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.

Brønsted acid-induced transannulation of the phytochemical zerumbone.

The sesquiterpene zerumbone was treated with HCl in ethyl acetate under the light-protected condition, and the time-dependent conversions were analyzed by gas chromatography. Nine products were isolated, and their structures were revealed by several NMR measurements such as 1H NMR, 13C{1H} NMR, distortionless enhancement by polarization transfer (DEPT)-135, 1H-1H correlation spectroscopy (COSY), 1H-13C heteronuclear multiple quantum coherence (HMQC), and 1H-13C heteronuclear multiple bond coherence (HMBC). The X-ray crystallography determined the stereochemistries of the three products and the two derivatives. After all, this acidic reaction was found to provide the (2Z,6E,10E)-isomer, the two HCl adducts, the two 7,6-bicyclic compounds, the valence isomers cycloheptatriene and norcaradiene, and the two dihydronaphthalenes. Based on the product analyses of the reactions from the isolated intermediates as well as the mechanistic considerations, these products were arranged into two paths: one of the paths ended in the two dihydronaphthalenes the same as previously reported under the Lewis acid condition; the other ended in the 7,6-bicyclic compound, the epimer of which was known. In addition, density functional theory (DFT) calculations indicated that the (2Z,6E,10E)-isomer was more stable than the (2E,6E,10Z)-isomer as well as that the activation energy for the isomerization at the C2-C3 double bond decreased to half by protonation. The closely examined reaction mechanisms under the simple acidic condition were established upon the intensive characterization of the intermediates and products, and these findings would add to the attractive value of zerumbone and would help understand the unknown biosynthetic pathway around sesquiterpenoids.

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.

Remarkable Potential of Zerumbone to Generate a Library with Six Natural Product-like Skeletons by Natural Material-Related Diversity-Oriented Synthesis.

Diversity-oriented synthesis (DOS) is an effective strategy for the quick creation of diverse and high three-dimensional compounds from simple starting materials. The selection of a starting material is the key to constructing useful, chemically diverse compound libraries for the development of new drugs. Here, we report a novel, general, and facile strategy for the creation of diverse compounds with high structural diversity from readily available natural products, such as zerumbone, as the synthetic starting material. Zerumbone is the major component of the essential oil from wild ginger, Zingiber zerumbet Smith. It is noteworthy that zerumbone has a powerful latent reactivity, partly because of its three double bonds, two conjugated and one isolated, and a double conjugated carbonyl group in an 11-membered ring structure. In fact, zerumbone has been shown to be a successful example of natural material-related DOS (NMRDOS). We will report that zerumbone can be converted in one chemical step from four zerumbone derivatives into rare and markedly different scaffolds by transannulation.

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.

Synthesis and Systematic Structural Analysis of Cationic Half-Sandwich Ruthenium Chalcogenocarbonyl Complexes.

Although the chemistry of transition-metal complexes with carbonyl (CO) and thiocarbonyl (CS) ligands has been well developed, their heavier analogues, namely selenocarbonyl (CSe) and tellurocarbonyl (CTe) complexes remain scarce. The limited availability of such CSe and CTe complexes has so far hampered our understanding of the differences between such chalcogenocarbonyl (CE: E=O, S, Se, Te) ligands. Herein, we report the synthesis and properties of a series of cationic half-sandwich ruthenium CE complexes of the type [CpRu(CE)(H2 IMes)(CNCH2 Ts)][BArF 4 ] (Cp=η5 -C5 H5 - ; H2 IMes=1,3-dimesitylimidazolin-2-ylidene; ArF =3,5-(CF3 )2 C6 H3 ). A combination of X-ray diffraction analyses, NMR spectroscopic analyses, and DFT calculations revealed an increasing π-accepting ability of the CE ligands in the order O

Synthesis and properties of anionic ruthenium thionitrosyl and selenonitrosyl complexes that contain tetraanionic 2-hydroxybenzamidobenzene ligands.

Although transition-metal complexes that contain thiocarbonyl (CS) and selenocarbonyl (CSe) ligands have been well studied, only three neutral or cationic selenonitrosyl (NSe) complexes have been reported, while anionic NSe complexes remain elusive. Herein, we report the first examples of anionic NSe-ligated ruthenium complexes, which were obtained from the reaction of anionic ruthenium nitrido complexes, elemental selenium, and 4-(N,N-dimethylamino)pyridine (DMAP). The structures of one of these ruthenium NSe complexes, as well as of the corresponding thionitrosyl (NS) and nitrosyl (NO) complexes, were systematically examined by X-ray diffraction analyses and theoretical calculations. In contrast to previous reportes, the NSe ligand in these complexes is a better π-acceptor than the NO and NS ligands and exhibits a stronger trans influence.

P-C reductive elimination in Ru(ii) complexes to convert triarylphosphine ligands into five- or six-membered phosphacycles.

Rare examples of P-C reductive elimination in ruthenium complexes to generate phosphonium salts are presented. Triarylphosphines are converted into benzophospholium or phosphaphenalenium ligands via cyclometalation and 1,2-insertion of an alkyne followed by P-C reductive elimination. The intermediate in each step was successfully characterized using NMR and X-ray diffraction studies.

A ruthenium tellurocarbonyl (CTe) complex with a cyclopentadienyl ligand: systematic studies of a series of chalcogenocarbonyl complexes [CpRuCl(CE)(H2IMes)] (E = O, S, Se, Te).

The first tellurocarbonyl complex with a half-sandwich structure [CpRuCl(CTe)(H2IMes)] was synthesized by a ligand substitution reaction. The practically complete series of the CpCE complexes [CpRuCl(CE)(H2IMes)] (E = O, S, Se, Te) were systematically explored. The tellurium atom in the CTe complex could be smoothly replaced with lighter chalcogen atoms.

R/X exchange reactions in cis-[M(R)2{P(X)(NMeCH2)2}2] (M = Pd, Pt), via a phosphenium intermediate.

R/X exchange reactions in cis-[M(R)2{P(X)(NMeCH2)2}2] (M = Pd, Pt; R = aryl, alkyl; X = Cl, Br) were achieved for the first time to give cis-[M(X)2{P(R)(NMeCH2)2}2]. DFT calculations suggested that the exchange reaction proceeds via a phosphenium intermediate.

Competition between vinylidene rearrangement and 1,2-insertion of carbon-disubstituted internal alkynes at a Cp*Ir(III) complex.

Competition between vinylidene rearrangement/1,1-insertion and 1,2-alkyne insertion into the Ir-Ar bond of [Cp*Ir(ppy-F4)](+) was observed on reaction with diarylacetylenes. The former process afforded the iridacycle 2via the subsequent 1,4-Ir migration, whereas the latter led to the pyridoisoquinolinium complex 4. Detailed analysis revealed that 4 isomerizes to 2 by heating at 50 °C.

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.

DFT study of internal alkyne-to-disubstituted vinylidene isomerization in [CpRu(PhC≡CAr)(dppe)]+.

Internal alkyne-to-vinylidene isomerization in the Ru complexes ([CpRu(η(2)-PhC≡CC(6)H(4)R-p)(dppe)](+) (Cp = η(5)-C(5)H(5); dppe = Ph(2)PCH(2)CH(2)PPh(2); R = OMe, Cl, CO(2)Et)) has been investigated using a combination of quantum mechanics and molecular mechanics methods (QM/MM), such as ONIOM(B3PW91:UFF), and density functional theory (DFT) calculations. Three kinds of model systems (I-III), each having a different QM region for the ONIOM method, revealed that considering both the quantum effect of the substituent of the aryl group in the η(2)-alkyne ligand and that of the phenyl groups in the dppe ligand is essential for a correct understanding of this reaction. Several plausible mechanisms have been analyzed by using DFT calculations with the B3PW91 functional. It was found that the isomerization of three complexes (R = OMe, CO(2)Et, and Cl) proceeds via a direct 1,2-shift in all cases. The most favorable process in energy was path 3, which involves the orientation change of the alkyne ligand in the transition state. The activation energies were calculated to be 13.7, 15.0, and 16.4 kcal/mol, respectively, for the three complexes. Donor-acceptor analysis demonstrated that the aryl 1,2-shift is a nucleophilic reaction. Furthermore, our calculation results indicated that an electron-donating substituent on the aryl group stabilizes the positive charge on the accepting carbon rather than that on the migrating aryl group itself at the transition state. Therefore, unlike the general nucleophilic reaction, the less-electron-donating aryl group has an advantage in the migration.

Correlation between the rate order and the number of molecules in the reaction of trimethyl phosphite with water in acetonitrile solvent.

Density functional theory calculations of the title reaction, P(OCH3)3 + (H2O)(n) in CH3CN, were conducted, where n is the number of water molecules. Two routes, the routes suggested by (A) Aksnes and (B) Arbuzov, were traced with various n values. Both routes consist of two transition states (TSs) and one intermediate. Route B was found to be more likely than route A. In the former, the activation free energy (ΔG(‡)) of n = 3 is slightly smaller than that of n = 2. The n = 3 TS geometry is composed of a nucleophile H2O, a proton donor H2O, and an auxiliary one. Indeed, the geometry appears to be plausible for ready proton relays along hydrogen bonds, but it is inconsistent with the observed third-order rate constant. Catalytic water molecules were added to the n = 2 and 3 bond-interchange circuits. Then route B with n = 2 + 2 was found to be best. By n = 2 + 10 and n = 3 + 12 models, the n = 2 based route B was confirmed to be likely.

A new mechanism for the Favorskii rearrangement.

The title reaction was investigated by the use of ONIOM-RB3LYP calculations. A reaction system composed of alpha-chlorocyclohexanone, a methoxide ion and 8 MeOH solvent molecules was adopted. Two reaction channels, the semibenzilic acid mechanism (A) and cyclopropanone mechanism (B), were compared. B is found to be more favorable than A. The rate-determining step of B is the (MeOH)(3) addition transition state (TS3B) to the cyclopropanone intermediate. While TS3B involves a concerted function of MeO(-) addition and proton relays, it has a large activation energy. A new route was found, where the chloride ion evolved at the cyclopropane formation step (TS2B) works as a nucleophile to the cyclopropanone intermediate. Thus, a cyclopentane-carbonyl chloride intermediate is formed with a small activation energy. A new cyclopropanone mechanism is proposed.

Reaction paths of the water-assisted solvolysis of N,N-dimethylformamide.

Density functional theory calculations were conducted on the title reactions with explicit inclusion of a variety of water molecules, H-CO-NMe2+MeOH+(H2O)n-->H-CO-OMe+HNMe2+(H2O)n. Geometries of transition states, reactant-like complexes and product-like ones were determined by the use of RB3LYP/6-31G(d) SCRF=dipole. Concerted paths were examined with n=0-3. Their Gibbs activation energies are larger than the experimental value. Stepwise paths were also investigated with n=2-4. The n=4 model has the energy close to the experimental value. However, when the catalytic water molecules were added to the n=4 one, the stepwise path was switched to the concerted one. A systematic comparison of the concerted path with n=2+1, 2+2, 2+3, 2+4, 2+5, 2+4+4, and 2+5+5 models was made, and the water-dimer based reaction path was found to be most favorable. The contrast between the concerted path of the amide solvolysis (and hydrolysis) and the stepwise one of the ester hydrolysis was discussed in terms of the frontier-orbital theory.

Theoretical study of the role of solvent H2O in neopentyl and pinacol rearrangements.

The neopentyl and the pinacol rearrangements as examples of Wagner-Meerwein rearrangements were investigated by the use of DFT calculations. As the first reaction, a model of neopentyl chloride (1b) and (H2O)12 was employed. In the reaction, the patterns of C--Cl scission, methyl migration, and C--OH formation were analyzed. The calculations have shown that the 2-methyl-2-butanol (6) is formed in two steps with the transient intermediate, neopentyl alcohol (3). The first step is the nucleophilic substitution reaction and is the rate-determining one. The second step is the dual migration of methyl and OH2 groups. The primary and tertiary carbocations were calculated to be absent in the neopentyl rearrangement starting from the hydrolysis. As the second reaction, the pinacol rearrangement of two substrates 2,3-dimethyl-2,3-butanediol (7) and 2,3-diphenyl-2,3-butanediol (12) was investigated. Acidic aqueous solvent was modeled by H3O+ and 12H2O. The reaction paths were promoted by a hydrogen-bond circuit of H3O+(H2O)2 and were determined as completely concerted processes. Protonated species and carbocations as intermediates also do not intervene during the pinacol rearrangement. Active functions of proton relays along the hydrogen bonds in the two rearrangements were demonstrated.

A FMO-controlled reaction path in the benzil-benzilic acid rearrangement.

Reaction paths for the title rearrangement along with its methyl analogue were investigated by density functional theory calculations. The reaction model is R-CO-CO-R + OH(-)(H2O)4 --> R2C(OH)-COO- + (H2O)4 (R = Me and Ph), where the water tetramer is employed both for solvation to OH- and for the proton relay along hydrogen bonds. The reaction is composed of OH- addition, C-C rotation, carbanion [1,2] migration, and proton relay toward the product anions. The rate-determining step was calculated to be the carbanion migration. Apparently, carbanion [1,2] migration is unlikely relative to the carbonium ion one. However, LUMOs of the 1,2-diketones have large and nodeless lobes at the reaction center, the C1-C2 bond. The specific LUMO character is reflected both in the [2+1]-like one-center nucleophilic addition and in the carbanion [1,2] shift. The proton relay involved in the isomerization from the oxo intermediate to the carboxylate was calculated to take place via the water tetramer.