p-benzoquinone anion-radical is formed.Translated from Teoreticheskaya i Eksperimental'naya Khimiya, Vol. 26, No. 2, pp. 249–251, March–April, 1990.The authors wish to express their gratitude of I. I. Bil'kis for his participation in the discussions of the results of this work.     

Mapping disulfide bonds in insulin with the route 66 method: Selective cleavage of S-C bonds using alkali and alkaline earth metal enolate complexes

Simple and fast identification of disulfide linkages in insulin is demonstrated with a peptic digest using the Route 66 method. This is accomplished by collisional activation of singly and doubly charged cationic Na⁺ and Ca²⁺ complexes generated using electrospray ionization mass spectrometry (ESI-MS). Collisional activation of doubly charged metal complexes of peptides with intermolecular disulfide linkages yields two sets of singly charged paired products separated by 66 mass units resulting from selective S-C bond cleavages. Highly selective elimination of 66 mass units, which corresponds to the molecular weight of hydrogen disulfide (H₂S₂), is observed from singly charged metal complexes of peptides with disulfide linkages. The mechanism proposed for these processes is initiated by formation of a metal-stabilized enolate at Cys, followed by cleavage of the S-C bond. Further activation of the products yields sequence information that facilitates locating the position of the disulfide linkages in the peptic digest fragments. For example, the doubly charged Ca²⁺ complex of the peptic digest product GIVEQCCASVCSL/FVNQHLCGSHL yields paired products separated by 66 mass units resulting from selective S-C bond cleavages at an intermolecular disulfide linkage under low-energy collision-induced dissociation. Further activation of the product comprising the A chain reveals the presence of a second disulfide bridge, an intramolecular linkage. Experimental and theoretical studies of the disulfide linked model peptides provide mechanistic details for the selective cleavage of the S-C bond.     

Kinetics of amide and peptide cleavage by alkaline hydrogen peroxide

The hydroperoxide anion cleaves unactivated amides and peptides although it is completely unreactive toward ethyl esters. The cleavage by HO2(-) proceeds faster than by OH(-) and involves additional routes with general acid assistance by H2O2 and general base assistance by OH(-) and HO2(-). Cleavage of polypeptides occurs at the N-terminal peptide bond. [reaction: see text]     

Semi-empirical Scf-Mo study of the mass spectral fragmentation of tetramethyldiphosphine

Structures and enthalpies of formation have been calculated, in the MNDO approximation using UHF wave-functions for open shell species, for tetramethyldiphosphine, Me₄P₂, and the major ions in its mass spectrum: Me₄P₂⁺, Me₃P₂H⁺, Me₃P₂⁺, Me₂P₂H₂⁺ (3 forms), Me₂P₂H⁺ (3 forms), Me₂P₂⁺ (3 forms), MePPCH₂⁺ (3 forms), MeP₂⁺ and MePCH₂⁺, together with all the corresponding neutral fragments. Appearance potentials are calculated for all the ions, and possible fragmentation pathways deduced.     

Collision-activated cleavage of a peptide/antibiotic disulfide linkage: possible evidence for intramolecular disulfide bond rearrangement upon collisional activation

Ceftiofur is an important veterinary beta-lactam antibiotic whose bioactive metabolite, desfuroylceftiofur, has a free thiol group. Desfuroylceftiofur (DFC) was reacted with two peptides, [Arg8]-vasopressin and reduced glutathione, both of which have cysteine residues to form disulfide-linked peptide/antibiotic complexes. The products of the reaction, [vasopressin + (DFC-H) + (DFC-H) + H]+, [(vasopressin+H) + (DFC-H) + H]+ and [(glutathione-H) + (DFC-H) + H]+, were analyzed using collision-activated dissociation (CAD) with a quadrupole ion trap tandem mass spectrometer. MS/MS of [vasopressin + (DFC-H) + (DFC-H) + H]+ resulted in facile dissociative loss of one and two covalently bound DFC moieties. Loss of one DFC resulted from either homolytic or heterolytic dissociation of the peptide/antibiotic disulfide bond with equal or unequal partitioning of the two sulfur atoms between the fragment ion and neutral loss. Hydrogen migration preceded heterolytic dissociation. Loss of two DFC moieties from [vasopressin + (DFC-H) + (DFC-H) + H]+ appears to result from collision-activated intramolecular disulfide bond rearrangement (IDBR) to produce cyclic [vasopressin + H]+ (at m/z 1084) as well as other cyclic fragment ions at m/z 1084 +/- 32 and +64. The cyclic structure of these ions could only be inferred as MS/MS may result in rearrangement to non-cyclic structures prior to dissociative loss. IDBR was also detected from MS(3) experiments of [vasopressin + (DFC-H) + (DFC-H) + H]+ fragment ions. MS/MS of [(glutathione-H) + (DFC-H) + H]+ resulted in cleavage of the peptide backbone with retention of the DFC moiety as well as heterolytic cleavage of the peptide/antibiotic disulfide bond to produce the fragment ion: [(DFC-2H) + H]+. These results demonstrate the facile dissociative loss by CAD of DFC moieties covalently attached to peptides through disulfide bonds. Published in 2004 by John Wiley & Sons, Ltd.     

Copper-catalyzed 1,2-hydroxysulfenylation of alkene using disulfide via cleavage of the S-S bond

Copper-catalyzed 1,2-hydroxysulfenylation of alkenes can be carried out by the use of disulfides and acetic acid in air. This reaction regio- and anti-selectively gave the corresponding 1,2-acetoxysulfides. Furthermore, the present method enables the use of both organosulfide groups of disulfide.     

The reverse of polymer degradation: in situ crosslinked gel formation through disulfide cleavage

In contrast to the usual inclusion of disulfide bonds within a polymer structure to facilitate bio-degradation, we have designed a self-curing "one pot" hyperbranched polymer capable of forming crosslinked gels under reducing conditions abundant in tumoural tissue.     

Formation of gamma-lactones through CAN-mediated oxidative cleavage of hemiketals

The generation of substituted gamma-lactones can be accomplished through application of a tandem chain extension-aldol reaction, followed by CAN-mediated oxidative cleavage of the aldol product. The oxidative cleavage requires the intermediacy of a hemiketal and the presence of an alpha-heteroatom. Formation of the gamma-lactone through the oxidative cleavage is used to assign stereochemistry of the aldol reaction and as the final step in a short synthesis of members of the phaseolinic acid family of natural products.     

Formation of an acyclic disulfide from an 4-acylamino-3-oxothiophan

It has been established that 4-benzoylamino-3-oxothiophan is cleaved at a S-C bond by methanol in the presence of sodium methoxide with the formation of an acyclic disulfide.