A DFT study of the active role of the phosphate group of an internal aldimine in a transamination reaction.

A transamination reaction from an internal aldimine ([PLP]) and (S)-alanine to pyridoxamine phosphate (PMP) and pyruvic acid was investigated by DFT calculations. As [PLP], a model where the lysine (-Lys) part was approximated by -CH[-NH-C(O)-CH3]-C(O)-NH-CH3 was adopted. (H2O)4 was also included to trace reaction paths involving proton transfers. 13 elementary processes were obtained. For (the external aldimine → quinoid), (quinoid → ketimine) and (ketimine → carbinol amine) processes, the water dimer was found to connect a phosphate-group oxygen with the moving proton. The connection promoted the Grotthuss-type proton transfer in transition states. It was revealed that the phosphate group is not a mere substituent but has the central role in the transfer.

A DFT study on the degradation mechanism of vitamin B2.

Degradation reaction paths starting from riboflavin (RF) were investigated using DFT (density functional theory) as the first attempt to reveal their elementary processes. Photochemical reactions were followed in the lowest triplet spin state, "(T)". Two intermediates [Int1(T) and Int2(T)] were found in the course, RF(T) â†’ FMF (7,8-dimethyl-10-formylflavin, T). From FMF(T), there are two degradation channels. Release of ketene(T) and carbon monoxide leads to LC (lumichrome, S0) and LF (lumiflavin, T), respectively. The base-catalyzed (ground state) degradation of FMF was investigated with HO-(H2O)3. The Grotthuss-type proton transfer along hydrogen bonds controlled the degradation reaction. All the transition states of cleavage of C-C and C-N covalent bonds were determined, and the degradation mechanism was clarified.

How Is the Oxidation Related to the Tautomerization in Vitamin B9?

The relationship between the lactim-lactam tautomerization and the free-radical scavenging reaction in vitamin B9 [folic acid (FA)] was investigated by density functional theory calculations. 6-Methylpterin was also adopted for the detailed analyses of various reaction paths. For pterin, the transition state of the tautomerization with two water molecules (n = 2) was calculated to be of the lowest activation energy. The proton-transfer circuit of n = 2 is retained (not broken) even with the addition of outer water molecules, n = 2 + 2, 2 + 4, 2 + 8, and 2 + 14. At the oxidation of the system composed of 6-methylpterin + (H2O)2 + HO•, the radical character of HO• is directly transmitted to the pterin ring along with the C-O → H → O → H → O → H → OH proton transfer. The patterns of the electron transfer (pterin ring → OX•) and the concomitant proton transfer via the water dimer were commonly obtained for the oxidant (OX•) = HO•, Cl3C-O2•, N3•, or SO4-•. The hydrogen atom transfer mechanism was ruled out. Two conformations of the puckered form with the -C(═O)-OH···N intramolecular hydrogen bonds of FA were found to have the stability similar to that of the linear conformer. Both the tautomerization and the oxidation were calculated to occur competitively in the three conformers.

How is vitamin B1 oxidized to thiochrome? Elementary processes revealed by a DFT study.

The oxidation reaction of thiamine (vitamin B1) to thiochrome was investigated by DFT calculations. Three reaction systems, [A] thiamine + methyl peroxy radical + (H2O)8, [B] thiamine + cyanogen bromide + HO-(H2O)8 and [C] thiamine + mercury(ii) chloride + HO-(H2O)8, were investigated. wB97X-D/6-311+G** for [A] and [B] and wB97X-D/SDD&6-311(+)G** for [C] geometry optimizations were carried out with the solvent effect (water). The effect is of the self-consistent reaction field (SCRF) with the polarizable continuum model (PCM). In [A], the H3C-O2˙ adduct of thiamine undergoes simultaneous cleavage of the C-H and O-O bonds, leading to a very stable 2(3H)-thiazolone intermediate. The same intermediate was obtained after the cleavage of the C-H and O-H bonds of the HO adduct of thiamine in [B] and [C]. After the formation of the key intermediate, the N-protonated thiochrome was afforded via three steps. In reflection of the water-soluble character of vitamin B1, proton transfers along hydrogen bonds of the water cluster enhance those steps.

Corona Discharge and Field Electron Emission in Ambient Air Using a Sharp Metal Needle: Formation and Reactivity of CO3 -• and O2 -•.

CO3 -• and O2 -• are known to be strong oxidizing reagents in biological systems. CO3 -• in particular can cause serious damage to DNA and proteins by H• abstraction reactions. However, H• abstraction of CO3 -• in the gas phase has not yet been reported. In this work we report on gas-phase ion/molecule reactions of CO3 -• and O2 -• with various molecules. CO3 -• was generated by the corona discharge of an O2 reagent gas using a cylindrical tube ion source. O2 -• was generated by the application of a 15 kHz high frequency voltage to a sharp needle in ambient air at the threshold voltage for the appearance of an ion signal. In the reactions of CO3 -•, a decrease in signal intensities of CO3 -• accompanied by the simultaneous increase of that of HCO3 - was observed when organic compounds with H-C bond energies lower than ∼100 kcal mol-1 such as n-hexane, cyclohexane, methanol, ethanol, 1-propanol, 2-propanol, and toluene were introduced into the ion source. This clearly indicates the occurrence of H• abstraction. O2 -• abstracts H+ from acid molecules such as formic, acetic, trifluoroacetic, nitric and amino acids. Gas-phase CO3 -• may play a role as a strong oxidizing reagent as it does in the condensed phase. The major discharge product CO3 -• in addition to O2 -•, O3, and NO x • that are formed in ambient air may cause damage to biological systems.

DFT Study of the Hydroxyl Radical Addition to 2'-Deoxyguanosine and the Guanine Base in Four Double-Stranded B-Form Dimers.

Density functional theory (DFT) calculations of reactions between 2'-deoxyguanosine (dR-Gua) and hydroxyl radical (HO•) with water molecules (H2O)n, n = 0, 1, and 2, were carried out. The HO• addition to three carbon sites, C(4), C(5), and C(8), and the subsequent ring cleavage of the three HO adducts were investigated. The addition to C(5) is of the smallest activation energy according to the largest lobe of the dR-Gua highest occupied molecular orbital (HOMO) at C(5). However, its adduct has small stability, and the C(8) adduct has the largest one. The C(8) adduct and the ring-opened amide have similar stability, which would lead to the apparent small yield of the former. Calculations were also performed on HO• additions to the C(4) and C(8) sites of the guanine moiety of four dimer sequence models of B-form DNA with nucleotide moieties (a) 5'-GA-3', (b) 5'-GG-3', (c) 5'-GT-3', and (d) 5'-GC-3'. For instance, the (a) 5'-GA-3' model has a molecular formula C39H50N15Na2O21P2. The HO• attack to C(4) is ruled out owing to the reinforced deformation of the parallel stacking of base pairs. The clear selectivity that the (b) 5'-GG-3' sequence is most reactive was found with the inclusion of the water dimer.

Dipping probe electrospray ionization/mass spectrometry for direct on-site and low-invasive food analysis.

Rapid, direct, on-site and noninvasive food analysis is strongly needed for quality control of food. To satisfy this demand, the technique of dipping probe electrospray ionization/mass spectrometry (dPESI/MS) was developed. The sample surface was pricked with a fine acupuncture needle and a sample of ∼200 pL was captured at the needle tip. After drying the sample, the needle tip was dipped into the solvent for ∼50 ms and was moved upward. A high-voltage was applied to the needle to generate electrospray when the needle reached the highest position, and mass spectra were measured with a time-of-flight mass spectrometer. For evaluation of the method, the technique was used to analyze foods such as vegetables, salmon flesh, cow's milk, yogurt, and soy-bean milk. The detected major ions for cow's milk and yogurt were [(Lac)n + Ca]2+ with n = 1-6 (where (Lac) is lactose), indicating that Ca2+ is tightly bound by Lac molecules.

Non-proximate mass spectrometry using a heated 1-m long PTFE tube and an air-tight APCI ion source.

Direct and rapid trace-level gas analysis is highly needed in various fields such as safety and security, quality control, food analysis, and forensic medicine. In many cases, the real samples are bulky and are not accessible to the space-limited ion source of the mass spectrometer. In order to circumvent this problem, we developed an airtight atmospheric-pressure chemical ionization (APCI) ion source equipped with a flexible 1-m-long, 2-mm-i.d. PTFE sniffing tube. The ambient air bearing sample gas was sucked into the heated PTFE tube (130 °C) and was transported to the air-tight ion source without using any extra pumping system or a Venturi device. Analytes were ionized by an ac corona discharge located at 1.5 mm from the inlet of the mass spectrometer. By using the airtight ion source, all the ionized gas in the ion source was introduced into the vacuum of the mass spectrometer via only the evacuation of the mass spectrometer (1.6 l min-1). Sub-pg limits of detection were obtained for carbaryl and trinitrotoluene. Owing to its flexibility and high sensitivity, the sniffing tube coupled with a mass spectrometer can be used as the stethoscope for the high-sensitive gas analysis. The experimental results obtained for drugs, hydrogen peroxide and small alkanes were discussed by DFT calculations.

Mass spectrometric monitoring of oxidation of aliphatic C6-C8 hydrocarbons and ethanol in low pressure oxygen and air plasmas.

Experimental and theoretical studies on the oxidation of saturated hydrocarbons (n-hexane, cyclohexane, n-heptane, n-octane and isooctane) and ethanol in 28 Torr O2 or air plasma generated by a hollow cathode discharge ion source were made. Ions corresponding to [M + 15]+ and [M + 13]+ in addition to [M - H]+ and [M - 3H]+ were detected as major ions where M is the sample molecule. The ions [M + 15]+ and [M + 13]+ were assigned as oxidation products, [M - H + O]+ and [M - 3H + O]+ , respectively. By the tandem mass spectrometry analysis of [M - H + O]+ and [M - 3H + O]+ , H2 O, olefins (and/or cycloalkanes) and oxygen-containing compounds were eliminated from these ions. Ozone as one of the terminal products in the O2 plasma was postulated as the oxidizing reagent. As an example, the reactions of C6 H14+• with O2 and of C6 H13+ (CH3 CH2 CH+ CH2 CH2 CH3 ) with ozone were examined by density functional theory calculations. Nucleophilic interaction of ozone with C6 H13+ leads to the formation of protonated ketone, CH3 CH2 C(=OH+ )CH2 CH2 CH3 . In air plasma, [M - H + O]+ became predominant over carbocations, [M - H]+ and [M - 3H]+ . For ethanol, the protonated acetic acid CH3 C(OH)2+ (m/z 61.03) was formed as the oxidation product. The peaks at m/z 75.04 and 75.08 are assigned as protonated ethyl formate and protonated diethyl ether, respectively, and that at m/z 89.06 as protonated ethyl acetate. Copyright © 2016 John Wiley & Sons, Ltd.

Nitrogen incorporation in saturated aliphatic C6-C8 hydrocarbons and ethanol in low-pressure nitrogen plasma generated by a hollow cathode discharge ion source.

Ion/molecule reactions of saturated hydrocarbons (n-hexane, cyclohexane, n-heptane, n-octane and isooctane) in 28-Torr N2 plasma generated by a hollow cathode discharge ion source were investigated using an Orbitrap mass spectrometer. It was found that the ions with [M+14](+) were observed as the major ions (M: sample molecule). The exact mass analysis revealed that the ions are nitrogenated molecules, [M+N](+) formed by the reactions of N3 (+) with M. The reaction, N3 (+) + M → [M+N](+) + N2 , were examined by the density functional theory calculations. It was found that N3 (+) abstracts the H atom from hydrocarbon molecules leading to the formation of protonated imines in the forms of R'R″CNH2 (+) (i.e. C-H bond nitrogenation). This result is in accord with the fact that elimination of NH3 is the major channel for MS/MS of [M+N](+) . That is, nitrogen is incorporated in the C-H bonds of saturated hydrocarbons. No nitrogenation was observed for benzene and acetone, which was ascribed to the formation of stable charge-transfer complexes benzene⋅⋅⋅⋅N3 (+) and acetone⋅⋅⋅⋅N3 (+) revealed by density functional theory calculations. Copyright © 2016 John Wiley & Sons, Ltd.

Low-pressure barrier discharge ion source using air as a carrier gas and its application to the analysis of drugs and explosives.

In this work, a low-pressure air dielectric-barrier discharge (DBD) ion source using a capillary with the inner diameter of 0.115 and 12 mm long applicable to miniaturized mass spectrometers was developed. The analytes, trinitrotoluene (TNT), 1,3,5-trinitroperhydro-1,3,5-triazine (RDX), 1,3,5,7-tetranitroperhydro-1,3,5,7-tetrazocine (HMX), pentaerythritol tetranitrate (PETN), nitroglycerine (NG), hexamethylene triperoxide diamine (HMTD), caffeine, cocaine and morphine, introduced through the capillary, were ionized by a low-pressure air DBD. The ion source pressures were changed by using various sizes of the ion sampling orifice. The signal intensities of those analytes showed marked pressure dependence. TNT was detected with higher sensitivity at lower pressure but vice versa for other analytes. For all analytes, a marked signal enhancement was observed when a grounded cylindrical mesh electrode was installed in the DBD ion source. Among nine analytes, RDX, HMX, NG and PETN could be detected as cluster ions [analyte + NO3 ](-) even at low pressure and high temperature up to 180 °C. The detection indicates that these cluster ions are stable enough to survive under present experimental conditions. The unexpectedly high stabilities of these cluster ions were verified by density functional theory calculation.

Frontier orbitals and transition states in the oxidation and degradation of L-ascorbic acid: a DFT study.

DFT calculations were carried out to investigate reaction paths of L-ascorbic acid (AAH2), hydroxyl radicals and water clusters. Frontier-orbital analyses were also performed to examine the regioselectivity of the OH˙ addition. Transition states of the electrolytic dissociation of AAH2 and intermediate carboxylic acids were found to have very small activation energies through proton transfers along hydrogen bonds. The ionized species (anions) are subject to the electrophilic attack of OH˙. The elementary processes of AAH2 → A˙(-) → dehydroascorbic acid → diketogulonic acid → threonic, oxalic, xylonic and lyxonic acids were investigated and discussed. The processes involved in the conversion of dehydroascorbic acid into a bicyclic hemiketal were also examined as a side-chain participating reaction. The oxidation and degradation of vitamin C up to threonic acid were described mainly as a donor (AAH2)-acceptor (OH˙) reaction.

A DFT study on proton transfers in hydrolysis reactions of phosphate dianion and sulfate monoanion.

B3LYP calculations were carried out on hydrolysis reactions of monosubstituted(R) phosphate dianion and sulfate monoanion. In the reacting system, water clusters (H2O)22 and (H2O)35 are included to trace reaction paths. For both P and S substrates with R = methyl group, elementary processes were calculated. While the phosphate undergoes the substitution at the phosphorus, the sulfate does at the methyl carbon. For the S substrate with R = neopentyl group, the product tert-amyl alcohol was found to be formed via a dyotropic rearrangement from the neopentyl alcohol intermediate. For R = aryl groups, transition-state geometries were calculated to be similar between P and S substrates. Calculated activation energies are in good agreement with experimental values. After the rate-determining transition state of the substitution, the hydronium ion H3O(+) is formed at the third water molecule. It was suggested that alkyl and aryl substrates are of the different reactivity of the hydrolysis.

Proton transfers in the Strecker reaction revealed by DFT calculations.

The Strecker reaction of acetaldehyde, NH3, and HCN to afford alanine was studied by DFT calculations for the first time, which involves two reaction stages. In the first reaction stage, the aminonitrile was formed. The rate-determining step is the deprotonation of the NH3 (+) group in MeCH(OH)-NH3 (+) to form 1-aminoethanol, which occurs with an activation energy barrier (ΔE (≠)) of 9.6 kcal/mol. The stereochemistry (R or S) of the aminonitrile product is determined at the NH3 addition step to the carbonyl carbon of the aldehyde. While the addition of CN(-) to the carbon atom of the protonated imine 7 appears to scramble the stereochemistry, the water cluster above the imine plane reinforces the CN(-) to attack the imine group below the plane. The enforcement hinders the scrambling. In the second stage, the aminonitrile transforms to alanine, where an amide Me-CH(NH2)-C(=O)-NH2 is the key intermediate. The rate-determining step is the hydrolysis of the cyano group of N(amino)-protonated aminonitrile which occurs with an ΔE (≠) value of 34.7 kcal/mol. In the Strecker reaction, the proton transfer along the hydrogen bonds plays a crucial role.

S(N)1-S(N)2 and S(N)2-S(N)3 mechanistic changes revealed by transition states of the hydrolyses of benzyl chlorides and benzenesulfonyl chlorides.

Hydrolysis reactions of benzyl chlorides and benzenesulfonyl chlorides were theoretically investigated with the density functional theory method, where the water molecules are explicitly considered. For the hydrolysis of benzyl chlorides (para-Z-C6H4-CH2-Cl), the number of water molecules (n) slightly influences the transition-state (TS) structure. However, the para-substituent (Z) of the phenyl group significantly changes the reaction process from the stepwise (S(N)1) to the concerted (S(N)2) pathway when it changes from the typical electron-donating group (EDG) to the typical electron-withdrawing one (EWG). The EDG stabilizes the carbocation (MeO-C6H4-CH2(+)), which in turn makes the S(N)1 mechanism more favorable and vice versa. For the hydrolysis of benzenesulfonyl chlorides (para-Z-C6H4-SO2-Cl), both the Z group and n influence the TS structure. For the combination of the large n value (n > 9) and EDG, the S(N)2 mechanism was preferred. Conversely, for the combination of the small n value and EWG, the S(N)3 one was more favorable.

Substrate dependent reaction channels of the Wolff-Kishner reduction reaction: A theoretical study.

Wolff-Kishner reduction reactions were investigated by DFT calculations for the first time. B3LYP/6-311+G(d,p) SCRF=(PCM, solvent = 1,2-ethanediol) optimizations were carried out. To investigate the role of the base catalyst, the base-free reaction was examined by the use of acetone, hydrazine (H2N-NH2) and (H2O)8. A ready reaction channel of acetone → acetone hydrazine (Me2C=N-NH2) was obtained. The channel involves two likely proton-transfer routes. However, it was found that the base-free reaction was unlikely at the N2 extrusion step from the isopropyl diimine intermediate (Me2C(H)-N=N-H). Two base-catalyzed reactions were investigated by models of the ketone, H2N-NH2 and OH(-)(H2O)7. Here, ketones are acetone and acetophenone. While routes of the ketone → hydrazone → diimine are similar, those from the diimines are different. From the isopropyl diimine, the N2 extrusion and the C-H bond formation takes place concomitantly. The concomitance leads to the propane product concertedly. From the (1-phenyl)ethyl substituted diimine, a carbanion intermediate is formed. The para carbon of the phenyl ring of the anion is subject to the protonation, which leads to a 3-ethylidene-1,4-cyclohexadiene intermediate. Its [1,5]-hydrogen migration gives the ethylbenzene product. For both ketone substrates, the diimines undergoing E2 reactions were found to be key intermediates.

An aniline dication-like transition state in the Bamberger rearrangement.

A Bamberger rearrangement of N-phenylhydroxylamine, Ph-N(OH)H, to p-aminophenol was investigated by DFT calculations for the first time. The nitrenium ion, C6H5-NH(+), suggested and seemingly established as an intermediate was calculated to be absent owing to the high nucleophilicity of the water cluster around it. First, a reaction of the monoprotonated system, Ph-N(OH)H + H3O(+)(H2O) n (n = 4 and 14) was examined. However, the rate-determining transition states involving proton transfers were calculated to have much larger activation energies than the experimental one. Second, a reaction of the diprotonated system, Ph-N(OH)H + (H3O(+))2(H2O)13, was traced. An activation energy similar to the experimental one was obtained. A new mechanism of the rearrangement including the aniline dication-like transition state was proposed.

Interest in new heterodinuclear transition-metal/main-group-metal complexes: DFT study of electronic structure and mechanism of fluoride sensing function.

Systematic DFT calculations were carried out on a series of heterodinuclear complexes [(o-(Ph2P)C6H4)3M(1)M(2)Cl](+) (M(1) = As, Sb, or Bi; M(2) = Pd or Pt) to investigate the mechanism of colorimetric sensing function for the fluoride anion. The fluoride anion binds with the M(1) center to afford a hypervalent M(1) species with large stabilization energy. For instance, the stabilization energy by the fluoride adduct formation is -15.5 kcal mol(-1) for 3 (M(1) = Sb; M(2) = Pd) and -16.2 kcal mol(-1) for 6 (M(1) = Sb; M(2) = Pt), where a negative value represents stabilization. Interestingly, the allosteric coordination of the third phosphine with the M(2) center is induced by the fluoride adduct formation. For chloride, bromide, and thiocyanide anions, the binding energies are positive (~4.5 kcal mol(-1)), and the allosteric coordination does not occur. The allosteric coordination plays a crucial role in the absorption spectrum change induced by the fluoride adduct formation. For instance, the fluoride adduct formation quenches the absorption band of 3 around 400 nm and newly exhibits two absorption peaks at longer wavelength, 475 and 451 nm. These two peaks are assigned to ligand-field transitions (d(xy)→ d(z(2)) and d(x(2)-y(2))→ d(z(2))) including metal-to-ligand charge transfer character. We discussed the reasons why the allosteric coordination can occur only in the fluoride adduct and induces these two absorptions in the longer wavelength region. In addition, the Bi-Pd combination is also recommended for a fluoride sensing material, while the Sb-Pt combination is recommended for cyanide sensing.

A new intermediate in the Prins reaction.

Two Prins reactions were investigated by the use of DFT calculations. A model composed of R-CH=CH2 + H3O(+)(H2O)13 + (H2C=O)2, R = Me and Ph, was adopted to trace reaction paths. For both alkenes, the concerted path forming 1,3-diols was obtained as the rate determining step (TS1). TS stands for a transition state. From the 1,3-diol, a bimolecular elimination (TS2) leads to the allylic alcohol as the first channel. In the second channel, the 1,3-diol was converted via TS3 into an unprecedented hemiacetal intermediate, HO-CH2-O-CH(R)-CH2-CH2-OH. This intermediate undergoes ring closure (TS4), affording the 1,3-dioxane product. The intermediate is of almost the same stability as the product, and two species were suggested to be in a state of equilibrium. While the geometry of TS1 appears to be forwarded to that of a carbocation intermediate, the cation disappeared through the enlargement of the water cluster. Dynamical calculations of a classical trajectory using the atom-centered density matrix propagation molecular dynamics model on the four TSs were carried out, and results of IRC calculations were confirmed by them.

Presence or absence of a novel charge-transfer complex in the base-catalyzed hydrolysis of N-ethylbenzamide or ethyl benzoate.

Reaction paths of base-catalyzed hydrolyses of isoelectronic substrates, Ph-C(=O)-X-Et [X = O (ethyl benzoate) and X = NH (N-ethylbenzamide)], were traced by DFT calculations. To simulate bond interchanges accompanied by proton transfers, a cluster model of Ph-C(=O)-X-Et + OH(-)(H(2)O)(16) was employed. For X = O, three elementary processes and for X = NH four ones were obtained. The rate-determining step of X = O is the first TS (TS1, the OH(-) addition step), while that of X = NH is TS2. TS2 of X = NH leads to a novel Mulliken charge-transfer complex, Ph-(OH)(O=)C∙∙∙N(H(2))-Et. The superiority or inferiority between the direct nucleophilic process or the general base-catalyzed process for TS1 was examined with the model Ph-C(=O)-X-Et + OH(-)(H(2)O)(n), n = 3, 5, 8, 12, 16, 24 and 32. The latter process was calculated to be more favorable regardless of the number (n, except n = 3) of water molecules. The counter ion Na(+) works unfavorably on the ester hydrolysis, particularly on TS1. A minimal model of TS1 was proposed and was found to be insensitive to n.