A simple and cost effective method for the quantification of 8-hydroxy-2'-deoxyguanosine from urine using liquid chromatography tandem mass spectrometry

A rapid and high-throughput method for the determination of urinary levels of the oxidative stress biomarker, 8-hydroxy-2'-deoxyguanosine (8-OH-dG), has been developed and validated using liquid chromatography combined with electrospray ionization tandem mass spectrometry (LC-MS/MS). The assay features a cheap and readily available non-isotopic internal standard, a single-step filtration sample preparation, and a total analysis time of 6 min including column re-equilibration. The method was validated based on linearity, accuracy (100-106%), precision (CV < 7%), sample preparation stability (< or =5%, 72 h). Intra-laboratory patient ranges were established comparing children and adults (n = 345).     

An ab initio SCF study on the tautomerisation of the 8-oxo-guanine and xanthine

All possible H₉-tautomers of 8-oxo-guanine and xanthine were studied by means of PM3 semiempirical and DFT (density functional theory) quantum chemistry methods. Additionally, the five most stable tautomers of both guanine derivatives were estimated on 3-21G, 6-31G, 6-31G^** and MP2 (6-31G^**) ab initio levels. The impact of the environment polarity on the tautomeric equilibrium was also taken into account. Among the variety of tautomeric isomers most probable are diketo forms of both studied derivatives in non-polar and polar surroundings.

The tautomeric equilibrium was unchanged after connection of the sugar backbone. The most preferred diketo forms of 8-oxo-guanosine and xanthidine are in syn conformations both in polar and non-polar environments. The increase of the syn conformations over anti ones may have the source in the formation of the internal hydrogen bonds between H′5 and N₃ atoms. The calculated values of the pseudorotation phase angle were between 144 and 180° in all cases. This corresponds to C′2-endo conformations of all optimised structures.

The N-glycosidic bond stability of most stable tautomers was compared to standard guanosine. Most tautomers of 8-oxo-guanosine and xanthidine are characterised by more stable C₁′-N₉ bond. This indicates that both these derivatives are hardly susceptible to spontaneous depurination and its removal from the DNA will depend mostly on the activity of DNA repair enzymes.     

An ab initio study of excited states of guanine in the gas phase and aqueous media: Electronic transitions and mechanism of spectral oscillations

Ground state geometries of the four tautomeric forms keto‐N9H, keto‐N7H, enol‐N9H, and enol‐N7H of guanine were optimized in the gas phase at the RHF level using a mixed basis set consisting of the 4‐31G basis set for all the atoms except the nitrogen atom of the amino group for which the 6‐311+G* basis set was used. These calculations were also extended to hydrogen‐bonded complexes of three water molecules with each of the keto‐N9H (G9‐3W) and keto‐N7H (G7‐3W) forms of guanine. Relative stabilities of the four above‐mentioned tautomers of guanine as well as those of G9‐3W and G7‐3W complexes in the ground state in the gas phase were studied employing the MP2 correlation correction. In aqueous solution, relative stabilities of these systems were studied using the MP2 correlation correction and polarized continuum model (PCM) or the isodensity surface polarized continuum model (IPCM) of the self‐consistent reaction field (SCRF) theory. Geometry optimization in the gas phase at the RHF level using the 6‐31+G* basis set for all atoms and the solvation calculations in water at the MP2 level using the same basis set were also carried out for the nonplanar keto‐N9H and keto‐N7H forms of guanine. Thus, it is shown that among the different tautomers of guanine, the keto‐N7H form is most stable in the gas phase, while the keto‐N9H form is most stable in aqueous solution. It appears that both the keto‐N9H and keto‐N7H forms of guanine would be present in the ground state, particularly near the aqueous solution–air interface. Vertical excitation and excited state geometry optimization calculations were performed using configuration interaction involving single electron excitation (CIS). It is found that the absorption spectrum of guanine would arise mainly due to its keto‐N9H form but the keto‐N7H form of the same would also make some contribution to it. The enol‐N9H and enol‐N7H forms of the molecule are not expected to occur in appreciable abundance in the gas phase or aqueous media. The normal fluorescence spectrum of guanine in aqueous solution with a peak near 332 nm seems to originate from the lowest singlet excited state of the keto‐N7H form of the molecule while the fluorescence of oxygen‐rich aqueous solutions of guanine with a peak near 450 nm appears to originate from the lowest singlet excited state of the keto‐N9H form of the molecule. The origin of the slow damped spectral oscillation observed in the absorption spectrum of guanine has been explained. © 2000 John Wiley & Sons, Inc. J Comput Chem 21: 826–846, 2000     

Monitoring of 8-oxo-7,8-dihydro-2'-deoxyguanosine in urine by high-performance liquid chromatography after pre-column derivatization with glyoxal reagents

A new, simple and sensitive pre-column fluorescence derivatization high-performance liquid chromatographic method for the determination of the oxidative DNA stress marker, 8-oxo-7,8-dihydro-2'-deoxyguanosine, was developed. Solid-phase extraction using an Oasis HLB cartridge avoided troublesome sample preparation steps, interference from charged species and frequent and essential electrode maintenance in electrochemical procedures. 8-Oxo-7,8-dihydro-2'-deoxyguanosine and other guanine compounds were selectively derivatized with glyoxal reagents (phenylglyoxal, 3,4-methylenedioxyglyoxal, 2-naphtylglyoxal and 6-methoxynaphthylglyoxal) at 40-60 degrees C. Derivatization with 6-methoxynaphthylglyoxal at 40 degrees C for 30 min gave the strongest fluorescence product. The fluorescence derivatives from reaction with 6-methoxynaphthylglyoxal were separated on a Capcell Pak C18 SG 120A column (4.6 mm i.d. x 150 mm, 5 microm) with acetonitrile-5 mM phosphate buffer (pH 6.0; 3:7, v/v) as mobile phase. The detection wavelength of the fluorescence derivative of 8-oxo-7,8-dihydro-2'-deoxyguanosine was lambda(ex) 400 nm and lambda(em) 510 nm. The detection limit of 8-oxo-7,8-dihydro-2'-deoxyguanosine was 1 ng/mL using 50 mL of urine. The calibration graphs were linear up to 30 microg/mL for 8-oxo-7,8-dihydro-2'-deoxyguanosine. The relative standard deviation of 20 ng/mL of 8-oxo-7,8-dihydro-2'-deoxyguanosine was 7.0%. The proposed method was compared with the enzymatic ELISA 8-oxo-7,8-dihydro-2'-deoxyguanosine analysis method (8-OH-dG Check, JaICA, Shizuoka, Japan). The correlation coefficient was 0.79 (n = 20) and y = 0.85x + 5.34. The proposed method was applied to the monitoring of 8-oxo-7,8-dihydro-2'-deoxyguanosine in urine from male heavy smokers.     

An ab initio study of electronic spectra and excited-state properties of 7-azaindole in vapour phase and aqueous solution

The geometries of 7-azaindole (7AI), its tautomer (7AT), and 7AI–H₂O and 7AT–H₂O complexes were optimised in the ground state and some low-lying singlet excited states using the 3-21G basis set. Differences of total energies of the optimised ground and excited states and the vertical excitation energies of these systems were used to explain the observed electronic spectra. Effect of solvation of these systems in bulk water was studied using the polarized continuum model (PCM). The mode of binding of a water molecule in the S₂(n–π^*) excited state of 7AI was found to be quite different from those in its ground and π–π^* excited states. It is shown that crossing of the lowest two singlet excited-state potential surfaces S₁(π–π^*) and S₂(n–π^*) of 7AI occurs in the vapour phase under geometry relaxation while on interaction with water, the S₂(n–π^*) excited state is raised up appreciably going even above the S₃(π–π^*) excited state. Ground- and excited-state molecular electrostatic potential mapping was carried out, which led to valuable information regarding the nature of excited states of the above-mentioned systems.     

Comparative study of the electronic structure of pregnanolones by ab initio theory

Pregnanedione (5β‐pregnane, 3,20‐dione), pregnanolone (3β‐hydroxy‐5β‐pregnan‐20‐one), and epipregnanolone (3α‐hydroxy‐5β‐pregnan‐20‐one) result from the 5β‐reduction of progesterone [4‐pregnene, 3‐20‐dione (P)]. These P metabolites induce anesthesia and smooth muscle relaxation (nongenomic actions). In the present study, geometries and electronic structure of these steroids were assessed by ab initio calculations using the 6‐31G* basis set. Consequently, bond distances, valence angles, and dihedral angles were measured. In addition total energy, frontier orbitals, i.e., highest occupied molecular orbital (HOMO), lowest unoccupied molecular orbital (LUMO), dipole moment, and electrostatic potentials were calculated. Total energy was higher for P, followed by pregnanedione. Pregnanolones, the hydroxylated progestins, showed the lower energies. Concerning frontier orbitals, P showed the highest HOMO energy and the lowest LUMO energy. Pregnanedione showed lower HOMO and LUMO energy values than pregnanolone and epipregnanolone. P showed both HOMO and LUMO located at the A ring, including the π bond at C4, C5, and the carbonyl at C3. The HOMO in pregnanedione was included mostly in the A ring and the C3 carbonyl group, while the LUMO was shared by the carbonyl groups at C3 and C20. The frontier orbitals of pregnanolone and epipregnanolone were quite similar. The HOMO in both steroids included the B, C, and D rings and the carbonyl at C20. The LUMO was also similar in both pregnanolones including mostly the carbonyl at C20. The dipole moment was shorter for P and pregnanedione and directed toward the acetyl side chain at C17. Pregnanolone and epipregnanolone showed the dipole moment vector larger and directed toward the A ring. The electrostatic potentials were related mostly with the lone pairs of electrons from the oxygens. By the total energy and frontier orbitals energies of the hormones studied, it is concluded that the metabolism of progesterone toward its 5β‐reduced metabolites might be rationalized from the theoretical chemistry point of view. Besides, the importance of the A/B ring cis configuration, dipole moment, and electrostatic potential are highlighted as possible improving elements of molecular interactions to explain the nongenomic biological action of 5β‐reduced progestins. ©1999 John Wiley & Sons, Inc. Int J Quant Chem 71: 433–440, 1999     

Theoretical study of the kojic acid structure in gas phase and aqueous solution

Density functional calculations at the B3LYP/6‐311++G** level have been performed to determine the ground‐state conformational preference for kojic acid, a widely used skin‐whitening, antibrowning, and antibacterial agent. It is found that the gas phase consists almost entirely of the 5‐hydroxy‐2‐(hydroxymethyl)‐4H‐pyran‐4‐one tautomer, although several rotamers of this are prevalent. In aqueous solution, however, other tautomers are also present. The validity of the calculations is confirmed by the observed FTIR, NMR, and UV–vis spectra, which show good correspondence with the theoretical spectra. The electronic interactions are interpreted in terms of charge and bond order analysis as well as the composition of the HOMO and LUMO. The calculations show that kojic acid has partial aromatic character and is a good nucleophile. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2011     

An ab initio and density functional theory study of keto-enol equilibria of hydroxycyclopropenone in gas and aqueous solution phase

Keto-enol tautomerism in hydroxycyclopropenone (2-hydroxy-2-cyclopropen-1-one) has been studied using ab initio methods, the B3LYP functional of density functional theory, as well as complete basis set (CBS-QB3 and CBS-APNO) and G3 methods. Absolute and relative energies were calculated with each of the methods, whereas computations of geometries and harmonic frequencies for hydroxycyclopropenone and 1,2-cyclopropanedione were computed in the gas phase but were limited to HF, MP2 and CCSD levels of theory, and the B3LYP functional, in combination with the 6-31++G** basis set. Using the MP2/6-31++G** gas phase optimized structure, each species was then optimized fully in aqueous solution by employing the polarizable continuum model (PCM) self-consistent reaction field approach, in which HF, MP2 and B3LYP levels of theory were utilized, with the same 6-31++G** basis set. In both gas and aqueous solution phases, the keto form is higher in energy for all of the model chemistries considered. The presence of the solvent, however, is found to have very little effect on the bond lengths, angles and harmonic frequencies. From the B3LYP/6-31++G** Gibbs free energy, the keto-enol tautomeric equilibrium constant for 2-hydroxy-2-cyclopropen-1-one <==> 1,2-cyclopropanedione is computed to be K(T)(gas) = 2.35 x 10(-6), K(T)(aq) = 5.61 x 10(-14). It is concluded that the enol form is overwhelmingly predominant in both environments, with the effect of the solvent shifting the direction of equilibrium even more strongly in the favor of hydroxycyclopropenone. The almost exclusive nature of this species is attributed to stabilization resulting from aromaticity. Confirmation is provided by comparison of the simulated vibrational spectra of hydroxycyclopropenone with the measured infrared spectrum in an argon matrix.     

An ab initio LCAO-MO-SCF study of the electronic structure of phosphirane and thiirane

Wave functions have been determined for the C₂H₄PH and C₂H₄S cyclic molecules, using (951/52/3) and (95/52/3) uncontracted Gaussian basis sets for each molecule. From Mulliken population analyses and electron-density plots, it is shown that the valence orbitals of C₂H₄PH and C₂H₄S are closely related and that these are similar to the respective orbitals of cyclopropane.

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Zusammenfassung Für die zyklischen Moleküle C₂H₄PH und C₂H₄S wurden mit den nichtkontrahierten Basissätzen ((951/52/3) und (95/52/3)) von Gaußfunktionen Wellenfunktionen bestimmt. Die Mullikenschen Populationsanalysen sowie Diagramme der Elektronendichte zeigen, daß die Valenzorbitale von C₂H₄PH und C₂H₄S in enger Beziehung stehen und daß diese den entsprechenden Orbitalen des Cyclopropans ähnlich sind.

     

Capillary electrophoresis with end-column amperometric detection of urinary 8-hydroxy-2'-deoxyguanosine

Urinary 8-hydroxy-2'-deoxyguanosine (8OHdG) is an excellent marker of oxidative DNA damage. Until now, urinary 8OHdG has been measured by high-performance liquid chromatography with electrochemical detection. A simple and sensitive method for the analysis of urinary 8OHdG by capillary electrophoresis with end-column amperometric detection has been developed in our laboratory. A single-step solid-phase extraction procedure was optimized and used for extracting 8OHdG from human urine. To improve the sensitivity of this method, a new focusing technique based on a dynamic pH junction was used. The limit of detection was 20 nM (signal-to-noise ratio S/N = 3), the linear range was 50 nM-10 microM, and the correlation coefficient was better than 0.999. The relative standard deviation (RSD) was found to be 0.57% for migration time, and 4.79% for peak current. To show the usefulness of the method, the urinary concentration of 8OHdG in nine healthy persons and ten cancer patients was determined. The urinary concentration of 8OHdG in cancer patients was significantly higher than that in healthy persons.     

An ab initio study of the stability and electronic structure of univalent magnesium salts

Large basis and well-correlated ab initio electronic structure calculations have been performed on the simple Mg(I) salts, Mg₂F₂ and Mg₂Cl₂. The electron withdrawing power of the halogens gives rise to significant metal-metal bonding and consequently these as yet unobserved, univalent salts are calculated to be 10–12 kcal more stable than if the second magnesium atom were absent from the molecule. With this stability, these species provide an energetically more accessible Mg atom for subsequent reaction than does solid magnesium where the atomization energy is 35 kcal. Thus, formal univalency of magnesium affords a route to activated magnesium.     

Assay of urinary 8‐hydroxy‐2′‐deoxyguanosine by capillary electrophoresis with spectrophotometric detection using a high‐sensitivity detection cell and solid‐phase extraction

A sensitive capillary electrophoretic method featuring spectrophotometric detection using a commercial Z‐cell was devised for the assay of 8‐hydroxy‐2′‐deoxyguanosine (8OHdG) in human urine. Solid‐phase extraction (SPE) based on hydrophilic‐lipophilic‐balanced RP sorbent was utilized for urine sample pretreatment and analyte preconcentration. The separation was carried out in conventional fused‐silica capillaries employing a Z‐cell with hydrodynamic sample injection (at 50 mbar for 12 s). The BGE (pH* 9.2, adjusted with 1 M NaOH) contained 0.15 M boric acid and 10% v/v ACN. The detection wavelength was 282 nm. The calibration curve for 8OHdG (measured in spiked urine) was linear in the range 10–1000 ng/mL; R² = 0.9993. The LOD was 3 ng/mL (11 nmol/L) of 8OHdG. Determination of the 8OHdG urinary levels was possible even in healthy individuals.     

An ab initio study of the hyperfine structure in the X2 Pi electronic state of CCCH

The results of an ab initio study of the magnetic hyperfine structure in the X (2)Pi electronic state of CCCH are reported. The potential surfaces for two components of the X (2)Pi electronic state were computed by means of an extensive configuration interaction approach. The electronically averaged hyperfine coupling constants of H and (13)C for (12)C (12)C (12)CH, (13)C (12)C (12)CH, (12)C (13)C (12)CH, and (12)C (12)C (13)CH are obtained as functions of two bending vibrational modes by the density functional theory method. The vibronic wave functions are calculated with the help of a variational approach which takes into account the Renner-Teller effect and spin-orbit coupling. The model Hamiltonian is expressed in terms of the normal bending coordinates. It is found that, due to the generally strong geometry dependence of the hyperfine coupling constants, it is necessary to carry out the vibronic averaging of the corresponding functions in order to obtain the values which can be compared to the results of the measurements. The results of the present study help to reliably interpret the experimental data previously published. They also predict the yet unobserved hyperfine structure in excited vibronic states.     

An ab initio study of water clusters in gas phase and bulk aqueous media: (H2O)n,n=1–12

Geometries of several clusters of water molecules including single minimum energy structures of n‐mers (n=1–5), several hexamers and two structures of each of heptamer to decamer derived from hexamer cage and hexamer prism were optimized. One structural form of each of 11‐mer and 12‐mer were also studied. The geometry optimization calculations were performed at the RHF/6‐311G* level for all the cases and at the MP2/6‐311++G** level for some selected cases. The optimized cluster geometries were used to calculate total energies of the clusters in gas phase employing the B3LYP density functional method and the 6‐311G* basis set. Frequency analysis was carried out in all the cases to ensure that the optimized geometries corresponded to total energy minima. Zero‐point and thermal free energy corrections were applied for comparison of energies of certain hexamers. The optimized cluster geometries were used to solvate the clusters in bulk water using the polarized continuum model (PCM) of the self‐consistent reaction field (SCRF) theory, the 6‐311G* basis set, and the B3LYP density functional method. For the cases for which MP2/6‐311++G** geometry optimization was performed, solvation calculations in water were also carried out using the B3LYP density functional method, the 6‐311++G** basis set, and the PCM model of SCRF theory, besides the corresponding gas‐phase calculations. It is found that the cage form of water hexamer cluster is most stable in gas phase among the different hexamers, which is in agreement with the earlier theoretical and experimental results. Further, use of a newly defined relative population index (RPI) in terms of successive total energy differences per water molecule for different cluster sizes suggests that stabilities of trimers, hexamers, and nonamers in gas phase and those of hexamers and nonamers in bulk water would be favored while those of pentamer and decamer in both the phases would be relatively disfavored. © 2001 John Wiley & Sons, Inc. Int J Quant Chem 81: 90–104, 2001     

Site specificity of alpha-H abstraction reaction among secondary structure motif--an ab initio study

The initial step of protein oxidation is studied through alpha-H abstraction by an OH radical with various secondary structure motifs of proteins. It is found that there exist preferential alpha-Hs in this kind of abstractions. The typical abstraction mechanism involves three steps: forming a pre-reactive complex before abstraction, the abstraction reaction, and the H(2)O detachment from a post-reactive complex to form the product, C(alpha)-center radical. Using the stability of the pre-reactive complex and the reaction barrier, we provide some explanation for this site preference. The feasibility of alpha-H abstraction by OH radical depends not only on the types of secondary structure, but also on the reaction condition, such as in aqueous or in gas phase. Moreover, the reactivity of the abstraction also depends on the location of alpha-H in the secondary structure motifs. The preferential alpha-Hs to be abstracted in beta-sheet are those immediate to the amide or carbonyl group, and without involving hydrogen bonding, whereas in reverse turns, the preferential alpha-Hs are near the C-terminal of type I and near the N-terminal of type II. In general, the alpha-Hs in alpha-helix are more difficult to be abstracted than those in beta-sheet and polypeptide in linear form. It is consistent with the trend of their bond dissociation energies. Our theoretical rate constant of N-acetyldiglycin-methylamide (Ac(Gly)(2)NHCH(3)) in aqueous solution (6.75 x 10(8) M(-1) s(-1)) is close to the experimental observation of N-acetyldiglycinamide (Ac(Gly)(2)NH(2)) (8.6 x 10(8) M(-1) s(-1)).     

An ab initio study of ground state, electronic and thermodynamical properties of GaP and Ga2P

In the present paper, we report an ab initio calculation of the ground state, electronic and thermodynamical properties like constant volume lattice specific heat, vibrational energy, internal energy, and entropy for GaP and Ga₂P is presented. These properties are obtained after calculating the phonon spectrum over the entire Brillouin zone. The calculations were performed using the ABINIT program package, which is based on density functional theory (DFT) method and the use of pseudopotentials and plane wave expansion. Difference in the ground state properties such as electronic structure and thermodynamical properties are discussed. The thermodynamical properties follow the expected trend. There is a good agreement between present theoretical and limited available experimental data in the case of ground state such as lattice constant and bulk modulus and electronic properties. With the increase of Ga atoms in the unit cell the semiconducting nature of Ga₂P turns to metallic. There is a noticeable difference in the thermodynamical properties in the case of both gallium compounds.     

Comparative semiempirical and ab initio study of the structural and chemical properties of uric acid and its anions

Semiempirical, density functional theory (DFT), and ab initio calculations have been performed to assess the relative stabilities of 15 possible tautomer forms of neutral uric acid, and of the different urate mono‐ and dianion forms. These methods have also been used to compute ionization potentials (IPs) for uric acid and its derived anions. Overall, we have found that semiempirical calculations, in particular PM3, perform well as compared with B3LYP or MP2 computations toward these different structural and chemical properties of uric acid: the triketo form of uric acid is the most stable tautomer form of neutral uric acid. Three other tautomer forms are relatively close in energy, within the range 2–6 kcal/mol above the triketo form, with a mean energy deviation of only 1.3 kcal/mol between PM3 and DFT or ab initio results; the monoanion form of uric acid obtained by abstracting one proton in position 3 (denoted UAN) is the most stable form among all four possible urate monoanions both in gas phase and in solution; the dianion form of uric acid obtained by abstracting two protons, respectively, in positions 3 and 9 of uric acid (denoted UANN) is the most stable urate dianion form both in gas phase and in solution. However, these two most stable species do not have the lowest IPs in solution: among monoanions and dianions, respectively, the species with the lowest IPs are UAN and UANN. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007     

An ab initio study of the electronic structure of BCl3(2+) and its decomposition pathways

Ab initio methods have been used to characterise the lowest energy potential energy surfaces of 1BCl3(2+) and 3BCl3(2+). The methods used are MP2, CCSD, CCSD(T) and MCSCF with 6-311G(d), cc-pVTZ and aug-cc-pVTZ basis sets. While the singlet surface is relatively straight-forward, the triplet surface is very complicated, with many stationary points in close energetic proximity. The singlet surface can fragment to the following products (1BCl + 1Cl+ + 1Cl+), (1Cl+ + 1B+ + 1Cl2), (2BCl+ + 2Cl), while the triplet surface can fragment to (1BCl2+ + 3Cl+) and (2BCl2(2+) + 2Cl). 2BCl2(2+) can further fragment to (1Cl+ + 2BCl+). These results are in good agreement with previous experimental data from coincidence mass spectroscopy. [symbol: see text]1 diagnostic values have been calculated for all of the stationary points of BCl3(2+), using the method of Lee and Taylor. These data, together with CCSD/CCSD(T) energy differences and MCSCF calculations, are used to conclude that most of the stationary points on the singlet surface are well represented using single reference methods. The stationary points of the triplet system have [symbol: see text]1 diagnostic values greater than those for the singlet system, as expected when using the closed-shell [symbol: see text]1 diagnostic method of Lee and Taylor. However, all of the structures have acceptable single reference wavefunctions if the open-shell upper limit of Rienstra-Kiracofe et al. (0.045) is used, a conclusion fully supported by CCSD/CCSD(T) energy differences. CCSD(T) energies determined for the fragmentation asymptotes have been compared with experimental data collated from the NIST Theoretical and Scientific Data website, and the generally very good agreement between theory and experiment reinforces the reliability of the CCSD(T) method.     

A semiempirical study of 2,2′-dichlorodiethyl sulfide SN2 and neighboring group hydrolysis reaction mechanisms in the gas phase and in aqueous solution

A PM3 and SM3-PM3 semiempirical molecular orbital study of the 2,2′-dichlorodiethyl sulfide conventional S_N2 and neighboring group hydrolysis reaction mechanisms in the gas phase and in aqueous solution is described. The calculations predict substantially faster reactions in aqueous solution, with the neighboring group mechanism always being preferred. Detailed consideration is given to the geometries, relative energies, and partial atomic charges of all species involved in the reaction mechanisms considered and the extent to which aqueous solvation impacts these quantities. The results are consistent with expectation and with reported calculations concerning the intramolecular S_N2 reaction of 2-chloroethyl methyl sulfide. We also present the lowest energy mustard chlorohydrin structures according to PM3 and AM1 conformational analysis.