Sulfoxide Oxygen Research Articles

A new acesulfamato complex: [Cu(acesulfamato)2(H2O)4]. Structural and spectroscopic characterization

The crystal structure of tetraaqua-bis(6-methyl-1,2,3-oxathiazin-4(3H)-onato 2,2-dioxide) copper(II) complex, for short [Cu(ace)2(H2O)4], was determined by X-ray diffraction methods. The complex crystallizes in the monoclinic C2/c space group with a = 11.9838(4), b = 9.5240(3), c = 15.1686(6) Å, β = 102.975(4)° and Z = 4 molecules per unit cell. The structure was determined from 1609 reflections with I > 2σ(I) and refined to an agreement R1-factor of 0.0345. [Cu(ace)2(H2O)4] is a new member in the family of acesulfamate complexes of first row transition metals, namely [M(ace)2(H2O)4], M: Co, Ni, Zn. It differs from the other members in the bonding of acesulfamate to metal through one of its sulfoxide oxygen atoms. The new complex was further characterized by its infrared, Raman and electronic absorption spectra, which were discussed in comparison with those of other related species.

Crystal structure of pantoprazole sodium sesquihydrate Form I, C16H14F2N3O4SNa(H2O)1.5

The crystal structure of pantoprazole sodium sesquihydrate has been solved and refined using synchrotron X-ray powder diffraction data and optimized using density functional techniques. Pantoprazole sodium sesquihydrate crystallizes in space groupPbca(#61) witha= 33.4862(6),b= 17.29311(10),c= 13.55953(10) Å,V= 7852.06(14) Å3, andZ= 16. The crystal structure is characterized by layers parallel to thebc-plane. One layer contains the Na coordination spheres. The two independent sodium ions are trigonal bipyramidal and octahedral. The NaO3N2and NaO4N2coordination spheres share an edge to form pairs. The sodium bond valence sums are 1.17 and 1.15. The difluoromethyl groups are probably disordered. Two water molecules act as hydrogen bond donors to pyridine nitrogen atoms and sulfoxide oxygen atoms. The third water molecule participates in bifurcated hydrogen bonds, but one of its hydrogen atoms does not participate in hydrogen bonds. The powder pattern is included in the Powder Diffraction File™ as entry 00-065-1424.

Dimethyl Sulfoxide Oxygen Donor‐Based Annulation of Ketones and Ammonium Persulfate: Regioselective Synthesis of 2,4‐disubstituted Oxazoles

AbstractAn efficient protocol for the synthesis of substituted oxazoles via an annulation of ketones, DMSO, and ammonium is reported. DMSO is first found to serve as oxygen donor in annulation resulting in regioselective synthesis of 2,4‐disubstituted oxazoles. With the optimized conditions in hand, 22 examples of 2,4‐disubstituted oxazoles are obtained from readily available substrates. The protocol can be also applied in cross‐condensation reactions between methyl ketones and non‐methyl ketones resulting 4 examples of 2,4,5‐trisubstituted oxazoles. Moreover, we have successfully applied the protocol into gram‐scale representing good yields, that showing the potential practicality in organic synthesis. Based on control experiments and literature, a plausible reaction mechanism was proposed in our work.magnified image

A theoretical study on the coordination behavior of some phosphoryl, carbonyl and sulfoxide derivatives in lanthanide complexation.

The selectivity of phosphoryl P(O)R3, sulfoxide S(O)R2, and carbonyl C(O)R2 (R = NH2, CH3, OH, and F) derivatives with lanthanide cations (La3+, Eu3+, Lu3+) was studied by density functional theory calculations. Theoretical approaches were also used to investigate energy and the nature of metal-ligand interaction in the model complexes. Atoms in molecules and natural bond orbital (NBO) analyses were accomplished to understand the electronic structure of ligands, L, and the related complexes, L-Ln3+. NBO analysis demonstrated that the negative charge on phosphoryl, carbonyl, and sulfoxide oxygen (OP, OC, and OS) has maximum and minimum values when the connected -R groups are -NH2 and -F. The metal-ligand distance declines as, -F > -OH > -CH3 > -NH2. Charge density at the bond critical point and on the lanthanide cation in the L-Ln3+ complexes varies in the order -F < -OH < -CH3 < -NH2, due to greater ligand to metal charge transfer, which is well explained by energy decomposition analysis. It was also illustrated that E(2) values of Lp(N) → σ*(Y-N) vary in the order P=O ˃ S=O ˃ C=O and the related values of Lp(N) → σ*(Y=O) change as C=O ˃ S=O ˃ P=O in (NH2)nYO ligands (Y = P, C, and S). Trends in the L-Ln3+ CP-corrected bond energies are in good accordance with the optimized OY⋯Ln distances. It seems that, comparing the three types of ligands studied, NH2-substituted are the better coordination ligands. Graphical Abstract Density functional theory (B3LYP) calculations were used to compare structural, electronic and energy aspects of lanthanide (La, Eu, Lu) complexes of phosphine derivatives with those of carbonyls and sulfoxides in which the R- groups connected to the P=O, C=O and S=O are -NH2, -CH3, -OH and -F.

The first spontaneous resolution of a sulfoxide: Dianin's compound analogue, (R)-4-(4-hy-droxy-phen-yl)-2,2,4-tri-methyl-thia-chroman-1-oxide.

The title sulfoxide, C18H20O2S, was prepared by controlled oxidation of thia-Dianin's compound using hydrogen peroxide in glacial acetic acid. On recrystallization from glacial acetic acid, it was found to form unsolvated, spontaneously resolved crystals, the initial crystal structure analysis revealing the presence of both sulfoxide epimers in the crystal. On multiple recrystallization a single epimer was observed, with crystallization occurring in the unchanged ortho-rhom-bic space group P212121, with Z' = 1. The mol-ecule possesses a distal conformation, referring to the juxtaposition of the p-hydoxyphenyl substituent with respect to its syn-related methyl group, with the sulfoxide oxygen atom anti to the aromatic substituent. The mol-ecular packing features O-H⋯O hydrogen bond chains running parallel to the b axis of the unit cell.

Синтез и строение комплексов рутения [Ph4P][trans-RuCl4(dmso-S)2] и [Ph4Sb(dmso-O)][trans-RuCl4(dmso-S)2

Ruthenium complexes [Ph 4 P][ trans- RuCl 4 (dmso-S) 2 ] ( 1 ) and [Ph 4 Sb(dmso-O)][ trans- RuCl 4 (dmso-S) 2 ] ( 2 ) have been synthesized by interaction of tetraphenylphosphonium and tetraphenylstibonium chlorides in dimethylsulfoxide. Their structures have been characterized. According to the X-ray data, the phosphorus atoms in cation 1 have a slightly distorted tetrahedral coordination (P–C 1.756(16)–1.794(19) Å, CPС 105.4(7)°–111.8(5)°), and the antimony atoms in cation 2 have a distorted trigonal-bipyramidal coordination with the dimethyl sulfoxide oxygen atom in the axial position (Sb–O 2.633(15) Å, Sb–C 2.094(15)–2.146(15) Å, CSbO 178.54(16)°). In the [ trans -RuCl 4 (dmso- S ) 2 ] – octahedral anion complexes 1 and 2 dimethylsulfoxide ligands are coordinated to the metal atoms by sulfur atoms (Ru–S 2.349(3), Ru–Cl 2.353(5), 2.355(3) Å and 2.332(3)–2.344(6), 2.336(4)–2.353(3) Å, respectively; angles SRuS and trans-ClRuCl constitute 180°.

Outsmarted by nootropics? An investigation into the thermal degradation of modafinil, modafinic acid, adrafinil, CRL-40,940 and CRL-40,941 in the GC injector: formation of 1,1,2,2-tetraphenylethane and its tetra fluoro analog.

2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil) is commonly prescribed for the treatment of narcolepsy. Increasing popularity and off-label use as a cognitive enhancer has resulted in a reputation as an intelligence boosting 'wonder drug'. Common alternatives available from online shops and other retail outlets include 2-[(diphenylmethyl)sulfinyl]-N-hydroxyacetamide (adrafinil), 2-{[bis(4-fluorophenyl)methyl]sulfinyl}acetamide (CRL-40,940), 2-{[bis(4-fluorophenyl)methyl]sulfinyl}-N-hydroxyacetamide (CRL-40,941), and N-methyl-4,4-difluoro-modafinil (modafiendz), respectively. Gas chromatography-mass spectrometry (GC-MS) is a common tool used in forensic and clinical analysis but there is a potential for inducing analysis-related ambiguities. This study reports on the thermal degradation of modafinil, modafinic acid, adrafinil, CRL-40,940, and CRL-40,941 due to exposure to the heated GC injection port dissolved in a variety of solvents. Key degradation products common to modafinil, modafinic acid, and adrafinil analysis included diphenylmethanol and 1,1,2,2-tetraphenylethane (TPE), the latter of which was verified by its synthesis and characterization by x-ray crystallography. The investigated compounds were also characterized by 1 H and 13 C NMR. Diphenylmethane and thiobenzophenone were also identified in some instances. TPE formation was suggested to involve the generation of a benzhydrylium ion and its reaction with the sulfoxide oxygen of the parent compound to give an oxysulfonium intermediate. Correspondingly, the fluorinated TPE analogue was formed during heat-induced degradation of modafiendz, CRL-40,940 and CRL-40,941, respectively. When a mixture of modafinil (non-fluorinated) and modafiendz (fluorinated) were subjected to GC analysis, 4,4'-(2,2-diphenylethane-1,1-diyl)bis(fluorobenzene) was detected as a third cross reaction product in addition to the two expected TPE analogues. These observations served as a reminder that the seemingly straightforward implementation of GC-MS analysis can lead to challenges during routine analysis.

Structural and spectroscopic characterization of isotypic sodium, rubidium and cesium acesulfamates

AbstractThree new acesulfamate salts, NaC4H4NO4S, RbC4H4NO4S and CsC4H4NO4S, were prepared by reactions in aqueous solutions and thoroughly characterized. Their crystal and molecular structures were determined by single crystal X-ray diffraction methods. They crystallize in the monoclinic space groupP21/awitha= 7.2518(2),b= 8.9414(4),c= 10.5929(4) Å,β= 99.951(3)°,V= 676.52(4) Å3for the Na salt;a= 7.4663(3),b= 9.6962(4),c= 10.4391(4) Å,β= 95.150(3)°,V= 752.68(5) Å3for the Rb salt anda= 7.5995(4),b= 9.9439(4),c= 10.8814(6) Å,β= 91.298(5)°,V= 822.08(7) Å3for the Cs salt, andZ= 4 molecules per unit cell. The three compounds are isotypic to each other and to the previously reported potassium salt. The metal ions are in irregular polyhedral coordination with six neighboring acesulfamate anions through their nitrogen and carbonyl and sulfoxide oxygen atoms. The FTIR spectra of the compounds were also recorded and are briefly discussed.

Synthesis and structure of palladium complexes [Ph3PhCH2P]+[PdCl3(DMSO)]− · DMSO, [Ph4P]+[PdCl3(DMSO)]−, and [Ph4Sb(DMSO)]+[PdCl3(DMSO)

[Ph3PhCH2P]+[PdCl3(DMSO)]− · DMSO (I), [Ph4P]+[PdCl3(DMSO)]− (II), and [Ph4Sb(DMSO)]+[PdCl3(DMSO)]− (III) complexes have been synthesized via the reaction of palladium chloride with equimolar amounts of triphenylbenzylphosphonium chloride, tetraphenylphosphonium chloride, and tetraphenylstibonium chloride, respectively. According to X-ray diffraction data, the cations of complexes I (CPC = 104.90(8)°–111.61(9)°) and II (CPC = 105.12(10)°–111.46(10)°) have slightly distorted tetrahedral structures with P-C bond lengths of 1.786(2)–1.809(2) and 1.791(2)–1.799(2) A, respectively. The antimony atom in the [Ph4Sb(DMSO)]+ cation has a trigonal bipyramidal surrounding with the dimethyl sulfoxide (DMSO) oxygen atom in an axial position (Sb...O 2.567(2) A). The palladium atoms in the square mononuclear anions of complexes I, II, and III are tetracoordinate, and Pd-Cl distances are 2.3101(5)–2.3104(5) A, 2.2950(7)–2.2038(7) A, and 2.2986(9)–2.3073(9) A, respectively. The DMSO ligands are coordinated to the palladium atom through the sulfur atom (Pd-S, 2.2318(5) (I), 2.2383(6) (II), and 2.2410(9) A (III)).

A Molecular Dynamics and Quantum Mechanics/Molecular Mechanics Study of the Catalytic Reductase Mechanism of Methionine Sulfoxide Reductase A: Formation and Reduction of a Sulfenic Acid

The catalytic mechanism of MsrA in Mycobacterium tuberculosis, in which S-methionine sulfoxide (Met-O) is reduced to methionine (Met), has been investigated using docking, molecular dynamics (MD) simulations, and ONIOM (quantum mechanics/molecular mechanics) methods. In addition, the roles of specific active site residues, including an aspartyl (Asp87) near the recycling cysteine, tyrosyls (Tyr44 and Tyr92), and glutamyl (Glu52), have been examined, as well as the general effects of the protein and active site on the nature and properties of mechanistic intermediates. The mechanism is initiated by the transfer of a proton from the catalytic cysteine's thiol (Cys13SH) via a bridging water to the R group carboxylate of Glu52. The now anionic sulfur of Cys13 nucleophilically attacks the substrate's sulfur with concomitant transfer of a proton from Glu52 to the sulfoxide oxygen, generating a sulfurane. The active site enhances the proton affinity of the sulfurane oxygen, which can readily accept a proton from the phenolic hydroxyls of Tyr44 or Tyr92 to give a sulfonium cation. Subsequently, Asp87 and the recycling cysteine (Cys154) can facilitate nucleophilic attack of a solvent water at the Cys13S center of the sulfonium to give a sulfenic acid (Cys13SOH) and Met. For the subsequent reduction of Cys13SOH with intramolecular disulfide bond formation, Asp87 can help facilitate nucleophilic attack of Cys154S at the sulfur of Cys13SOH by deprotonating its thiol. This reduction is found likely to occur readily upon suitable positioning of the active site hydrogen bond network and the sulfur centers of both Cys13 and Cys154. The calculated rate-limiting barrier is in good agreement with experiment.

Diastereoselective Reduction of Chiral 2-(1-Alkenoyl)- and 2-(1-Alkynoyl)-1,3-Oxathiane 3-Oxides Derived from (1R)-(+)-Camphor

(lithium tri-sec-butyl-borohydride) has been explained by invoking a chelatemodel, where the sulfoxide oxygen and the carbonyl oxygentake part in the chelation with metal cation. On the contrary,diisobutylaluminum hydride (DIBAL-H), a non-chelatingagent, has been suggested to react according to a Solladiemodel,

Mechanism of the Gold(I)-Catalyzed Rearrangement of Alkynyl Sulfoxides: A DFT Study

The mechanisms of the gold(I)-catalyzed rearrangement of homopropargyl sulfoxides have been investigated using density functional theory calculations done at the B3LYP/6-31G(d, p) (SDD for Au) level of theory. Solvent effects on these reactions have been explored by calculations that included a polarizable continuum model (PCM) for the solvent (CH2Cl2). Two plausible pathways which lead to the formation of benzothiepinones or benzothiopines via an α-carbonyl Au carbenoid through 5-exo-dig cyclization or 6-endo-dig cyclization were proposed. Our calculation results suggested the following. (1) The first step of the cycle is nucleophilic addition of the sulfoxide oxygen onto the triple bond to form an alkenyl gold intermediate through 5-exo-dig cyclization or 6-endo-dig cyclization. The alkenyl gold species is then capable of pushing out the sulfide moiety, forming an α-carbonyl Au carbenoid. Finally, α-carbonyl Au carbenoids undergo intramolecular Friedel–Crafts alkylation to produce the observed products ...

An effective force field for molecular dynamics simulations of dimethyl sulfone

A rigid five-site united atom model for dimethyl sulfone (DMSO2) compatible with the GROMOS force field is parametrized and tested. The parameters were optimized with respect to experimental quantities such as liquid density, heat of vaporization, shear viscosity and excess free energy. Good agreement with pure component properties is achieved except for the static dielectric permittivity which is calculated too low. Together with the SPC model for water the new DMSO2 model was used to study aqueous mixtures at low concentrations and compared to aqueous mixtures of DMSO. It is concluded that interaction parameters for sulfoxide oxygen are not directly transferable to sulfonyl oxygen.

Liquid chromatographic resolution of proton pump inhibitors including omeprazole on a ligand exchange chiral stationary phase

A ligand exchange chiral stationary phase (CSP) developed previously in this laboratory by bonding (R)-phenylglycinol derivative, sodium N-[(R)-2-hydroxy-1-phenylethyl]-N-undecylaminoacetate, to silica gel was successfully applied to the resolution of proton pump inhibitors (PPIs) including omeprazole, pantoprazole, lansoprazole and rabeprazole. For example, the separation factors ( α) for the resolution of omeprazole, pantoprazole, lansoprazole and rabeprazole were 4.27, 5.28, 2.77 and 4.06, respectively, and the resolutions ( R S) were 2.53, 2.55, 1.93, and 2.01, respectively, when 65% acetonitrile aqueous solution containing 0.5 mM CuSO 4 and 0.05 mM triethylamine was used as a mobile phase. Based on the chromatographic behaviors for the resolution of PPI analogues on CSP 1, a chiral recognition mechanism utilizing the sulfoxide oxygen and the benzimidazole ring nitrogen of PPIs as bidentate coordination donors to form an enantioselective ternary complex with the central Cu(II) ion and the chiral stationary bidentate ligand was proposed.

10.1007/s11173-008-1008-x

The crystal structures of (5-bromosalicylidenethiosemicarbazido)aquacopper(II) sulfato(5-bromosalicylidenethiosemicarbazido)aquacuprate(II) tetrahydrate (I), (5-nitrosalicylidenethiosemicarbazido)dimethylsulfoxide(methanol)copper(II) sulfate (II), and catena(μ-thiocyanato)(5-nitrosalicylidenethiosemicarbazido)copper(II) (III) were determined. In structure I, the independent part of the unit cell contains four water molecules of crystallization and the cation-anion complex [Cu(H2O)(L)][Cu(H2O)(L)(SO4)] containing two nonequivalent copper complexes (A and B). In these, the metal atom coordinates monodeprotonated 5-bromosalicylaldehyde thiosemicarbazone (HL) and water molecules, and in anion B also a sulfate ion. In complex ions A and B, sulfur, azomethine nitrogen, and phenolic oxygen of the salicylidene thiosemicarbazone fragment, and also water molecule form a distorted planar square around the metal atom. The axial vertex of the pyramid in anion B is occupied by the oxygen atom of the monodentate sulfate anion. In structure II, the independent part of the unit cell contains the (5-nitrosalicylidenethiosemicarbazido)dimethylsulfoxide(methanol)copper(II) complex cation and the sulfate anion. The coordination polyhedron of the central atom is a slightly distorted tetragonal pyramid whose base is formed by sulfur, azomethine nitrogen, phenolic oxygen of thiosemicarbazone, and dimethyl sulfoxide oxygen. The axial position is occupied by the methanol oxygen atom. In structure III, the copper atom coordinates 5-nitrosalicylaldehyde thiosemicarbazone and the thiocyanate ion, which combines complexes into infinite polymer chains along the [010] direction. The copper coordination polyhedron in III is a slightly distorted tetragonal pyramid whose base is formed by sulfur, azomethine nitrogen, phenolic oxygen of thiosemicarbazone, and nitrogen of thiocyanate ion, the axial vertex is occupied by sulfur of thiocyanate ion of the neighboring complex.

Matrix Metalloproteinase 2 (MMP2) Inhibition: DFT and QM/MM Studies of the Deprotonation-Initialized Ring-Opening Reaction of the Sulfoxide Analogue of SB-3CT

(4-Phenoxyphenylsulfonyl)methylthiirane (SB-3CT) is the selective inhibitor of matrix metalloproteinase 2 (MMP2). The inhibition mechanism of MMP2 by SB-3CT involves C-H deprotonation with concomitant opening of the three-membered heterocycle. In this study, the energetics of the deprotonation-induced ring-opening of (4-phenoxyphenylsulfinyl)methylthiirane, the sulfoxide analogue of SB-3CT, are examined computationally using DFT and QM/MM calculations. A model system, 2-(methylsulfinylmethyl)thiirane, is used to study the stereoelectronic and conformational effects of reaction barriers in methanol. For the model system in methanol solution (using the polarizable continuum model), the reaction barriers range from 17 to 23 kcal/mol with significant stereoelectronic effects. However, the lowest barriers of the (R,R) and (S,R) diastereomers are similar. Two diastereomers of the sulfoxide analogue of SB-3CT are studied in the active site of MMP2 by QM/MM methods with an accurate partial charge fitting procedure. The ring-opening reactions of these two diastereomers have similar reaction energetics. Both are exothermic from the reactant to the ring-opening product (thiolate). The protonation of the thiolate by a water molecule is endothermic in both cases. However, the deprotonation/ring-opening barriers in the MMP2 active site using QM/MM methods for the (R,R) and (S,R) inhibitions are quite different (23.3 and 28.5 kcal/mol, respectively). The TSs identified in QM/MM calculations were confirmed by vibrational frequency analysis and following the reaction path. The (R,R) diastereomer has a hydrogen bond between the sulfoxide oxygen and the backbone NH of Leu191, while the (S,R) has a hydrogen bond between the sulfoxide oxygen and a water molecule. The dissimilar strengths of these hydrogen bonds as well as minor differences in the TS structures contribute to the difference between the barriers. Compared to SB-3CT, both diastereomers of the sulfoxide analogue have higher reaction barriers and have less exothermic reaction energies. This agrees well with the experiments, where SB-3CT is a more effective inhibitor of MMP2 than its sulfoxide analogue.

Dipyrazinyl Sulfoxide Complexes of Silver(I), Zinc(II), and Cadmium(II): Ligation Modes and Anion Tuning

The new ligand dipyrazinyl sulfoxide (also named sulfinyldipyrazine and abbreviated as pyz(2)SO) and a series of its metal complexes including {[Ag(pyz(2)SO)](NO(3)).CH(3)CN}(infinity) (1), {[Ag(pyz(2)SO)](PF(6))}(infinity) (2), [Ag(3)(pyz(2)SO)(2)(ClO(4))(3)](infinity) (3), [Ag(pyz(2)SO)(CF(3)CO(2))](infinity) (4), {[Zn(pyz(2)SO)(H(2)O)(4)](NO(3))(2).H(2)O}(infinity) (5), {[Zn(pyz(2)SO)(H(2)O)(2)](ClO(4))(2)}(infinity) (6), and {[Cd(pyz(2)SO)(2)(H(2)O)](ClO(4))(2).H(2)O}(infinity) (7) have been synthesized and characterized by single-crystal X-ray analysis. The counteranions in these complexes prefer to be embraced by a pair of pi-acidic heterocyclic rings via anion-pi interactions, which consequently affect the process of supramolecular assembly. Seven distinct ligation modes of pyz(2)SO involving various bonding combinations of the sulfoxide oxygen and/or pyrazinyl nitrogen atoms (labeled A-G) are observed. Diverse coordination motifs such as (4,4) network, ladder-type, necklace-like, linear, and zigzag-chain structures are found in 1-7. Interestingly, the sulfoxide group of the pyz(2)SO ligand exhibits unusual dipolar sulfinyl...sulfinyl and S=O...pi(pyrazinyl) intermolecular interactions in the supramolecular assemblies of neat pyz(2)SO, 1, and 3-5.

NMR and FTIR studies of coordinate-bonding and intramolecular and intermolecular hydrogen bonding in zinc(II)(3,5-diisopropylsalicylate)2

Carboxylate and salicylic OH coordinate bonding as well as intramolecular and intermolecular hydrogen bonding of bis-3,5-diisopropylsalicylatozinc(II), [ZnII(3,5-DIPS)2], with Lewis bases were studied to determine mechanisms accounting for antioxidant reactivity of ZnII(3,5-DIPS)2. Apparent thermodynamic parameters: K eq, ΔS 0, ΔH 0, and ΔG 0 were determined for these equilibria with bonding of two molecules of dimethyl sulfoxide-d6 (DMSO) or ethyl acetate-d8 (EA) to the ZnII using NMR and FTIR. We conclude that addition of two equivalents of DMSO or EA to non-polar solutions of ZnII(3,5-DIPS)2 results in bonding of DMSO or EA to ZnII via sulfoxide or ester carbonyl oxygen atoms with ternary complex formation, leading to weakening of carboxylate and salicylic OH coordinate bonding to ZnII and strengthening intramolecular hydrogen bonding between protons of salicylic OH groups and carboxylate oxygens. Subsequent addition of two or three additional equivalents of DMSO or EA leads to intermolecular hydrogen bonding between protons of salicylic OH groups.

High‐throughput approaches towards the definitive identification of pharmaceutical drug metabolites. 1. Evidence for an ortho effect on the fragmentation of 4‐benzenesulfinyl‐3‐methylphenylamine using electrospray ionisation mass spectrometry

A 50 m/z unit loss from protonated 4-benzenesulfinyl-3-methylphenylamine has been observed and investigated using electrospray ionisation quadrupole ion trap mass spectrometry (ESI-QIT-MS). It was hypothesised that the specific fragmentation was affected by the presence of an ortho methyl group in relation to the sulfoxide functionality, i.e. an ortho effect influences the preferred dissociation pathway. This was because the des-methyl homologue did not display a 50 m/z unit loss. This fragmentation was shown to be a two-step process with sequential losses of a hydroxyl radical and a thiol radical. Molecular modelling calculations showed that the most favourable site of protonation for 4-benzenesulfinyl-3-methylphenylamine was the sulfoxide oxygen, which would facilitate the loss of a hydroxyl radical. Subsequent deuterium-exchange experiments confirmed that the loss was a hydroxyl radical and afforded definitive assignment of the site of protonation. Furthermore, the involvement of a single exchangeable hydrogen atom in the overall 50 m/z unit loss was demonstrated. Thus, supportive evidence was provided for the involvement of the ortho methyl group in the second stage of the fragmentation, leading to the loss of the thiol radical. Accurate mass measurements, performed using electrospray ionisation Fourier transform ion cyclotron resonance mass spectrometry (ESI-FTICR-MS), verified the elemental formulae of the individual losses. The ion structure following the 50 m/z unit loss was proposed to be a protonated aminofluorene and was supported by comparing the product ion spectrum of commercially available protonated 2-aminofluorene with the MS4 data of protonated 4-benzenesulfinyl-3-methylphenylamine. Fragmentation mechanisms are proposed. The relevance of the loss with regards to pharmaceutical drug metabolite identification is discussed.

Determination of 13C NMR Shifts for Carbons Beta and Gamma to Oxygen in Poly(Olefin Sulfone)s

We have established parameters that enable the prediction of 13C NMR chemical shifts for carbons β and γ to a sulfoxide or sulfone oxygen(s). Carbons β were found to be moved upfield by ∼ 21 ppm and those γ downfield by ∼ 7.7 ppm in chloroform. We tested these parameters by sequentially oxidizing poly(butyl thirane) to its corresponding polysulfone and assigned the new peaks observed in the 13C NMR on the basis of their proximity to the oxygen atom(s).